Online Mendelian Inheritance in Man (OMIM) (original) (raw)

Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38) : 11:61,799,627-61,817,003 (from NCBI)

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Cloning and Expression

The de novo unsaturation of fatty acids is regulated by individual desaturase enzymes that introduce double bonds between defined carbons of the fatty acyl chain. Using partial cDNA sequences identified by Stohr et al. (1998) by retina/RPE-specific direct cDNA selection within a 1.4-Mb region on chromosome 11q12-q13.1, Marquardt et al. (2000) identified 3 members of the fatty acid desaturase gene family, FADS1, FADS2 (606149), and FADS3 (606150). Both FADS1 and FADS2 encode deduced 444-amino acid proteins, and FADS3 encodes a deduced 445-amino acid protein. The 3 proteins share a high degree of sequence identity, and all have significant homology to known desaturase enzymes, including 3 histidine motifs characteristic of membrane-bound desaturases, up to 4 transmembrane domains, and an N-terminal cytochrome b5-like domain, which is a common structural feature in a subset of desaturases from plants, animals, and yeast. By Northern blot analysis, Stohr et al. (1998) identified 4.0-kb and 3.1-kb transcripts of FADS1 and FADS2, respectively, in lung, cerebellum, retina, and the RPE cell line ARPE-19 with almost equal abundance.

Marquardt et al. (2000) noted that FADS1 and the human delta-5 desaturase cloned by Cho et al. (1999) share identical nucleotide sequences in the ORF with the exception of 6 alterations.

Mapping

Marquardt et al. (2000) identified the FADS1 gene on chromosome 11q12-q13.1.

Molecular Genetics

For a discussion of a possible association between variation in the FADS1 gene and plasma levels of polyunsaturated fatty acids, see 612795.

Associations Pending Confirmation

Suhre et al. (2011) reported a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with nontargeted metabolomics. They identified 37 genetic loci associated with blood metabolite concentrations, of which 25 showed effect sizes that were unusually high for GWAS and accounted for 10 to 60% differences in metabolite levels per allele copy. These associations provided new functional insights for many disease-related associations that had been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism, and Crohn disease. Suhre et al. (2011) identified an association between rs174547 in the FADS1 gene with 1-arachidonylglycerophosphoethanolamine/1-linoleoylglycerophosphoethanolamine ratio, p = 8.5 x 10(-116). This FADS1 substrate/product pair ratio was among the top associations in their study and was associated with LDL cholesterol, HDL cholesterol and triglycerides, fasting glucose and homeostatic model assessment B (HOMA-B) Crohn disease, and resting heart rate.

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--defined by 28 closely linked SNPs across 38.9 kb--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 (606149). 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.