Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Unit of Bioinformatics, Fondazione IRCSS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Diabetes Metab. 2022 Sep;48(5):101353. doi: 10.1016/j.diabet.2022.101353. Epub 2022 Apr 26.
This study investigated whether rare, deleterious variants in monogenic diabetes-genes are associated with early-onset type 2 diabetes (T2D).
A nested case-control study was designed from 9712 Italian patients with T2D. Individuals with age at diabetes onset ≤35 yrs (n = 300; cases) or ≥65 yrs (n = 300; controls) were selected and screened for variants in 27 monogenic diabetes-genes by targeted resequencing. Rare (minor allele frequency-MAF <1%) and possibly deleterious variants were collectively tested for association with early-onset T2D. The association of a genetic risk score (GRS) based on 17 GWAS-SNPs for T2D was also tested.
When all rare variants were considered together, each increased the risk of early-onset T2D by 65% (allelic OR =1.64, 95% CI: 1.08-2.48, p = 0.02). Effects were similar when the 600 study participants were stratified according to their place of recruitment (Central-Southern Italy, 182 cases vs. 142 controls, or Rome urban area, 118 vs. 158, p for heterogeneity=0.53). Progressively less frequent variants showed increasingly stronger effects in the risk of early-onset T2D for those with MAF <0.001% (OR=6.34, 95% CI: 1.87-22.43, p = 0.003). One unit of T2D-GRS significantly increased the risk of early-onset T2D (OR 1.09, 95% CI: 1.01-1.18; p = 0.02). This association was stronger among rare variants carriers as compared to non-carriers (p = 0.02).
Rare variants in monogenic-diabetes genes are associated with an increased risk of early-onset T2D, and interact with common T2D susceptibility variants in shaping it. These findings might help develop prediction tools to identify individuals at high risk of developing T2D in early adulthood.
本研究旨在探讨单基因糖尿病相关基因中的罕见有害变异是否与早发 2 型糖尿病（T2D）相关。
采用巢式病例对照研究设计，纳入 9712 名意大利 T2D 患者。选取发病年龄≤35 岁（n=300；病例）或≥65 岁（n=300；对照）的个体，通过靶向重测序对 27 个单基因糖尿病相关基因中的变异进行筛查。罕见（次要等位基因频率-MAF<1%）和可能有害的变异被共同检测与早发 T2D 的相关性。还检测了基于 17 个 T2D 全基因组关联研究-SNPs 的遗传风险评分（GRS）的相关性。
当所有罕见变异一起考虑时，每种变异使早发 T2D 的风险增加 65%（等位基因 OR=1.64，95%CI：1.08-2.48，p=0.02）。当根据其招募地点将 600 名研究参与者分层（意大利中南部，182 例病例与 142 例对照，或罗马市区，118 例与 158 例，p 异质性=0.53）时，结果相似。对于 MAF<0.001%的患者，罕见且越来越常见的变异使早发 T2D 的风险逐渐增加（OR=6.34，95%CI：1.87-22.43，p=0.003）。一个 T2D-GRS 单位显著增加早发 T2D 的风险（OR 1.09，95%CI：1.01-1.18；p=0.02）。与非携带者相比，携带者中这种关联更强（p=0.02）。
单基因糖尿病相关基因中的罕见变异与早发 T2D 风险增加相关，并与常见的 T2D 易感性变异相互作用，共同影响其发生。这些发现可能有助于开发预测工具，以识别在成年早期发生 T2D 的高风险个体。
