Association analysis of genetic variants with metabolic syndrome components in the Moroccan population

Abstract

This study aimed to analyze the association between UBE2E2, G6PC2, PROX1, DUSP9, ADCY5 and APOC3 polymorphisms and the risk of metabolic syndrome (MetS) in Moroccan patients. The study was applied on 316 unrelated individuals from Morocco, 177 MetS patients and 139 controls. The metabolic syndrome was diagnosed according to the International Diabetes Federation (IDF) criteria. All subjects were genotyped for the following polymorphisms: rs7612463 (UBE2E2), rs560887 (G6PC2), rs340874 (PROX1), rs5945326 (DUSP9), rs11708067 (ADCY5) and rs5128 (APOC3) using TaqMan allelic discrimination assay and PCR-RFLP. The rs5128 (APOC3) and rs340874 (PROX1) polymorphisms were found to be significantly associated with susceptibility to MetS (P = 0.003 and P = 0.033, respectively), with odds ratios (ORs) of 4.39 (95% CI = 1.66–11.56) and 2.81 (95% CI = 1.09–7.27), respectively. Two variants presented a tendency to be protector factors against MetS risk: rs5945326 in DUSP9 gene (OR = 0.32; 95% CI = 0.17–0.62;  = 0.001) and rs11708067 in ADCY5 gene (OR = 0.51; 95% CI = 0.28–0.95; P = 0.034). No association was detected between rs7612463 (UBE2E2) and rs560887 (G6PC2) SNPs and MetS increased risk. This study suggests a potential role of rs5128, rs340874, rs5945326 and rs11708067 variants in MetS susceptibility in the Moroccan population.

Introduction

The metabolic syndrome (MetS) is a major public-health problem, it is characterized by a collection of abnormalities ranging from: central obesity, elevated fasting blood glucose concentration and raised blood pressure, to increased triglycerides and reduced high-density lipoprotein (HDL) cholesterol [1].

Many organizations have suggested criteria for the diagnosis of MetS, such as World Health Organisation (WHO), National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII), European Group for the Study of Insulin Resistance (EGIR), American Association of Clinical Endocrinologists (AACE), American Heart Association/National Heart, Lung, and Blood Institut (AHA/NHLBI) and International Diabetes Federation (IDF) [1], [2], [3], [4]. MetS is a cluster of cardiovascular risk factors; it is highly associated with cardiovascular disease (CVD) and type 2 diabetes (T2D) [5], [6].

The prevalence of MetS is increasing worldwide, it varies between 21% and 38.5% [7], [8], [9]. Among Moroccan women in urban areas, the prevalence of MetS was 17.8% [10]. According to a recent study including 820 patients older than 19 years, the prevalence of MetS among the Moroccan population is 35.73% (18.56% among men and 40.12% among women) [11].

Recently, several genetic variants associated with MetS risk have been identified by genome-wide association studies (GWAS), by targeting multiple genes and loci [12], [13]. However, their involvement in MetS must be replicated in different populations. Among them, several loci, including APOC3, UBE2E2, G6PC2, PROX1, DUSP9 and ADCY5 have been shown to be associated with metabolic syndrome in different ethnic groups.

The APOC3 (apolipoprotein C3), is a 79-amino-acid protein synthesized by liver and intestine, is an important marker of TG-rich lipoproteins levels [14]. The overexpression of the APOC3 gene resulted in higher triglyceride levels [15]. The UBE2E2 gene encodes ubiquitin-conjugating enzyme E2E2, which plays an important role in secretion, keeping normal insulin biosynthesis and signalling in pancreatic beta cells [16], [17]. The G6PC2 (glucose-6-phosphatase catalytic unit 2) is expressed in the cells of pancreatic islets [18] and plays a role in glucoregulation [19]. The PROX1 gene encodes the prospero homeobox protein 1 (60-amino acids), is expressed in liver and strongly correlated with blood vessel development and adipogenesis [20]. The DUSP9 gene, encodes a member of dual-specificity phosphatase 9, with (MKP-4) synonym, mitogen-activated protein kinase phosphatase 4,which plays a central role in controlling insulin [21]. This gene is expressed in different tissues that are sensitive to insulin: liver, adipose and muscle. A study revealed that MKP-4 plays a key role in protecting versus the development of insulin resistance [22], it is associated also with type 2 diabetes (T2D), and cancer [23].

DUSP9 is very influential in polycystic ovary syndrome (PCOS). The location of the gene on the X chromosome and its role in the action of insulin make it an excellent candidate to explain the MetS, obesity and PCOS [24].

The ADCY5 gene, encodes adenylate cyclase 5, the rs11708067 variant within the ADCY5 gene has been shown to be associated with low birth weight, type 2 diabetes, gestational diabetes [25], [26], [27].

This study aimed to analyze the association between polymorphisms located in different genes (APOC3, UBE2E2, G6PC2, PROX1, DUSP9 and ADCY5) and risk of MetS in Moroccan patients.