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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

Association and conditional plot combined for the FADS2 and CPT1A loci with erythrocyte membrane 11-eicosenoic acid (20:1 ω-9).The association results of the unconditional analysis are colored according to the LD, which was calculated separately for the two regions in each plot for the candidate SNPs, rs174570 and rs80356779, respectively. The p-values are based on imputation data. Green dots represent the results of the conditional analyses, and the circle denotes the SNP conditioned on A) rs174570 and B) rs80356779.
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pgen.1006119.g004: Association and conditional plot combined for the FADS2 and CPT1A loci with erythrocyte membrane 11-eicosenoic acid (20:1 ω-9).The association results of the unconditional analysis are colored according to the LD, which was calculated separately for the two regions in each plot for the candidate SNPs, rs174570 and rs80356779, respectively. The p-values are based on imputation data. Green dots represent the results of the conditional analyses, and the circle denotes the SNP conditioned on A) rs174570 and B) rs80356779.

Mentions: Further exploration of the region revealed an unusual LD phenomenon, where FADS2 rs174570 and CPT1A rs80356779 were linked in the ancestral Inuit population despite the chromosomal distance of approximately 7 Mb. Both variants were fixed or at extremely low frequency for the derived allele in the ancestral Inuit population, while the ancestral allele of rs80356779 was entirely fixed, and the ancestral allele of rs174570 was very common in European populations (Table 4). Conditional analysis reduced the association signal for both loci, as seen for 11-eicosenoic acid (20:1 ω-9; Fig 4). In general, most of the CTP1A associations were still significant when conditioning on the FADS2 variant, while many of the FADS2 associations disappeared when conditioning on the FADS2 variant (Fig 4 and S4 Fig).


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)

Association and conditional plot combined for the FADS2 and CPT1A loci with erythrocyte membrane 11-eicosenoic acid (20:1 ω-9).The association results of the unconditional analysis are colored according to the LD, which was calculated separately for the two regions in each plot for the candidate SNPs, rs174570 and rs80356779, respectively. The p-values are based on imputation data. Green dots represent the results of the conditional analyses, and the circle denotes the SNP conditioned on A) rs174570 and B) rs80356779.
© Copyright Policy
Related In: Results  -  Collection

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

pgen.1006119.g004: Association and conditional plot combined for the FADS2 and CPT1A loci with erythrocyte membrane 11-eicosenoic acid (20:1 ω-9).The association results of the unconditional analysis are colored according to the LD, which was calculated separately for the two regions in each plot for the candidate SNPs, rs174570 and rs80356779, respectively. The p-values are based on imputation data. Green dots represent the results of the conditional analyses, and the circle denotes the SNP conditioned on A) rs174570 and B) rs80356779.
Mentions: Further exploration of the region revealed an unusual LD phenomenon, where FADS2 rs174570 and CPT1A rs80356779 were linked in the ancestral Inuit population despite the chromosomal distance of approximately 7 Mb. Both variants were fixed or at extremely low frequency for the derived allele in the ancestral Inuit population, while the ancestral allele of rs80356779 was entirely fixed, and the ancestral allele of rs174570 was very common in European populations (Table 4). Conditional analysis reduced the association signal for both loci, as seen for 11-eicosenoic acid (20:1 ω-9; Fig 4). In general, most of the CTP1A associations were still significant when conditioning on the FADS2 variant, while many of the FADS2 associations disappeared when conditioning on the FADS2 variant (Fig 4 and S4 Fig).

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