Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease
Analysis of HLA and Non-HLA Alleles Can Identify Individuals at High Risk for Celiac Disease
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DOI：
10.1053/j.gastro.2009.05.040
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发表时间：
2009-09-01
期刊：
影响因子：
29.4
通讯作者：
Wijmenga, Cisca
中科院分区：
文献类型：
--
作者：
Romanos, Jihane;Van Diemen, Cleo C.;Wijmenga, Cisca
背景与目的：乳糜泻（CD）是一种常见的慢性小肠疾病，由对谷蛋白肽的异常细胞反应引起，并且通常未被诊断。它是一种复杂的遗传性疾病，尽管95%的患者携带异二聚体人类白细胞抗原（HLA）-DQ 2的风险。CD的全基因组关联研究已经确定了9个非HLA基因座，这些基因座也会导致CD风险，其中大多数与其他免疫相关疾病相同。我们的目标是使用HLA和非HLA风险等位基因预测CD的遗传风险。方法：我们从荷兰、英国和爱尔兰人群中的2,308例病例和4,585例对照中选择了10个独立的多态性，并根据HLA-DQ 2基因型将个体分为3个风险组。我们使用每个个体的非HLA风险等位基因的总数来分析其对CD风险的累积效应，在logistic回归分析中调整性别和人群组。我们在436例意大利病例和532例对照中验证了我们的研究结果。研究结果：CD病例携带的非HLA风险等位基因比对照组多：携带≥ 13个风险等位基因的个体比携带0-5个风险等位基因的个体具有更高的CD风险（比值比，6.2; 95%置信区间，4.1-9.3）。在一个模型中结合HLA和非HLA风险基因型，与仅使用HLA识别高风险个体相比，敏感性增加6.2%，特异性略有下降。结论：我们可以使用CD的非HLA危险因素来提高高危个体的识别。我们的风险模型是在高危家庭和基于人群的筛查中实现更好诊断和预后的第一步。
BACKGROUND & AIMS: Celiac disease (CD) is a common chronic disorder of the small intestine, resulting from aberrant cellular responses to gluten peptides, and often remains undiagnosed. It is a complex genetic disorder, although 95% of the patients carry the risk heterodimer human leukocyte antigen (HLA)-DQ2. Genome-wide association studies on CD have identified 9 non-HLA loci that also contribute to CD risk, most of which are shared with other immune-related diseases. Our aim is to predict the genetic risk for CD using HLA and non-HLA risk alleles. METHODS: We selected 10 independent polymorphisms in 2,308 cases and 4,585 controls from Dutch, UK, and Irish populations and categorized the individuals into 3 risk groups, based on their HLA-DQ2 genotype. We used the summed number of non-HLA risk alleles per individual to analyze their cumulative effect on CD risk, adjusting for gender and population group in logistic regression analysis. We validated our findings in 436 Italian cases and 532 controls. RESULTS: CD cases carried more non-HLA risk alleles than controls: individuals carrying >= 13 risk alleles had a higher CD risk (odds ratio, 6.2; 95% confidence interval, 4.1-9.3) compared with those carrying 0-5 risk alleles. Combining HLA and non-HLA risk genotypes in one model increases sensitivity by 6.2% compared with using only HLA for identification of high-risk individuals with slight decrease in specificity. CONCLUSIONS: We can use non-HLA risk factors for CD to improve identification of high-risk individuals. Our risk model is a first step toward better diagnosis and prognosis in high-risk families and population-based screening.