Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, POB 63, 00014 Helsinki, Finland.
Diabetologia. 2012 Sep;55(9):2386-93. doi: 10.1007/s00125-012-2587-0. Epub 2012 May 29.
AIMS/HYPOTHESIS: Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus.
We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts.
In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease.
CONCLUSIONS/INTERPRETATION: A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.
目的/假设：父母 2 型糖尿病使 1 型糖尿病患者发生糖尿病肾病的风险增加。最近已经确定了一些导致 2 型糖尿病的单核苷酸多态性（SNP）。然而，目前尚不清楚这些 SNP 是否也会使 1 型糖尿病患者易患糖尿病肾病。
我们对芬兰人群全基因组关联研究中与 2 型糖尿病相关的 9 个 SNP 进行了基因分型，并在 2963 例 1 型糖尿病患者中检测了这些 SNP 与糖尿病肾病以及严重视网膜病变和心血管疾病的相关性。在另外 3 个队列的 2980 例患者中，对有显著意义的 SNP 进行了复制研究。
在发现队列中，位于 CDKN2A/B 基因附近的 rs10811661 与糖尿病肾病相关。在对本研究中进行的所有测试进行稳健的 Bonferroni 校正后，这种关联仍然存在（OR 1.33 [95%CI 1.14, 1.56]，p = 0.00045，p（36tests）= 0.016）。在荟萃分析中，糖尿病肾病的综合结果具有统计学意义，固定效应 p 值为 0.011（OR 1.15 [95%CI 1.02, 1.29]）。当将终末期肾病患者与对照组进行比较时，这种关联尤其强烈（OR 1.35 [95%CI 1.13, 1.60]，p = 0.00038）。同一位点也与严重视网膜病变相关（OR 1.37 [95%CI 1.10, 1.69]，p = 0.0040），但在 Bonferroni 校正后，这种关联不再具有统计学意义（p（36tests）= 0.14）。其他选择的 SNP 均与肾病、严重视网膜病变或心血管疾病无关。
结论/解释：导致 2 型糖尿病的 SNP rs10811661 位于 CDKN2A/B 附近，与 1 型糖尿病患者的糖尿病肾病相关。
