Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms.
Family studies of type 1 diabetes reveal additive and epistatic effects between MGAT1 and three other polymorphisms.
复制标题
1 型糖尿病的家族研究揭示了 MGAT1 和其他三种多态性之间的加性和上位效应。
DOI：
10.1038/gene.2014.7
复制
发表时间：
2014
影响因子：
5
通讯作者：
Demetriou,M
中科院分区：
文献类型：
--
作者：
Yu,Z;Li,CF;Mkhikian,H;Zhou,RW;Newton,BL;Demetriou,M
在最近一项关于多发性硬化症（MS）的研究中，我们观察到四个基因变体之间的加性效应和上位性相互作用，这些基因通过改变Asn-(N)连接蛋白的糖基化而聚集在一起，诱导t细胞亢进：即高尔基酶MGAT1、细胞毒性t淋巴细胞抗原4 （CTLA-4）、白细胞介素2受体-α (IL2RA)和白细胞介素7受体-α (IL7RA)。由于CTLA-4、IL2RA和IL7RA变异与1型糖尿病（T1D）有关，我们研究了T1D中的联合效应。采用一种基于家族的数据集的新型条件逻辑回归，对来自1型糖尿病遗传联盟数据集的1423个多重家族进行了上位性和加性效应的观察。IL2RA和IL7RA变体在MS和T1D中具有单变量相关性，而MGAT1和CTLA-4变体分别仅与MS或T1D相关。然而，与MS相似，MGAT1变异单倍型与CTLA4相互作用（P= 0.03），与IL2RA和IL7RA组合相互作用（P= 0.01）。MGAT1、CTLA4、IL2RA、IL7RA的联合效应以及两者之间的相互作用经多条件logistic回归分析具有显著的统计学意义（P< 5× 10−10）。MGAT1-CTLA-4相互作用在179个糖尿病肾脏遗传学家系中被重复（P= 0.01）。这些数据与T细胞n糖基化缺陷导致T1D发病一致。
In a recent study on multiple sclerosis (MS), we observed additive effects and epistatic interactions between variants of four genes that converge to induce T-cell hyperactivity by altering Asn-(N)-linked protein glycosylation: namely, the Golgi enzyme MGAT1, cytotoxic T-lymphocyte antigen 4 (CTLA-4), interleukin-2 receptor-α (IL2RA) and interleukin-7 receptor-α (IL7RA). As the CTLA-4, IL2RA and IL7RA variants are associated with type 1 diabetes (T1D), we examined for joint effects in T1D. Employing a novel conditional logistic regression for family-based data sets, epistatic and additive effects were observed using 1423 multiplex families from the Type 1 Diabetes Genetic Consortium data set. The IL2RA and IL7RA variants had univariate association in MS and T1D, whereas the MGAT1 and CTLA-4 variants associated with only MS or T1D, respectively. However, similar to MS, the MGAT1 variant haplotype interacted with CTLA4 (P= 0.03), and a combination of IL2RA and IL7RA (P= 0.01). The joint effects of MGAT1, CTLA4, IL2RA, IL7RA and the two interactions using a multiple conditional logistic regression were statistically highly significant (P< 5× 10− 10). The MGAT1–CTLA-4 interaction was replicated (P= 0.01) in 179 trio families from the Genetics of Kidneys in Diabetes study. These data are consistent with defective N-glycosylation of T cells contributing to T1D pathogenesis.