Chun-Kwan O, Baoqi Fan, Sandra T. F. Tsoi, Claudia H. T. Tam, Raymond Wan, Eric S. H. Lau, Mai Shi, Cadmon K. P. Lim, Gechang Yu, Jane P. Y. Ho, Elaine Y. K. Chow, Alice P. S. Kong, Risa Ozaki, Wing Yee So, Ronald C. W. Ma, Andrea O. Y. Luk, Juliana C. N. Chan
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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.</p><h3 data-test=\"abstract-sub-heading\">Methods</h3><p>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 <i>r</i><sup>2</sup>>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.</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>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, <i>p</i>=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], <i>p</i>=0.001), kidney events (1.09 [95% CI 1.02, 1.16], <i>p</i>=0.013) and cardiovascular–kidney events (1.10 [95% CI 1.03, 1.16], <i>p</i>=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, <i>p</i>=0.003) and 1.62 (95% CI 1.16, 2.26, <i>p</i>=0.005), respectively, for cardiovascular–kidney events compared with 1.38 (95% CI 0.97, 1.98, <i>p</i>=0.075) and 1.06 (95% CI 0.72, 1.57, <i>p</i>=0.752) in the ‘bottom-20%-wPRS plus baseline disease duration ≥10 years’ group.</p><h3 data-test=\"abstract-sub-heading\">Conclusions/interpretation</h3><p>Common variants of MDG increased risk for YOD and cardiovascular–kidney events.</p><h3 data-test=\"abstract-sub-heading\">Graphical Abstract</h3>\n","PeriodicalId":11164,"journal":{"name":"Diabetologia","volume":"15 1","pages":""},"PeriodicalIF":8.4000,"publicationDate":"2024-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular–kidney complications\",\"authors\":\"Chun-Kwan O, Baoqi Fan, Sandra T. 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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, <i>p</i>=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], <i>p</i>=0.001), kidney events (1.09 [95% CI 1.02, 1.16], <i>p</i>=0.013) and cardiovascular–kidney events (1.10 [95% CI 1.03, 1.16], <i>p</i>=0.003). 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引用次数: 0
摘要
目的/假说单基因糖尿病是由通常与β细胞生物学有关的基因发生罕见突变引起的。方法利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 34 个 MDG 的 135 个常见变异（小等位基因频率为 0.01）组成，基于 r2>0.2 的联系不平衡的发现性病例对照队列中的 453 名 YOD 成人（中位数 [IQR] 年龄 39.7 [34.9-46.9] 岁）和 405 名无 YOD 成人（中位数 [IQR] 年龄 56.7 [50.3-61.结果在发现队列中，135 个常见变异与 YOD 的 OR 值介于 1.00 到 2.61 之间。在验证队列（920 名 YOD 患者和 4910 名非 YOD 患者）中，与底部-10%-wPRS 相比，顶部-10%-wPRS 与 YOD 的 OR 值为 1.42（95% CI 1.03，1.95，p=0.033）。在 2313 名 2 型糖尿病患者（中位数[IQR]：年龄 53.4 [45.4-61.7] 岁；病程 4.0 [1.0-9.0] 年）中，观察中位数（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）的发生率增加有关。）以 "底20%-wPRS加基线病程<5年 "组为参照，"顶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.结论/解释MDG的常见变异增加了YOD和心血管-肾脏事件的风险。
A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular–kidney complications
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.
期刊介绍：
Diabetologia, the authoritative journal dedicated to diabetes research, holds high visibility through society membership, libraries, and social media. As the official journal of the European Association for the Study of Diabetes, it is ranked in the top quartile of the 2019 JCR Impact Factors in the Endocrinology & Metabolism category. The journal boasts dedicated and expert editorial teams committed to supporting authors throughout the peer review process.
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