Shared and distinct genetic variants in type 1 diabetes and celiac disease.
Shared and distinct genetic variants in type 1 diabetes and celiac disease.
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DOI：
10.1056/nejmoa0807917
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发表时间：
2008-12-25
期刊：
影响因子：
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通讯作者：
Todd JA
中科院分区：
文献类型：
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作者：
Smyth DJ;Plagnol V;Walker NM;Cooper JD;Downes K;Yang JH;Howson JM;Stevens H;McManus R;Wijmenga C;Heap GA;Dubois PC;Clayton DG;Hunt KA;van Heel DA;Todd JA
炎症性疾病1型糖尿病（T1 D）和乳糜泻在人群中共分离，表明共同的遗传起源。两者均与染色体6p 21上的HLA II类基因相关，本文测试了非HLA位点是否共享。我们通过对8，064例T1 D病例、9，339例对照和2，519个家族进行基因分型和统计分析，评估了T1 D中的8个乳糜泻风险位点。我们还调查了2，560例乳糜泻病例和9，339例对照的18个T1 D位点。三个乳糜泻位点，被列为染色体/候选基因：1 q31/RGS 1，2 q12/IL 18 RAP和6 q25/TAGAP，与T1 D相关（P < 10−4）。3 p21/CCR 5 32碱基对插入/缺失变异体被新鉴定为T1 D基因座（P = 1.81 × 10−8），也与乳糜泻相关，18 p11/PTPN 2和2 q33/CTLA 4也是如此，使共有的基因座总数达到7个，包括12 q24/SH 2B 3。与乳糜泻相比，2 q12/IL 18 RAP和6 q25/TAGAP等位基因关联在T1 D中处于相反方向。在T1 D中，11 p15/INS、10 p15/IL 2 RA和1 q13/PTPN 22具有明显的作用，在乳糜泻中，3q 25/IL 12 A和3q 28/LPP具有明显的作用。T1 D和乳糜泻的遗传易感性具有共同的等位基因。这些数据表明，常见的生物学机制，如自身免疫相关的组织损伤和对饮食抗原的不耐受可能是T1 D的特征。
The inflammatory disorders type 1 diabetes (T1D) and celiac disease co-segregate in populations, suggesting a common genetic origin. Both are associated with the HLA class II genes on chromosome 6p21, and the present paper tested whether non-HLA loci are shared. We evaluated eight celiac disease risk loci in T1D by genotyping and statistical analyses of 8,064 T1D cases, 9,339 controls and 2,519 families. We also investigated 18 T1D loci in 2,560 celiac disease cases and 9,339 controls. Three celiac disease loci, listed as chromosome/candidate gene: 1q31/RGS1, 2q12/IL18RAP and 6q25/TAGAP, were associated with T1D (P < 10−4). The 3p21/CCR5 32 base pair insertion/deletion variant was newly identified as a T1D locus (P = 1.81 × 10−8), and was also associated with celiac disease, as were 18p11/PTPN2 and 2q33/CTLA4, bringing the total loci shared to seven, including 12q24/SH2B3. The 2q12/IL18RAP and 6q25/TAGAP allele associations were in the opposite direction in T1D as compared to celiac disease. Distinct effects included 11p15/INS, 10p15/IL2RA and 1q13/PTPN22 in T1D and 3q25/IL12A and 3q28/LPP in celiac disease. Genetic susceptibility to T1D and celiac disease shares common alleles. These data suggest that common biological mechanisms, such as autoimmunity related tissue damage and intolerance to dietary antigens may be a feature of T1D.