Van Belzen Martine J, Meijer Jos W R, Sandkuijl Lodewijk A, Bardoel Alfons F J, Mulder Chris J J, Pearson Peter L, Houwen Roderick H J, Wijmenga Cisca
Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Gastroenterology. 2003 Oct;125(4):1032-41. doi: 10.1016/s0016-5085(03)01205-8.
The pathogenesis of celiac disease is still unknown despite its well-known association with human leukocyte antigen (HLA)-DQ2 and DQ8. It is clear that non-HLA genes contribute to celiac disease development as well, but none of the previous genome-wide screens in celiac disease have resulted in identification of these genes.
We, therefore, performed a 2-stage, genome-wide screen in 101 affected sibpairs from 82 Dutch families who met strict diagnostic criteria. The small intestinal biopsy samples, on which the original celiac disease diagnoses had been based, showed a Marsh III lesion in all patients on reevaluation by 1 pathologist. For association analysis of markers in regions linked to celiac disease, 216 independent MIII patients and 216 age- and sex-matched controls were available.
As expected, highly significant linkage to the HLA-region was detected (multipoint maximum lod score [MMLS] = 8.14). More importantly, significant linkage was also present at 19p13.1 (MMLS = 4.31), with the peak at marker D19S899. Moreover, this marker was also significantly associated with celiac disease in the case-control study (corrected P = 0.016). Furthermore, we identified suggestive linkage to 6q21-22, which is approximately 70 cM downstream from the HLA region (MMLS = 3.10).
Significant linkage of celiac disease to chromosome region 19p13.1 was detected in our genome-wide screen. These results were confirmed by the association of D19S899 to celiac disease in an independent case-control cohort. Furthermore, we identified a possible second celiac disease locus on chromosome region 6q21-22.
尽管乳糜泻与人类白细胞抗原（HLA）-DQ2和DQ8的关联已为人熟知，但其发病机制仍不清楚。显然，非HLA基因也对乳糜泻的发展有影响，但之前对乳糜泻进行的全基因组筛查均未成功鉴定出这些基因。
因此，我们对来自82个荷兰家庭的101对患病同胞进行了两阶段全基因组筛查，这些家庭均符合严格的诊断标准。最初用于诊断乳糜泻的小肠活检样本经1名病理学家重新评估后，所有患者均显示为马什III级病变。对于与乳糜泻相关区域的标记物进行关联分析时，有216例独立的马什III级患者以及216名年龄和性别匹配的对照可供使用。
正如预期的那样，检测到与HLA区域存在高度显著的连锁关系（多点最大似然比分数[MMLS]=8.14）。更重要的是，在19p13.1处也存在显著的连锁关系（MMLS=4.31），标记物D19S899处出现峰值。此外，在病例对照研究中，该标记物也与乳糜泻显著相关（校正P=0.016）。此外，我们还发现了与6q21-22存在提示性连锁关系，该区域距离HLA区域约70厘摩（MMLS=3.10）。
在我们的全基因组筛查中检测到乳糜泻与染色体区域19p13.1存在显著连锁关系。这些结果在一个独立的病例对照队列中通过D19S89九与乳糜泻的关联得到了证实。此外，我们在染色体区域6q21-22上发现了一个可能的第二个乳糜泻基因座。
