Association of FURIN and ZPR1 polymorphisms with metabolic syndrome

Abstract

Although genome-wide association studies (GWASs) have identified various genes and loci in predisposition to metabolic syndrome (MetS) or each component of this condition, the genetic basis of MetS in individuals remains to be identified definitively. The aim of the present study was to examine the possible association of MetS in individuals with 29 polymorphisms that were previously identified as susceptibility loci for coronary artery disease or myocardial infarction by meta-analyses of GWASs. The study population comprised 1,822 subjects with MetS and 1,096 controls. Subjects with MetS had ≥3 of the 5 components of the diagnostic criteria for MetS, whereas control individuals had 0-1 of the 5 components. The genotypes for the 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Comparisons of allele frequencies by the χ test revealed that rs17514846 (A→C) of the furin (paired basic amino acid-cleaving enzyme) gene (; P=0.0006), rs964184 (C→G) of the ZPR1 zinc finger gene (; P=0.0078) and rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (P=0.0486) were significantly (P<0.05) associated with the prevalence of MetS. Multivariable logistic regression analysis with adjustment for age, gender and smoking status revealed that rs17514846 of (P=0.0016; odds ratio, 0.76; dominant model) and rs964184 of (P=0.0164; odds ratio, 1.21; dominant model) were significantly associated with MetS. The minor allele of rs17514846 of was significantly associated with a decrease in the serum concentration of triglycerides (P=0.0293) and to an increase in the serum concentration of high-density lipoprotein (HDL) cholesterol (P=0.0460). The minor allele of rs964184 of was significantly associated with increases in the serum concentration of triglycerides (P=6.2×10) and fasting plasma glucose level (P=0.0028) and to a decrease in the serum concentration of HDL cholesterol (P=0.0105). and may thus be susceptibility loci for MetS.

Plasma levels of the proprotein convertase furin and incidence of diabetes and mortality

“…A point mutation at the insulin pro-receptor processing site, later identified as a furin cleavage site [6], was reported in an individual suffering from extreme insulin-resistant diabetes and resulted in the absence of the proreceptor processing [7]. An association between a polymorphism in the furin gene and decreased triglycerides and increased high-density lipoprotein cholesterol (HDL-C) serum concentration was recently established [8]. Moreover, in a recent epidemiological study, elevated circulating furin levels were demonstrated to be associated with a score for the metabolic syndrome as well as with increased BMI and blood triglyceride concentration [9].…”

The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9

“…Thus, furin is a major regulator of cardiac functions, via the processing of multiple substrates. Recently, a GWAS revealed that a nucleotide A to C substitution in intron 1 of the FURIN gene (rs17514846) was significantly associated with the development of the metabolic syndrome, with the protective minor A allele correlating with a 21% decreased serum TG (Ueyama et al, 2015). Interestingly, furin inactivates lipoprotein lipase, which is implicated in the hydrolysis of TG into fatty acids from TG-rich lipoproteins (Jin et al, 2005;Lei et al, 2011).…”

Meta-Analysis on the Association of C-Reactive Protein Polymorphisms with Metabolic Syndrome

“…1,2 It is associated with endothelial dysfunction, angiogenesis that might lead to increased risk for diabetes mellitus, insulin resistance, and cardiovascular diseases. 3 Ridker et al reported slight increase in moderate C-reactive protein (CRP) levels in relation to the number of MetS components in a follow-up study on healthy American women. 4 CRP consists of five 23 kDa subunits which has a crucial role in the human immune system.…”

“…2 Given that CRP is found to have an important role in MetS, the association between polymorphisms of inflammatory marker gene and MetS were studied. 3 Among various gene association studies, one of the most reported genes is CRP. The human CRP gene is on chromosome 1q21-1q23, approximately 1.9 KB, and has two exons, which are linked by a 280 base pair intron.…”