Ayabe T, Fukami M, Ogata T, Kawamura T, Urakami T, Kikuchi N, Yokota I, Ihara K, Takemoto K, Mukai T, Nishii A, Kikuchi T, Mori T, Shimura N, Sasaki G, Kizu R, Takubo N, Soneda S, Fujisawa T, Takaya R, Kizaki Z, Kanzaki S, Hanaki K, Matsuura N, Kasahara Y, Kosaka K, Takahashi T, Minamitani K, Matsuo S, Mochizuki H, Kobayashi K, Koike A, Horikawa R, Teno S, Tsubouchi K, Mochizuki T, Igarashi Y, Amemiya S, Sugihara S
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Diabet Med. 2016 Dec;33(12):1717-1722. doi: 10.1111/dme.13175. Epub 2016 Jul 15.
The aim of this study was to clarify the significance of previously reported susceptibility variants in the development of autoimmune Type 1 diabetes in non-white children. Tested variants included rs2290400, which has been linked to Type 1 diabetes only in one study on white people. Haplotypes at 17q12-q21 encompassing rs2290400 are known to determine the susceptibility of early-onset asthma by affecting the expression of flanking genes.
We genotyped 63 variants in 428 Japanese people with childhood-onset autoimmune Type 1 diabetes and 457 individuals without diabetes. Possible association between variants and age at diabetes onset was examined using age-specific quantitative trait locus analysis and ordered-subset regression analysis.
Ten variants, including rs2290400 in GSDMB, were more frequent among the people with Type 1 diabetes than those without diabetes. Of these, rs689 in INS and rs231775 in CTLA4 yielded particularly high odds ratios of 5.58 (corrected P value 0.001; 95% CI 2.15-14.47) and 1.64 (corrected P value 5.3 × 10 ; 95% CI 1.34-2.01), respectively. Age-specific effects on diabetes susceptibility were suggested for rs2290400; heterozygosity of the risk alleles was associated with relatively early onset of diabetes, and the allele was linked to the phenotype exclusively in the subgroup of age at onset ≤ 5.0 years.
The results indicate that rs2290400 in GSDMB and polymorphisms in INS and CTLA4 are associated with the risk of Type 1 diabetes in Japanese children. Importantly, cis-regulatory haplotypes at 17q12-q21 encompassing rs2290400 probably determine the risk of autoimmune Type 1 diabetes predominantly in early childhood.
本研究旨在阐明先前报道的易感性变异在非白人儿童自身免疫性1型糖尿病发病中的意义。检测的变异包括rs2290400，该变异仅在一项针对白人的研究中与1型糖尿病相关。已知包含rs2290400的17q12 - q21单倍型通过影响侧翼基因的表达来决定早发性哮喘的易感性。
我们对428名患有儿童期自身免疫性1型糖尿病的日本人以及457名无糖尿病个体的63个变异进行了基因分型。使用年龄特异性数量性状位点分析和有序子集回归分析来检验变异与糖尿病发病年龄之间可能存在的关联。
包括GSDMB基因中的rs2290400在内的10个变异在1型糖尿病患者中比无糖尿病者更为常见。其中，胰岛素基因（INS）中的rs689和细胞毒性T淋巴细胞相关蛋白4基因（CTLA4）中的rs231775的优势比特别高，分别为5.58（校正P值0.001；95%置信区间2.15 - 14.47）和1.64（校正P值5.3×10；95%置信区间1.34 - 2.01）。提示rs2290400对糖尿病易感性有年龄特异性影响；风险等位基因的杂合性与糖尿病相对较早发病相关，且该等位基因仅在发病年龄≤5.0岁的亚组中与表型相关。
结果表明，GSDMB基因中的rs2290400以及INS和CTLA4基因中的多态性与日本儿童1型糖尿病风险相关。重要的是，包含rs2290400的17q12 - q21顺式调控单倍型可能主要在幼儿期决定自身免疫性1型糖尿病的风险。
