OBJECTIVE Obesity is a key predictor of type 2 diabetes (T2D). However, metabolic complications are not solely due to increased BMI. We hypothesized that differences between genetically predicted BMI and observed BMI (BMI-diff) could reflect deviation from individual set point and may predict incident T2D. RESEARCH DESIGN AND METHODS From the UK Biobank cohort, we selected participants of European ancestry without T2D (n = 332,154). The polygenic risk score for BMI was calculated via Bayesian regression and continuous shrinkage priors (PRS-CS). According to the BMI-diff, the 10-year risk of T2D was assessed using multivariable Cox proportional hazards model. Independent data from the Korean Genome and Epidemiology Study (KoGES) cohort from South Korea (n = 7,430) were used for replication. RESULTS Participants from the UK Biobank were divided into train (n = 268,041) and test set (n = 115,119) to establish genetically predicted BMI. In the test set, the genetically predicted BMI explained 7.1% of the variance of BMI, and there were 3,599 T2D cases (3.1%) during a 10-year follow-up. Participants in the higher quintiles of BMI-diff (more obese than genetically predicted) had significantly higher risk of T2D than those in the lowest quintile after adjusting for observed BMI: the adjusted hazard ratio of the 1st quintile (vs. 5th quintile) was 1.61 (95% CI, 1.26–2.05, P < 0.001). Results were consistent among individuals in the KoGES study. Moreover, higher BMI than predicted was associated with impaired insulin sensitivity. CONCLUSIONS Having a higher BMI than genetically predicted is associated with an increased risk of T2D. These findings underscore the potential to reassess T2D risk based on individual levels of obesity using genetic thresholds for BMI.

中文翻译：

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基因预测的 BMI 与观察到的 BMI 之间的差异可以预测 2 型糖尿病的发生


目的 肥胖是 2 型糖尿病 (T2D) 的关键预测因素。然而，代谢并发症并不仅仅归因于体重指数增加。我们假设基因预测的 BMI 和观察到的 BMI (BMI-diff) 之间的差异可以反映与个体设定点的偏差，并可以预测 T2D 的发生。研究设计和方法 我们从英国生物银行队列中选择了没有 T2D 的欧洲血统参与者 (n = 332,154)。 BMI 的多基因风险评分通过贝叶斯回归和连续收缩先验 (PRS-CS) 计算。根据BMI-diff，使用多变量Cox比例风险模型评估T2D的10年风险。来自韩国的韩国基因组和流行病学研究 (KoGES) 队列 (n = 7,430) 的独立数据用于复制。结果 来自英国生物银行的参与者被分为训练组（n = 268,041）和测试组（n = 115,119），以建立基因预测的 BMI。在测试集中，基因预测的 BMI 解释了 BMI 方差的 7.1%，并且在 10 年随访期间共有 3,599 例 T2D 病例（3.1%）。在调整观察到的 BMI 后，BMI 差异较高五分位数（比基因预测更肥胖）的参与者患 T2D 的风险显着高于最低五分位数的参与者：第一个五分位数（与第五个五分位数）的调整后风险比为 1.61 （95% CI，1.26–2.05，P< 0.001）。 KoGES 研究中的个体结果是一致的。此外，体重指数高于预期与胰岛素敏感性受损有关。结论 BMI 高于基因预测与 T2D 风险增加相关。这些发现强调了使用 BMI 遗传阈值根据个体肥胖水平重新评估 T2D 风险的潜力。