Introduction

Type 2 diabetes mellitus (T2DM) is a complex metabolic disease mainly characterized by hyperglycemia arising from insulin resistance and/or insufficient insulin secretion [1]. Long-term chronic hyperglycemia can lead to multiple system damage and failure, such as heart, eyes, kidneys, nerves, and blood vessels [2]. Survey data show that the prevalence of T2DM has been rapidly rising worldwide and is projected to grow to 440 million by 2030 [3]. T2DM has become one of the serious public health problems. T2DM is the result of the interaction between genetic and environmental factors, a large number of studies have revealed that multiple single nucleotide polymorphisms (SNPs) are related to the development of T2DM [4, 5].

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that is mainly expressed in the liver, small intestinal epithelial cells, neural tissue, and kidney cells [6]. The function of PCSK9 is thought to increase the amount of low-density lipoprotein cholesterol (LDL-C) in the blood by degrading the low-density lipoprotein receptor (LDLR) that transports LDL-C [7]. In recent years, PCSK9 is one of the promising hot targets in the field of cardiovascular research [8], and the PCSK9 antibody has been used to treat some patients with familial hypercholesterolemia and statin tolerance [9,10,11,12]. Qiu et al. [13] found genetic polymorphisms of PCSK9 associated with cardiovascular disease. Several studies have demonstrated that polymorphisms of PCSK9 was associated with the plasma lipid levels in Chinese [14, 15].

Interestingly, it has been found that PCSK9 is also associated with the biological processes of glucose metabolism. Saavedra et al. [16] found that the incidence of diabetes and prediabetes was twice as high in familial hypercholesterolemia (FH) individuals carrying the PCSK9-InsLEU gene mutation as in non-carriers. Mohamed et al. demonstrated that PCSK9 relative expression levels and the E670G (rs505151) AG genotype are cardiovascular disease risk factors among Egyptian diabetics [17]. However, the relationship between PCSK9 genetic polymorphisms and T2DM remains unclear. Thus, the current case–control study was designed to explore the possible correlation of PCSK9 gene polymorphisms with T2DM among Uygur Chinese populations in **

Blood samples were collected from all participants, and genomic DNA was extracted from peripheral blood leukocytes using a whole blood genome extraction kit (Bei**g Bioteke Corporation, Bei**g, China). We obtained four tag SNPs of PCSK9 (rs11583680, rs2483205, rs2495477, and rs562556) according to Haploview 4.0 software and the International HapMap Project website (http://hapmap.ncbi.nlm.nih.gov/index.html.en) by using minor allele frequency (MAF) ≥ 0.05 and linkage disequilibrium patterns with r2 ≥ 0.8 as a cut-off. The four SNPs of the PCSK9 gene were genotyped by improved multiple ligase detection reaction (iMLDR) genoty** assays.

Laboratory examination

Peripheral venous blood samples (5 mL) were collected in EDTA-containing tubes from all participants following overnight fasting greater than 8 h for biochemical assays. Biochemical variables, including serum concentrations of creatinine (Cr), blood urea nitrogen (BUN), uric acid (UA), fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were measured by using standard methods in the Department of Clinical Laboratory at the First Affiliated Hospital of ** type 2 diabetes mellitus. JAMA. 2001;286(3):327–34." href="#ref-CR32" id="ref-link-section-d8423468e4462">32,33,34]. While PCSK9 can induce a variety of cells and tissues to secretes pro-inflammatory factors, it is therefore speculated that PCSK9 may be involved in the pathogenesis of T2DM by promoting an inflammatory response [35, 36]. Some studies are supporting those loss-of-function genetic variants of the PCSK9 gene are associated with increased risk of T2DM [37]. It may be because PCSK9 deficiency can lead to increased expression of LDLR in pancreatic β-cells which leads to accumulation of cholesteryl esters, inhibition of islet function and insulin secretion, and causes elevated blood glucose [38].

In the present study, we genotyped polymorphisms of four SNPs in the PCSK9 gene and found that rs2483205 and rs2495477 were associated with T2DM. Rs2495477 is located in the fifth intron of the PCSK9 gene and affects the splicing process of RNA, which may lead to reduced PCSK9 mRNA levels [39]. Rs2483205 is also located in the intronic region of the PCSK9 gene and regulates the promoter flanking regions. It has been shown that rs2483205 is associated with decreased LDL cholesterol concentrations [40]. The CC genotype and CC + TT genotype of rs2483205, the rs2495477 AA genotype were very common in the T2DM patients compared with the control subjects in the Uygur population in **njiang. After adjusting for confounders, the rs248320 CC, the rs2483205 CC + TT, and the rs2495477 AA were still independent risk factors for T2DM. We hypothesize that rs2483205 and rs2495477 polymorphisms may be involved in the development of diabetes by decreasing plasma PCSK9 levels, leading to impaired islet function.

There are some limitations to the study. Firstly, our study population was limited to the First Affiliated Hospital of **njiang Medical University and may have suffering some risk factors of T2DM. Secondly, as this was an observational study, we cannot definitively establish cause and effect. Thirdly, the present study lacked functional validation of studied SNPs, additional studies need to be conducted to demonstrate the molecular mechanism between PCSK9 gene polymorphisms and T2DM.

Conclusions

In conclusion, our study suggests that genetic polymorphisms in the PCSK9 gene are associated with T2DM in Uygur subjects in **njiang. Subjects with CC genotype or CC + TT genotype of rs2483205 as well as subjects with AA genotype of rs2495477 were associated with an increased risk of T2DM. However, the mechanisms that may link PCSK9 gene polymorphisms to T2DM remain unclear.

OR, odds ration; CI, confidence interval