Dataset Information

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

ABSTRACT: Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 Hispanic American participants from the Multi-Ethnic Study of Atherosclerosis. We demonstrate strong negative associations between Amerind genetic ancestry and LC-PUFA levels. The FADS rs174537 single nucleotide polymorphism (SNP) accounted for much of the AI ancestry effect on LC-PUFAs, especially for low levels of n-3 LC-PUFAs. Rs174537 was also strongly associated with several metabolic, inflammatory and anthropomorphic traits including circulating triglycerides (TGs) and E-selectin in MESA Hispanics. Our study demonstrates that Amerind ancestry provides a useful and readily available tool to identify individuals most likely to have FADS-related n-3 LC-PUFA deficiencies and associated cardiovascular risk.

SUBMITTER: Yang C

PROVIDER: S-EPMC8319323 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

Yang Chaojie C Hallmark Brian B Chai Jin Choul JC O'Connor Timothy D TD Reynolds Lindsay M LM Wood Alexis C AC Seeds Michael M Chen Yii-Der Ida YI Steffen Lyn M LM Tsai Michael Y MY Kaplan Robert C RC Daviglus Martha L ML Mandarino Lawrence J LJ Fretts Amanda M AM Lemaitre Rozenn N RN Coletta Dawn K DK Blomquist Sarah A SA Johnstone Laurel M LM Tontsch Chandra C Qi Qibin Q Ruczinski Ingo I Rich Stephen S SS Mathias Rasika A RA Chilton Floyd H FH Manichaikul Ani A

Communications biology 20210728 1

Long chain polyunsaturated fatty acids (LC-PUFAs) have critical signaling roles that regulate dyslipidemia and inflammation. Genetic variation in the FADS gene cluster accounts for a large portion of interindividual differences in circulating and tissue levels of LC-PUFAs, with the genotypes most strongly predictive of low LC-PUFA levels at strikingly higher frequencies in Amerind ancestry populations. In this study, we examined relationships between genetic ancestry and FADS variation in 1102 H ...[more]

PMID: 34321601

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Project description:Human diets in developed countries such as the US have changed dramatically over the past 75 years, leading to increased obesity, inflammation, and cardiometabolic dysfunction. Evidence over the past decade indicates that the interaction of genetic variation with changes in the intake of 18-carbon essential dietary omega-6 (n-6) and omega-3 (n-3) polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, has impacted numerous molecular and clinical phenotypes. Interactions are particularly relevant with the FADS1 and FADS2 genes, which encode key fatty acid desaturases in the pathway that converts LA and ALA to their long chain (≥20 carbons), highly unsaturated fatty acid (HUFA) counterparts. These gene by nutrient interactions affect the levels and balance of n-6 and n-3 HUFA that in turn are converted to a wide array of lipids with signaling roles, including eicosanoids, docosanoids, other oxylipins and endocannabinoids. With few exceptions, n-6 HUFA are precursors of pro-inflammatory/pro-thrombotic signaling lipids, and n-3 HUFA are generally anti-inflammatory/anti-thrombotic. We and others have demonstrated that African ancestry populations have much higher frequencies (vs. European-, Asian- or indigenous Americas-ancestry populations) of a FADS "derived" haplotype that is associated with the efficient conversion of high levels of dietary n-6 PUFA to pro-inflammatory n-6 HUFA. By contrast, an "ancestral" haplotype, carrying alleles associated with a limited capacity to synthesize HUFA, which can lead to n-3 HUFA deficiency, is found at high frequency in certain Hispanic populations and is nearly fixed in several indigenous populations from the Americas. Based on these observations, a focused secondary subgroup analysis of the VITAL n-3 HUFA supplementation trial stratifying the data based on self-reported ancestry revealed that African Americans may benefit from n-3 HUFA supplementation, and both ancestry and FADS variability should be factored into future clinical trials design.

Project description:IntroductionPolyunsaturated fatty acids (PUFA) and highly unsaturated fatty acid (HUFA) synthetic products and their signaling metabolites play vital roles in immunity, inflammation, and brain development/function. Frequency differences of variants within the fatty acid desaturase (FADS) gene cluster affect levels of HUFAs, their biologically active products, and numerous physiological phenotypes. Fundamental questions remain regarding the impact of this genetic variation on the health of Hispanic/Latino populations.MethodsData and biospecimens (plasma, red blood cells, buffy coat-derived DNA) from 135 participants (83.7% female) were used to assess the relationship(s) between dietary PUFA levels, a FADS haplotype tagging SNP, rs174537, and the capacity of Hispanic/Latino populations to generate HUFAs in plasma and RBC as well as its potential impact on anthropomorphic phenotypes.ResultsThe dietary habits of the cohort showed that participant diets contained a high ratio (9.3 ± 0.2, mean ± SEM) of linoleic acid (n-6) to alpha-linolenic acid (n-3) and also contained extremely low levels of n-3 HUFAs (eicosapentaenoic acid, EPA and docosahexaenoic acid, DHA), both features of the Modern Western Diet. Compared to African and European American cohorts, the frequency of the TT rs174537 genotype was highly enriched (53% of subjects) in this Hispanic/Latino cohort and was strongly associated with lower circulating HUFA levels. For example, plasma levels of arachidonic acid (ARA: 20:4, n-6) and EPA (20:5, n-3) were 37% and 23%, respectively, lower in the TT versus the GG genotype. HUFA biosynthetic efficiency, as determined by metabolic product to precursor ratios, was highly dependent (p < 0.0001) on the rs174537 genotype (GG > GT > TT) for both circulating n-6 and n-3 HUFAs. In contrast, the RBC Omega-3 Index (EPA + DHA) was extremely low (2.89 ± 1.65, mean ± sd) in this population and independent of rs174537 genotype. Importantly, the rs174537 genotype was also related to female height with TT genotype participants being 4.5 cm shorter (p = 0.0001) than the GG + GT participants.DiscussionTaken together, this study illustrates that dietary PUFA + HUFA × FADS gene- interactions place a large proportion (>50%) of Hispanic/Latino populations at high risk of a deficiency in both circulating and cellular levels of n-3 HUFAs.

Project description:BackgroundHispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations.MethodsWhole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here.ResultsT2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences.ConclusionsT2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.

Project description:Polygenic risk scores (PRS) have predominantly been derived from genome-wide association studies (GWAS) conducted in European ancestry (EUR) individuals. In this study, we present an in-depth evaluation of PRS based on multi-ancestry GWAS for five cardiometabolic phenotypes in the Penn Medicine BioBank (PMBB) followed by a phenome-wide association study (PheWAS). We examine the PRS performance across all individuals and separately in African ancestry (AFR) and EUR ancestry groups. For AFR individuals, PRS derived using the multi-ancestry LD panel showed a higher effect size for four out of five PRSs (DBP, SBP, T2D, and BMI) than those derived from the AFR LD panel. In contrast, for EUR individuals, the multi-ancestry LD panel PRS demonstrated a higher effect size for two out of five PRSs (SBP and T2D) compared to the EUR LD panel. These findings underscore the potential benefits of utilizing a multi-ancestry LD panel for PRS derivation in diverse genetic backgrounds and demonstrate overall robustness in all individuals. Our results also revealed significant associations between PRS and various phenotypic categories. For instance, CAD PRS was linked with 18 phenotypes in AFR and 82 in EUR, while T2D PRS correlated with 84 phenotypes in AFR and 78 in EUR. Notably, associations like hyperlipidemia, renal failure, atrial fibrillation, coronary atherosclerosis, obesity, and hypertension were observed across different PRSs in both AFR and EUR groups, with varying effect sizes and significance levels. However, in AFR individuals, the strength and number of PRS associations with other phenotypes were generally reduced compared to EUR individuals. Our study underscores the need for future research to prioritize 1) conducting GWAS in diverse ancestry groups and 2) creating a cosmopolitan PRS methodology that is universally applicable across all genetic backgrounds. Such advances will foster a more equitable and personalized approach to precision medicine.

Project description:BackgroundMetabolic regulation plays a significant role in energy homeostasis, and adolescence is a crucial life stage for the development of cardiometabolic disease (CMD). This study aims to investigate the genetic determinants of metabolic biomarkers-adiponectin, leptin, ghrelin, and orexin-and their associations with CMD risk factors.MethodsWe characterized the genetic determinants of the biomarkers among Hispanic/Latino adolescents of the Santiago Longitudinal Study (SLS) and identified the cumulative effects of genetic variants on adiponectin and leptin using biomarker polygenic risk scores (PRS). We further investigated the direct and indirect effect of the biomarker PRS on downstream body fat percent (BF%) and glycemic traits using structural equation modeling.ResultsWe identified putatively novel genetic variants associated with the metabolic biomarkers. A substantial amount of biomarker variance was explained by SLS-specific PRS, and the prediction was improved by including the putatively novel loci. Fasting blood insulin and insulin resistance were associated with PRS for adiponectin, leptin, and ghrelin, and BF% was associated with PRS for adiponectin and leptin. We found evidence of substantial mediation of these associations by the biomarker levels.ConclusionsThe genetic underpinnings of metabolic biomarkers can affect the early development of CMD, partly mediated by the biomarkers.ImpactThis study characterized the genetic underpinnings of four metabolic hormones and investigated their potential influence on adiposity and insulin biology among Hispanic/Latino adolescents. Fasting blood insulin and insulin resistance were associated with polygenic risk score (PRS) for adiponectin, leptin, and ghrelin, with evidence of some degree of mediation by the biomarker levels. Body fat percent (BF%) was also associated with PRS for adiponectin and leptin. This provides important insight on biological mechanisms underlying early metabolic dysfunction and reveals candidates for prevention efforts. Our findings also highlight the importance of ancestrally diverse populations to facilitate valid studies of the genetic architecture of metabolic biomarker levels.

Dataset Information

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

Publications

Impact of Amerind ancestry and FADS genetic variation on omega-3 deficiency and cardiometabolic traits in Hispanic populations.

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