Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, CO 80045-6511, USA.
Clin Chem. 2011 Feb;57(2):176-85. doi: 10.1373/clinchem.2010.148221. Epub 2011 Jan 4.
Type 1 diabetes, a multifactorial disease with a strong genetic component, is caused by the autoimmune destruction of pancreatic β cells. The major susceptibility locus maps to the HLA class II genes at 6p21, although more than 40 non-HLA susceptibility gene markers have been confirmed.
Although HLA class II alleles account for up to 30%-50% of genetic type 1 diabetes risk, multiple non-MHC loci contribute to disease risk with smaller effects. These include the insulin, PTPN22, CTLA4, IL2RA, IFIH1, and other recently discovered loci. Genomewide association studies performed with high-density single-nucleotide-polymorphism genotyping platforms have provided evidence for a number of novel loci, although fine mapping and characterization of these new regions remain to be performed. Children born with the high-risk genotype HLADR3/4-DQ8 comprise almost 50% of children who develop antiislet autoimmunity by the age of 5 years. Genetic risk for type 1 diabetes can be further stratified by selection of children with susceptible genotypes at other diabetes genes, by selection of children with a multiple family history of diabetes, and/or by selection of relatives that are HLA identical to the proband.
Children with the HLA-risk genotypes DR3/4-DQ8 or DR4/DR4 who have a family history of type 1 diabetes have more than a 1 in 5 risk for developing islet autoantibodies during childhood, and children with the same HLA-risk genotype but no family history have approximately a 1 in 20 risk. Determining extreme genetic risk is a prerequisite for the implementation of primary prevention trials, which are now underway for relatives of individuals with type 1 diabetes.
1 型糖尿病是一种具有强烈遗传成分的多因素疾病，由胰腺β细胞的自身免疫破坏引起。主要易感位点位于 6p21 的 HLA Ⅱ类基因，尽管已经证实了 40 多个非 HLA 易感基因标记物。
尽管 HLA Ⅱ类等位基因占 1 型糖尿病遗传风险的 30%-50%，但多个非 MHC 基因座也对疾病风险有较小的影响。这些包括胰岛素、PTPN22、CTLA4、IL2RA、IFIH1 和其他最近发现的基因座。使用高密度单核苷酸多态性基因分型平台进行的全基因组关联研究提供了一些新的基因座的证据，尽管这些新区域的精细映射和特征仍有待进行。在 5 岁时出现胰岛自身免疫的儿童中，携带高风险基因型 HLADR3/4-DQ8 的儿童几乎占 50%。通过选择具有易感基因型的儿童、选择具有多个糖尿病家族史的儿童、或选择与先证者 HLA 相同的亲属，1 型糖尿病的遗传风险可以进一步分层。
具有 HLA 风险基因型 DR3/4-DQ8 或 DR4/DR4 的儿童，如果有 1 型糖尿病的家族史，那么在儿童期发展胰岛自身抗体的风险超过 1/5，如果具有相同的 HLA 风险基因型但没有家族史，那么风险约为 1/20。确定极端遗传风险是实施一级预防试验的前提，目前正在对 1 型糖尿病患者的亲属进行此类试验。
