Literatuur overzicht

Wang T.J., Zhang F., Richars B.J., et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study Lancet  2010 Jul 17;376(9736):180-8. doi: 10.1016/S0140-6736(10)60588-0




Background: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.


Methods: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.


Findings: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9×10(-109) for rs2282679, in GC); 11q12 (p=2.1×10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3×10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0×10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3×10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0×10(-26)) compared with those in the lowest quartile.

Interpretation: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.


Bastaki M, Huen k., Manzanillo P., Chande N., Chen C., Balmes J.R., Tager I.B., Holland N. Genotype-activity relationship for Mn-superoxide dismutase, glutathione peroxidase 1 and catalase in humans Pharmacogenet Genomics. 2006 Apr;16(4):279-86. doi: 10.1097/01.fpc.0000199498.08725.9c.




Objectives: This study examined the association between genetic polymorphisms and enzyme activity for antioxidant enzymes that share a common detoxification pathway: manganese superoxide dismutase (MnSOD), glutathione peroxidase-1 (GPX1) and catalase.


Methods: MnSOD, GPX1, and catalase activities were measured in isolated erythrocytes of 231 healthy, non-smoking student volunteers (55% women, ages 17-21, majority Asian or Caucasian). DNA from blood clots was genotyped by Taqman PCR (C47T : MnSOD and C593T : GPX1) and standard PCR (-262C>T : catalase). Associations between genotype and enzyme activity were analyzed by multiple linear regression, adjusted for baseline factors including gender and ethnicity.


Results: Minor allele frequencies ranged from 13% for catalase (T) to 18% for GPX1 (T), and 33% for MnSOD(C) with significant variation between ethnicities. Median GPX1 activity was 13.2 U/g Hb with a six-fold difference between lowest and highest levels. Catalase activity ranged eight-fold (median: 86.3 k/g Hb), while median MnSOD activity was 2.8 U/mg Hb with a 56-fold range of values. MnSOD enzyme activity was 15% higher in females than males (95%CI : -1%, 32%), and 33% higher in CT or TT individuals (C47T) versus CC individuals (95%CI : 7-59%). On average, catalase activity was 18.1 k/g Hb lower for TT subjects (-262C>T) versus CC subjects (95% CI: -32.3, -4.0). All enzyme activities were correlated (r=0.3-0.4, P<0.001).


Conclusions: Interindividual variability of antioxidant enzyme activity in healthy young adults was partially explained by significant associations with three known genetic polymorphisms, and was further modified by gender and ethnicity. A substantial component of this variability may be attributable to differences in diet, environmental exposures, and additional genetic factors.


Pichler I, et al. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Hum Mol Genet. 2011 Mar 15;20(6):1232-40 doi: 10.1093/hmg/ddq552. Epub 2010 Dec 28.



The genetic determinants of variation in iron status are actively sought, but remain incompletely understood. Meta-analysis of two genome-wide association (GWA) studies and replication in three independent cohorts was performed to identify genetic loci associated in the general population with serum levels of iron and markers of iron status, including transferrin, ferritin, soluble transferrin receptor (sTfR) and sTfR-ferritin index. We identified and replicated a novel association of a common variant in the type-2 transferrin receptor (TFR2) gene with iron levels, with effect sizes highly consistent across samples. In addition, we identified and replicated an association between the HFE locus and ferritin and confirmed previously reported associations with the TF, TMPRSS6 and HFE genes. The five replicated variants were tested for association with expression levels of the corresponding genes in a publicly available data set of human liver samples, and nominally statistically significant expression differences by genotype were observed for all genes, although only rs3811647 in the TF gene survived the Bonferroni correction for multiple testing. In addition, we measured for the first time the effects of the common variant in TMPRSS6, rs4820268, on hepcidin mRNA in peripheral blood (n = 83 individuals) and on hepcidin levels in urine (n = 529) and observed an association in the same direction, though only borderline significant. These functional findings require confirmation in further studies with larger sample sizes, but they suggest that common variants in TMPRSS6 could modify the hepcidin-iron feedback loop in clinically unaffected individuals, thus making them more susceptible to imbalances of iron homeostasis.


Beben B., McRae A.F., et al. Variants in TF and HFE Explain ∼40% of Genetic Variation in Serum-Transferrin Levels  Am J Hum Genet. 2009 Jan 9; 84(1): 60–65. doi: 10.1016/j.ajhg.2008.11.011



Only a small proportion of genetic variation in complex traits has been explained by SNPs from genome-wide association studies (GWASs). We report the results from two GWASs for serum markers of iron status (serum iron, serum transferrin, transferrin saturation with iron, and serum ferritin), which are important in iron overload (e.g., hemochromatosis) and deficiency (e.g., anemia) conditions. We performed two GWASs on samples of Australians of European descent. In the first GWAS, 411 adolescent twins and their siblings were genotyped with 100K SNPs. rs1830084, 10.8 kb 3′ of TF, was significantly associated with serum transferrin (p total association test = 1.0 × 10−9; p within-family test = 2.2 × 10−5). In the second GWAS on an independent sample of 459 female monozygotic (MZ) twin pairs genotyped with 300K SNPs, we found rs3811647 (within intron 11 of TF, HapMap CEU r2 with rs1830084 = 0.86) was significantly associated with serum transferrin (p = 3.0 × 10−15). In the second GWAS, we found two additional and independent SNPs on TF (rs1799852 and rs2280673) and confirmed the known C282Y mutation in HFE to be independently associated with serum transferrin. The three variants in TF (rs3811647, rs1799852 and rs2280673) plus the HFE C282Y mutation explained ∼40% of genetic variation in serum transferrin (p = 7.8 × 10−25). These findings are potentially important for our understanding of iron metabolism and of regulation of hepatic protein secretion, and also strongly support the hypothesis that the genetic architecture of some endophenotypes may be simpler than that of disease.


Evans. D.M., Zhu G., Dy V. et al. Genome-wide association study identifies loci affecting blood copper, selenium and zinc Hum Mol Genet. 2013 Oct 1; 22(19): 3998–4006. Published online 2013 May 29. doi: 10.1093/hmg/ddt239



Genetic variation affecting absorption, distribution or excretion of essential trace elements may lead to health effects related to sub-clinical deficiency. We have tested for allelic effects of single-nucleotide polymorphisms (SNPs) on blood copper, selenium and zinc in a genome-wide association study using two adult cohorts from Australia and the UK. Participants were recruited in Australia from twins and their families and in the UK from pregnant women. We measured erythrocyte Cu, Se and Zn (Australian samples) or whole blood Se (UK samples) using inductively coupled plasma mass spectrometry. Genotyping was performed with Illumina chips and >2.5 m SNPs were imputed from HapMap data. Genome-wide significant associations were found for each element. For Cu, there were two loci on chromosome 1 (most significant SNPs rs1175550, P = 5.03 × 10−10, and rs2769264, P = 2.63 × 10−20); for Se, a locus on chromosome 5 was significant in both cohorts (combined P = 9.40 × 10−28 at rs921943); and for Zn three loci on chromosomes 8, 15 and X showed significant results (rs1532423, P = 6.40 × 10−12; rs2120019, P = 1.55 × 10−18; and rs4826508, P = 1.40 × 10−12, respectively). The Se locus covers three genes involved in metabolism of sulphur-containing amino acids and potentially of the analogous Se compounds; the chromosome 8 locus for Zn contains multiple genes for the Zn-containing enzyme carbonic anhydrase. Where potentially relevant genes were identified, they relate to metabolism of the element (Se) or to the presence at high concentration of a metal-containing protein (Cu).


Lyssenko V., Lupi R., Marchetti P., et al. Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest. 2007 Aug;117(8):2155-63. doi: 10.1172/JCI30706



Genetic variants in the gene encoding for transcription factor-7–like 2 (TCF7L2) have been associated with type 2 diabetes (T2D) and impaired β cell function, but the mechanisms have remained unknown. We therefore studied prospectively the ability of common variants in TCF7L2 to predict future T2D and explored the mechanisms by which they would do this. Scandinavian subjects followed for up to 22 years were genotyped for 3 SNPs (rs7903146, rs12255372, and rs10885406) in TCF7L2, and a subset of them underwent extensive metabolic studies. Expression of TCF7L2 was related to genotype and metabolic parameters in human islets. The CT/TT genotypes of SNP rs7903146 strongly predicted future T2D in 2 independent cohorts (Swedish and Finnish). The risk T allele was associated with impaired insulin secretion, incretin effects, and enhanced rate of hepatic glucose production. TCF7L2 expression in human islets was increased 5-fold in T2D, particularly in carriers of the TT genotype. Overexpression of TCF7L2 in human islets reduced glucose-stimulated insulin secretion. In conclusion, the increased risk of T2D conferred by variants in TCF7L2 involves the enteroinsular axis, enhanced expression of the gene in islets, and impaired insulin secretion.

Stein D. Newman T., Savitz J.Warriors versus worriers: the role of COMT gene variantsCNS Spectr. 2006 Oct;11(10):745-8. doi: 10.1017/s1092852900014863.


Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.


Cauchi S., El Achhab Y., Choquet H., et al. TCF7L2 is reproducibly associated with type 2 diabetes in various ethnic groups: a global meta-analysis J Mol Med (Berl). 2007 Jul;85(7):777-82. doi: 10.1007/s00109-007-0203-4. Epub 2007 May 3.



TCF7L2 variants have been consistently associated with type 2 diabetes (T2D) in populations of different ethnic descent. Among them, the rs7903146 T allele is probably the best proxy to evaluate the effect of this gene on T2D risk in additional ethnic groups. In the present study, we investigated the association between the TCF7L2 rs7903146 polymorphism and T2D in Moroccans (406 normoglycemic individuals and 504 T2D subjects) and in white Austrians (1,075 normoglycemic individuals and 486 T2D subjects). Then, we systematically reviewed the association of this single nucleotide polymorphism (SNP) with T2D risk in a meta-analysis, combining our data with data from previous studies. The allelic odds ratios (ORs) for T2D were 1.56 [1.29-1.89] (p = 2.9 x 10(-6)) and 1.52 [1.29-1.78] (p = 3.0 x 10(-7)) in Moroccans and Austrians, respectively. No heterogeneity was found between these two different populations by Woolf test (chi (2) = 0.04, df = 1, p = 0.84). We found 28 original published association studies dealing with the TCF7L2 rs7903146 polymorphism in T2D. A meta-analysis was then performed on 29,195 control subjects and 17,202 cases. No heterogeneity in genotypic distribution was found (Woolf test: chi (2) = 31.5, df = 26, p = 0.21; Higgins statistic: I2 = 14.1%). A Mantel-Haenszel procedure was then performed to provide a pooled odds ratio (OR) of 1.46 [1.42-1.51] (p = 5.4 x 10(-140)). No publication bias was detected, using the conservative Egger’s regression asymmetry test (t = -1.6, df = 25, p = 0.11). Compared to any other gene variants previously confirmed by meta-analysis, TCF7L2 can be distinguished by its tremendous reproducibility of association with T2D and its OR twice as high. In the near future, large-scale genome-wide association studies will fully extend the genome coverage, potentially delivering other common diabetes-susceptibility genes like TCF7L2


Hribal M. L., Presta I., Procopio M.A., et al. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B Diabetologia. 2011 Apr;54(4):795-802. doi: 10.1007/s00125-010-2038-8. Epub 2011 Jan 14.



Aims/hypothesis: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry.


Methods: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay.


Results: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples).


Conclusions/interpretation: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.


Zhou Y., Park S., Su J., et al. TCF7L2 is a master regulator of insulin production and processing Hum Mol Genet. 2014 Dec 15;23(24):6419-31. doi: 10.1093/hmg/ddu359. Epub 2014 Jul 11.



Genome-wide association studies have revealed >60 loci associated with type 2 diabetes (T2D), but the underlying causal variants and functional mechanisms remain largely elusive. Although variants in TCF7L2 confer the strongest risk of T2D among common variants by presumed effects on islet function, the molecular mechanisms are not yet well understood. Using RNA-sequencing, we have identified a TCF7L2-regulated transcriptional network responsible for its effect on insulin secretion in rodent and human pancreatic islets. ISL1 is a primary target of TCF7L2 and regulates proinsulin production and processing via MAFA, PDX1, NKX6.1, PCSK1, PCSK2 and SLC30A8, thereby providing evidence for a coordinated regulation of insulin production and processing. The risk T-allele of rs7903146 was associated with increased TCF7L2 expression, and decreased insulin content and secretion. Using gene expression profiles of 66 human pancreatic islets donors’, we also show that the identified TCF7L2-ISL1 transcriptional network is regulated in a genotype-dependent manner. Taken together, these results demonstrate that not only synthesis of proinsulin is regulated by TCF7L2 but also processing and possibly clearance of proinsulin and insulin. These multiple targets in key pathways may explain why TCF7L2 has emerged as the gene showing one of the strongest associations with T2D.


Wardle J., Carnell S., Haworth C.M.A., et al. Obesity associated genetic variation in FTO is associated with diminished satiety J Clin Endocrinol Metab. 2008 Sep;93(9):3640-3. doi: 10.1210/jc.2008-0472. Epub 2008 Jun 26.



Context: Polymorphisms within the FTO gene have consistently been associated with obesity across multiple populations. However, to date, it is not known whether the association between genetic variation in FTO and obesity is mediated through effects on energy intake or energy expenditure.


Objective: Our objective was to examine the association between alleles of FTO known to increase obesity risk and measures of habitual appetitive behavior.


Methods: The intronic FTO single nucleotide polymorphism (rs9939609) was genotyped in 3337 United Kingdom children in whom measures of habitual appetitive behavior had been assessed using two scales (Satiety Responsiveness and Enjoyment of Food) from the Child Eating Behaviour Questionnaire, a psychometric tool that has been validated against objective measures of food intake. Associations of FTO genotype with indices of adiposity and appetite were assessed by ANOVA.


Results: As expected, the A allele was associated with increased adiposity in this cohort and in an independent case-control replication study of United Kingdom children of similar age. AA homozygotes had significantly reduced Satiety Responsiveness scores (P = 0.008, ANOVA). Mediation analysis indicated that the association of the AA genotype with increased adiposity was explained in part through effects on Satiety Responsiveness.


Conclusions: We have used a unique dataset to examine the relationship between a validated measure of children’s habitual appetitive behavior and FTO obesity risk genotype and conclude that the commonest known risk allele for obesity is likely to exert at least some of its effects by influencing appetite.


Den Hoed M., Westerterp-Plantenga M.S., Bouwman F.G., et al. Postprandial responses in hunger and satiety are associated with the rs9939609 single nucleotide polymorphism in FTO The American Journal of Clinical Nutrition, Volume 90, Issue 5, November 2009, Pages 1426–1432, https://doi.org/10.3945/ajcn.2009.28053



Background: The common rs9939609 single nucleotide polymorphism (SNP) in the fat mass and obesity–associated (FTO) gene is associated with adiposity, possibly by affecting satiety responsiveness.


Objective: The objective was to determine whether postprandial responses in hunger and satiety are associated with rs9939609, taking interactions with other relevant candidate genes into account.


Design: Sixty-two women and 41 men [age: 31 ± 14 y; body mass index (in kg/m2): 25.0 ± 3.1] were genotyped for 5 SNPs in FTO, DNMT1, DNMT3B, LEP, and LEPR. Individuals received fixed meals provided in energy balance. Hunger and satiety were determined pre- and postprandially by using visual analog scales.


Results: A general association test showed a significant association between postprandial responses in hunger and satiety with rs9939609 (P = 0.036 and P = 0.050, respectively). Individuals with low postprandial responses in hunger and satiety were overrepresented among TA/AA carriers in rs9939609 (FTO) compared with TT carriers (dominant and additive model: P = 0.013 and P = 0.020, respectively). Moreover, multifactor dimensionality reduction showed significant epistatic interactions for the postprandial decrease in hunger involving rs9939609 (FTO), rs992472 (DNMT3B), and rs1137101 (LEPR). Individuals with a low postprandial decrease in hunger were overrepresented among TA/AA (dominant), CC/CA (recessive), and AG/GG (dominant) carriers in rs9939609 (FTO), rs992472 (DNMT3B), and rs1137101 (LEPR), respectively (n = 39), compared with TT, AA, and/or AA carriers in these SNPs, respectively (P = 0.00001). Each SNP had an additional effect.


Conclusions: Our results confirm a role for FTO in responsiveness to hunger and satiety cues in adults in an experimental setting. The epistatic interaction suggests that DNA methylation, an epigenetic process, affects appetite.


Frayling T.M., Timpson N.J., Weedon N.M., et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity 2007 May 11;316(5826):889-94. doi: 10.1126/science.1141634. Epub 2007 Apr 12. DOI: 10.1126/science.1141634



Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.


Lemaitre R.N., Tanaka T., Tang W., et al. Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium PLoS Genet. 2011 Jul;7(7):e1002193. doi: 10.1371/journal.pgen.1002193. Epub 2011 Jul 28.



Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from α-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p = 3 x 10⁻⁶⁴) and lower levels of eicosapentaenoic acid (EPA, p = 5 x 10⁻⁵⁸) and docosapentaenoic acid (DPA, p = 4 x 10⁻¹⁵⁴). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p = 2 x 10⁻¹²) and DPA (p = 1 x 10⁻⁴³) and lower docosahexaenoic acid (DHA, p = 1 x 10⁻¹⁵). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p = 1 x 10⁻⁸). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.


Harsløf L.B.S., ,Larsen L.H., Ritz C., et al. FADS genotype and diet are important determinants of DHA status: a cross-sectional study in Danish infants Am J Clin Nutr. 2013 Jun;97(6):1403-10. doi: 10.3945/ajcn.113.058685. Epub 2013 May 1. 



Background: Infant docosahexaenoic acid (DHA) status is supported by the DHA content of breast milk and thus can decrease once complementary feeding begins. Furthermore, it is unclear to what extent endogenous DHA synthesis contributes to status.


Objective: We investigated several determinants, including FADS genotypes on DHA status at 9 mo and 3 y.


Design: This was a cross-sectional study with Danish infants from 2 prospective studies [Essentielle Fedtsyrer i OvergangskosteN (EFiON) and the Småbørns Kost Og Trivsel (SKOT) cohort] in which we measured red blood cell (RBC) DHA status at 9 mo (n = 409) and 3 y (n = 176) and genotyped 4 FADS tag single nucleotide polymorphisms (SNPs): rs3834458, rs1535, rs174575, and rs174448 (n = 401). Information about breastfeeding was obtained by using questionnaires, and fish intake was assessed by using 7-d precoded food diaries.


Results: FADS genotype, breastfeeding, and fish intake explained 25% of the variation in infant RBC DHA status [mean ± SD: 6.6 ± 1.9% of fatty acids (FA%)]. Breastfeeding explained most of the variation (∼20%), and still being breastfed at 9 mo was associated with a 0.7 FA% higher DHA compared with no longer being breastfed (P < 0.001). The FADS SNPs rs1535 and rs3834458 were highly correlated (r = 0.98). Homozygous carriers of the minor allele of rs1535 had a DHA increase of 1.8 FA% (P = 0.001) relative to those with the wild-type allele, whereas minor allele carriers of rs174448 and rs174575 had a decrease of 1.1 FA% (P = 0.005) and 2.0 FA% (P = 0.001), respectively. Each 10-g increment in fish intake was associated with an increased DHA status of 0.3 FA%. At 3 y, fish intake was the only significant determinant of DHA status (0.2 FA%/10 g).


Conclusion: Breastfeeding, FADS genotype, and fish intake are important determinants of DHA status in late infancy. The EFiON study was registered at clinicaltrials.gov as NCT 00631046.


Eynon N., Ruiz J.R., Femia P., et al. The ACTN3 R577X polymorphism across three groups of elite male European athletes PLoS One. 2012;7(8):e43132. doi: 10.1371/journal.pone.0043132. Epub 2012 Aug 16.



The ACTN3 R577X polymorphism (rs1815739) is a strong candidate to influence elite athletic performance. Yet, controversy exists in the literature owing to between-studies differences in the ethnic background and sample size of the cohorts, the latter being usually low, which makes comparisons difficult. In this case:control genetic study we determined the association between elite athletic status and the ACTN3 R577X polymorphism within three cohorts of European Caucasian men, i.e. Spanish, Polish and Russian [633 cases (278 elite endurance and 355 power athletes), and 808 non-athletic controls]. The odds ratio (OR) of a power athlete harbouring the XX versus the RR genotype compared with sedentary controls was 0.54 [95% confidence interval (CI): 0.34-0.48; P=0.006]. We also observed that the OR of an endurance athlete having the XX versus the RR genotype compared with power athletes was 1.88 (95%CI: 1.07-3.31; P=0.028). In endurance athletes, the OR of a “world-class” competitor having the XX genotype versus the RR+RX genotype was 3.74 (95%CI: 1.08-12.94; P=0.038) compared with those of a lower (“national”) competition level. No association (P>0.1) was noted between the ACTN3 R577X polymorphism and competition level (world-class versus national-level) in power athletes. Our data provide comprehensive support for the influence of the ACTN3 R577X polymorphism on elite athletic performance.


Valladares M, et al., Association of eating behaviour with clock gene polymorphism 3111 T > C in children based on nutritional status Ann Hum Biol . 2020 Feb;47(1):76-80. doi: 10.1080/03014460.2019.1706764. Epub 2019 Dec 31.



Background: The CLOCK (circadian locomotor output cycle kaput) gene is a central regulator of circadian rhythm. The CLOCK gene has been related to energy intake and therefore to nutritional status. However, its specific associations with aspects of food behaviour in children have been scarcely investigated.Aim: To determine the association between the CLOCK gene polymorphism 3111 T > C and eating behaviours in children based on nutritional status.Methods: A cross-sectional study of the association between a CLOCK gene variant and eating behaviour in children (n = 256) was performed. Eating behaviour was evaluated by the Child Eating Behaviour Questionnaire (CEBQ). In addition, the genotype of the CLOCK 3111 T > C (TT, CC, TC) gene polymorphism and BMI were determined.Results: The obese carriers of the C allele of the polymorphism had lower scores in the dimensions “response to satiety” and “slowness to eat” (p < 0.001), both of which constitute an anti-intake dimension and are related to food satiety.Conclusions: The C allele CLOCK gene could be considered a genetic risk factor for satiety-altered eating behaviour dimensions.


Lozano T.R., et al. Evening chronotype associates with obesity in severely obese subjects: interaction with CLOCK 3111T/C Int J Obes (Lond). 2016 Oct;40(10):1550-1557. doi: 10.1038/ijo.2016.116. Epub 2016 Jun 24.



Background: Chronotype has been related to obesity and metabolic disturbances. However, little is known about the relationship between circadian preferences and genetic background in CLOCK genes with obesity and weight loss among severely obese patients after bariatric surgery.


Objectives: The research goals were (1) to examine whether evening chronotype is related to obesity and weight loss evolution in severely obese followed during 6 years after bariatric surgery and (2) to examine potential interactions between circadian preferences and CLOCK 3111T/C for obesity in this population.


Subjects/methods: Participants (n=252, 79% female; age (mean±s.d.): 52±11 years; body mass index (BMI): 46.4±6.0 kg m-2) were grouped into evening and morning types. Obesity and weight loss parameters, energy and macronutrients intake, energy expenditure, chronotype, meal timing, sleep duration and CLOCK genotype were studied.


Results: Evening-type subjects showed significantly higher initial body weight (P=0.015) and BMI (P=0.014) than morning types. Moreover, evening-type, when compared with morning types, lost less weight (percentage of excess weight loss) after bariatric surgery (P=0.015). Weight-loss progression between the two chronotype groups differed significantly from the fourth year after the bariatric surgery toward a higher weight regain among evening types (P<0.05). We also detected a significant interaction between CLOCK 3111T/C SNP and chronotype for body weight at baseline (P<0.001). Specifically, among carriers of the risk allele C, evening types showed higher body weight than morning types (P=0.012). In addition, CLOCK 3111T/C SNP significantly associated with obesity and sleep duration in the older subjects.


Conclusions: Evening chronotype is associated with higher obesity in severely obese subjects and with lower weight loss effectiveness after bariatric surgery. In addition, circadian preferences interact with CLOCK 3111T/C for obesity. The circadian and genetic assessment could provide tailored weight loss recommendations in subjects who underwent bariatric surgery.


Merino J., et al. Genome-wide meta-analysis of macronutrient intake of 91,114 European ancestry participants from the cohorts for heart and aging research in genomic epidemiology consortium. Int J Med Sci. 2018; 15(10): 999–1004.


Macronutrient intake, the proportion of calories consumed from carbohydrate, fat, and protein, is an important risk factor for metabolic diseases with significant familial aggregation. Previous studies have identified two genetic loci for macronutrient intake, but incomplete coverage of genetic variation and modest sample sizes have hindered the discovery of additional loci. Here, we expanded the genetic landscape of macronutrient intake, identifying 12 suggestively significant loci (P < 1 × 10−6) associated with intake of any macronutrient in 91,114 European ancestry participants. Four loci replicated and reached genome-wide significance in a combined meta-analysis including 123,659 European descent participants, unraveling two novel loci; a common variant in RARB locus for carbohydrate intake and a rare variant in DRAM1 locus for protein intake, and corroborating earlier FGF21 and FTO findings. In additional analysis of 144,770 participants from the UK Biobank, all identified associations from the two-stage analysis were confirmed except for DRAM1. Identified loci might have implications in brain and adipose tissue biology and have clinical impact in obesity-related phenotypes. Our findings provide new insight into biological functions related to macronutrient intake.


Hazra A., Kraft P., Lazarus R., et al. Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway Human Molecular Genetics, Volume 18, Issue 23, 1 December 2009, Pages 4677–4687. 



Low plasma B-vitamin levels and elevated homocysteine have been associated with cancer, cardiovascular disease and neurodegenerative disorders. Common variants in FUT2 on chromosome 19q13 were associated with plasma vitamin B12 levels among women in a genome-wide association study in the Nurses’ Health Study (NHS) NCI-Cancer Genetic Markers of Susceptibility (CGEMS) project. To identify additional loci associated with plasma vitamin B12, homocysteine, folate and vitamin B6 (active form pyridoxal 5′-phosphate, PLP), we conducted a meta-analysis of three GWA scans (total n = 4763, consisting of 1658 women in NHS-CGEMS, 1647 women in Framingham-SNP-Health Association Resource (SHARe) and 1458 men in SHARe). On chromosome 19q13, we confirm the association of plasma vitamin B12 with rs602662 and rs492602 (P-value = 1.83 × 10−15 and 1.30 × 10−14, respectively) in strong linkage disequilibrium (LD) with rs601338 (P = 6.92 × 10−15), the FUT2 W143X nonsense mutation. We identified additional genome-wide significant loci for plasma vitamin B12 on chromosomes 6p21 (P = 4.05 × 10−08), 10p12 (P-value=2.87 × 10−9) and 11q11 (P-value=2.25 × 10−10) in genes with biological relevance. We confirm the association of the well-studied functional candidate SNP 5,10-methylene tetrahydrofolate reductase (MTHFR) Ala222Val (dbSNP ID: rs1801133; P-value=1.27 × 10−8), on chromosome 1p36 with plasma homocysteine and identify an additional genome-wide significant locus on chromosome 9q22 (P-value=2.06 × 10−8) associated with plasma homocysteine. We also identified genome-wide associations with variants on chromosome 1p36 with plasma PLP (P-value=1.40 × 10−15). Genome-wide significant loci were not identified for plasma folate. These data reveal new biological candidates and confirm prior candidate genes for plasma homocysteine, plasma vitamin B12 and plasma PLP.


Surendran S. ,Adaikalakoteswari A.,Saravanan P., et al. An update on vitamin B12-related gene polymorphisms and B12 status Genes & Nutrition volume 13, Article number: 2 (2018)



Background Vitamin B12 is an essential micronutrient in humans needed for health maintenance. Deficiency of vitamin B12 has been linked to dietary, environmental and genetic factors. Evidence for the genetic basis of vitamin B12 status is poorly understood. However, advancements in genomic techniques have increased the knowledge-base of the genetics of vitamin B12 status. Based on the candidate gene and genome-wide association (GWA) studies, associations between genetic loci in several genes involved in vitamin B12 metabolism have been identified.


Objective The objective of this literature review was to identify and discuss reports of associations between single-nucleotide polymorphisms (SNPs) in vitamin B12 pathway genes and their influence on the circulating levels of vitamin B12.


Methods Relevant articles were obtained through a literature search on PubMed through to May 2017. An article was included if it examined an association of a SNP with serum or plasma vitamin B12 concentration. Beta coefficients and odds ratios were used to describe the strength of an association, and a P < 0.05 was considered as statistically significant. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data.


Results From 23 studies which fulfilled the selection criteria, 16 studies identified SNPs that showed statistically significant associations with vitamin B12 concentrations. Fifty-nine vitamin B12-related gene polymorphisms associated with vitamin B12 status were identified in total, from the following populations: African American, Brazilian, Canadian, Chinese, Danish, English, European ancestry, Icelandic, Indian, Italian, Latino, Northern Irish, Portuguese and residents of the USA.


Conclusion Overall, the data analyzed suggests that ethnic-specific associations are involved in the genetic determination of vitamin B12 concentrations. However, despite recent success in genetic studies, the majority of identified genes that could explain variation in vitamin B12 concentrations were from Caucasian populations. Further research utilizing larger sample sizes of non-Caucasian populations is necessary in order to better understand these ethnic-specific associations.


Teran-Garcia M., Santoro N., Rankinen T. et al. Hepatic Lipase Gene Variant 514C>T Is Associated With Lipoprotein and Insulin Sensitivity Response to Regular Exercise. Diabetes. 2005 Jul;54(7):2251-5. doi: 10.2337/diabetes.54.7.2251.


We investigated the associations between the hepatic lipase gene (LIPC) 514C>T polymorphism and lipases, lipoproteins, and insulin sensitivity (Si) responses to exercise training. Hepatic lipase and lipoprotein lipase activities, plasma lipoprotein levels, and Si were measured in the sedentary state and post–exercise training in the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study (n  662). The LIPC 514C allele frequency was 0.516 (blacks) and 0.796 (whites). Baseline and post–exercise training hepatic lipase activities were 40% higher in CC homozygotes (P < 0.0001) in both races. Black CC homozygotes had lower baseline lipoprotein lipase activity, HDL cholesterol, HDL3, and apolipoprotein (apo)A-1 concentrations. White CC homozygotes had lower baseline HDL cholesterol, apoA-1, LDL cholesterol, and apoB levels that remained low post–exercise training. Baseline Si was not associated with the LIPC genotypes. However, training-induced improvements in Si both in blacks and whites were greater in CC homozygotes (1.25  0.2 and 0.22  0.2 U  min1  ml1) than in the TT genotype (0.27  0.3 and 0.97  0.3 U  min1 ml1) (P  0.008 and P  0.002, respectively). The LIPC 514C allele was associated with higher hepatic lipase


Brinkley T., Halverstadt A., Phares D., et al. Hepatic lipase gene -514C>T variant is associated with exercise training-induced changes in VLDL and HDL by lipoprotein lipase J Appl Physiol. 2011 Dec;111(6):1871-6. doi: 10.1152/japplphysiol.00567.2011. Epub 2011 Sep 29.



Our objective was to test the hypothesis that a common polymorphism in the hepatic lipase (HL) gene (LIPC -514C>T, rs1800588) influences aerobic exercise training-induced changes in TG, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) through genotype-specific increases in lipoprotein lipase (LPL) activity and that sex may affect these responses. Seventy-six sedentary overweight to obese men and women aged 50-75 yr at risk for coronary heart disease (CHD) underwent a 24-wk prospective study of the LIPC -514 genotype-specific effects of exercise training on lipoproteins measured enzymatically and by nuclear magnetic resonance, postheparin LPL and HL activities, body composition by dual energy x-ray absorptiometry and computer tomography scan, and aerobic capacity. CT genotype subjects had higher baseline total cholesterol, HDL-C, HDL(2)-C, large HDL, HDL particle size, and large LDL than CC homozygotes. Exercise training elicited genotype-specific decreases in VLDL-TG (-22 vs. +7%; P < 0.05; CC vs. CT, respectively), total VLDL and medium VLDL, and increases in HDL-C (7 vs. 4%; P < 0.03) and HDL(3)-C with significant genotype×sex interactions for the changes in HDL-C and HDL(3)-C (P values = 0.01-0.02). There were also genotype-specific changes in LPL (+23 vs. -6%; P < 0.05) and HL (+7 vs. -24%; P < 0.01) activities, with LPL increasing only in CC subjects (P < 0.006) and HL decreasing only in CT subjects (P < 0.007). Reductions in TG, VLDL-TG, large VLDL, and medium VLDL and increases in HDL(3)-C and small HDL particles correlated significantly with changes in LPL, but not HL, activity only in CC subjects. This suggests that the LIPC -514C>T variant significantly affects training-induced anti-atherogenic changes in VLDL-TG, VLDL particles, and HDL through an association with increased LPL activity in CC subjects, which could guide therapeutic strategies to reduce CHD risk.


Kaplan R.C, et al. A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. Hum Mol Genet. 2011 Mar 15; 20(6): 1241–1251.

Published online 2011 Jan 7.


Abstract Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10−8 (P = 3.3 × 10−101). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10−26). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10−21) and higher IGF-I (P = 4.9 × 10−9) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10−11, IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10−10, SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10−7), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.


Yingchang Y., Dollé M., Imholz S., et.al Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations Volume 49, issue 12, P2582-2589, December 01, 2008


The known genetic variants determining plasma HDL cholesterol (HDL-C) levels explain only part of its variation. Three hundred eighty-four single nucleotide polymorphisms (SNPs) across 251 genes based on pathways potentially relevant to HDL-C metabolism were selected and genotyped in 3,575 subjects from the Doetinchem cohort, which was examined thrice over 11 years. Three hundred fifty-three SNPs in 239 genes passed the quality-control criteria. Seven SNPs [rs1800777 and rs5882 in cholesteryl ester transfer protein (CETP); rs3208305, rs328, and rs268 in LPL; rs1800588 in LIPC; rs2229741 in NRIP1] were associated with plasma HDL-C levels with false discovery rate (FDR) adjusted q values (FDR_q) < 0.05. Five other SNPs (rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, rs6060717 near SCAND1, and rs3213451 in MBTPS2 in women) were associated with plasma HDL-C levels with FDR_q between 0.05 and 0.2. Two less well replicated associations (rs3135506 in APOA5 and rs1800961 in HNF4A) known from the literature were also observed, but their significance disappeared after adjustment for multiple testing (P = 0.008, FDR_q = 0.221 for rs3135506; P = 0.018, FDR_q = 0.338 for rs1800961, respectively). In addition to replication of previous results for candidate genes (CETP, LPL, LIPC, HNF4A, and APOA5), we found interesting new candidate SNPs (rs2229741 in NRIP1, rs3213451 in MBTPS2, rs17585739 in SC4MOL, rs11066322 in PTPN11, rs4961 in ADD1, and rs6060717 near SCAND1) for plasma HDL-C levels that should be evaluated further.


Castro-Orós I., Pérez-López J., Mateo-Gallego R., et al. A genetic variant in the LDLRpromoter is responsible for part of the LDL-cholesterol variability in primary hypercholesterolemia. BMC Medical Genomics volume 7, Article number: 17 (2014)



Background GWAS have consistently revealed that LDLR locus variability influences LDL-cholesterol in general population. Severe LDLR mutations are responsible for familial hypercholesterolemia (FH). However, most primary hypercholesterolemias are polygenic diseases. Although Cis-regulatory regions might be the cause of LDL-cholesterol variability; an extensive analysis of the LDLR distal promoter has not yet been performed. We hypothesized that genetic variants in this region are responsible for the LDLR association with LDL-cholesterol found in GWAS.


Methods Four-hundred seventy-seven unrelated subjects with polygenic hypercholesterolemia (PH) and without causative FH-mutations and 525 normolipemic subjects were selected. A 3103 pb from LDLR (-625 to +2468) was sequenced in 125 subjects with PH. All subjects were genotyped for 4 SNPs (rs17242346, rs17242739, rs17248720 and rs17249120) predicted to be potentially involved in transcription regulation by in silico analysis. EMSA and luciferase assays were carried out for the rs17248720 variant. Multivariable linear regression analysis using LDL-cholesterol levels as the dependent variable were done in order to find out the variables that were independently associated with LDL-cholesterol.


Results The sequencing of the 125 PH subjects did not show variants with minor allele frequency ≥ 10%. The T-allele from g.3131C > T (rs17248720) had frequencies of 9% (PH) and 16.4% (normolipemic), p < 0.00001. Studies of this variant with EMSA and luciferase assays showed a higher affinity for transcription factors and an increase of 2.5 times in LDLR transcriptional activity (T-allele vs C-allele). At multivariate analysis, this polymorphism with the lipoprotein(a) and age explained ≈ 10% of LDL-cholesterol variability.


Conclusion Our results suggest that the T-allele at the g.3131 T > C SNP is associated with LDL-cholesterol levels, and explains part of the LDL-cholesterol variability. As a plausible cause, the T-allele produces an increase in LDLR transcriptional activity and lower LDL-cholesterol levels.


Collins M., Posthumus M., Schwellnus M. The COL1A1 gene and acute soft tissue ruptures Br J Sports Med. 2010 Nov;44(14):1063-4. doi: 10.1136/bjsm.2008.056184. Epub 2009 Feb 4.



Three studies have suggested that the rare TT genotype of the functional Sp1 binding site polymorphism within intron 1 of COL1A1 is associated with cruciate ligament ruptures (CL), shoulder dislocations (SD) and/or Achilles tendon ruptures. Similar genotype distributions were reported for the control and the injury groups in all three studies. In this report, the data from these studies were combined and analyzed. The TT genotype, when compared to the control group (4.1%, n=24 of 581), was significantly under-represented in the (1) CL (0.3%, n=1 of 350, OR=15.0, P=0.0002), (2) CL and SD (0.4% TT genotype, n=2 of 476, OR=10.2, P<0.0001), and (3) CL, SD and Achilles tendon ruptures (0.4% TT genotype, n=2 of 517, OR=11.1, P<0.0001) groups. This combined analysis indicates that the TT genotype appears to be protective against acute soft tissue ruptures and should be incorporated into multifactorial models determining risk of acute soft tissue ruptures.


Hribal M.L., et al. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B Diabetologia. 2011 Apr;54(4):795-802. doi: 10.1007/s00125-010-2038-8. Epub 2011 Jan 14.



Aims/hypothesis: The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry.


Methods: Sample 1 comprised 845 non-diabetic offspring of type 2 diabetes patients recruited in five European centres participating in the EUGENE2 study. Samples 2 and 3 comprised, respectively, 864 and 524 Italian non-diabetic participants. All individuals underwent an OGTT. Screening for the rs10811661 polymorphism was performed using a TaqMan allelic discrimination assay.


Results: The rs10811661 polymorphism did not show a significant association with age, BMI and insulin sensitivity. Participants carrying the TT genotype showed a significant reduction in insulin release, measured by an OGTT-derived index, compared with carriers of the C allele, in the three samples. When these results were pooled with those of three published studies, and meta-analysed with a random-effects model, the T allele was significantly associated with reduced insulin secretion (-35.09 [95% CI 14.68-55.52], p = 0.0008 for CC+CT vs TT; and -29.45 [95% CI 9.51-49.38], p = 0.0038, for the additive model). In addition, in our three samples, participants carrying the TT genotype exhibited an increased risk for impaired glucose tolerance (IGT) compared with carriers of the C allele (OR 1.55 [95% CI 1.20-1.95] for the meta-analysis of the three samples).


Conclusions/interpretation: Our data, together with the meta-analysis of previously published studies, show that the rs10811661 polymorphism is associated with impaired insulin release and IGT, suggesting that this variant may contribute to type 2 diabetes by affecting beta cell function.


Pai J.K., Mukamal K.J., Rexrode K.M., et. al. C-reactive protein (CRP) gene polymorphisms, CRP levels, and risk of incident coronary heart disease in two nested case-control studies PLoS One. 2008 Jan 2;3(1):e1395. doi: 10.1371/journal.pone.0001395.



Background: C-reactive protein (CRP), an acute phase reactant and marker of inflammation, has been shown to predict risk of incident cardiovascular events. However, few studies have comprehensively examined six common single-nucleotide polymorphisms (SNPs) in the CRP gene, haplotypes, and plasma CRP levels with risk of coronary heart disease (CHD).


Methods and findings: We conducted parallel nested case-control studies within two ongoing, prospective cohort studies of U.S. women (Nurses’ Health Study) and men (Health Professionals Follow-up Study). Blood samples were available in a subset of 32,826 women and 18,225 men for biomarker and DNA analyses. During 8 and 6 years of follow-up, 249 women and 266 men developed incident nonfatal myocardial infarction or fatal CHD, and controls (498 women, 531 men) were matched 2:1 on age, smoking, and date of blood draw from participants free of cardiovascular disease at the time the case was diagnosed. Among both women and men, minor alleles were significantly associated with higher CRP levels for SNPs 1919A>T and 4741G>C, but associated with lower CRP levels for SNPs 2667G>C and 3872C>T. SNP 2667G>C was individually associated with increased risk of CHD in both women [OR 1.57 (95% CI 1.01-2.44); p = 0.047] and men [1.93 (95% CI 1.30-2.88); p = 0.001]. Two of the five common haplotypes were associated with lower CRP levels, and Haplotype 4 which included minor alleles for 2667 and 3872 was associated with significantly lower CRP levels and an elevated risk of CHD. The remaining SNPs or haplotypes were not associated with CHD in both populations.


Conclusions: Common variation in the CRP gene was significantly associated with plasma CRP levels; however, the association between common SNPs and CRP levels did not correspond to a predicted change in CHD risk. The underlying inflammatory processes which predict coronary events cannot be captured solely by variation in the CRP gene.


Arkadianos L., Valdes M., Marinos E., et al. Improved weight management using genetic information to personalize a calorie controlled diet Nutr J. 2007; 6: 29. Published online 2007 Oct 18. doi: 10.1186/1475-2891-6-29



Background Gene-environment studies demonstrate variability in nutrient requirements depending upon individual variations in genes affecting nutrient metabolism and transport. This study investigated whether the inclusion of genetic information to personalize a patient’s diet (nutrigenetics) could improve long term weight management.

Methods Patients with a history of failures at weight loss were offered a nutrigenetic test screening 24 variants in 19 genes involved in metabolism. 50 patients were in the nutrigenetic group and 43 patients attending the same clinic were selected for comparison using algorithms to match the characteristics: age, sex, frequency of clinical visits and BMI at initial clinic visit. The second group of 43 patients did not receive a nutrigenetic test. BMI reduction at 100 and > 300 days and blood fasting glucose were measured.

Results After 300 days of follow-up individuals in the nutrigenetic group were more likely to have maintained some weight loss (73%) than those in the comparison group (32%), resulting in an age and gender adjusted OR of 5.74 (95% CI 1.74–22.52). Average BMI reduction in the nutrigenetic group was 1.93 kg/m2(5.6% loss) vs. an average BMI gain of 0.51 kg/m2(2.2% gain) (p < 0.023). Among patients with a starting blood fasting glucose of > 100 mg/dL, 57% (17/30) of the nutrigenetic group but only 25% (4/16) of the non-tested group had levels reduced to < 100 mg/dL after > 90 days of weight management therapy (OR for lowering glucose to < 100 mg/dL due to diet = 1.98 95%CI 1.01, 3.87, p < 0.046).

Conclusion Addition of nutrigenetically tailored diets resulted in better compliance, longer-term BMI reduction and improvements in blood glucose levels.


Jones N., Kiely J., Suraci B, et al. A genetic-based algorithm for personalized resistance training Biol Sport. 2016 Jun;33(2):117-26. doi: 10.5604/20831862.1198210. Epub 2016 Apr 1.



Association studies have identified dozens of genetic variants linked to training responses and sport-related traits. However, no intervention studies utilizing the idea of personalised training based on athlete’s genetic profile have been conducted. Here we propose an algorithm that allows achieving greater results in response to high- or low-intensity resistance training programs by predicting athlete’s potential for the development of power and endurance qualities with the panel of 15 performance-associated gene polymorphisms. To develop and validate such an algorithm we performed two studies in independent cohorts of male athletes (study 1: athletes from different sports (n = 28); study 2: soccer players (n = 39)). In both studies athletes completed an eight-week high- or low-intensity resistance training program, which either matched or mismatched their individual genotype. Two variables of explosive power and aerobic fitness, as measured by the countermovement jump (CMJ) and aerobic 3-min cycle test (Aero3) were assessed pre and post 8 weeks of resistance training. In study 1, the athletes from the matched groups (i.e. high-intensity trained with power genotype or low-intensity trained with endurance genotype) significantly increased results in CMJ (P = 0.0005) and Aero3 (P = 0.0004). Whereas, athletes from the mismatched group (i.e. high-intensity trained with endurance genotype or low-intensity trained with power genotype) demonstrated non-significant improvements in CMJ (P = 0.175) and less prominent results in Aero3 (P = 0.0134). In study 2, soccer players from the matched group also demonstrated significantly greater (P < 0.0001) performance changes in both tests compared to the mismatched group. Among non- or low responders of both studies, 82% of athletes (both for CMJ and Aero3) were from the mismatched group (P < 0.0001). Our results indicate that matching the individual’s genotype with the appropriate training modality leads to more effective resistance training. The developed algorithm may be used to guide individualised resistance-training interventions.


Murgia C., Adamski M. Translation of Nutritional Genomics into Nutrition Practice: The Next Step Nutrients 2017, 9(4)



Genetics is an important piece of every individual health puzzle. The completion of the Human Genome Project sequence has deeply changed the research of life sciences including nutrition. The analysis of the genome is already part of clinical care in oncology, pharmacology, infectious disease and, rare and undiagnosed diseases. The implications of genetic variations in shaping individual nutritional requirements have been recognised and conclusively proven, yet routine use of genetic information in nutrition and dietetics practice is still far from being implemented. This article sets out the path that needs to be taken to build a framework to translate gene–nutrient interaction studies into best-practice guidelines, providing tools that health professionals can use to understand whether genetic variation affects nutritional requirements in their daily clinical practice.


Joffe Y., Herholdt H, What Will It Take to Build an Expert Group of Nutrigenomic Practitioners? Lifestyle Genomics 2020;13:122–128



Background: The past two decades have seen exponential growth in the number of genetic testing companies, but only a small percentage of these tests are being sold through health care professionals (HCPs). As each new genetic testing company appears, it is becoming more difficult for the practitioner and consumer to evaluate the credibility of the claims being made and the value of the tests being offered. Summary: HCPs appear to have minimal nutrigenomics knowledge and little confidence in choosing and interpreting nutrigenetic tests. To remedy this, HCPs need access to credible education, professional support, networking, career development, mentorship, and a regulated testing environment. This will enable them to evaluate the credibility of genetic tests and testing companies, provide genetic results in context, and apply appropriate clinical translation. Key Message: In order to establish an expert group of nutrigenomic practitioners, collaboration is required between educational institutions, professional organizations, and genetic testing companies. This will provide the necessary support, skills, and knowledge to ensure that the best value is extracted from nutrigenetic tests in an ethical and responsible manner.


Görman U., Mathers J., Grimaldi K., et al. Do we know enough? A scientific and ethical analysis of the basis for genetic-based personalized nutrition Genes & Nutrition volume 8, pages373–381 (2013)



This article discusses the prospects and limitations of the scientific basis for offering personalized nutrition advice based upon individual genetic information. Two divergent scientific positions are presented, with an ethical comment. The crucial question is whether the current knowledge base is sufficiently strong for taking an ethically responsible decision to offer personalized nutrition advice based upon gene–diet–health interaction. According to the first position, the evidence base for translating the outcomes of nutrigenomics research into personalized nutritional advice is as yet immature. There is also limited evidence that genotype-based dietary advice will motivate appropriate behavior changes. Filling the gaps in our knowledge will require larger and better randomized controlled trials. According to the second position, personalized nutrition must be evaluated in relation to generally accepted standard dietary advice—partly derived from epidemiological observations and usually not proven by clinical trials. With personalized nutrition, we cannot demand stronger evidence. In several specific cases of gene–diet interaction, it may be more beneficial for individuals with specific genotypes to follow personalized advice rather than general dietary recommendations. The ethical comment, finally, considers the ethical aspects of deciding how to proceed in the face of such uncertainty. Two approaches for an ethically responsible way forward are proposed. Arguing from a precautionary approach, it is suggested that personalized dietary advice should be offered only when there is strong scientific evidence for health effects, followed by stepwise evaluation of unforeseen behavioral and psychological effects. Arguing from theoretical and applied ethics as well as psychology, it is also suggested that personalized advice should avoid paternalism and instead focus on supporting the autonomous choice of each person.