Bonnycastle Lori L, Willer Cristen J, Conneely Karen N, Jackson Anne U, Burrill Cecily P, Watanabe Richard M, Chines Peter S, Narisu Narisu, Scott Laura J, Enloe Sareena T, Swift Amy J, Duren William L, Stringham Heather M, Erdos Michael R, Riebow Nancy L, Buchanan Thomas A, Valle Timo T, Tuomilehto Jaakko, Bergman Richard N, Mohlke Karen L, Boehnke Michael, Collins Francis S
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-2152, USA.
Diabetes. 2006 Sep;55(9):2534-40. doi: 10.2337/db06-0178.
Prior reports have suggested that variants in the genes for maturity-onset diabetes of the young (MODY) may confer susceptibility to type 2 diabetes, but results have been conflicting and coverage of the MODY genes has been incomplete. To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals. For each of the five genes, we selected 1) nonredundant single nucleotide polymorphisms (SNPs) (r(2)< 0.8 with other SNPs) from the HapMap database or another linkage disequilibrium map, 2) SNPs with previously reported type 2 diabetes association, and 3) nonsynonymous coding SNPs. We tested 128 SNPs for association with type 2 diabetes in 786 index cases from type 2 diabetic families and 619 normal glucose-tolerant control subjects. We followed up 35 of the most significant SNPs by genotyping them on another 384 case subjects and 366 control subjects from Finland. We also supplemented our previous HNF4A results by genotyping 12 SNPs on additional Finnish samples. After correcting for testing multiple correlated SNPs within a gene, we find evidence of type 2 diabetes association with SNPs in five of the six known MODY genes: GCK, HNF1A, HNF1B, NEUROD1, and HNF4A. Our data suggest that common variants in several MODY genes play a modest role in type 2 diabetes susceptibility.
先前的报告表明，年轻的成年发病型糖尿病（MODY）相关基因的变异可能会增加患2型糖尿病的易感性，但结果一直存在争议，且对MODY基因的覆盖并不完整。为补充我们之前对HNF4A的研究，我们检测了其他五个已知的MODY基因与芬兰人群2型糖尿病的关联性。对于这五个基因中的每一个，我们从HapMap数据库或另一个连锁不平衡图谱中选择了1）非冗余单核苷酸多态性（SNP）（与其他SNP的r²<0.8），2）先前报道与2型糖尿病相关的SNP，以及3）非同义编码SNP。我们在来自2型糖尿病家族的786例索引病例和619例糖耐量正常的对照受试者中检测了128个SNP与2型糖尿病的关联性。我们通过在另外384例病例受试者和366例来自芬兰的对照受试者中对35个最显著的SNP进行基因分型来进行随访。我们还通过在另外的芬兰样本中对12个SNP进行基因分型来补充我们之前关于HNF4A的结果。在对一个基因内多个相关SNP的检测进行校正后，我们发现六个已知MODY基因中的五个基因（GCK、HNF1A、HNF1B、NEUROD1和HNF4A）中的SNP与2型糖尿病存在关联证据。我们的数据表明，几个MODY基因中的常见变异在2型糖尿病易感性中起适度作用。
