Evidence for novel genetic loci associated with metabolic traits in Yup'ik people

Aslibekyan, Stella; Vaughan, Laura K.; Wiener, Howard W.; Lemas, Dominick J.; Klimentidis, Yann C.; Havel, Peter J.; Stanhope, Kimber L.; O’Brien, Diane M.; Hopkins, Scarlett E.; Boyer, Bert B.; Tiwari, Hemant K.

doi:10.1002/ajhb.22429

Cited by 10 publications

(12 citation statements)

References 39 publications

(41 reference statements)

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“…However, as a validated biomarker of marine food (fish and marine mammal) intake for the Yup’ik population of SW Alaska, the RBC δ 15 N value has been used to examine how gene × diet interactions are associated with risk factors for obesity and chronic disease (2, 71, 81, 82), and it was recently used to demonstrate that high and low consumers of marine foods exhibit very different patterns of gene methylation (3). We found that the RBC δ 15 N value captured most of the same diet - risk factor associations that were previously identified for Yup’ik people using RBC EPA and DHA (84), but that in addition, high RBC δ 15 N values were associated with high adiponectin, which promotes insulin sensitivity, and were inversely associated with blood pressure (102).…”

Section: Stable Isotope Ratios In Human Dietary Studiesmentioning

confidence: 99%

Stable Isotope Ratios as Biomarkers of Diet for Health Research

2015

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Diet is a leading modifiable risk factor for chronic disease, but it remains difficult to measure accurately due to the error and bias inherent in self-reported methods of diet assessment. Consequently there is a pressing need for more objective biomarkers of diet for use in health research. The stable isotope ratios of light elements are a promising set of candidate biomarkers because they vary naturally and reproducibly among foods, and those variations are captured in molecules and tissues with high fidelity. Recent studies have identified valid isotopic measures of short and long-term sugar intake, meat intake, and fish intake in specific populations. These studies provide a strong foundation for validating stable isotopic biomarkers in the general United States population. Approaches to improve specificity for specific foods are needed, for example, by modeling intake using multiple stable isotope ratios, or by isolating and measuring specific molecules linked to foods of interest.

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Section: Stable Isotope Ratios In Human Dietary Studiesmentioning

confidence: 99%

Stable Isotope Ratios as Biomarkers of Diet for Health Research

2015

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“…Intakes of EPA and DHA are high and quite variable in YupÕik people (6); therefore, associations with health are of particular interest for further study (8)(9)(10)(11). Because d 15 N is relatively simple and inexpensive to assay, several recent studies have used d 15 N as a surrogate measure of n-3 PUFA intake (10,12,13). However, EPA and DHA derive from marine fats, whereas elevated d 15 N derives from marine protein, and these components are sometimes rendered and eaten separately (e.g., as seal oil and seal meat).…”

Section: Introductionmentioning

confidence: 99%

A Stable Isotope Biomarker of Marine Food Intake Captures Associations between n–3 Fatty Acid Intake and Chronic Disease Risk in a Yup’ik Study Population, and Detects New Associations with Blood Pressure and Adiponectin

O’Brien

Kristal

Nash

et al. 2014

The Journal of Nutrition

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The nitrogen isotope ratio (δ(15)N) of RBCs has been proposed as a biomarker of marine food intake in Yup'ik people based on strong associations with RBC eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). However, EPA and DHA derive from marine fats, whereas elevated δ(15)N derives from marine protein, and these dietary components may have different biologic effects. Whether δ(15)N is similarly associated with chronic disease risk factors compared with RBC EPA and DHA is not known. We used covariate-adjusted linear models to describe biomarker associations with chronic disease risk factors in Yup'ik people, first in a smaller (n = 363) cross-sectional study population using RBC EPA, DHA, and δ(15)N, and then in a larger (n = 772) cross-sectional study population using δ(15)N only. In the smaller sample, associations of RBC EPA, DHA, and δ(15)N with obesity and chronic disease risk factors were similar in direction and significance: δ(15)N was positively associated with total, HDL, and LDL cholesterol, apolipoprotein A-I, and insulin-like growth factor binding protein-3 (IGFBP-3), and inversely associated with triglycerides. Based on comparisons between covariate-adjusted β-coefficients, EPA was more strongly associated with circulating lipids and lipoproteins, whereas δ(15)N was more strongly associated with adipokines, the inflammatory marker interleukin-6, and IGFBP-3. In the larger sample there were new findings for this population: δ(15)N was inversely associated with blood pressure and there was a significant association (with inverse linear and positive quadratic terms) with adiponectin. In conclusion, δ(15)N is a valid measure for evaluating associations between EPA and DHA intake and chronic disease risk in Yup'ik people and may be used in larger studies. By measuring δ(15)N, we report beneficial associations of marine food intake with blood pressure and adiponectin, which may contribute to a lower incidence of some chronic diseases in Yup'ik people.

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“…Detailed descriptions of the genotyping procedures and data cleaning of CANHR Yup’ik samples have also previously been published [26]. Briefly, we used the Illumina Linkage IV panel to genotype 6090 SNPs spanning the entire genome, with an average genetic distance of 0.58 cM.…”

Section: Methodsmentioning

confidence: 99%

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

et al. 2018

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Aims/hypothesisIn a recent study using a standard additive genetic model, we identified a TBC1D4 loss-of-function variant with a large recessive impact on risk of type 2 diabetes in Greenlanders. The aim of the current study was to identify additional genetic variation underlying type 2 diabetes using a recessive genetic model, thereby increasing the power to detect variants with recessive effects.MethodsWe investigated three cohorts of Greenlanders (B99, n = 1401; IHIT, n = 3115; and BBH, n = 547), which were genotyped using Illumina MetaboChip. Of the 4674 genotyped individuals passing quality control, 4648 had phenotype data available, and type 2 diabetes association analyses were performed for 317 individuals with type 2 diabetes and 2631 participants with normal glucose tolerance. Statistical association analyses were performed using a linear mixed model.ResultsUsing a recessive genetic model, we identified two novel loci associated with type 2 diabetes in Greenlanders, namely rs870992 in ITGA1 on chromosome 5 (OR 2.79, p = 1.8 × 10−8), and rs16993330 upstream of LARGE1 on chromosome 22 (OR 3.52, p = 1.3 × 10−7). The LARGE1 variant did not reach the conventional threshold for genome-wide significance (p < 5 × 10−8) but did withstand a study-wide Bonferroni-corrected significance threshold. Both variants were common in Greenlanders, with minor allele frequencies of 23% and 16%, respectively, and were estimated to have large recessive effects on risk of type 2 diabetes in Greenlanders, compared with additively inherited variants previously observed in European populations.Conclusions/interpretationWe demonstrate the value of using a recessive genetic model in a historically small and isolated population to identify genetic risk variants. Our findings give new insights into the genetic architecture of type 2 diabetes, and further support the existence of high-effect genetic risk factors of potential clinical relevance, particularly in isolated populations.Data availabilityThe Greenlandic MetaboChip-genotype data are available at European Genome-Phenome Archive (EGA; https://ega-archive.org/) under the accession EGAS00001002641.Electronic supplementary materialThe online version of this article (10.1007/s00125-018-4659-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

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Evidence for novel genetic loci associated with metabolic traits in Yup'ik people

Cited by 10 publications

References 39 publications

Stable Isotope Ratios as Biomarkers of Diet for Health Research

Stable Isotope Ratios as Biomarkers of Diet for Health Research

A Stable Isotope Biomarker of Marine Food Intake Captures Associations between n–3 Fatty Acid Intake and Chronic Disease Risk in a Yup’ik Study Population, and Detects New Associations with Blood Pressure and Adiponectin

Identification of novel high-impact recessively inherited type 2 diabetes risk variants in the Greenlandic population

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