Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset
Differential association of HLA with three subtypes of type 1 diabetes: fulminant, slowly progressive and acute-onset
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DOI：
10.1007/s00125-009-1539-9
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发表时间：
2009-12-01
期刊：
影响因子：
8.2
通讯作者：
Makino, H.
中科院分区：
文献类型：
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作者：
Kawabata, Y.;Ikegami, H.;Makino, H.
我们试图澄清HLA对三种1型糖尿病亚型（急性发作型、暴发性和缓慢进展型）遗传易感性贡献的异同。我们对545名日本1型糖尿病患者（338名急性发作，80名暴发性，127名缓慢进展）和396名对照组进行HLA- drb1， -DQB1, -A， -B和-C基因分型，以及扩展HLA 8.5 Mb区域的101个候选单核苷酸多态性（snp）基因分型。DRB1*0405-DQB1*0401、DRB1*0802-DQB1*0302和DRB1*0901-DQB1*0303与急性发作型1型糖尿病相关，其中DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302基因型优势比最高，为42.7。DRB1*1501-DQB1*0602和DRB1*1502-DQB1*0601与急性发作型1型糖尿病呈负相关。在缓慢进展的1型糖尿病中也观察到类似的趋势。相比之下，只有DRB1*0405-DQB1*0401与暴发性1型糖尿病相关，其中DRB1*0405-DQB1*0401/DRB1*0405-DQB1*0401基因型优势比最高，为11.2。DRB1*0802-DQB1*0302、DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302、DRB1*1501-DQB1*0602与暴发性1型糖尿病无相关性。I类等位基因和扩展HLA区域的一组snp与暴发性1型糖尿病的关联也不同于急性发作和缓慢进展型糖尿病。一个和两个易感单倍型的存在赋予了缓慢进展型1型糖尿病的易感性，而两个易感单倍型的存在则赋予了急性发作型和暴发性1型糖尿病的易感性。这些数据表明，HLA与暴发性1型糖尿病的相关性与其他1型糖尿病亚型的相关性在质量上不同，而HLA对缓慢进展型1型糖尿病的贡献在质量上与急性发作型1型糖尿病相似，但在数量上不同。
We sought to clarify similarities and differences in the contribution of HLA to genetic susceptibility to three subtypes of type 1 diabetes: acute-onset, fulminant and slowly progressive.We genotyped 545 Japanese patients with type 1 diabetes (338 acute-onset, 80 fulminant, 127 slowly progressive) and 396 control participants at HLA-DRB1, -DQB1, -A, -B and -C, and at 101 candidate single nucleotide polymorphisms (SNPs) in an 8.5 Mb region of the extended HLA.DRB1*0405-DQB1*0401, DRB1*0802-DQB1*0302 and DRB1*0901-DQB1*0303 were associated with acute-onset type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 genotype achieving the highest odds ratio of 42.7. DRB1*1501-DQB1*0602 and DRB1*1502-DQB1*0601 were negatively associated with acute-onset type 1 diabetes. A similar tendency was observed for slowly progressive type 1 diabetes. In contrast, only DRB1*0405-DQB1*0401 was associated with fulminant type 1 diabetes, with the DRB1*0405-DQB1*0401/DRB1*0405-DQB1*0401 genotype showing the highest odds ratio of 11.2. DRB1*0802-DQB1*0302, DRB1*0405-DQB1*0401/DRB1*0802-DQB1*0302 and DRB1*1501-DQB1*0602 were not associated with fulminant type 1 diabetes. The association of class I alleles and a panel of SNPs in an extended HLA region with fulminant type 1 diabetes was also different from that seen for the acute-onset and slowly progressive forms. The presence of both one and two susceptible haplotypes conferred susceptibility to slowly progressive type 1 diabetes, whereas the presence of two susceptible haplotypes was required to confer susceptibility to acute-onset and fulminant type 1 diabetes.These data suggest that HLA associations with fulminant type 1 diabetes are qualitatively different from those with other subtypes of type 1 diabetes, whereas the HLA contribution to slowly progressive type 1 diabetes is qualitatively similar to, but quantitatively different from, that in acute-onset type 1 diabetes.