Background
Metabolic Syndrome (MetS) is a complex disorder that is characterized by obesity, hyperglycemia, dyslipidemia, hypertension and insulin resistance [
1]. It can increase the risk of type 2 diabetes and cardiovascular disease (CVD) [
2]. In recent years, the prevalence of MetS is high (26.8% in females) in urban areas of China, and sex heterogeneity has been found in the relationships between risk factors and MetS [
3]. Much research of Genome-Wide Association Studies (GWAS) and candidate gene studies have been conducted in Indian [
4], Finnish [
5], Chinese [
6‐
9], Taiwanese and Caucasian youth [
10]. However, these mechanisms were not consistent among the previous studies, and most of the studies were based on cross-sectional studies. Thus, this study aimed to investigate whether the selected SNPs would be associated with MetS in Chinese women based on a cohort study.
KCNQ1 is a gene that provides instructions for making potassium channels. The gene is expressed in a wild variety of tissues such as cardiac muscle, inner ear, kidney, lung, stomach, and intestine. Cardiac long QT syndrome and congenital deafness are associated with
KCNQ1 gene. However,
KCNQ1 is also expressed in pancreas, and it could influence the insulin secretion [
11]. SNPs in
KCNQ1 are significantly associated with lower HOMA-B values [
12]. Most studies indicated that the
KCNQ1 gene was a diabetes susceptibility gene in different ancestors [
13,
14]. Rs231359, rs2237895, rs2237897, rs2237892, and rs231361 polymorphisms were confirmed among Chinese [
12,
15,
16]. Type 2 diabetes was the major consequence of MetS [
17], and MetS might be an important risk factor for type 2 diabetes [
18]. Meanwhile, insulin resistance is a central feature of MetS and the function of the polymorphisms in
KCNQ1 gene for MetS has not been investigated. Previous research had confirmed that both genetic and environmental factors contribute to the pathogenesis of MetS [
1,
19]. Some studies only involved few factors such as smoking or drinking.
In this study, we established a cohort study with 1381 females based on the routine health check-up systems in the urban Han Chinese. We aimed to investigate the association among the selected SNPs in the KCNQ1 gene with MetS in Chinese women after adjusting for potential confounding variables, as well as to provide a genetic basis to establish a prediction model of MetS for the personalized health management for women. Meanwhile, we also explored the relationship between SNP and MetS components.
Discussion
In this study, we discovered a novel association between KCNQ1-rs163182 and MetS, which suggests that rs163182 is an independent predictor for MetS. Meanwhile, rs163182 was also associated with MetS components (BMI and SBP) in Han Chinese women of northern urban area. Rs163182 may play a role in the biological metabolism.
In the current study, the etiology of MetS refers to environmental confounding factors, genetic susceptibility, as well as their interactions [
27,
28]. Identifying genes had the following functions: dramatically improve understanding of the mechanisms of MetS [
29], identify people at high risk, and prevent the development of diabetes and CVD. The relationships among SNPs, environmental factors and MetS had received considerable attention. In our study, we reviewed a large amount of literature about SNPs for MetS and its components (obesity, hyperglycemia, dyslipidemia, hypertension and insulin resistance). According to the preliminary study, rs163182, which carried C-allele in the
KCNQ1 gene, was more likely to develop MetS. In addition, it remained statistically significant after adjusting for potential risk factors. That indicates rs163182 in the
KCNQ1 gene is a novel independent predictor for MetS.
It has been confirmed that the
KCNQ1 gene was associated with diabetes in population of both Asian and European descent [
13,
14,
30]. Meanwhile, there were few studies about rs163182 [
15,
31]. In a genome-wide association study for type 2 diabetes in Han Chinese [
15], it validated the association between rs163182 and diabetes (
OR = 1.28), which was conducted in southern China. However, there was a heterogeneity compared with our study. In our study, the
KCNQ1 rs2237892, rs231361, rs2237895, rs231359, rs2237897, rs163182 and many environmental factors were surveyed. Although we did not find positive results of FPG, we discovered a novel association between rs163182 and MetS. In the study by Chen et al. [
32], the
KCNQ1 gene was associated with lipid parameters, TG, HDL-C, and apo A1 in a middle-aged Chinese Han population. A possibility has been mentioned that
KCNQ1 may be a molecule affecting insulin sensitivity [
33,
34]. The gene of
KCNQ1 not only plays an important role in blood glucose metabolism but also regulates other metabolic substances. The result that rs163182-C would increase the risk of MetS’ occurrence was understood. On the other hand, referring to the causal inference [
35], MetS was a risk factor for diabetes and the
KCNQ1 gene was associated with diabetes. Thus, the
KCNQ1 gene may influence the occurrence of MetS.
We also investigated the role of environmental variables to MetS. Widow or divorce, more housework, peri-menopause or menopause, multiple pregnancies (including birth and abortion), and reproductive system disease would increase the risk of MetS (
RR > 1.0), while highly-educated people, normal diet (means the taste preference is reasonable), and more fruit or meat would reduce the onset of MetS. That suggested the lifestyle or the information of fertility may influence the MetS, which was consistent with previous studies [
36,
37]. We also explored the interactions between rs163182 and these factors, of which the results were negative. That indicates the interactions between rs163182 and environmental factors to MetS are a minor effect.
Aiming to evaluate the prediction effect of rs163182, we calculated AUC with and without rs163182. The result reveals the KCNQ1 gene may provide a new method for modeling a risk prediction for MetS, which can use rs163182 to achieve the personalized health management in Han Chinese women of northern urban area.
The association between rs163182 and MetS components was also researched. The statistical significance was found among BMI and SBP in rs163182 genotype. The study of Sinha et al. [
38] used
KCNQ1 to exhibit both differential methylation and differential gene expression by comparing adipocytes between obese and never-obese women. The
KCNQ1 plays roles in cardiac tissue. Mutations in this gene may impair the function of heart. However, the specific mechanisms need to be further validated.
Considering the survival data in this study, Cox proportional model was applied. To our knowledge, few investigations were conducted by cohort study using Cox proportional model [
39] adjusting for other potential variables.
The study also has several limitations. Firstly, the participants comprised only women who came to the Center for Health Management of Shandong Provincial Qianfoshan Hospital, and might not represent the general population. In some way, it could restrict female to avoid gender confounding. Secondly, the time of follow-up in this study was not long enough, that result in the limited number of cases. So this study will be followed up continuously in the future. Thirdly, because of the large population in the Center for Health Management, the subjects were selected simply and randomly based on the database that may be a limitation in some way. In the follow-up study, a more sophisticated strategy could be employed to verify the result, such as a nest case-control study.