Case Control Study Open Access
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2015; 6(2): 358-366
Published online Mar 15, 2015. doi: 10.4239/wjd.v6.i2.358
Association of gene variants with susceptibility to type 2 diabetes among Omanis
Sawsan Al-Sinani, Nicolas Woodhouse, Ali Al-Mamari, Omaima Al-Shafie, Mohammed Al-Shafaee, Said Al-Yahyaee, Mohammed Hassan, Deepali Jaju, Khamis Al-Hashmi, Mohammed Al-Abri, Khalid Al-Rassadi, Syed Rizvi, Riad Bayoumi, Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat 123, Sultanate of Oman
Yengo Loic, Philippe Froguel, Genomics and Metabolic Disease, CNRS UMR8199, 59045 Lille Cedex, France
Yengo Loic, Philippe Froguel, Institute Pasteur of Lille, Lille2 University, 59000 Lille, France
Author contributions: Al-Sinani S and Bayoumi R performed the majority of design and experiments; Al-Sinani S, Woodhouse N, Al-Mamari A, Al-Shafie O and Al-Shafaee M helped in patients selection and samples collection; Al-Sinani S, Woodhouse N, Al-Mamari A, Al-Shafie O, Al-Shafaee M, Al-Yahyaee S, Hassan M, Jaju D, Al-Hashmi K, Al-Abri M, Al-Rassadi K and Bayoumi R designed the study and helped in writing the manuscript; Al-Sinani S, Rizvi S, Loic Y and Froguel P helped in statistical analysis.
Supported by The Research Council (TRC), Muscat, Oman, No. RC/MED/BIOC/10/01.
Ethics approval: The study was approved by the Ethics and Research Committee of the College of Medicine, Sultan Qaboos University, Muscat, Oman.
Informed consent: All involved persons gave their informed consent written prior to study inclusion.
Conflict-of-interest: The authors declare that they have no conflicts of interest concerning this article.
Data sharing: No.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sawsan Al-Sinani, PhD Biochemistry, Department of Biochemistry, College of Medicine and Health Sciences, Sultan Qaboos University, PO Box-35, Muscat 123, Sultanate of Oman. sawsan.alsinani@gmail.com
Telephone: +968-24-141113 Fax: +968-24-141114
Received: June 19, 2014
Peer-review started: June 20, 2014
First decision: July 18, 2014
Revised: November 20, 2014
Accepted: February 4, 2015
Article in press: February 9, 2015
Published online: March 15, 2015

Abstract

AIM: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omanis.

METHODS: Using case-control design, a total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped, by an allelic discrimination assay-by-design TaqMan method on fast real time polymerase chain reaction system, for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus. Inspite of the small number of normoglycemic controls in this study, this sample was sufficient for detection of genes and loci for common alleles influencing T2D with an odds ratio of ≥ 1.3 reaching at least 80% power. Data was collected from June 2010 to February 2012.

RESULTS: Using binary logistic regression analysis, four gene variants showed significant association with T2D risk: KCNJ11 (rs5219, P = 5.8 × 10-6, OR = 1.74), TCF7L2 (rs7903146, P = 0.001, OR = 1.46), CDKAL1 (rs10946398, P = 0.002, OR = 1.44) and CDKN2A/B (rs10811661, P = 0.020, OR = 1.40). The fixation index analysis of these four gene variants indicated significant genetic differentiation between diabetics and controls {[KCNJ11 (rs5219), P < 0.001], [TCF7L2 (rs7903146), P < 0.001], [CDKAL1 (rs10946398), P < 0.05], [CDKN2A/B (rs10811661), P < 0.05]}. The highest genotype variation % between diabetics and controls was found at KCNJ11 (2.07%) and TCF7L2 (1.62%). This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk. However, T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the Waist-to-Hip ratio (n = 532, P = 1.9 ×10-7, OR = 2.4), [among males (n = 234, P = 1.2 × 10-4, OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)].

CONCLUSION: Results confirmed the association of KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661) gene variants with susceptibility to T2D among Omani Arabs.

Key Words: Type 2 diabetes, Genetics, Oman, Case-control, Association, Gene, Variants

Core tip: To investigate the association of 10 known common gene variants with susceptibility to type 2 diabetes mellitus (T2D) among Omani Arabs using case-control design. A total of 992 diabetic patients and 294 normoglycemic Omani Arabs were genotyped for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634) CAPN10 (rs3792267) and HHEX (rs1111875). Four gene variants showed significant association with T2D risk: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661). The highest genotype variation % between diabetics and controls was found at KCNJ11 and TCF7L2 gene variants.
INTRODUCTION

Type 2 diabetes mellitus (T2D) is one of the most common non-communicable diseases globally. Insufficient compensatory insulin secretion due to insulin resistance causes T2D. Insulin resistance is, mostly, an early event due to environmental factors, such as obesity. Decline in β-cell function is gradual but generally a late event[1]. In addition to the environmental factors, there is strong evidence that genetic factors play an important role in the pathogenesis of T2D[2].

Candidate gene approach identified few T2D susceptibility gene variants: Pro12Ala (rs1801282) in the coding region of peroxisome proliferator-activated receptor γ gene and it is the more common proline allele that is associated with T2D[3]; E23K (rs5219) in the coding region of the subunit kir6.2 of the ATP-sensitive potassium channel gene of β-cells (KCNJ11)[4] and a series of polymorphisms and haplotypes (UCSNP-43 or rs3792267; UCSNP-19 or rs3842570 and UCSNP-63 or rs5030952) in the coding region of the cysteine protease calpain 10 (CAPN10)[5].

Genome-wide association studies (GWAS) of T2D susceptibility genes and loci and their meta-analysis identified a large number of gene variants and confirmed the previously discovered ones[6]. The common intronic variants within the transcription factor 7-like 2 (TCF7L2) gene was reported as the strongest genetic risk factor for T2D[7]. Other loci most consistently associated with T2D risk include variants within or near the solute carrier family 30/zinc transporter (SLC30A8), hematopoietically expressed homeobox (HHEX), cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1), insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), a genomic region between cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) and fat mass and obesity associated protein (FTO)[6,8].

In total, approximately, forty four common T2D susceptibility gene variants and loci have been identified to-date, but all these variants could only explain approximately 10%-15% of the heritability of T2D; which suggests that more variants remain to be discovered[9]. Rare large-effect mutations have recently been recognized as causes of many complex diseases[10-12].

According to the international diabetes federation, six out of the world’s top ten countries with the highest prevalence (%) of T2D among adults aged 20-79 years, in 2011, are in the Middle East and North Africa region; Kuwait (21.1%), Lebanon (20.2%), Qatar (20.2%), Saudi Arabia (20.0%), Bahrain (19.9%) and United Arab Emirates (19.2%). Small studies were conducted among Arabs, with a limited number of participants, to investigate genetic susceptibility for T2D[7,13-24].

The prevalence of diabetes in Oman, in 2011, was estimated to be 10.8%; with a further 9.7% of the population at high risk of diabetes with impaired glucose tolerance, (http://www.idf.org/diabetesatlas/content/what-is-diabetes). Oman has a high inbred population and consanguineous marriages are about half of all marriages[25]. Therefore, genetic factors might play an important role in the pathogenesis of T2D among Omanis.

In the present study, 10 known common gene variants, described previously, were examined for their association with susceptibility to T2D among Omani Arabs using case-control study design. Selection of variants was predominantly based on earlier GWAS studies, which extensively investigated T2D and showed a significant association of those variants with the highest odds ratios (ORs) among all the genes/loci discovered[4-8,26].

MATERIALS AND METHODS
Sample size

For determining the sample size, we employed the Power Calculator for Genetic Studies developed by Skol et al[27] (2006) in their Website http://www.sph.umich.edu/csg/abecasis/CaTS/index.html. We used a T2D prevalence of 10% in the adult population of the Region as reported previously[28,29]. We also anticipated disease allele frequencies of ≥ 0.25, and assumed a multiplicative disease model[30]. An optimum one-stage sample was deduced from the Power Calculator: 1000 cases and 1000 controls, will guarantee detection of genes and loci for common alleles influencing T2D with an OR of ≥ 1.2 reaching at least 80% power. However, we could not collect the required sample size, and only 992 cases and 294 controls were collected. This sample will guarantee detection of genes and loci for common alleles influencing T2D with an OR of ≥ 1.3 reaching at least 80% power.

Study population

A total of 992 T2D Omani Arab patients and 294 normoglycemic Omani Arab controls were included in this study. T2D patients were recruited from the Diabetes Clinic (n = 243) and inpatients (n = 749) at Sultan Qaboos Univesity Hospital (SQUH), Muscat, Oman. A history of T2D among patients was ascertained from the diagnosis and medical history deposited in the electronic records of the hospital information system. Exclusion criteria for T2D patients included: patients diagnosed with type 1 diabetes; maturity onset diabetes of the young; positive diabetic antibodies (islet cell antibodies and glutamic acid decarboxylase antibodies) or patients diagnosed with any type of cancer. Adult control participants (n = 294) were volunteers from the community and from those visiting Family Medicine Clinic at SQU, for regular medical checkup. The inclusion criteria for controls were: Omani, age ≥ 35 years, no family history of diabetes (first degree relatives) and with fasting glucose value of < 6.1 mmol/L, according to the World Health Organization 2006 criteria. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study. Almost all volunteers questioned had a relative with diabetes mellitus (DM). Data was collected from June 2010 to February 2012. Participants were informed about the project and written consents were obtained. The study was approved by the Ethics and Research Committee of the College of Medicine, Sultan Qaboos University, Muscat, Oman.

Anthropometric and biochemical parameters

T2D patients and normoglycemic control participants underwent demographic, anthropometric and biochemical investigations, summarized in Table 1. Anthropometric variables measured were: weight, height, waist and hip circumference. Obesity status was defined according to the international classification of an adult’s weight (http://apps.who.int/bmi/index.jsp?introPage=intro_3.html), [normal body mass index (BMI): 18.5-24.99 kg/m2, overweight: 25.00-29.99 kg/m2 and obese ≥ 30.00 kg/m2]. The biochemical investigations included: fasting glucose level and HbA1C. To compare T2D patients and normoglycemic control participants’ obesity status, we selected 294 T2D patients; age and sex matched with the normoglycemic control participants (n = 294). Waist-to-Hip ratio (WHR) was also calculated among T2D patients and control participants. Health risk based solely on the WHR, was identified according to the ranges specified at waist-to-hip ratio chart (http://www.bmi-calculator.net/waist-to-hip-ratio-calculator/waist-to-hip-ratio-chart.php) for males (low risk = 0.95 or below, moderate risk = 0.96-1.0, high risk= over 1.0) and females (low risk = 0.80 or below, moderate risk = 0.81-0.85, high risk = over 0.85).

Table 1 Anthropometric and biochemical characteristics of Omani type 2 diabetes mellitus patients and controls.
T2D patients
Controls
Mean ± SD or median (range)1
Mean ± SD or median (range)1
MalesFemalesTotalMalesFemalesTotal
Total number (n)473519992121173294
Age (yr)56 ± 1156 ± 1056 ± 1141 (35-80)144 (32-79)143 (32-80)1
Weight (kg)78.8 ± 15.4NS75.1 ± 17.076.8 ± 16.476.8 ± 14.270.3 ± 1373.7 ± 14.7
Height (cm)165 ± 9a152 ± 9157 (106-182)1NS167 ± 8154 ± 6159 ± 9
BMI (kg/m2)29.1 ± 4.8b32.8 ± 10.330 (15-58)127.6 ± 4.329.5 ± 5.229.3 ± 5.8
Waist circumference (cm)100 ± 12100 ± 13100 ± 1395 ± 1391 ± 1192 ± 12
Fasting blood glucose (mmol/L)8.7 (3-24)19.0 (3-25)18.8 (3-25)15.1 ± 0.314.9 ± 0.365.1 ± 0.41
HbA1C (%)8.3 ± 1.88.3 (4.9-15.5)18.2 (4.1-18.6)15.7 ± 0.465.7 (4.0-7.9)15.7 ± 0.44
Obesity status (%)
Underweight-0.50.32.111.4
Normal weight16.812.514.522.218.219.1
Overweight4530.236.143.834.538.9
Obese38.256.849.129.945.839.6
Missing---2.10.51
1Median (range = minimum-maximum) displayed in the table when the variable does not follow a normal distribution pattern. In all parameters, P < 0.001 between diabetics and controls, except: NS;
aP < 0.05 between diabetics and controls;
bP < 0.01 between diabetics and controls. NS: No significant difference between diabetics and controls; T2D: Type 2 diabetes mellitus; BMI: Body mass index.
Genotyping

All participants (n = 1286) were genotyped for the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398), CDKN2A/B (rs10811661), FTO (rs9939609 and rs8050136), IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Genotyping was done by an allelic discrimination assay-by-design TaqMan method on 7500HT fast real time polymerase chain reaction system (Applied Biosystems, United States). Accuracy was achieved by duplicating approximately 10% of the samples.

Statistical analysis

The SPSS statistical package software (v20.0) was used for statistical analysis of measured parameters. The measured anthropometric and biochemical parameters were tested for normal distribution using one sample Kolmogorov-Smirnov test. Independent sample t-test was used to test the significance of the difference in the mean values for the measured anthropometric and biochemical parameters between T2D patients and control participants with a normal distribution, while the Mann-Whitney U test was used for variables with skewed distribution.

The frequencies of the risk allele for each gene variant were calculated for T2D patients and normoglycemic control participants. The proportions of the genotypes of the gene variants were tested for departures from Hardy-Weinberg equilibrium (HWE) for both groups using population genetics software GenAlEx 6.3 (Genetic analysis in Excel, version 6.3)[31]. However, in case-control studies, HWE should be applied only to controls because a deviation from HWE in cases may indicate a genetic association[32,33].

Genotyping data were further analyzed using GenAlEx 6.3[31] and Arlequin 3.1 software[34]. For each polymorphism, GenAlEx was used to calculate fixation index (F), heterozygosity (He) and Fst, which provides a measure of genetic differentiation among subpopulations (T2D patients and control populations). Arlequin was used to calculate genotype’s % variation among the subpopulations and its level of significance.

Binary logistic regression analysis on the SPSS statistical package was used to test the association between each gene variant and susceptibility to T2D, adjusted for age, sex and BMI. Bonferroni correction was applied for multiple testing and adjusted P values were calculated to be 0.005. Beta coefficients, ORs and 95%CI were also estimated. An OR is a measure of association between an exposure and an outcome. It is measured as an exponential function of the regression beta coefficient value (ebeta coefficient).

The association between obesity status of participants and FTO gene variants (rs9939609 and rs8050136) was also tested. In addition, obesity and health risk status, based on the WHR, were tested for their association with T2D risk.

RESULTS

Anthropometric and biochemical characteristics of all participants are summarized in Table 1. About 48% of the T2D patients and 41% of the control participants were males. The mean age of T2D patients (56 years) was higher than that of the normoglycemic control participants (45 years). T2D patients had significantly higher weight, BMI, waist circumference, fasting glucose values and HbA1C % levels compared with control subjects (Table 1). Eighty five percent of the T2D Omani patients were overweight to obese in comparison to 78.5% of the control Omani participants. Half of the T2D patients and 39.6% of the control participants were obese. T2D risk was found to be significantly associated with obesity (P = 0.002, OR = 2.22); and with the WHR (n = 532, P = 1.9 × 10-7, OR = 2.4), [among males (n = 234, P = 1.2×10-4, OR = 2.0) and females (n = 298, P = 0.001, OR = 6.3)].

Among control participants, there were no significant deviation in the proportions of gene variant frequencies from HWE except in SLC30A8 (rs13266634) (P = 2.35×10-4, χ2 = 13.5) gene variant. However, among T2D patients, there were significant deviations in: KCNJ11 (rs5219) (P = 4.14 × 10-9, χ2 = 34.6), CDKAL1 (rs10946398) (P = 0.008, χ2 = 6.9) and IGF2BP2 (rs4402960) (P = 0.038, χ2 = 4.3) gene variants.

The risk allele frequencies of the tested variants for diabetic and control participants are summarized in Table 2. Using binary logistic regression analysis, four gene variants out of 10 showed statistically significant association (P < 0.05) with susceptibility to T2D: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661), Table 2. After correction for multiple testing, KCNJ11, TCF7L2 and CDKAL1 gene variants still showed a significant association (P < 0.005) with T2D.

Table 2 Risk allele frequencies for the tested gene variants among Omani type 2 diabetes mellitus patients and control participants.
GeneGene variantRisk/non-Risk allele frequency (f)
1P valueOR95%CI
(SNPs)risk alleleT2D patients (n = 992)Controls (n = 294)for OR
KCNJ11rs5219T/C0.3200.22225.8 × 10-61.741.37-2.22
TCF7L2rs7903146T/C0.4450.35420.0011.461.16-1.83
CDKAL1rs10946398C/A0.3640.31120.0021.441.15-1.80
CDKN2A/Brs10811661T/C0.8360.7990.0201.401.06-1.84
FTOrs9939609A/T0.4800.4350.3581.110.899-1.37
FTOrs8050136A/C0.4580.4250.7701.030.829-1.29
IGF2BP2rs4402960T/G0.4000.3570.2861.130.904-1.41
SLC30A8rs13266634C/T0.8570.8550.3291.160.859-1.57
CAPN10rs3792267 (-43)G/A0.8020.7900.4451.110.850-1.45
HHEXrs1111875T/C0.3010.2800.6361.060.839-1.33
1P value: Level of significance;
2P value remained significant after correction for multiple testing (< 0.005). The P value, OR and 95%CI were calculated for the association between each gene variant with T2D risk. f: Frequency; T2D: Type 2 diabetes mellitus; SNPs: Single nucleotide polymorphisms.

Fst values, showed statistically significant genetic differentiation between T2D patients and controls (Table 3), in the following gene variants: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661). These findings confirmed the results obtained using binary logistic regression analysis.

Table 3 Fixation index, heterozygosity, Fst and % variation among Omani type 2 diabetes mellitus patients and control participants.
GeneGene variantsT2D patients
Controls
Fst% variation among T2D and controls1P value
FHeFHe
KCNJ11rs52190.1900.3520.0910.3140.0122.070.000
TCF7L2rs79031460.0170.4860.0000.4760.0091.620.000
CDKAL1rs109463980.0840.4240.0560.4050.0030.480.020
CDKN2A/Brs108116610.0000.2750.0030.3200.0020.370.042
FTOrs99396090.0000.5020.0000.4970.0020.310.050
FTOrs80501360.0060.4930.0000.5030.0010.120.147
IGF2BP2rs44029600.0660.4480.0000.4760.0020.230.089
SLC30A8rs132666340.0610.2300.1880.2010.0000.001.000
CAPN10rs37922670.0570.3000.0000.3350.0000.000.517
HHEXrs11118750.0550.3980.0520.3820.0010.000.341
This provides a measure of genetic differentiation among population; 1P value: Level of significance; F: Fixation index; He: Heterozygosity; Fst: The inbreeding coefficient within subpopulation, relative to total; T2D: Type 2 diabetes mellitus.

This study was not able to detect an association of T2D risk with gene variants of IGF2BP2 (rs4402960), SLC30A8 (rs13266634), CAPN10 (rs3792267) and HHEX (rs1111875). Moreover, no association was found between FTO gene variants (rs9939609 and rs8050136) and T2D risk.

DISCUSSION

In this study, four gene variants showed significant association with T2D risk using binary logistic regression analysis after adjustment for confounding factors of age, sex and BMI: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661). The association of KCNJ11 (rs5219), TCF7L2 (rs7903146) and CDKAL1 (rs10946398) gene variants with T2D risk remained significant after correction for multiple testing. Fst, a measure of genetic differentiation among subpopulations (diabetics and controls), confirmed the significant risk difference between diabetics and controls at the four gene loci [KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661)]. The highest genetic variation between diabetics and controls was found in KCNJ11 and TCF7L2 gene variants (Table 3). However, none of the other gene variants previously reported in GWAS were found to be associated with risk to T2D in Omanis.

KCNJ11 (rs5219) gene variant was found to be associated with T2D risk among Omani Arabs with an OR of 1.74, which is higher than that reported in previous European studies. Our findings were consistent with what was reported among Saudi Arabs (OR = 1.7), although the risk allele frequency was found to be lower among Saudis compared to Omani Arabs[16]. However, in both Arab studies the association may be overestimated due to the small number of participants included or due to a high-inbred population. In contrast, no association of this gene variant with susceptibility to T2D was found among Tunisian Arabs[14]. Large scale studies and meta-analysis of the KCNJ11 gene variants have shown that the lysine variant of the rs5219 gene loci resulting in a 1.15 times higher risk of developing T2D[4,35] and GWAS studies confirmed this association[26,36,37]. The rs5219 variant is located within the N-terminal of the subunit kir6.2 of the ATP-sensitive potassium channel gene of β-cells and can cause spontaneous hyperactivity of pancreatic beta-cells and reduced sensitivity of KATP channels to ATP, resulting in impaired insulin secretion[38].

Although this study is relatively small, the association of TCF7L2 (rs7903146) gene variant with T2D risk among Omani Arabs is consistent with previous large GWAS studies[14,15,22,36,37,39-44]. The association of TCF7L2 gene variants with susceptibility to T2D was marginal between the rs12255372 gene variant and T2D risk among Emirati Arabs; but not in Saudi Arabs[13,17]. In contrast, subsequent studies among North African Arabs (Tunisians and Moroccans), Palestinians and Iranians, confirmed the association of TCF7L2 (rs7903146) gene variant with susceptibility to T2D[7,14,15,22]. Comprehensive genotyping studies across the TCF7L2 gene showed that the rs7903146 variant to be consistently associated with T2D among European with an OR of 1.37 (1.28 to 1.47)[45,46]. Meta-analysis of 27 different studies found a global OR of 1.46 (95%CI: 1.42-1.51)[7]. The common variants in the TCF7L2 gene predispose to T2D by reducing beta-cell function and insulin secretion. TCF7L2 mRNA levels in human pancreatic islets increase with the number of risk alleles and are fivefold higher in T2D patients than in controls pancreatic islets, and over-expression of TCF7L2 leads to reduced glucose stimulated insulin secretion[47].

CDKAL1 (rs10946398) gene variant’s OR was found to be 1.44 among Omani Arabs, which may be overestimated due to the small number of participants. Variants at CDKAL1 gene loci showed an association with T2D risk among Caucasians[26,36,37], Asians[48,49], African Americans[50] and Arabs[22,24]. A recent meta-analysis of CDKAL1 (rs10946398) gene variant showed a significant association of this variant with susceptibility to T2D risk (OR = 1.12)[51]. Another study among Russian population showed a significant association of the C allele with higher risk of T2D[52]. The CDKAL1 gene encodes cyclin-dependent kinase 5 (CDK5) regulatory subunit-associated protein 1-like 1. The CDK5 is a serine/threonine enzyme that inhibits both Ca2+ efflux into the beta-cell and insulin secretion, while inhibition of this enzyme results in enhanced insulin secretion[53].

The association of CDKN2A/B (rs10811661) gene variant with susceptibility to T2D risk among Omanis was also confirmed in this study (OR = 1.40), in agreement with a recent large study among North African Arabs[22]. In contrast, this gene variant was not found to be associated with T2D risk in other Arab studies[24,54]. Previous studies among European populations have shown an association with an OR of 1.20[26,36,37]. A recent meta-analysis concluded that the T allele of rs10811661 is a risk factor of T2D both in Asians and Europeans[55]. CDKN2A and CDKN2B genes encode p16INK4a and p15INK4b, which inhibit CDK4 and CDK5, respectively. CDK4 and CDK5 play an important role in β cell function and regeneration[55].

FTO gene variants (rs9939609 and rs8050136) have been shown to associate with BMI and obesity[8,56] and GWAS studies of T2D have also suggested the involvement of FTO gene in T2D pathogenesis through obesity[8,26]. It is surprising, therefore, that we could not detect an association of T2D risk with FTO gene variants (rs9939609 and rs8050136). This could be attributed to the fact that both diabetics and controls have similar distributions of body weight. The impact of the FTO gene variants on T2D risk through obesity, seen in other populations, was not observed here. Hennig et al[57] tested the effect of FTO variants on measures of BMI in a population of lean Gambians (Africans) and also found no association. However, this study showed a significant association between obesity and T2D risk; and between health risk, based on the WHR, and T2D risk among males and females.

In spite of the small number of participants examined in this case-control study, we were able to confirm the effect of four common gene variants on T2D risk among Omani Arabs. Oman has a homogeneous population due to a high level of inbreeding and the tradition of consanguineous marriages. The difficulty in recruiting Omani participants with no family history of diabetes was the main reason behind the small number of control participants in this study, where, almost everybody has a relative with DM. This might have raised risk allele frequencies of T2D gene variants and made it easier to detect.

All previous GWAS identified common gene variants, which could only explain 10%-15% of the heritability of T2D. Large studies with new strategies, other than the classic case-control study design, are required to find the hidden heritability due to rare variants behind developing T2D among Omani and other Arab populations.

Limitation of this study was the lack of oral glucose tolerance test, where we could not run the test among the control group. However, the strength of this study was that the control participants were with no family history of diabetes.

This study confirmed the effect of four common gene variants on T2D risk among Omani Arabs: KCNJ11 (rs5219), TCF7L2 (rs7903146), CDKAL1 (rs10946398) and CDKN2A/B (rs10811661). However, we could not detect the association of other known common gene variants with susceptibility to T2D.

ACKNOWLEDGMENTS

We are grateful to the Deanship of postgraduate studies at Sultan Qaboos University, Muscat, Oman for the PhD grant to SS. We thank Nassra Al Maani and Ranjitha K Sukumaran for their contribution to collection of patients data. Special thanks to Hameeda Al Barwany, Najma Al Kharousi, Zainab Al Hashami, Laila Al Hinai and Sameera Al Harrasy for their help in analyzing samples. We also thank George Khaukha, Mohammed Al Kindi, Mohammed Al Tobi, AbdulRahim Al Abri and Taruna Dutt for their support. We are grateful to the staff of the diabetes clinic at SQUH and FAMCO clinic at SQU for their help and support. We also are obliged to the office of educational supervision/Al Seeb, Directorate General of Education in Muscat, for their support and help in controls collection. We are indebted to all subjects who participated in this study.

COMMENTS
Background

Type 2 diabetes mellitus (T2D) is one of the most common non-communicable diseases globally. Insufficient compensatory insulin secretion due to insulin resistance causes T2D. In addition to the environmental factors, there is strong evidence that genetic factors play an important role in the pathogenesis of T2D.

Research frontiers

Oman has a high inbred population and consanguineous marriages are about half of all marriages. Therefore, genetic factors might play an important role in the pathogenesis of T2D among Omanis.

Innovations and breakthroughs

In the present study, 10 known common gene variants were examined for their association with susceptibility to T2D among Omani Arabs using case-control study design. Selection of variants was predominantly based on earlier Genome-wide association studies, which extensively investigated T2D and showed a significant association of those variants with the highest odds ratios among all the genes/loci discovered.

Applications

Large studies with new strategies, other than the classic case-control study design, are required to find the hidden heritability due to rare variants behind developing T2D among Omani and other Arab populations.

Terminology

T2D is one of the most common non-communicable diseases globally, and it is a result of insufficient compensatory insulin secretion due to insulin resistance. Candidate gene approach focuses on associations between genetic variation within pre-specified genes of interest and phenotypes or disease states. Genome-wide association studies scan the entire genome for common genetic variation.

Peer-review

This is a well-written and interesting paper evaluating the association between a variety of gene polymorphisms and the risk for type 2 diabetes mellitus.

Footnotes

P- Reviewer: Tziomalos K, Velasco I S- Editor: Song XX L- Editor: A E- Editor: Liu SQ

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