PLoS Genet:揭示基因变异可导致肾病产生  

GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway

作　　者：Kiryluk K 

机构地区：[1]Dept. of Medicine, Div. of Nephrology, College of Physicians and Surgeons, Columbia University, New York, New York, United States of America

出　　处：《现代生物医学进展》2017年第18期I0002-I0002,共1页Progress in Modern Biomedicine

摘　　要：IgA肾病（IgA nephropathy），也被称作伯杰氏病（Berger＇s disease）。是一种自身免疫肾病，而且也是肾功能衰竭的一种常见的原因。在一项新的研究中，来自美国、中国、日本、德国、法国和意大利的研究人员揭示出新的遗传线索而有助了解IgA肾病。这些发现对理解和治疗IgA肾病和具有类似的分子缺陷的其他疾病（如炎症性肠病、某些血液疾病和癌症）非常有意义。Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10-11) and C1GALT1C1 (rs5910940, P = 2.7 x 10-8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer.

关 键 词：IgA肾病 基因变异 可导 血液疾病 肾功能衰竭 自身免疫 研究人员 意大利 

分 类 号：Q75[生物学—分子生物学]