Leptin receptor Arg109 homozygotes display decreased total mortality as well as lower incidence of cardiovascular disease and related death

Abstract

Two leptin receptor single nucleotide polymorphisms, Lys109Arg and Gln223Arg, have been shown to associate with several risk factors for cardiovascular disease. In addition, we have previously shown that Arg109 and Arg223 homozygotes displayed lower intima-media thickness in our well-defined OPERA (Oulu Project Elucidating Risk of Atherosclerosis) study. This current research investigated the impact of these LEPR polymorphisms on cardiovascular events and related death as well as to total mortality in the 19-year follow-up of OPERA. Subjects were randomly selected, middle-aged drug-treated hypertensives and their age- and sex-matched control subjects recruited to the OPERA study between 1990 and 1993. Mortality and hospital events of 1045 subjects were followed up until 2009. A total of 151 coronary heart disease (CHD) and 211 cardiovascular disease (CVD) events or deaths including 58 CHD and 69 CVD deaths occurred. Furthermore, during this follow-up, a total of 165 subjects died. Logistic regression analysis was performed to assess the impact of Lys109Arg and Gln223Arg on the events and death. Further modeling was performed with Cox regression for Lys109Arg. The logistic regression analysis revealed a significant protective impact of Arg109Arg genotype on CHD (OR 0.433; CI 95% 0.217-0.863) and CVD (OR 0.540; CI 95% 0.309-0.942) events or death as well as on total mortality (OR 0.390; CI 95% 0.196-0.775) when adjusted with age, sex and study group. Even after further adjustment with BMI, smoking status, systolic blood pressure and low-density lipoprotein cholesterol, the protective effect of Arg109Arg on CHD events or death and total mortality still remained statistically significant (OR 0.463; CI 95% 0.230-0.931 and OR 0.442; CI 95% 0.218-0.896, respectively). Arg109Arg was also shown to confer protection against CHD mortality (HR 0.224; CI95% 0.055-0.919) and overall mortality (HR 0.413; CI95% 0.218-0.783) also in Cox regression analysis. In conclusion, the Arg109Arg genotype of LEPR seems to be protective from cardiovascular events and death and this phenomenon seems to be independent of the traditional risk factors for atherosclerosis.

Keywords: ANOVA; Analysis of variance; Arg; Arginine; BMI; Body mass index; CHD; CI; CRH1; CVA; CVD; Cardiovascular disease; Cerebrovascular accident; Confidence interval; Coronary heart disease; Cytokine receptor homologous 1; F; Forward; Gln; Glutamine; HDL-C; HR; HWE; Hardy–Weinberg equilibrium; Hazard ratio; High-density lipoprotein cholesterol; ICD; International Classification of Diseases; LDL-C; LEPR; Lep; Leptin; Leptin receptor; Low-density lipoprotein cholesterol; Lys; Lysine; MI; Mortality; Myocardial infarction; OPERA; OR; Odds ratio; Oulu Project Elucidating Risk of Atherosclerosis; R; RIA; Radioimmunoassay; Reverse; SBP; SNP; Single nucleotide polymorphism; Systolic blood pressure; VLDL; Very low-density lipoprotein.