Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Mol Genet Metab. 2011 Apr;102(4):453-60. doi: 10.1016/j.ymgme.2010.12.009. Epub 2010 Dec 21.
The aim was to investigate the genetic background of familial clustering of type 2 diabetes.
We recruited Japanese families with a 3-generation history of diabetes. Genome-wide linkage analysis was performed assuming an autosomal dominant model. Genes in the linkage region were computationally prioritized using Endeavour. We sequenced the candidate genes, and the frequencies of detected nucleotide changes were then examined in normoglycemic controls.
To exclude known genetic factors, we sequenced 6 maturity onset diabetes of the young (MODY) genes in 10 familial cases. Because we detected a MODY3 mutation HNF1A R583G in one case, we excluded this case from further investigation. Linkage analysis revealed a significant linkage region on 2p25-22 (LOD score=3.47) for 4 families. The 23.6-Mb linkage region contained 106 genes. Those genes were scored by computational prioritization. Eleven genes, i.e., top 10% of 106 genes, were selected and considered primary candidates. Considering their functions, we eliminated 3 well characterized genes and finally sequenced 8 genes. GCKR ranked highly in the computational prioritization. Mutations (minor allele frequency less than 1%) in exons and the promoter of GCKR were found in index cases of the families (3 of 18 alleles) more frequently than in controls (0 of 36 alleles, P=0.033). In one pedigree with 9 affected members, the mutation GCKR g.6859C>G was concordant with affection status. No mutation in other 7 genes that ranked highly in the prioritization was concordant with affection status in families.
We propose that GCKR is a susceptibility gene in Japanese families with clustered diabetes. The family based approach seems to be complementary with a large population study.
研究 2 型糖尿病家族聚集的遗传背景。
我们招募了有 3 代糖尿病史的日本家族。假设常染色体显性遗传模式，进行全基因组连锁分析。使用 Endeavour 对连锁区域内的基因进行计算优先级排序。我们对候选基因进行测序，然后检查正常血糖对照者中检测到的核苷酸变化频率。
为了排除已知的遗传因素，我们对 10 个家族病例中的 6 个年轻发病的成年型糖尿病（MODY）基因进行了测序。由于我们在一个病例中检测到 MODY3 突变 HNF1A R583G，因此将该病例排除在进一步研究之外。连锁分析显示，4 个家族存在显著的 2p25-22 连锁区域（LOD 评分=3.47）。23.6-Mb 的连锁区域包含 106 个基因。通过计算优先级对这些基因进行评分。选择排名前 10%的 11 个基因作为主要候选基因。考虑到它们的功能，我们排除了 3 个特征明确的基因，最终对 8 个基因进行了测序。在计算优先级中，GCKR 排名较高。在家族的索引病例（18 个等位基因中有 3 个）中，GCKR 外显子和启动子的突变（次要等位基因频率小于 1%）比对照组（36 个等位基因中无突变，P=0.033）更为常见。在一个有 9 个受影响成员的家系中，突变 GCKR g.6859C>G 与发病状态一致。在家族中，排名较高的其他 7 个基因的突变与发病状态不一致。
我们提出 GCKR 是日本家族性糖尿病聚集的易感基因。基于家系的方法似乎与大型人群研究互补。
