A Multifaceted Approach regarding the Association of the DsbA-L Gene with the Risk of Obesity-related Diseases Based on Clinical Pharmacogenetics

Abstract

Adiponectin, the most abundant adipose tissue-derived adipocytokine, improves insulin sensitivity and has anti-in-‰ammatory properties. Disulˆde-bond A oxidoreductase-like protein (DsbA-L) is a key molecule in the multimerization of adiponectin (i.e., activation of adiponectin). In mice, liver-speciˆc knockout of the Dsba-L gene impaired the mitochondrial function in hepatocytes and exacerbated the high-fat-diet-induced fatty liver. In addition, the DsbA-L mRNA level is negatively correlated with body mass index (BMI) in humans. We recently investigated the clinical impact of the DsbA-L gene on lifestyle-related diseases in Japanese subjects. We conˆrmed the in‰uence of the common DsbA-L rs1917760 polymorphism on the multimerization of adiponectin, as well as the association of the polymorphism with the risk of obesity and non-alcoholic fatty liver disease, using prediction models based on a non-linear mixed eŠect model and/or structural equation models among elderly participants in a health screening program. We also observed a decreasing eŠect of DsbA-L polymorphism on the DsbA-L mRNA level in peripheral blood mononuclear cells, and an increasing eŠect of the polymorphism on the prevalence of excessive weight among schizophrenia patients at a high risk for obesity. Theseˆndings suggest that DsbA-L may be a key molecule associated with the development and progression of obesity and its related diseases. Therefore, genotyping the DsbA-L polymorphism and identifying patients at a high risk of developing obesity may help prevent obesity and its complications by facilitating targeted prevention and treatment programs for high-risk individuals.