Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.
Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis.
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DOI：
10.1371/journal.pgen.1002765
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发表时间：
2012
期刊：
影响因子：
4.5
通讯作者：
Gharavi AG
中科院分区：
文献类型：
--
作者：
Kiryluk K;Li Y;Sanna-Cherchi S;Rohanizadegan M;Suzuki H;Eitner F;Snyder HJ;Choi M;Hou P;Scolari F;Izzi C;Gigante M;Gesualdo L;Savoldi S;Amoroso A;Cusi D;Zamboli P;Julian BA;Novak J;Wyatt RJ;Mucha K;Perola M;Kristiansson K;Viktorin A;Magnusson PK;Thorleifsson G;Thorsteinsdottir U;Stefansson K;Boland A;Metzger M;Thibaudin L;Wanner C;Jager KJ;Goto S;Maixnerova D;Karnib HH;Nagy J;Panzer U;Xie J;Chen N;Tesar V;Narita I;Berthoux F;Floege J;Stengel B;Zhang H;Lifton RP;Gharavi AG
IgA 肾病 (IgAN) 是全世界肾衰竭的主要原因，在亚洲人中很常见，在欧洲人中中等流行，在非洲人中罕见。目前尚不清楚这些差异是否代表基因、环境或确定方面的差异。在最近的 GWAS 中，我们在 Chr.6p21（HLA-DQB1/DRB1、PSMB9/TAP1 和 DPA1/DPB2 位点）、Chr.1q32（CFHR3/R1 位点）和 Chr.22q12（HORMAD2 位点）上定位了 5 个 IgAN 易感位点。这些 IgAN 位点与其他免疫介导疾病的风险相关，例如 I 型糖尿病、多发性硬化症或炎症性肠病。我们在亚洲、欧洲和非裔美国人血统的 8 个新的独立队列 (N = 4,789) 中测试了这些基因座的关联，然后对 12 个队列 (N = 10,755) 进行了风险评分模型荟萃分析，并对 85 个世界人口进行了地理空间分析。四个易感位点在组合队列中稳健复制，所有五个位点在全基因组范围内显着（P = 5×10−32–3×10−10），仅在 PSMB9/TAP1 基因座检测到异质性（I2 = 0.60）。条件分析在 HLA-DQB1/DRB1 基因座内确定了两个新的独立风险等位基因，定义了该区间内的多种风险和保护性单倍型。我们还检测到显着的遗传相互作用，其中 HORMAD2 保护性等位基因的优势比在 CFHR3/R1 缺失的纯合子中发生逆转 (P = 2.5×10−4)。七位单核苷酸多态性 (SNP) 遗传风险评分解释了总体 IgAN 风险的 4.7%，随着距非洲向东和向北距离的增加而急剧增加 (r = 0.30，P = 3×10−128)。该模型与已知的东西方疾病风险梯度相似。此外，南北轴的预测得到了登记数据的证实，该数据显示北欧 IgAN 所致肾衰竭的患病率有所增加，类似于多发性硬化症和 I 型糖尿病。 IgAN 易感位点的变异与世界人群疾病患病率的差异相关。这些发现为 IgAN 的遗传、生物学和流行病学研究提供了信息，并允许与与 IgAN 共享遗传风险位点和地理模式的其他复杂性状进行交叉比较。 IgA 肾病 (IgAN) 是亚洲肾衰竭的最常见原因，在欧洲患病率较低，在非洲血统人群中非常罕见。该领域长期存在的一个问题是这些差异是否代表基因、环境或确定方面的变异。在最近一项针对 5,966 名个体的全基因组关联研究中，我们确定了该性状的 5 个易感位点。在本文中，我们研究了迄今为止报道的最大的 IgAN 病例对照队列，该队列由 10,775 名欧洲、亚洲和非裔美国人血统的个体组成。我们确认，所有五个基因座都是该多种族队列中疾病风险的重要贡献者。此外，我们在 HLA-DQB1/DRB1 基因座内发现了两个新的独立易感性等位基因，以及 Chr.1p36 和 Chr.22q22 上的基因座之间的新遗传相互作用。我们开发了 7 个 SNP 遗传风险评分，可以解释近 5% 的疾病风险变异。在对 85 个世界人口的地理空间分析中，遗传风险评分与全球疾病流行模式密切相关。遗传风险评分还预测欧洲出现意想不到的北向风险梯度。这一基因预测通过登记数据的检查得到了验证，该数据表明，与其他免疫介导的疾病（如多发性硬化症和 I 型糖尿病）类似，北欧国家 IgAN 导致的肾衰竭的增加以前未被认识到。
IgA nephropathy (IgAN), major cause of kidney failure worldwide, is common in Asians, moderately prevalent in Europeans, and rare in Africans. It is not known if these differences represent variation in genes, environment, or ascertainment. In a recent GWAS, we localized five IgAN susceptibility loci on Chr.6p21 (HLA-DQB1/DRB1, PSMB9/TAP1, and DPA1/DPB2 loci), Chr.1q32 (CFHR3/R1 locus), and Chr.22q12 (HORMAD2 locus). These IgAN loci are associated with risk of other immune-mediated disorders such as type I diabetes, multiple sclerosis, or inflammatory bowel disease. We tested association of these loci in eight new independent cohorts of Asian, European, and African-American ancestry (N = 4,789), followed by meta-analysis with risk-score modeling in 12 cohorts (N = 10,755) and geospatial analysis in 85 world populations. Four susceptibility loci robustly replicated and all five loci were genome-wide significant in the combined cohort (P = 5×10−32–3×10−10), with heterogeneity detected only at the PSMB9/TAP1 locus (I2 = 0.60). Conditional analyses identified two new independent risk alleles within the HLA-DQB1/DRB1 locus, defining multiple risk and protective haplotypes within this interval. We also detected a significant genetic interaction, whereby the odds ratio for the HORMAD2 protective allele was reversed in homozygotes for a CFHR3/R1 deletion (P = 2.5×10−4). A seven–SNP genetic risk score, which explained 4.7% of overall IgAN risk, increased sharply with Eastward and Northward distance from Africa (r = 0.30, P = 3×10−128). This model paralleled the known East–West gradient in disease risk. Moreover, the prediction of a South–North axis was confirmed by registry data showing that the prevalence of IgAN–attributable kidney failure is increased in Northern Europe, similar to multiple sclerosis and type I diabetes. Variation at IgAN susceptibility loci correlates with differences in disease prevalence among world populations. These findings inform genetic, biological, and epidemiological investigations of IgAN and permit cross-comparison with other complex traits that share genetic risk loci and geographic patterns with IgAN. IgA nephropathy (IgAN) is the most common cause of kidney failure in Asia, has lower prevalence in Europe, and is very infrequent among populations of African ancestry. A long-standing question in the field is whether these differences represent variation in genes, environment, or ascertainment. In a recent genome-wide association study of 5,966 individuals, we identified five susceptibility loci for this trait. In this paper, we study the largest IgAN case-control cohort reported to date, composed of 10,775 individuals of European, Asian, and African-American ancestry. We confirm that all five loci are significant contributors to disease risk across this multi-ethnic cohort. In addition, we identify two novel independent susceptibility alleles within the HLA-DQB1/DRB1 locus and a new genetic interaction between loci on Chr.1p36 and Chr.22q22. We develop a seven–SNP genetic risk score that explains nearly 5% of variation in disease risk. In geospatial analysis of 85 world populations, the genetic risk score closely parallels worldwide patterns of disease prevalence. The genetic risk score also predicts an unsuspected Northward risk gradient in Europe. This genetic prediction is verified by examination of registry data demonstrating, similarly to other immune-mediated diseases such as multiple sclerosis and type I diabetes, a previously unrecognized increase in IgAN–attributable kidney failure in Northern European countries.
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影响因子：
4.5
作者：
Barcellos LF;May SL;Ramsay PP;Quach HL;Lane JA;Nititham J;Noble JA;Taylor KE;Quach DL;Chung SA;Kelly JA;Moser KL;Behrens TW;Seldin MF;Thomson G;Harley JB;Gaffney PM;Criswell LA
通讯作者：
Criswell LA
影响因子：
7
作者：
Huedo-Medina, Tania B.;Sanchez-Meca, Julio;Botella, Juan
通讯作者：
Botella, Juan
影响因子：
13.6
作者：
Borchers, Andrea T.;Uibo, Raivo;Gershwin, M. E.
通讯作者：
Gershwin, M. E.
DOI：
10.1161/atvbaha.107.160580
发表时间：
2008-03-01
影响因子：
8.7
作者：
Kastl, Stefan P.;Speidl, Walter S.;Wojta, Johann
通讯作者：
Wojta, Johann
影响因子：
13.6
作者：
Feehally, John;Farrall, Martin;Ratcliffe, Peter J.
通讯作者：
Ratcliffe, Peter J.