Diabetes genetic score, diabetes, and arterial stiffness: a Mendelian randomisation analysis in Chinese

Abstract

BackgroundThe nature and underlying mechanisms of the association between type 2 diabetes and the risk of increased arterial stiffness are unclear. We aimed to study this association using the Mendelian randomisation approach. MethodsWe did a Mendelian randomisation analysis in 11 385 participants, aged 40 years or more, recruited from two communities in Baoshan district, Shanghai, China, in 2011–13. We genotyped 34 common variants associated with type 2 diabetes that had previously been identified and validated in east Asians, and created the type 2 diabetes genetic risk score. Arterial stiffness was assessed non-invasively with measurement of brachial-ankle pulse wave velocity (baPWV). The effect of type 2 diabetes on the increased risk of arterial stiffness was quantified by instrumental variable estimator. The institutional review board of Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, approved the study protocol. All participants gave written informed consent. FindingsWe found that each ten-point increase in the genetic risk score was associated with a 1·39 times increment in type 2 diabetes risk and an odds ratio (OR) for increased arterial stiffness of 1·21 (95% CI 1·06–1·38). Compared with the lowest quartile of the genetic risk score, the highest quartile was associated with a 1·22 (95% CI 1·06–1·40) times increment risk of increased arterial stiffness. Linear regression adjusted for age, sex, and body-mass index showed that every ten-point increase of the genetic risk score was associated with a rise in baPWV by 36·71 cm/s (p<0·0001). Mendelian randomisation analysis showed a causal relation between type 2 diabetes and risk of increased arterial stiffness (OR 1·23 [95% CI 1·04–1·46], p=0·02), which was smaller than the association seen between type 2 diabetes and arterial stiffness risk (2·09 [1·88–2·32], p<0·0001). InterpretationType 2 diabetes has a causal effect on the presence of arterial stiffness, measured by increased baPWV in a Mendelian randomisation analysis with a large sample size, and has an important relation with increased arterial stiffness. Large prospective studies are needed to convincingly establish the associations and to enhance our insights into the underlying biological pathways. FundingThe China National Clinical Research Center for Metabolic Diseases, the National Key New Drug Creation and Manufacturing Program of Ministry of Science and Technology of China, the National High Technology Research and Development Program of China (863 Program), the National Natural Science Foundation of China, and the Shanghai Pujiang Project.