The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans

Rasika A Mathias, Susan Sergeant, Ingo Ruczinski, Dara G Torgerson, Christina E Hugenschmidt, Meghan Kubala, Dhananjay Vaidya, Bhoom Suktitipat, Julie T Ziegler, Priscilla Ivester, Douglas Case, Lisa R Yanek, Barry I Freedman, Megan E Rudock, Kathleen C Barnes, Carl D Langefeld, Lewis C Becker, Donald W Bowden, Diane M Becker, Floyd H Chilton, Rasika A Mathias, Susan Sergeant, Ingo Ruczinski, Dara G Torgerson, Christina E Hugenschmidt, Meghan Kubala, Dhananjay Vaidya, Bhoom Suktitipat, Julie T Ziegler, Priscilla Ivester, Douglas Case, Lisa R Yanek, Barry I Freedman, Megan E Rudock, Kathleen C Barnes, Carl D Langefeld, Lewis C Becker, Donald W Bowden, Diane M Becker, Floyd H Chilton

Abstract

Background: Arachidonic acid (AA) is a long-chain omega-6 polyunsaturated fatty acid (PUFA) synthesized from the precursor dihomo-gamma-linolenic acid (DGLA) that plays a vital role in immunity and inflammation. Variants in the Fatty Acid Desaturase (FADS) family of genes on chromosome 11q have been shown to play a role in PUFA metabolism in populations of European and Asian ancestry; no work has been done in populations of African ancestry to date.

Results: In this study, we report that African Americans have significantly higher circulating levels of plasma AA (p = 1.35 × 10(-48)) and lower DGLA levels (p = 9.80 × 10(-11)) than European Americans. Tests for association in N = 329 individuals across 80 nucleotide polymorphisms (SNPs) in the Fatty Acid Desaturase (FADS) locus revealed significant association with AA, DGLA and the AA/DGLA ratio, a measure of enzymatic efficiency, in both racial groups (peak signal p = 2.85 × 10(-16) in African Americans, 2.68 × 10(-23) in European Americans). Ancestry-related differences were observed at an upstream marker previously associated with AA levels (rs174537), wherein, 79-82% of African Americans carry two copies of the G allele compared to only 42-45% of European Americans. Importantly, the allelic effect of the G allele, which is associated with enhanced conversion of DGLA to AA, on enzymatic efficiency was similar in both groups.

Conclusions: We conclude that the impact of FADS genetic variants on PUFA metabolism, specifically AA levels, is likely more pronounced in African Americans due to the larger proportion of individuals carrying the genotype associated with increased FADS1 enzymatic conversion of DGLA to AA.

Figures

Figure 1
Figure 1
Population-based Differences in Plasma Fatty Acid Concentrations. Trait distribution differences between African American (N = 174) and European American (N = 155) individuals from the GeneSTAR study showing distributions in age- and gender-adjusted ω6 PUFAs (LA, GLA, DGLA and AA) and FADS1 enzymatic efficiency (AA/DGLA). Each sample is represented by a single dot in blue for African Americans and red for European Americans. Sample means and confidence interval for the sample mean are presented as the horizontal black line and surrounding green box, respectively. Genes known to play a pivotal role in the desaturation and elongation step in the metabolism of AA are illustrated. Individual PUFAs were expressed as percent of total fatty acids in a sample, and the ratio of AA mass/DGLA mass was calculated as a measure of FADS1 enzymatic efficiency.
Figure 2
Figure 2
Geographic Differences in the Allelic Frequencies of a FADS Gene Cluster SNP. Geographic distribution (a) of derived allele frequencies (shown in orange) for rs174537 in the 52 populations represented in the Human Genome Diversity Panel Data. The data suggest the fixation of derived rs174537 G allele within the African continent. Similarly, the continental distribution for rs174537 genotypes (b) shows a dramatic shift in the predominant homozygous state from Africa to the Americas.
Figure 3
Figure 3
Plasma Fatty Acid Concentrations Vary by Genotype at rs174537. Trait distribution differences between African Americans (N = 174) and European Americans (N = 155) participating in the GeneSTAR study, showing genotypic differences in according to DGLA, AA, and AA/DGLA phenotype at marker rs174537 by race. Each sample is represented by a single dot in blue for African Americans and red for European Americans. Sample means and confidence interval for the sample mean are presented as the horizontal black line and surrounding green box, respectively.
Figure 4
Figure 4
Peak Association by Race. Tests for association for AA, DGLA and FADS1 enzymatic activity (AA/DGLA) in the ascertained sample from GeneSTAR in African Americans and European Americans for 100 SNPs on chromosome 11q13. Strength of Association depicted as in the legend, LD patterns (low to strong ranging from white to red) along with LD blocks (black triangles), and physical location of SNPs (blue lines) relative to the three FADS genes (see insert).

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Source: PubMed

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