Koeleman B P, Herr M H, Zavattari P, Dudbridge F, March R, Campbell D, Barnett A H, Bain S C, Mulargia A P, Loddo M, Amos W, Cucca F, Todd J A
Wellcome Trust Centre for Molecular Mechanisms in Disease, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge CB2 2XY, UK.
Ann Hum Genet. 2000 May;64(Pt 3):215-21. doi: 10.1017/S0003480000008101.
Several studies have indicated that additional genes in the major histocompatibility complex (MHC) region, other than the class II genes HLA-DQB1 and -DRB1 (the IDDM1 locus), may contribute to susceptibility and resistance to type 1 diabetes. The relative magnitude of these non- DR/DQ effects is uncertain and their map location is unknown owing to the extraordinary linkage disequilibrium that extends over the 3.5 Mb of the MHC. The homozygous parent test has been proposed as a method for detection of additional risk factors conditional on HLA-DQB1 and -DRB1. However, this method is inefficient since it uses only parents homozygous for the primary disease locus, the DQB1-DRB1 haplotype. To overcome this limitation, Conditional ETDT was used in the present report to test for association conditional on the DQB1-DRB1 haplotype, thereby allowing all parents to be included in the analysis. First, we confirm in UK and Sardinian type 1 diabetic families that allelic variation at HLA-DRB1 has a very significant effect on the association of DQB1 and vice versa. The Conditional ETDT was then applied to the HLA TNF (tumour necrosis factor) region and microsatellite marker D6S273 region, both of which have been reported to contribute to IDDM1 independent of the HLA-DQB1-DRB1 genes. We found no evidence for a major role for either of these two regions in IDDM1.
多项研究表明，主要组织相容性复合体（MHC）区域中除了II类基因HLA - DQB1和 - DRB1（IDDM1位点）之外的其他基因，可能对1型糖尿病的易感性和抗性有影响。由于MHC区域长达3.5 Mb的高度连锁不平衡，这些非DR/DQ效应的相对大小尚不确定，其图谱位置也未知。纯合亲本检验已被提议作为一种检测基于HLA - DQB1和 - DRB1的其他风险因素的方法。然而，这种方法效率低下，因为它仅使用主要疾病位点DQB1 - DRB1单倍型的纯合亲本。为克服这一局限性，本报告中使用条件ETDT来检验基于DQB1 - DRB1单倍型的关联性，从而使所有亲本都能纳入分析。首先，我们在英国和撒丁岛的1型糖尿病家族中证实，HLA - DRB1的等位基因变异对DQB1的关联性有非常显著的影响，反之亦然。然后将条件ETDT应用于HLA TNF（肿瘤坏死因子）区域和微卫星标记D6S273区域，这两个区域都曾被报道独立于HLA - DQB1 - DRB1基因对IDDM1有影响。我们没有发现这两个区域中的任何一个在IDDM1中起主要作用的证据。
