Demarais Zachariah S, Conlon Carolyn, Rivier Cyprien A, Clocchiatti-Tuozzo Santiago, Renedo Daniela, Torres-Lopez Victor, Sheth Kevin N, Meeker Daniella, Zhao Hongyu, Ohno-Machado Lucila, Acosta Julian N, Huo Shufan, Falcone Guido J
Frank H. Netter MD School of Medicine, Quinnipiac University, North Haven, CT.
Department of Neurology, Yale School of Medicine, New Haven, CT.
Neurology. 2025 Feb 25;104(4):e210276. doi: 10.1212/WNL.0000000000210276. Epub 2025 Jan 31.
Type 2 diabetes mellitus (T2DM) is highly genetically determined, and polygenic susceptibility to T2DM (PSD) increases the risk of worse glycemic control and adverse vascular outcomes. Its role in stroke patients remains unknown. We aim to determine whether higher PSD is associated with worse glycemic control in stroke survivors.
We conducted a 2-stage genetic association study. In a cross-sectional design, we selected stroke survivors from the UK Biobank (enrollment between 2006 and 2010) to evaluate the relationship between PSD and glycemic control. Second, we replicated the results using data from All of Us (enrollment between 2018 and 2022). Exposures were low, intermediate, and high PSD, modeled through percentiles (<20, 20-80, >80) of a polygenic risk score of 2,522 independent risk variants associated with T2DM at genome-wide levels ( < 5 × 10). Outcomes were hemoglobin A1c (HbA1c) levels, uncontrolled diabetes (HbA1c ≥7.0%), and resistant diabetes (uncontrolled despite antidiabetic treatment).
Stage 1 included 6,908 stroke survivors (mean age 61 years, 42% female), including 977 (14%) with diabetes. Compared with low PSD, participants with high PSD had an increase of 0.49 in HbA1c (β = 0.49, standard error 0.03, -trend <0.001), 6.9 times the odds of uncontrolled diabetes (odds ratio [OR] 6.92, 95% CI 4.71-10.52), and 7.8 times the odds of resistant diabetes (OR 7.76, 95% CI 4.92-12.89). Stage 2 (replication) confirmed the association with HbA1c in 4,451 stroke survivors, including 2,163 (49%) with diabetes (mean age 64 years, 53% female, -trend <0.05 for all tests).
Among stroke survivors, a higher PSD was associated with poorer glycemic control. Further research should determine precision medicine strategies using PSD to improve clinical management of stroke patients.
2型糖尿病（T2DM）在很大程度上由基因决定，T2DM的多基因易感性（PSD）会增加血糖控制不佳和不良血管结局的风险。其在中风患者中的作用尚不清楚。我们旨在确定较高的PSD是否与中风幸存者较差的血糖控制相关。
我们进行了一项两阶段的基因关联研究。在横断面设计中，我们从英国生物银行（2006年至2010年登记）中选取中风幸存者，以评估PSD与血糖控制之间的关系。其次，我们使用“我们所有人”（2018年至2022年登记）的数据重复该结果。暴露因素为低、中、高PSD，通过全基因组水平上与T2DM相关的2522个独立风险变异的多基因风险评分百分位数（<20、20 - 80、>80）进行建模（<5×10）。结局指标为糖化血红蛋白（HbA1c）水平、未控制的糖尿病（HbA1c≥7.0%）和难治性糖尿病（尽管接受抗糖尿病治疗仍未得到控制）。
第一阶段纳入了6908名中风幸存者（平均年龄61岁，42%为女性），其中977人（14%）患有糖尿病。与低PSD相比，高PSD参与者的HbA1c增加了0.49（β = 0.49，标准误0.03，P趋势<0.001），未控制糖尿病的几率增加了6.9倍（优势比[OR] 6.92，95%置信区间4.71 - 10.52），难治性糖尿病的几率增加了7.8倍（OR 7.76，95%置信区间4.92 - 12.89）。第二阶段（重复验证）在4451名中风幸存者中证实了与HbA1c的关联，其中2163人（49%）患有糖尿病（平均年龄64岁，53%为女性，所有检验的P趋势<0.05）。
在中风幸存者中，较高的PSD与较差的血糖控制相关。进一步的研究应确定使用PSD的精准医学策略，以改善中风患者的临床管理。
