Abstract

Aims

Diabetes is a known risk factor for coronary artery disease (CAD). There is accumulating evidence that CAD pathogenesis differs for individuals with type 1 diabetes (T1D). However, the genetic background has not been extensively studied. We aimed to discover genetic loci increasing CAD susceptibility, especially in T1D, to examine the function of these discoveries and to study the role of the known risk loci in T1D.

Methods and results

We performed the largest genome-wide association study to date for CAD in T1D, comprising 4869 individuals with T1D (cases/controls: 941/3928). Two loci reached genome-wide significance, rs1970112 in CDKN2B-AS1 [odds ratio (OR) = 1.32, P = 1.50 × 10⁻⁸], and rs6055069 on DEFB127 promoter (OR = 4.17, P = 2.35 × 10⁻⁹), with consistent results in survival analysis. The CDKN2B-AS1 variant replicated (P = 0.04) when adjusted for diabetic kidney disease in three additional T1D cohorts (cases/controls: 434/3123). Furthermore, we explored the function of the lead discoveries with a cardio-phenome-wide analysis. Among the eight suggestive loci (P < 1 × 10⁻⁶), rs70962766 near B3GNT2 associated with central blood pressure, rs1344228 near CNTNAP5 with intima media thickness, and rs2112481 on GRAMD2B promoter with serum leucocyte concentration. Finally, we calculated genetic risk scores for individuals with T1D with the known susceptibility loci. General population risk variants were modestly but significantly associated with CAD also in T1D (P = 4.21 × 10⁻⁷).

Conclusion

While general population CAD risk loci had limited effect on the risk in T1D, for the first time, variants at the CDKN2B-AS1 locus were robustly associated with CAD in individuals with T1D. The novel finding on β-defensin DEFB127 promoter provides a link between diabetes, infection susceptibility, and CAD, although pending on future confirmation.

中文翻译：

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对 1 型糖尿病冠状动脉疾病的全基因组关联研究表明，β-防御素 127 是一个风险位点。

摘要

目标

糖尿病是冠状动脉疾病 (CAD) 的已知危险因素。越来越多的证据表明，1 型糖尿病 (T1D) 患者的 CAD 发病机制不同。然而，遗传背景尚未得到广泛研究。我们旨在发现增加 CAD 易感性的基因位点，特别是在 T1D 中，以检查这些发现的功能并研究已知风险位点在 T1D 中的作用。

方法和结果

我们对 T1D 中的 CAD 进行了迄今为止最大的全基因组关联研究，包括 4869 名 T1D 个体（病例/对照：941/3928）。两个基因座达到全基因组显着性，CDKN2B-AS1中的 rs1970112 [优势比 (OR) = 1.32，P  =  1.50 × 10 ^-8 ]，和 DEFB127 启动子上的rs6055069 (OR = 4.17，P  =  2.35 × 10 ^-9 )，在生存分析中具有一致的结果。复制的CDKN2B-AS1变体 ( P  = 0.04）在另外三个 T1D 队列（病例/对照：434/3123）中针对糖尿病肾病进行调整时。此外，我们通过心脏表型分析探索了先导发现的功能。在 8 个提示位点 ( P  <  1 × 10 ^-6 ) 中，B3GNT2 附近的 rs70962766与中心血压相关，CNTNAP5 附近的 rs1344228与内膜中层厚度相关，而GRAMD2B 启动子上的 rs2112481与血清白细胞浓度相关。最后，我们计算了具有已知易感位点的 T1D 个体的遗传风险评分。一般人群风险变异在 T1D 中也与 CAD 适度但显着相关（P  =  4.21 × 10^-7 )。

结论

虽然一般人群 CAD 风险基因座对 T1D 风险的影响有限，但CDKN2B-AS1基因座的变异首次与 T1D 个体的 CAD 密切相关。β-防御素DEFB127启动子的新发现提供了糖尿病、感染易感性和 CAD 之间的联系，尽管有待未来确认。