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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遗传预测和观察到的 BMI 之间的差异预测 2 型糖尿病事件


目的 肥胖是 2 型糖尿病 （T2D） 的关键预测因子。然而，代谢并发症不仅仅是由于 BMI 增加。我们假设遗传预测的 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，并可能预测事件 T2D。研究设计和方法 从英国生物样本库队列中，我们选择了没有 T2D 的欧洲血统的参与者 （n = 332,154）。通过贝叶斯回归和连续收缩先验 （PRS-CS） 计算 BMI 的多基因风险评分。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 来自英国生物样本库的参与者被分为训练组 （n = 268,041） 和测试集 （n = 115,119） 以建立遗传预测的 BMI。在测试集中，遗传预测的 BMI 解释了 7.1% 的 BMI 方差，并且在 3,599 年的随访期间有 3.1 例 T2D 病例 （10%）。在调整观察到的 BMI 后，BMI-diff 较高五分位数（比遗传预测的更肥胖）的参与者患 T2D 的风险明显高于最低五分位数的参与者：第 1 个五分位数（与第 5 个五分位数相比）的调整后风险比为 1.61（95% CI，1.26-2.05，P < 0.001）。在 KoGES 研究中，个体之间的结果一致。此外，高于预测的 BMI 与胰岛素敏感性受损相关。结论 BMI 高于遗传预测与 T2D 风险增加相关。这些发现强调了使用 BMI 的遗传阈值根据个体肥胖水平重新评估 T2D 风险的可能性。