Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan
Genome-wide scan revealed that polymorphisms in the PNPLA3, SAMM50, and PARVB genes are associated with development and progression of nonalcoholic fatty liver disease in Japan
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DOI：
10.1007/s00439-013-1294-3
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发表时间：
2013-07-01
期刊：
影响因子：
5.3
通讯作者：
Hotta, Kikuko
中科院分区：
文献类型：
--
作者：
Kitamoto, Takuya;Kitamoto, Aya;Hotta, Kikuko
我们通过进行全基因组关联研究（GWAS），检查了日本人群中非酒精性脂肪性肝病（NAFLD）的遗传背景。对于GWAS，分析了392名日本NAFLD受试者和934名对照个体。对于重复研究，监测了172名NAFLD受试者和1，012名对照受试者。经过质量控制后，使用趋势检验分析了常染色体中的261，540个单核苷酸多态性（SNP）。以基因型、年龄、性别和体重指数（BMI）为自变量，采用多元Logistic回归分析进行关联分析。进行多元线性回归分析，以评估显著SNP对生化性状和组织学参数的等位基因效应，并通过年龄、性别和BMI进行调整。PNPLA 3基因中的Rs738409与校正后的NAFLD最强相关（P = 6.8 x 10（-14），OR = 2.05）。PNPLA 3基因中的rs 2896019和rs381062，SAMM 50基因中的rs738491、rs3761472和rs 2143571，PARVB基因中的rs6006473、rs 5764455和rs6006611也具有显著的P值（< 2.0 x 10 - 10）和高比值比（1.84-2.02）。发现这些SNP处于相同的连锁不平衡区，并且与NAFLD患者血清甘油三酯降低和天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）升高相关。这些SNP与脂肪变性分级和NAFLD活动评分（NAS）相关。Rs738409、rs 2896019、rs738491、rs6006473、rs 5764455和rs6006611与纤维化相关。SAMM 50和PARVB基因的多态性与NAFLD的发生和进展有关。
We examined the genetic background of nonalcoholic fatty liver disease (NAFLD) in the Japanese population, by performing a genome-wide association study (GWAS). For GWAS, 392 Japanese NAFLD subjects and 934 control individuals were analyzed. For replication studies, 172 NAFLD and 1,012 control subjects were monitored. After quality control, 261,540 single-nucleotide polymorphisms (SNPs) in autosomal chromosomes were analyzed using a trend test. Association analysis was also performed using multiple logistic regression analysis using genotypes, age, gender and body mass index (BMI) as independent variables. Multiple linear regression analyses were performed to evaluate allelic effect of significant SNPs on biochemical traits and histological parameters adjusted by age, gender, and BMI. Rs738409 in the PNPLA3 gene was most strongly associated with NAFLD after adjustment (P = 6.8 x 10(-14), OR = 2.05). Rs2896019, and rs381062 in the PNPLA3 gene, rs738491, rs3761472, and rs2143571 in the SAMM50 gene, rs6006473, rs5764455, and rs6006611 in the PARVB gene had also significant P values (< 2.0 x 10(-10)) and high odds ratios (1.84-2.02). These SNPs were found to be in the same linkage disequilibrium block and were associated with decreased serum triglycerides and increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in NAFLD patients. These SNPs were associated with steatosis grade and NAFLD activity score (NAS). Rs738409, rs2896019, rs738491, rs6006473, rs5764455, and rs6006611 were associated with fibrosis. Polymorphisms in the SAMM50 and PARVB genes in addition to those in the PNPLA3 gene were observed to be associated with the development and progression of NAFLD.