Genetics of type 1 diabetes.
Genetics of type 1 diabetes.
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DOI：
10.1373/clinchem.2010.148221
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发表时间：
2011-02
影响因子：
9.3
通讯作者：
Rewers MJ
中科院分区：
文献类型：
--
作者：
Steck AK;Rewers MJ
1型糖尿病是一种多因素疾病，具有很强的遗传成分，是由胰腺β细胞的自身免疫破坏引起的。主要的易感位点定位于HLA II类基因的6p21位点，尽管已有超过40个非HLA易感基因标记被证实。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基因座对疾病风险的影响较小。其中包括胰岛素、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为许多新基因座提供了证据，尽管这些新区域的精细定位和表征仍有待进行。出生时携带高风险基因型HLADR3/4-DQ8的儿童占到5岁前出现抗胰岛自身免疫的儿童的近50%。通过选择具有其他糖尿病基因易感基因型的儿童，选择具有多重糖尿病家族史的儿童，和/或选择HLA与先证相同的亲属，可以进一步分层1型糖尿病的遗传风险。具有1型糖尿病家族史的具有hla风险基因型DR3/4-DQ8或DR4/DR4的儿童在儿童期发生胰岛自身抗体的风险超过1 / 5，具有相同hla风险基因型但没有家族史的儿童的风险约为1 / 20。确定极端遗传风险是实施一级预防试验的先决条件，目前正在对1型糖尿病患者的亲属进行一级预防试验。
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.