Aims/hypothesis

Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events.

Methods

Using whole-exome sequencing data, we constructed a weighted polygenic risk score (wPRS) consisting of 135 common variants (minor allele frequency >0.01) of 34 MDG based on r²>0.2 for linkage disequilibrium in a discovery case–control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9–46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3–61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events.

Results

In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4–61.7] years; disease duration 4.0 [1.0–9.0] years) observed for a median (IQR) of 17.5 (14.4–21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular–kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the ‘bottom-20%-wPRS plus baseline disease duration <5 years’ group as referent, the ‘top-20%-wPRS plus baseline disease duration 5 to <10 years’ group had unadjusted and adjusted HR of 1.60 (95% CI 1.17, 2.19, p=0.003) and 1.62 (95% CI 1.16, 2.26, p=0.005), respectively, for cardiovascular–kidney events compared with 1.38 (95% CI 0.97, 1.98, p=0.075) and 1.06 (95% CI 0.72, 1.57, p=0.752) in the ‘bottom-20%-wPRS plus baseline disease duration ≥10 years’ group.

Conclusions/interpretation

Common variants of MDG increased risk for YOD and cardiovascular–kidney events.

Graphical Abstract

中文翻译：

---

源自单基因糖尿病基因常见变异的多基因风险评分与早发性 2 型糖尿病和心血管-肾脏并发症相关

 目标/假设

单基因糖尿病是由通常与 β 细胞生物学有关的基因的罕见突变引起的。单基因糖尿病基因 （MDG） 的常见变异可能共同影响早发型 2 型糖尿病 （YOD，40 岁之前诊断）以及心血管和肾脏事件的风险。

 方法

使用全外显子组测序数据，我们构建了一个加权多基因风险评分 （wPRS），该评分由 135 个常见变体（次要等位基因频率 >0.01）组成，为 34 MDG，基于 r²>0.2，用于连锁不平衡，在 453 名患有 YOD 的成年人（中位 [IQR] 年龄 39.7 [34.9-46.9] 岁）和 405 名无 YOD 的成年人（中位 [IQR] 年龄 56.7 [50.3-61.0] 岁）中， 随后在独立的横断面队列中验证 YOD 的基于阵列的基因分型，以及 2 型糖尿病个体的心血管和肾脏事件前瞻性队列。

 结果

在发现队列中，YOD 的 135 种常见变异的 OR 范围为 1.00 至 2.61。在验证队列 （920 名 YOD 和 4910 名非 YOD） 中，与最低 10%-wPRS 相比，前 10%-wPRS 与 YOD 的 OR 为 1.42 相关 （95% CI 1.03， 1.95，p=0.033）。 在 2313 名 2 型糖尿病患者（中位 [IQR]：年龄 53.4 [45.4–61.7] 岁;病程 4.0 [1.0–9.0] 年）中，中位 （IQR） 为 17.5 （14.4–21.8） 年，标准化 wPRS 与心血管事件 （1.16 [95% CI 1.06， 1.27]，p=0.001）、肾脏事件 （1.09 [95% CI 1.02， 1.16]，p=0.013） 和心血管-肾脏事件 （1.10 [95% CI 1.03， 1.16]，p=0.003）。使用“最低 20%-wPRS 加基线病程 <5 年”组作为参考，“前 20%-wPRS 加基线病程 5 至 <10 年”组的未调整和调整 HR 分别为 1.60（95% CI 1.17、2.19，p=0.003）和 1.62（95% CI 1.16,2.26，p=0.005），而心血管-肾脏事件为 1.38（95% CI 0.97，p=0.005），而心血管-肾脏事件为 1.38（95% CI 0.97， 1.98，p=0.075）和 1.06（95% CI 0.72,1.57，p=0.752）在“最低 20%-wPRS 加基线病程 ≥10 年”组中。

结论/解释

MDG 的常见变体增加了 YOD 和心血管-肾脏事件的风险。

 图形摘要