Association of genetic variants with dyslipidemia and chronic kidney disease in a longitudinal population-based genetic epidemiological study

We previously identified 9 genes and chromosomal region 3q28 as susceptibility loci for myocardial infarction, ischemic stroke, or chronic kidney disease (CKD) in Japanese individuals by genome-wide or candidate gene association studies. In the present study, we examined the association of 13 polymorphisms at these 10 loci with the prevalence of hypertriglyceridemia, hyper-low-density lipoprotein (LDL) cholesterolemia, hypo-high-density lipoprotein (HDL) cholesterolemia, or CKD in community-dwelling Japanese individuals. The study subjects comprised 6,027 individuals who were recruited to the Inabe Health and Longevity Study, a longitudinal genetic epidemiological study of atherosclerotic, cardiovascular and metabolic diseases. The subjects were recruited from individuals who visited the Health Care Center at Inabe General Hospital for an annual health checkup, and they were followed up each year (mean follow-up period, 5 years). Longitudinal analysis with a generalized estimating equation and with adjustment for covariates revealed that rs6929846 of butyrophilin, subfamily 2, member Al gene (BTN2A1) was significantly associated with the prevalence of hypertriglyceridemia (P=0.0001), hyper-LDL cholesterolemia (P=0.0004), and CKD (P=0.0007); rs2569512 of interleukin enhancer binding factor 3 (ILF3) was associated with hyper-LDL cholesterolemia (P=0.0029); and rs2074379 (P=0.0019) and rs2074388 (P=0.0029) of alpha-kinase 1 (ALPK1) were associated with CKD. Longitudinal analysis with a generalized linear mixed-effect model and with adjustment for covariates among all individuals revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=0.0011), LDL cholesterol (P=3.3x10(-5)), and creatinine (P=0.0006), as well as with the estimated glomerular filtration rate (eGFR) (P=0.0004); rs2569512 of ILF3 was shown to be associated with the serum concentration of LDL cholesterol (P=0.0221); and rs2074379 (P=0.0302) and rs2074388 (P=0.0336) of ALPKI were shown to be associated with the serum concentration of creatinine. Similar analysis among individuals not taking any anti-dyslipidemic medication revealed that rs6929846 of BTN2A1 was significantly associated with the serum concentrations of triglycerides (P=8.3x10(-5)) and LDL cholesterol (P=0.0004), and that rs2569512 of ILF3 was associated with the serum concentration of LDL cholesterol (P=0.0010). BTN2A1 may thus be a susceptibility gene for hypertriglyceridemia, hyper-LDL cholesterolemia and CKD in Japanese individuals.