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Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders.

Andersen MK, Jørsboe E, Sandholt CH, Grarup N, Jørgensen ME, Færgeman NJ, Bjerregaard P, Pedersen O, Moltke I, Hansen T, Albrechtsen A - PLoS Genet. (2016)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.

No MeSH data available.


Related in: MedlinePlus

HbA1c association for ACSL6 (rs76430747) and CPT1A (rs80356779).Data are shown as raw means stratified by genotype, and as effect sizes estimated without assuming an additive effect model.
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pgen.1006119.g003: HbA1c association for ACSL6 (rs76430747) and CPT1A (rs80356779).Data are shown as raw means stratified by genotype, and as effect sizes estimated without assuming an additive effect model.

Mentions: The first association signal mapped to a novel locus on chromosome 5. The lead SNP (rs251015) was located in intronic region in FNIP1, and the derived allele showed strongest association with higher levels of oleic acid (18:1 ω-9). The imputation data revealed another SNP in the locus, rs76430747, located in an intronic region of ACSL6. The derived allele of rs76430747 was associated with lower levels of oleic acid (18:1 ω-9), and higher levels of lignoceric acid (24:0) and 11-eicosenoic acid (20:1 ω-9; Table 2 and Fig 1). Conditional analyses showed that rs76430747 may explain the observed association with oleic acid (Fig 2), whereas the results for lignoceric acid and 11-eicosenoic acid were less clear (S3 Fig). Interestingly, the derived allele of rs76430747 was, in addition to FA levels, associated with higher HbA1c (Fig 3 and Table 3).


Identification of Novel Genetic Determinants of Erythrocyte Membrane Fatty Acid Composition among Greenlanders.

Andersen MK, Jørsboe E, Sandholt CH, Grarup N, Jørgensen ME, Færgeman NJ, Bjerregaard P, Pedersen O, Moltke I, Hansen T, Albrechtsen A - PLoS Genet. (2016)

HbA1c association for ACSL6 (rs76430747) and CPT1A (rs80356779).Data are shown as raw means stratified by genotype, and as effect sizes estimated without assuming an additive effect model.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4920407&req=5

pgen.1006119.g003: HbA1c association for ACSL6 (rs76430747) and CPT1A (rs80356779).Data are shown as raw means stratified by genotype, and as effect sizes estimated without assuming an additive effect model.
Mentions: The first association signal mapped to a novel locus on chromosome 5. The lead SNP (rs251015) was located in intronic region in FNIP1, and the derived allele showed strongest association with higher levels of oleic acid (18:1 ω-9). The imputation data revealed another SNP in the locus, rs76430747, located in an intronic region of ACSL6. The derived allele of rs76430747 was associated with lower levels of oleic acid (18:1 ω-9), and higher levels of lignoceric acid (24:0) and 11-eicosenoic acid (20:1 ω-9; Table 2 and Fig 1). Conditional analyses showed that rs76430747 may explain the observed association with oleic acid (Fig 2), whereas the results for lignoceric acid and 11-eicosenoic acid were less clear (S3 Fig). Interestingly, the derived allele of rs76430747 was, in addition to FA levels, associated with higher HbA1c (Fig 3 and Table 3).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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.

No MeSH data available.


Related in: MedlinePlus