O Chun-Kwan, Fan Baoqi, Tsoi Sandra T F, Tam Claudia H T, Wan Raymond, Lau Eric S H, Shi Mai, Lim Cadmon K P, Yu Gechang, Ho Jane P Y, Chow Elaine Y K, Kong Alice P S, Ozaki Risa, So Wing Yee, Ma Ronald C W, Luk Andrea O Y, Chan Juliana C N
Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
Diabetologia. 2025 Feb;68(2):367-381. doi: 10.1007/s00125-024-06320-3. Epub 2024 Nov 23.
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.
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 r>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.
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.
目的/假设：单基因糖尿病由通常与β细胞生物学相关的基因中的罕见突变引起。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岁之前确诊）以及心血管和肾脏事件的风险。
利用全外显子测序数据，我们构建了一个加权多基因风险评分（wPRS），该评分由34个MDG的135个常见变异（次要等位基因频率>0.01）组成，基于一个453名患有YOD的成年发现病例对照队列（年龄中位数[四分位间距]为39.7[34.9 - 46.9]岁）和405名无YOD的个体（年龄中位数[四分位间距]为56.7[50.3 - 61.0]岁）中的连锁不平衡r>0.2构建而成，随后在一个独立的横断面队列中进行验证，该队列对YOD进行基于芯片的基因分型，并在一个2型糖尿病个体的前瞻性队列中对心血管和肾脏事件进行验证。
在发现队列中，135个常见变异对YOD的比值比范围为1.00至2.61。在验证队列（920名YOD患者和4910名非YOD患者）中，与最低10% - wPRS相比，最高10% - wPRS与YOD的比值比为1.42（95%置信区间1.03，1.95，p = 0.033）。在2313名患有2型糖尿病的个体（年龄中位数[四分位间距]：53.4[45.4 - 61.7]岁；病程4.0[1.0 - 9.0]年）中，观察了中位数（四分位间距）为17.5（14.4 - 21.8）年，标准化wPRS与心血管事件（1.16[95%置信区间1.06，1.27]，p = 0.001）、肾脏事件（1.09[95%置信区间1.02，1.16]，p = 0.013）和心血管 - 肾脏事件（1.10[95%置信区间1.03，1.16]，p = 0.003）的风险增加相关。以“最低20% - wPRS加基线病程<5年”组作为对照，“最高20% - wPRS加基线病程5至<10年”组与心血管 - 肾脏事件的未调整和调整后的风险比分别为1.60（95%置信区间1.17，2.19，p = 0.003）和1.62（95%置信区间1.16，2.26，p = 0.005），而“最低20% - wPRS加基线病程≥10年”组分别为1.38（95%置信区间0.97，1.98，p = 0.075）和1.06（95%置信区间0.72，1.57，p = 0.752）。
结论/解读：MDG的常见变异增加了YOD以及心血管 - 肾脏事件的风险。
