Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK
Allelic expression imbalance at high-density lipoprotein cholesterol locus MMAB-MVK
复制标题
DOI：
10.1093/hmg/ddq067
复制
发表时间：
2010-05-15
影响因子：
3.5
通讯作者：
Mohlke, Karen L.
中科院分区：
文献类型：
--
作者：
Fogarty, Marie P.;Xiao, Rui;Mohlke, Karen L.
全基因组关联研究（GWAS）已经确定了许多与各种复杂性状相关的基因座，这些复杂性状的潜在易感基因仍然未知。在高密度脂蛋白胆固醇（HDL-C）水平的GWAS中，一个强相关的基因座包含至少两个生物学上引人注目的候选者，甲基丙二酸尿症cblB型（MMAB）和甲羟戊酸激酶（MVK）。为了检测在这个位点的顺式作用调节的证据，我们测量了相对等位基因表达的转录单核苷酸多态性在五个基因使用人类肝细胞样本杂合子转录的SNP。如果HDL-C相关SNP等位基因以顺式差异调节mRNA水平，则对于转录的SNP和HDL-C相关SNP均杂合的样品应显示转录的SNP的等位基因表达不平衡（AEI）。我们设计了统计检验，以检测AEI在一个全面的连锁不平衡（LD）的情况下之间的转录SNP和HDL-C相关的SNP（rs7298565）在相位未知的样本。我们在MMAB中观察到22%的显著AEI（P = 1.4 x 10（-13），转录SNP rs 11067231），与较低HDL-C水平相关的等位基因与较高的MMAB转录水平相关。相同的rs7298565等位基因也与较高的MMAB mRNA水平（P = 0.0081）和较高的MMAB蛋白水平（P = 0.0020）相关。MVK、UBE 3B、KCTD 10和ACACB的AEI无显著性差异（P >= 0.05）。这些数据表明，MMAB是最有可能影响HDL-C水平的基因在这个位点，并表明，在含有一个以上的候选基因的位点测量AEI可以优先考虑基因的功能研究。
Genome-wide association studies (GWAS) have identified numerous loci associated with various complex traits for which the underlying susceptibility gene(s) remain unknown. In a GWAS for high-density lipoprotein-cholesterol (HDL-C) level, one strongly associated locus contains at least two biologically compelling candidates, methylmalonic aciduria cblB type (MMAB) and mevalonate kinase (MVK). To detect evidence of cis-acting regulation at this locus, we measured relative allelic expression of transcribed SNPs in five genes using human hepatocyte samples heterozygous for the transcribed SNP. If an HDL-C-associated SNP allele differentially regulates mRNA level in cis, samples heterozygous both for a transcribed SNP and an HDL-C-associated SNP should display allelic expression imbalance (AEI) of the transcribed SNP. We designed statistical tests to detect AEI in a comprehensive set of linkage disequilibrium (LD) scenarios between the transcribed SNP and an HDL-C-associated SNP (rs7298565) in phase unknown samples. We observed significant AEI of 22% in MMAB (P = 1.4 x 10(-13), transcribed SNP rs11067231), and the allele associated with lower HDL-C level was associated with greater MMAB transcript level. The same rs7298565 allele was also associated with higher MMAB mRNA level (P = 0.0081) and higher MMAB protein level (P = 0.0020). In contrast, MVK, UBE3B, KCTD10 and ACACB did not show significant AEI (P >= 0.05). These data suggest MMAB is the most likely gene influencing HDL-C levels at this locus and demonstrate that measuring AEI at loci containing more than one candidate gene can prioritize genes for functional studies.