Abstract
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.
Highlights
Fatty acids (FAs) are important for normal body function, as they serve as essential structural entities of cellular membranes, as energy sources, and as signaling molecules
We assessed the levels of 22 FAs in the phospholipid fraction of erythrocyte membranes, and analyzing MetaboChip genotyping data, we identified six independent association signals with a p-value under the significance threshold of 4.3x10-7 (S1 Fig)
These genomic regions comprise two novel loci not previously linked to FA levels (ACSL6, DTD1), one known FA-linked locus where we identify a broad range of novel FA associations (CPT1A), and three loci for which we replicate known FA-associations (FADS2, LPCAT3, CERS4)
Summary
Fatty acids (FAs) are important for normal body function, as they serve as essential structural entities of cellular membranes, as energy sources, and as signaling molecules. Perturbation of FA homeostasis may modulate membrane functions, cell signaling, and gene expression, and regulation of FA metabolism is, critically important. Ω-3 alpha-linolenic acid (18:3) and ω-6 linoleic acid (cis-cis-18:2) are essential FAs, which can only be obtained from diet and subsequently elongated and desaturated to form other ω-3 and ω-6 FAs. The levels of FAs in an individual are influenced by diet and lifestyle [14,15], and have a clear hereditary component, which is estimated to account for 32–70% of FA variation [16,17]. The metabolic pathways regulating the circulating concentrations and membrane content of individual FAs, as well as the specific mechanisms linking FA levels to disease states are, poorly understood. That improved understanding of these pathways and mechanisms can be achieved by identifying genetic loci associated with inter-individual differences in FA levels in erythrocyte membranes
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