Sajuthi Satria P, Sharma Neeraj K, Comeau Mary E, Chou Jeff W, Bowden Donald W, Freedman Barry I, Langefeld Carl D, Parks John S, Das Swapan K
Department of Biostatistical Sciences, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
Department of Internal Medicine, Section on Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, United States.
Gene. 2017 Oct 20;632:50-58. doi: 10.1016/j.gene.2017.08.019. Epub 2017 Aug 26.
Dyslipidemia is a major contributor to the increased cardiovascular disease and mortality associated with obesity and type 2 diabetes. We hypothesized that variation in expression of adipose tissue transcripts is associated with serum lipid concentrations in African Americans (AAs), and common genetic variants regulate expression levels of these transcripts. Fasting serum lipid levels, genome-wide transcript expression profiles of subcutaneous adipose tissue, and genome-wide SNP genotypes were analyzed in a cohort of non-diabetic AAs (N=250). Serum triglyceride (TRIG) and high density lipoprotein-cholesterol (HDL-C) levels were associated (FDR<0.01) with expression level of 1021 and 1875 adipose tissue transcripts, respectively, but none associated with total cholesterol or LDL-C levels. Serum HDL-C-associated transcripts were enriched for salient biological pathways, including branched-chain amino acid degradation, and oxidative phosphorylation. Genes in immuno-inflammatory pathways were activated among individuals with higher serum TRIG levels. We identified significant cis-regulatory SNPs (cis-eSNPs) for 449 serum lipid-associated transcripts in adipose tissue. The cis-eSNPs of 12 genes were nominally associated (p<0.001) with serum lipid level in genome wide association studies in Global Lipids Genetics Consortium (GLGC) cohorts. Allelic effect direction of cis-eSNPs on expression of MARCH2, BEST1 and TMEM258 matched with effect direction of these SNP alleles on serum TRIG or HDL-C levels in GLGC cohorts. These data suggest that expressions of serum lipid-associated transcripts in adipose tissue are dependent on common cis-eSNPs in African Americans. Thus, genetically-mediated transcriptional regulation in adipose tissue may play a role in reducing HDL-C and increasing TRIG in serum.
血脂异常是肥胖和2型糖尿病相关心血管疾病增加及死亡率上升的主要促成因素。我们推测，非洲裔美国人（AA）脂肪组织转录本表达的变化与血清脂质浓度相关，且常见基因变异调节这些转录本的表达水平。在一组非糖尿病AA（N = 250）中分析了空腹血清脂质水平、皮下脂肪组织的全基因组转录表达谱和全基因组单核苷酸多态性（SNP）基因型。血清甘油三酯（TRIG）和高密度脂蛋白胆固醇（HDL-C）水平分别与1021个和1875个脂肪组织转录本的表达水平相关（错误发现率<0.01），但均与总胆固醇或低密度脂蛋白胆固醇水平无关。与血清HDL-C相关的转录本在包括支链氨基酸降解和氧化磷酸化等显著生物学途径中富集。免疫炎症途径中的基因在血清TRIG水平较高的个体中被激活。我们在脂肪组织中鉴定出449个血清脂质相关转录本的显著顺式调控SNP（顺式eSNP）。在全球脂质遗传学联盟（GLGC）队列的全基因组关联研究中，12个基因的顺式eSNP与血清脂质水平呈名义上的关联（p<0.001）。顺式eSNP对MARCH2、BEST1和TMEM258表达的等位基因效应方向与这些SNP等位基因在GLGC队列中对血清TRIG或HDL-C水平的效应方向相匹配。这些数据表明，非洲裔美国人脂肪组织中血清脂质相关转录本的表达依赖于常见的顺式eSNP。因此，脂肪组织中基因介导的转录调控可能在降低血清HDL-C和升高血清TRIG中起作用。
