Diet is a significant modifiable risk factor for type 2 diabetes (T2D), and its effect on disease risk is under partial genetic control. Identification of specific gene-diet interactions (GDIs) influencing risk biomarkers such as glycated hemoglobin (HbA1c) is a critical step towards developing precision nutrition for T2D prevention, but progress has been slow due to limitations in sample size and accuracy of dietary exposure measurement. We leveraged the large sample size of the UK Biobank (UKB) cohort and a diverse group of dietary exposures, including 30 individual dietary traits and 8 empirical dietary patterns, to conduct genome-wide interaction studies in ~340,000 European-ancestry participants to identify novel GDIs influencing HbA1c. We identified five variant-dietary trait pairs reaching genome-wide significance (p < 5×10^-8): two involved dietary patterns (meat pattern with rs147678157 and a fruit & vegetable-based pattern with rs3010439) and three involved individual dietary traits (bread consumption with rs62218803, dried fruit consumption with rs140270534, and milk type [dairy vs. other] with 4:131148078_TAGAA_T). All of these were affected minimally by adjustment for geographical and lifestyle-related confounders, and four of the five variants lacked any genetic main effect that would have allowed their detection in a traditional genome-wide association study for HbA1c. Notably, multiple loci near transient receptor potential subfamily M genes (TRPM2 and TRPM3) were identified as interacting with carbohydrate-containing food groups. Some of these interactions showed nominal replication in non-European ancestry UKB subsets, as well as association using alternative measures of glycemia (fasting glucose and follow-up HbA1c measurements). Our results highlight relevant GDIs influencing HbA1c for future investigation, while reinforcing known challenges in detecting and replicating GDIs.

中文翻译：

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英国生物库中的全基因组基因-饮食相互作用分析确定了对血红蛋白A1c的新作用

饮食是2型糖尿病（T2D）的重要可修正风险因素，其对疾病风险的影响受到部分基因控制。识别影响风险生物标记物（如糖化血红蛋白（HbA1c））的特定基因-饮食相互作用（GDI）是开发预防T2D的精确营养的关键步骤，但由于样本量和饮食暴露测量准确性的限制，进展缓慢。我们利用英国生物库（UKB）队列的大量样本和多样化的饮食暴露，包括30种饮食特征和8种经验饮食模式，在约340,000名欧洲血统参与者中进行了全基因组相互作用研究，以发现新的影响HbA1c的GDI。我们确定了五个变异-饮食性状对，达到了全基因组意义（p <5×10^-8）：两种涉及饮食模式（rs147678157为肉类模式，rs3010439为基于水果和蔬菜的模式）和三种涉及个人饮食特征（rs62218803食用面包，rs140270534食用干果以及牛奶类型[乳品与其他]） 4：131148078_TAGAA_T）。通过调整地理和与生活方式相关的混杂因素，所有这些受的影响都很小，并且五个变体中的四个没有任何遗传主效应，因此无法在传统的全基因组HbA1c关联研究中对其进行检测。值得注意的是，多个基因座附近的瞬时受体电位亚家族M基因（TRPM2和TRPM3）被确定为与含碳水化合物的食物组相互作用。这些互动中的某些互动显示了在非欧洲血统UKB子集中的名义复制，以及使用其他血糖测量方法（空腹血糖和后续HbA1c测量）进行关联。我们的结果突出了影响HbA1c的相关GDI，以供将来研究，同时加强了检测和复制GDI的已知挑战。