HLA Has Strongest Association with IgA Nephropathy in Genome-Wide Analysis
HLA Has Strongest Association with IgA Nephropathy in Genome-Wide Analysis
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DOI：
10.1681/asn.2010010076
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发表时间：
2010-10-01
影响因子：
13.6
通讯作者：
Ratcliffe, Peter J.
中科院分区：
文献类型：
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作者：
Feehally, John;Farrall, Martin;Ratcliffe, Peter J.
人口统计学和家庭研究支持存在遗传对IgA肾病发病机制的贡献，但候选基因的遗传关联研究结果不一致。为了系统地调查这种疾病的常见遗传变异，我们对来自英国肾小球肾炎DNA银行的IgA肾病患者队列进行了全基因组分析。我们使用了两组对照：受影响个体的父母和先前基因分型的，未受影响的，来自1958年英国出生队列和英国血液服务的祖先匹配的个体。我们对914名患者或家族对照进行了318,127个单核苷酸多态性（snp）的基因分型。筛选低基因型呼叫率和推断的非欧洲血统，留下533名基因型个体（187名受影响儿童）进行基于家庭的关联分析，244例病例和4980例对照进行病例对照分析。共有286,200个snp可用于分析，其利率为bb0 95%。全基因组分析显示MHC区域6p染色体上存在强烈的关联信号（P = 1 × 10(-9)）。两个相关性最强的snp在基于家庭和病例对照分析中均显示出一致的相关性。HLA归算分析显示，最强的关联信号来自DQ位点的组合，并支持独立的HLA- b信号。这些结果表明，HLA区域包含在欧洲人群中易患IgA肾病的最强共同易感等位基因。
Demographic and family studies support the existence of a genetic contribution to the pathogenesis of IgA nephropathy, but results from genetic association studies of candidate genes are inconsistent. To systematically survey common genetic variation in this disease, we performed a genome-wide analysis in a cohort of patients with IgA nephropathy selected from the UK Glomerulonephritis DNA Bank. We used two groups of controls: parents of affected individuals and previously genotyped, unaffected, ancestry-matched individuals from the 1958 British Birth Cohort and the UK Blood Service. We genotyped 914 affected or family controls for 318,127 single nucleotide polymorphisms (SNPs). Filtering for low genotype call rates and inferred non-European ancestry left 533 genotyped individuals (187 affected children) for the family-based association analysis and 244 cases and 4980 controls for the case-control analysis. A total of 286,200 SNPs with call rates >95% were available for analysis. Genome-wide analysis showed a strong signal of association on chromosome 6p in the region of the MHC (P = 1 x 10(-9)). The two most strongly associated SNPs showed consistent association in both family-based and case-control analyses. HLA imputation analysis showed that the strongest association signal arose from a combination of DQ loci with some support for an independent HLA-B signal. These results suggest that the HLA region contains the strongest common susceptibility alleles that predispose to IgA nephropathy in the European population.