PDF(Pubmed)
Abstract：
Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank (QBB) and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. Evaluation of a polygenic risk score devised from European GWAS data showed moderate performance when applied to QBB (adjusted-R2 = 0.082). These findings provide new insights into the genetic architecture of phytosterol metabolism while showing the importance including under-represented populations in future GWAS studies.
摘要：
谷甾醇血症是由ABCG5/ABCG8基因突变引起的罕见遗传性疾病。这些基因编码参与植物甾醇转运的蛋白质。这些基因的突变导致植物甾醇的排泄减少，会在体内积聚并导致各种健康问题，包括过早的冠状动脉疾病.我们在中东/北非人群中进行了首次全基因组关联研究（GWAS），以确定卡塔尔人植物甾醇水平的遗传决定因素。使用卡塔尔生物库（QBB）的Metabolon平台和卡塔尔基因组计划提供的基因组序列数据，对β-谷甾醇和菜油甾醇的血清水平进行了GWAS。对我们卡塔尔队列的数据进行了跨血统荟萃分析，并对先前发表的大型欧洲血统队列（9758名受试者）进行了汇总统计。使用条件分析，我们确定了两个独立的单核苷酸多态性与β-谷甾醇（rs145164937和rs4299376），在卡塔尔人群中，除了先前报道的变体外，还有另外两个人使用菜油甾醇（rs7598542和rs75901165）。所有这些都定位到ABCG5/8基因座，除了rs75901165，它位于步道内运输43（IFT43）基因内。荟萃分析复制了大多数报告的变异，我们的研究为SCARB1和ABO变异体与谷甾醇血症的相关性提供了重要支持.根据欧洲GWAS数据设计的多基因风险评分的评估显示，应用于QBB时表现中等（调整后的R2=0.082）。这些发现为植物甾醇代谢的遗传结构提供了新的见解，同时在未来的GWAS研究中显示了包括代表性不足的种群在内的重要性。
