Concannon Patrick, Erlich Henry A, Julier Cecile, Morahan Grant, Nerup Jørn, Pociot Flemming, Todd John A, Rich Stephen S
Benaroya Research Institute, Seattle, Washington, USA.
Diabetes. 2005 Oct;54(10):2995-3001. doi: 10.2337/diabetes.54.10.2995.
Type 1 diabetes is a common, multifactorial disease with strong familial clustering (genetic risk ratio [lambda(S)] approximately 15). Approximately 40% of the familial aggregation of type 1 diabetes can be attributed to allelic variation of HLA loci in the major histocompatibility complex on chromosome 6p21 (locus-specific lambda(S) approximately 3). Three other disease susceptibility loci have been clearly demonstrated based on their direct effect on risk, INS (chromosome 11p15, allelic odds ratio [OR] approximately 1.9), CTLA4 (chromosome 2q33, allelic OR approximately 1.2), and PTPN22 (chromosome 1p13, allelic OR approximately 1.7). However, a large proportion of type 1 diabetes clustering remains unexplained. We report here on a combined linkage analysis of four datasets, three previously published genome scans, and one new genome scan of 254 families, which were consolidated through an international consortium for type 1 diabetes genetic studies (www.t1dgc.org) and provided a total sample of 1,435 families with 1,636 affected sibpairs. In addition to the HLA region (nominal P = 2.0 x 10(-52)), nine non-HLA-linked regions showed some evidence of linkage to type 1 diabetes (nominal P < 0.01), including three at (or near) genome-wide significance (P < 0.05): 2q31-q33, 10p14-q11, and 16q22-q24. In addition, after taking into account the linkage at the 6p21 (HLA) region, there was evidence supporting linkage for the 6q21 region (empiric P < 10(-4)). More than 80% of the genome could be excluded as harboring type 1 diabetes susceptibility genes of modest effect (lambda(S) > or = 1.3) that could be detected by linkage. This study represents one of the largest linkage studies ever performed for any common disease. The results demonstrate some consistency emerging for the existence of susceptibility loci on chromosomes 2q31-q33, 6q21, 10p14-q11, and 16q22-q24 but diminished support for some previously reported locations.
1型糖尿病是一种常见的多因素疾病，具有很强的家族聚集性（遗传风险比[λ(S)]约为15）。1型糖尿病家族聚集性中约40%可归因于位于6号染色体p21上主要组织相容性复合体中HLA基因座的等位基因变异（基因座特异性λ(S)约为3）。基于对风险的直接影响，另外三个疾病易感基因座已得到明确证实，即胰岛素基因（INS，位于11号染色体p15，等位基因优势比[OR]约为1.9）、细胞毒性T淋巴细胞相关抗原4基因（CTLA4，位于2号染色体q33，等位基因OR约为1.2）和蛋白酪氨酸磷酸酶非受体型22基因（PTPN22，位于1号染色体p13，等位基因OR约为1.7）。然而，1型糖尿病的大部分聚集现象仍无法解释。我们在此报告对四个数据集进行的联合连锁分析，其中包括三个先前发表的全基因组扫描数据集以及一个对254个家庭进行的新的全基因组扫描数据集，这些数据集通过1型糖尿病遗传研究国际联盟（www.t1dgc.org）进行整合，共提供了1435个家庭、16
