van Belzen Martine J, Vrolijk Martine M, Meijer Jos W R, Crusius J Bart A, Pearson Peter L, Sandkuijl Lodewijk A, Houwen Roderick H J, Wijmenga Cisca
Department of Biomedical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Am J Gastroenterol. 2004 Mar;99(3):466-71. doi: 10.1111/j.1572-0241.2004.04072.x.
Celiac disease is caused by the interaction of multiple genes and environmental factors. Inheritance of the disease shows a complex pattern with a 10% sibling recurrence risk. The HLA-region is a major genetic risk locus in celiac disease, but genes outside this region are expected to contribute to the disease risk as well. The aim of this study was to identify the loci causing celiac disease in one large Dutch family with apparent dominant transmission of the disease.
The family comprised 17 patients in four generations, with possible transmission of the disease by both grandparents. Microsatellite markers evenly spread over all chromosomes were genotyped and linkage analysis was performed using both dominant and recessive disease models and a model-free analysis.
Disease susceptibility in the family was linked to the HLA-region (lod score of 2.33) and all patients were HLA-DQ2. A dominantly inherited non-HLA locus with a maximum lod score of 2.61 was detected at 9p21-13, which was shared by 16 patients. Model-free analysis identified another possible non-HLA locus, at 6q25.3, which was shared by 14 patients (p = 0.01). Neither of these regions was detected in a genomewide screen in Dutch affected sibpairs, but the 9p21 locus has been implicated in Scandinavian families.
Two potential non-HLA loci for celiac disease were identified in this large Dutch family. Our results provide replication of the Scandinavian 9p21 locus, and suggest that this locus plays a role in celiac disease patients from different Caucasian populations.
乳糜泻由多种基因与环境因素相互作用所致。该疾病的遗传呈现复杂模式，同胞复发风险为10%。HLA区域是乳糜泻的主要遗传风险位点，但该区域以外的基因预计也会增加疾病风险。本研究的目的是在一个疾病呈明显显性遗传的荷兰大家庭中确定导致乳糜泻的基因座。
该家族包括四代中的17名患者，疾病可能由祖父母双方遗传。对均匀分布于所有染色体的微卫星标记进行基因分型，并使用显性和隐性疾病模型以及无模型分析进行连锁分析。
该家族中的疾病易感性与HLA区域相关（对数记分2.33），所有患者均为HLA - DQ2。在9p21 - 13检测到一个显性遗传的非HLA基因座，最大对数记分为2.61，16名患者共有该基因座。无模型分析在6q25.3确定了另一个可能的非HLA基因座，14名患者共有该基因座（p = 0.01）。在荷兰患病同胞对的全基因组筛查中均未检测到这些区域，但9p21基因座在斯堪的纳维亚家庭中已有相关报道。
在这个荷兰大家庭中确定了两个潜在的乳糜泻非HLA基因座。我们的结果为斯堪的纳维亚9p21基因座提供了重复验证，并表明该基因座在不同白种人群的乳糜泻患者中发挥作用。
