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- Talmud, Philippa J., et al.
(författare)
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Gene-centric Association Signals for Lipids and Apolipoproteins Identified via the HumanCVD BeadChip
- 2009
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 85:5, s. 628-642
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Tidskriftsartikel (refereegranskat)abstract
- Blood lipids are important cardiovascular disease (CVD) risk factors with both genetic and environmental determinants. The Whitehall II study (n = 5592) was genotyped with the gene-centric HumanCVD BeadChip (Illumina). We identified 195 SNPs in 16 genes/regions associated with 3 major lipid fractions and 2 apolipoprotein components at p < 10(-5), with the associations being broadly concordant with prior genome-wide analysis. SNPs associated with LDL cholesterol and apolipoprotein B were located in LDLR, PCSK9, APOB, CELSR2, HWGCR, CETP, the TOMM40-APOE-C1-C2-C4 cluster, and the APOA5-A4-C3-A1 cluster; SNPs associated with HDL cholesterol and apolipoprotein AI were in CETP, LPL, LIPC, APOA5-A4-C3-A1, and ABCA1; and SNPs associated with triglycerides in GCKR, BAZIB, MLXIPL, LPL, and APOA5-A4-C3-A1. For 48 SNPs in previously unreported loci that were significant at p < 10(-4) in Whitehall II, in silico analysis including the British Women's Heart and Health Study, BRIGHT, ASCOT, and NORDIL studies (total n > 12,500) revealed previously unreported associations of SH2B3 (p < 2.2 x 10(-6)), BMPR2 (p < 2.3 x 10(-7)), BCL3/PVRL2 (flanking APOE; p < 4.4 x 10(-8)), and SMARCA4 (flanking LDLR; p < 2.5 x 10(-7)) with LDL cholesterol. Common alleles in these genes explained 6.1%-14.7% of the variance in the five lipid-related traits, and individuals at opposite tails of the additive allele score exhibited substantial differences in trait levels (e.g., > 1 mmol/L in LDL cholesterol [similar to 1 SD of the trait distribution]). These data suggest that multiple common alleles of small effect can make important contributions to individual differences in blood lipids potentially relevant to the assessment of CVD risk. These genes provide further insights into lipid metabolism and the likely effects of modifying the encoded targets therapeutically.
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| 2. |
- Kotronen, Anna, et al.
(författare)
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Genetic variation in the ADIPOR2 gene is associated with liver fat content and its surrogate markers in three independent cohorts
- 2009
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Ingår i: European Journal of Endocrinology. - 1479-683X. ; 160:4, s. 593-602
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Tidskriftsartikel (refereegranskat)abstract
- Aims: We investigated whether polymorph isms in candidate genes involved in lipid metabolism and type 2 diabetes are related to liver I, at content. Methods: Liver fat content was measured using proton magnetic resonance spectroscopy (H-1-MRS) in 302 Finns, in whom single nucleotide polymorphisms (SNPs) in acyl-CoA synthetase long-chain family member 4 (ACSL4). acliponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2), and the three peroxisome proliferator-activated receptors (PPARA, PPARD, and PPARG) were analyzed. To validate our findings, SNPs significantly associated with liver fat content were Studied in two independent cohorts and related to surrogate markers of liver fat content. Results: In the Finnish subjects, polymorphisms in ACSL4 (rs7887981), ADIPOR2 (rs767870), and PPARG (rs3856806) were significantly associated with liver fat content measured with H-1-MRS after adjusting for age, gender, and BMI, Anthropometric and circulating parameters were comparable between genotypes. In the first validation cohort of similar to 600 Swedish men, ACSL4 rs7887981 was related to fasting insulin and triglyceride concentrations, and ADIPOR2 rs767870 to serum gamma glutamyltransfer concentrations after adjusting for BMI. The SNP in PPARG (rs3856806) was not significantly associated with any relevant metabolic parameter in this cohort. In the second validation cohort of similar to 3000 subjects from Western Finland, ADIPOR2 rs767870, but not ACSL4 rs7887981 was related to fasting triglyceride concentrations. Conclusions: Genetic variation, particularly in the ADIPOR2 gene, contributes to variation in hepatic fat accumulation in humans.
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