Polyunsaturated Fatty Acids Plasma Level Quantitative Trait Locus 1

Description

Polyunsaturated fatty acids (PUFA), particularly those of the n-3 or omega-3 family, have been associated with decreased risk of cardiovascular and other chronic diseases (Tanaka et al., 2009).

Mapping

In a genomewide association study of plasma levels of 6 different polyunsaturated plasma fatty acids among 1,075 Italian men and women in the InCHIANTI study on aging, Tanaka et al. (2009) found evidence for an association with chromosome 11q12-q13.1 that contains genes encoding 3 fatty acid desaturases: FADS1 (606148), FADS2 (606149), and FADS3 (606150). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46)). Minor allele homozygotes had lower plasma AA compared to major allele homozygotes, and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9)) and eicosapentaenoic acid (EPA; p = 1.07 x 10(-14)). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein cholesterol (LDLC) and total cholesterol levels. The effects of rs174537 were confirmed in an independent sample of 1,076 white men and women from the U.S. in the GOLDN study. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding the ELOVL2 gene (611814). In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6)). These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFAs contribute to plasma concentrations of fatty acids.

Evolution

To determine the importance of genetic variability to fatty acid biosynthesis, Ameur et al. (2012) performed genomewide genotyping in 5,652 individuals and targeted resequencing in 960 individuals of the FADS region in 5 European population cohorts. The results showed that present-day humans have 2 common FADS haplotypes that differ dramatically in their ability to generate long-chain polyunsaturated fatty acids (LC-PUFAs). The more common haplotype, haplotype D, was associated with high lipid levels (p = 1 x 10(-65)), whereas the less common haplotype, haplotype A, was associated with low lipid levels (p = 1 x 10(-52)). In both the omega-3 and omega-6 pathways, haplotype D was strongly associated with lower levels of the precursors in fatty acid synthesis (linoleic acid and alpha-linoleic acid) and higher levels of eicosapentaenoic acid (EPA), gamma-linoleic acid (GLA), docosahexaenoic acid (DHA), and arachidonic acid (AA) (the products), indicating that this haplotype is more efficient in converting the precursors to LC-PUFAs. Individuals homozygous for haplotype D had 24% higher levels of DHA and 43% higher levels of AA than those homozygous for haplotype A. Analysis of the ratios of consecutive products in fatty acid synthesis showed that both the delta-5 and delta-6 desaturase steps are affected by the FADS haplotype. The 28 SNPs defining haplotypes A and D span a 38.9-kb region, including the promoter regions of FADS1 and FADS2. Estimated from the human genome diversity panel (HGDP), the geographic distributions of haplotypes A and D differ dramatically between continents. In African populations, haplotype A is essentially absent (1% of chromosomes), whereas in Europe, West, South, and East Asia, and Oceania, it occurs at a frequency of 25 to 50%. Among the 126 Native Americans included in HGDP, haplotype A accounts for 97% of chromosomes. The very high frequency of haplotype D in Africa and the high linkage disequilibrium in the FADS region indicated that this part of the genome has been subjected to positive selection. Haplotype A is the ancestral haplotype and haplotype D, which is associated with an increased FADS activity, is specific to humans and appeared on the lineage leading to modern humans approximately 255,000 years ago, well after the split from the common ancestor of humans and chimpanzees. Ameur et al. (2012) remarked that haplotype D is likely to have been advantageous to humans living in environments with a limited access to AA and DHA fatty acids, and this could explain the signature of positive selection seen for this haplotype in African populations. In the modern world, haplotype D has been associated with lifestyle-related diseases such as coronary artery disease.

Molecular Genetics

Polymorphism in Indigenous Arctic Populations

Fumagalli et al. (2015) scanned the genomes of Inuit from Greenland for signatures of adaptation to low annual temperatures and diets rich in protein and omega-3 polyunsaturated fatty acids (PUFAs). They found the strongest signal in a cluster of fatty acid desaturases (FADS1, FADS2, and FADS3) that determine PUFA levels. The selected alleles (rs7115739, rs174570, rs74771917, rs3168072, and rs12577276) have been associated with multiple metabolic and anthropometric phenotypes and had large effect sizes for weight and height; Fumagalli et al. (2015) replicated the effect on height in Europeans. By analyzing membrane lipids, Fumagalli et al. (2015) found that the selected alleles modulate fatty acid composition, which may affect the regulation of growth hormones. Thus, Fumagalli et al. (2015) showed that the Inuit have genetic and physiologic adaptations to a diet rich in PUFAs.

To identify regions harboring candidate genes influencing extreme cold climate adaptation phenotypes, Cardona et al. (2014) genotyped 200 individuals from 10 indigenous Siberian populations for more than 700,000 SNPs and analyzed the results for signals of positive selection. The strongest selection signals mapped to a 3-Mb region on chromosome 11 (chr11:66-69 Mb) that contains the CPT1A gene (600528).

Following up on the work of Cardona et al. (2014), Clemente et al. (2014) showed that the P479L (rs80356779) variant of CPT1A (600528.0012) is under strong positive selection. They noted that the derived allele is associated with hypoketotic hypoglycemia and high infant mortality, yet occurs at high frequency in Canadian and Greenland Inuits and was also found at 68% frequency in their indigenous northeast Siberian sample, but was absent from other publicly available genomic databases. Clemente et al. (2014) provided evidence of one of the strongest selective sweeps reported in humans, which drove the P479L variant to high frequency in circum-Arctic populations within the last 6,000 to 23,000 thousand years despite associated deleterious consequences, possibly as a result of the selective advantage it originally provided to either a high-fat diet or a cold environment. The traditional diet of indigenous Arctic peoples consists largely of marine mammals and is thus rich in n-3 polyenoic fatty acids, which are known to increase the activity of CPT1A. In this context, a CPT1A activity decrease due to the P479L mutation could be protective against overproduction of ketone bodies.

Andersen and Hansen (2018) reviewed the genetics of metabolic traits in Greenlanders and noted that the strongest signal of positive selection reported in Greenlanders and Siberians is the FADS-CPT1A locus on chromosome 11 (PUFAQTL1). The T allele of the CPT1A variant P479L (rs80356779), encoding leu479, is fixed in the ancestral Inuit population, along with the rs174570 mapping to FADS2, even though approximately 7 Mb separates these 2 variants (Andersen et al., 2016). This unusual long-range linkage disequilibrium phenomenon makes it difficult to determine whether the FADS and CPT1A selection signatures represent the same signal or 2 independent signals. However, in Europeans, in whom the P479L variant is monomorphic, a signal of selection has been observed in the FADS locus. Andersen and Hansen (2018) noted that the Inuit-specific leu479 form of CPT1A had in cell studies been shown to have markedly reduced enzymatic function, but in combination with reduced sensitivity to malonyl-CoA inhibition. At fasting, this results in moderately reduced beta-oxidation, whereas in the postprandial state the reduced inhibitory sensitivity has a greater impact, as malonyl-CoA concentration is high. Hence, in cell studies, the enzymatic activity of CPT1A has been shown to be 3- to 4-fold higher postprandially in leu479 homozygotes compared to pro479 homozygotes, thereby possibly explaining the background for positive selection at this locus, as increased CPT1A activity favors utilization of fat as an energy source and thereby seems favorable for the Inuit living on a diet rich in fat.