Holopainen P, Mustalahti K, Uimari P, Collin P, Mäki M, Partanen J
Department of Tissue Typing, Finnish Red Cross Blood Transfusion Service, Helsinki, Finland.
Gut. 2001 May;48(5):696-701. doi: 10.1136/gut.48.5.696.
Gluten sensitivity is a common multifactorial disorder, manifested in the small intestine or on the skin as typical coeliac disease or dermatitis herpetiformis, respectively. The only established genetic risk factor is HLA DQ2.
We tested genetic linkage of previously reported chromosomal loci 5q and 11q in Finnish families with gluten sensitivity. We also tested if genetic linkage to candidate loci on 5q, 11q, 2q33, and HLA DQ differed with respect to clinical manifestations or sex.
We studied 102 Finnish families with affected sibpairs. For heterogeneity analysis, families were divided into subgroups according to sex and the presence of dermatitis herpetiformis, the skin manifestation of gluten sensitivity.
Non-parametric linkage between microsatellite markers and disease was tested. Linkage heterogeneity between subgroups was tested using the M test. The transmission/disequilibrium test and association analysis were performed.
Evidence of linkage to 11q (MLS 1.37), but not to 5q, was found in the entire dataset of 102 families. Heterogeneity between subgroups was suggested: families with only the intestinal disease showed linkage mainly to 2q33 whereas families with dermatitis herpetiformis showed linkage to 11q and 5q, but not to 2q33. Linkage in all three non-HLA loci was strongest in families with predominantly male patients. HLA DQ2 conferred much stronger susceptibility to females than males.
Independent evidence for the suggested genetic linkage between 11q and gluten sensitivity was obtained. The possible linkage heterogeneity suggests genetic differences between intestinal and skin manifestations, and the gender dependent effect of HLA DQ2.
麸质敏感性是一种常见的多因素疾病，分别在小肠或皮肤上表现为典型的乳糜泻或疱疹样皮炎。唯一已确定的遗传风险因素是HLA DQ2。
我们在芬兰患有麸质敏感性的家庭中测试了先前报道的5号染色体位点和11号染色体位点的遗传连锁关系。我们还测试了5号染色体、11号染色体、2q33上的候选基因座以及HLA DQ的遗传连锁在临床表现或性别方面是否存在差异。
我们研究了102个有患病同胞对的芬兰家庭。为了进行异质性分析，根据性别和疱疹样皮炎（麸质敏感性的皮肤表现）的存在将家庭分为亚组。
测试微卫星标记与疾病之间的非参数连锁关系。使用M检验测试亚组之间的连锁异质性。进行传递/不平衡检验和关联分析。
在102个家庭的整个数据集中发现了与11号染色体连锁的证据（最大似然比分值为1.37），但未发现与5号染色体连锁的证据。提示亚组之间存在异质性：仅患有肠道疾病的家庭主要与2q33连锁，而患有疱疹样皮炎的家庭与11号染色体和5号染色体连锁，但与2q33不连锁。在男性患者占主导的家庭中，所有三个非HLA基因座的连锁最强。HLA DQ2赋予女性的易感性比男性强得多。
获得了11号染色体与麸质敏感性之间建议的遗传连锁的独立证据。可能的连锁异质性表明肠道和皮肤表现之间存在遗传差异，以及HLA DQ2的性别依赖性效应。
