Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Nephrology and Endocrinology, The University of Tokyo Hospital, Tokyo, Japan.
Sci Rep. 2016 Dec 9;6:38189. doi: 10.1038/srep38189.
Although recent studies showed anti-PLA2R antibody plays a crucial role in idiopathic membranous nephropathy (IMN), detailed HLA mapping and interaction between the HLA genes and PLA2R1 have not been investigated in IMN. We genotyped across the PLA2R1 gene and the HLA region, using 183 IMN patients and 811 healthy controls. Five SNPs around the PLA2R1 gene were significantly associated with IMN. In addition to the two SNPs previously reported to be strongly associated with IMN, rs3749119 and rs35771982 (OR 3.02 and 2.93, P = 3.24E-14 and 4.64E-14, respectively), two novel intronic SNPs (rs2715928 and rs16844715) were also identified as IMN-associated SNPs (OR = 2.30 and 2.51, P = 3.15E-10 and 5.66E-13, respectively). In the HLA gene analysis, DRB11501 and DQB10602 were strongly associated with IMN (P = 1.14E-11 and 1.25E-11, respectively). The interaction was strongest between HLA-DRB115:01 - HLA-DQB106:02 and the intronic SNP rs2715928 (OR = 17.53, P = 4.26E-26). Furthermore, positive interaction was also observed between HLA-DRB115:01 - HLA-DQB106:02 and the missense SNP rs35771982 (OR = 15.91, P = 2.76E-29), which is in strong linkage disequilibrium with 5'UTR SNP rs3749119, and intronic SNP rs16844715 (OR = 15.91, P = 2.30E-26) for IMN. Neither HLA-DRB115:01 nor HLA-DQB106:02 was associated with steroid responsiveness, overall survival and renal survival during the observation period of mean 11 years though limited number of analysis.
尽管最近的研究表明抗 PLA2R 抗体在特发性膜性肾病（IMN）中起着至关重要的作用，但在 IMN 中尚未详细研究 HLA 图谱和 HLA 基因与 PLA2R1 之间的相互作用。我们对 PLA2R1 基因和 HLA 区域进行了基因分型，共纳入 183 例 IMN 患者和 811 例健康对照。 PLA2R1 基因周围的 5 个 SNP 与 IMN 显著相关。除了先前报道与 IMN 强烈相关的两个 SNP(rs3749119 和 rs35771982)外，两个新的内含子 SNP(rs2715928 和 rs16844715)也被确定为与 IMN 相关的 SNP（OR 分别为 2.30 和 2.51，P 值分别为 3.15E-10 和 5.66E-13）。在 HLA 基因分析中，DRB11501 和 DQB10602 与 IMN 强烈相关（P 值分别为 1.14E-11 和 1.25E-11）。HLA-DRB115:01-DQB106:02 与内含子 SNP rs2715928 之间的相互作用最强（OR 为 17.53，P 值为 4.26E-26）。此外，HLA-DRB115:01-DQB106:02 与错义 SNP rs35771982 之间也观察到阳性相互作用（OR 为 15.91，P 值为 2.76E-29），rs35771982 与 5'UTR SNP rs3749119 和内含子 SNP rs16844715 强连锁不平衡（OR 为 15.91，P 值为 2.30E-26）。尽管分析数量有限，但在平均 11 年的观察期间，既没有 HLA-DRB115:01 也没有 HLA-DQB106:02 与激素反应性、总体生存率和肾脏生存率相关。
