Fatty acids (FAs) are involved in cellular processes important for normal body function, and perturbation of FA balance has been linked to metabolic disturbances, including type 2 diabetes. An individual’s level of FAs is affected by diet, lifestyle, and genetic variation. We aimed to improve the understanding of the mechanisms and pathways involved in regulation of FA tissue levels, by identifying genetic loci associated with inter-individual differences in erythrocyte membrane FA levels. We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes from 2,626 Greenlanders in relation to single nucleotide polymorphisms genotyped on the MetaboChip or imputed. We identified six independent association signals. Novel loci were identified on chromosomes 5 and 11 showing strongest association with oleic acid (rs76430747 in ACSL6, beta (SE): -0.386% (0.034), p = 1.8x10-28) and docosahexaenoic acid (rs6035106 in DTD1, 0.137% (0.025), p = 6.4x10-8), respectively. For a missense variant (rs80356779) in CPT1A, we identified a number of novel FA associations, the strongest with 11-eicosenoic acid (0.473% (0.035), p = 2.6x10-38), and for variants in FADS2 (rs174570), LPCAT3 (rs2110073), and CERS4 (rs11881630) we replicated known FA associations. Moreover, we observed metabolic implications of the ACSL6 (rs76430747) and CPT1A (rs80356779) variants, which both were associated with altered HbA1c (0.051% (0.013), p = 5.6x10-6 and -0.034% (0.016), p = 3.1x10-4, respectively). The latter variant was also associated with reduced insulin resistance (HOMA-IR, -0.193 (0.050), p = 3.8x10-6), as well as measures of smaller body size, including weight (-2.676 kg (0.523), p = 2.4x10-7), lean mass (-1.200 kg (0.271), p = 1.7x10-6), height (-0.966 cm (0.230), p = 2.0x10-5), and BMI (-0.638 kg/m2 (0.181), p = 2.8x10-4). In conclusion, we have identified novel genetic determinants of FA composition in phospholipids in erythrocyte membranes, and have shown examples of links between genetic variants associated with altered FA membrane levels and changes in metabolic traits.
Disruption of fatty-acid balance has in several previous studies been linked to human health conditions, including the metabolic syndrome, type 2 diabetes, and insulin resistance. Composition of fatty acids in lipid membranes is influenced, not only by diet and lifestyle, but also by genetic variation. By identifying genes linked to changes in the level of specific fatty acids, it may be possible to identify biological mechanisms and pathways central to regulation of fatty-acid composition in lipid membranes. We therefore aimed at finding such genes by studying Greenlanders. We identified six genomic regions harboring variants, which were associated with the level of at least one of 22 assessed erythrocyte membrane fatty acids, including two novel regions not previously linked to fatty acid levels. Moreover, we showed that two of the identified variants were associated with altered levels of glycosylated hemoglobin, and one of these variants was associated with reduced insulin resistance and decreased measures of body size. These results contribute to our understanding of fatty acid metabolism, and support a link between fatty acid balance and metabolic health.