Department of Nephrology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
National Health Commission Key Laboratory of Nephrology (Sun Yat-sen University), Guangdong Provincial Key Laboratory of Nephrology, Guangzhou, China.
J Am Soc Nephrol. 2020 Dec;31(12):2949-2963. doi: 10.1681/ASN.2019080799. Epub 2020 Sep 10.
Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk.
Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny.
Identification of three novel loci (rs6427389 on 1q23.1 [=8.18×10, OR=1.132], rs6942325 on 6p25.3 [=1.62×10, OR=1.165], and rs2240335 on 1p36.13 [=5.10×10, OR=1.114]), implicates , , and as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of , and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on . Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119).
A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs. These variants may explain susceptibility differences between Chinese and European populations.
18 个已知的 IgAN 易感性基因座仅占 IgAN 风险的一小部分。
对 2628 名中国血统的患者和 11563 名对照进行全基因组荟萃分析，并对 6879 名中国血统的患者和 9019 名对照以及 1039 名欧洲血统的患者和 1289 名对照进行复制分析。利用这些数据评估了易感性基因座与 IgAN 临床表型的相关性，并研究了这两个人群中 IgAN 易感性的遗传异质性。对 MHC/HLA 区域的基于 imputation 的分析扩展了审查范围。
鉴定出三个新的基因座（位于 1q23.1 的 rs6427389 [=8.18×10，OR=1.132]、位于 6p25.3 的 rs6942325 [=1.62×10，OR=1.165]和位于 1p36.13 的 rs2240335 [=5.10×10，OR=1.114]），提示 、 和 为 IgAN 的易感性基因。rs2240335 与 的表达水平相关，rs6427389 与 rs11264799 高度连锁不平衡，后者对 表现出强烈的表达定量追踪基因座效应。在 24 个确认的风险 SNP 中，有 6 个表现出遗传效应的显著异质性，并且 在人群之间有明显的等位基因异质性证据。基于 MHC 区域的 imputation 分析揭示了三个 HLA 多态性（HLA 等位基因 DPB1*02、AA_DRB1_140_32657458_T 和 AA_DQA1_34_32717152）和两个 SNP（rs9275464 和 rs2295119）的显著相关性。
GWAS 数据的荟萃分析揭示了 IgAN 的三个新的遗传风险基因座，以及 MHC 区域内的三个 HLA 多态性和两个 SNP，并证明了 24 个确认的风险 SNP 中有 7 个基因座的遗传异质性。这些变体可能解释了中国和欧洲人群之间的易感性差异。
