Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
Variants in ABCG8 and TRAF3 genes confer risk for gallstone disease in admixed Latinos with Mapuche Native American ancestry
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DOI：
10.1038/s41598-018-35852-z
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发表时间：
2019-01-28
影响因子：
4.6
通讯作者：
Francisco Miquel, Juan
中科院分区：
文献类型：
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作者：
Bustos, Bernabe I.;Perez-Palma, Eduardo;Francisco Miquel, Juan
拉丁美洲和智利美洲印第安人是世界上胆石病（GSD）和胆囊癌（GBC）患病率最高的国家。少数基因座与主要欧洲血统的人群中的GSD相关，然而，它们只能解释该疾病遗传成分的一小部分。在这里，我们进行了一个全基因组关联研究（GWAS）的GSD在1,095混合智利拉丁美洲人与马普切美洲原住民血统。通过胆囊切除术或腹部超声检查评估疾病状态。在由1，643个个体组成的独立复制样本中，对发现队列中超过提示性P < 1 x 10（-5）临界值的前10个候选变异进行基因分型。在两个欧洲GSD人群和一个智利GBC队列中进一步检查了具有阳性复制的变体。我们一致地复制了ABCG 8基因与GSD的关联（rs 11887534，P = 3.24 x 10（-8），OR = 1.74），并确定TRAF 3（rs 12882491，P = 1.11 x 10（-7），OR = 1.40）为混合智利拉丁美洲人中该疾病的新候选基因。ABCG 8和TRAF 3变体也会给GBC带来风险。基因表达分析表明，与健康对照组相比，GSD个体的胆囊（P = 0.015）和十二指肠粘膜（P = 0.001）中TRAF 3显著降低，其中根据小肠中的GTEx数据，风险等位基因的存在有助于观察到的效果。我们得出结论，ABCG 8和TRAF 3基因与GSD和GBC在混合拉丁美洲人和TRAF 3水平降低可以增强胆囊炎症GSD和GSD相关GBC中观察到。
Latin Americans and Chilean Amerindians have the highest prevalence of gallstone disease (GSD) and gallbladder cancer (GBC) in the world. A handful of loci have been associated with GSD in populations of predominantly European ancestry, however, they only explain a small portion of the genetic component of the disease. Here, we performed a genome-wide association study (GWAS) for GSD in 1,095 admixed Chilean Latinos with Mapuche Native American ancestry. Disease status was assessed by cholecystectomy or abdominal ultrasonography. Top-10 candidate variants surpassing the suggestive cutoff of P < 1 x 10(-5) in the discovery cohort were genotyped in an independent replication sample composed of 1,643 individuals. Variants with positive replication were further examined in two European GSD populations and a Chilean GBC cohort. We consistently replicated the association of ABCG8 gene with GSD (rs11887534, P = 3.24 x 10(-8), OR = 1.74) and identified TRAF3 (rs12882491, P = 1.11 x 10(-7), OR = 1.40) as a novel candidate gene for the disease in admixed Chilean Latinos. ABCG8 and TRAF3 variants also conferred risk to GBC. Gene expression analyses indicated that TRAF3 was significantly decreased in gallbladder (P = 0.015) and duodenal mucosa (P = 0.001) of GSD individuals compared to healthy controls, where according to GTEx data in the small intestine, the presence of the risk allele contributes to the observed effect. We conclude that ABCG8 and TRAF3 genes are associated with GSD and GBC in admixed Latinos and that decreased TRAF3 levels could enhance gallbladder inflammation as is observed in GSD and GSD-associated GBC.