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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 1  |  Page : 19-25

The covariant CDKN2A/B rs10811661 (C/T) gene polymorphism is associated with increased risk of type 2 diabetes mellitus in a Saudi Arabian population


1 Department of Clinical Chemistry, Faculty of Medicine, King Abdul Aziz University, Jeddah, Kingdom of Saudi Arabia
2 Department of Clinical Chemistry, Faculty of Medicine, University of Jeddah, Jeddah, Kingdom of Saudi Arabia; Department of Biochemistry, Beni Suef University, Beni Suef, Egypt
3 Department of Internal Medicine, Cardiology Unit, Faculty of Medicine, King Abdul Aziz University, Jeddah, Kingdom of Saudi Arabia
4 Department of Internal Medicine, Endocrinology Unit, Faculty of Medicine, King Abdul Aziz University, Jeddah, Kingdom of Saudi Arabia

Date of Submission31-Oct-2017
Date of Acceptance22-Dec-2017
Date of Web Publication26-Mar-2018

Correspondence Address:
Ahmed A Elmgeed Ahmed
Department of Clinical Chemistry, Faculty of Medicine, University of Jeddah, Postal code 21577, Jeddah, Kingdom of Saudi Arabia

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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/MXE.MXE_5_17

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  Abstract 

Background
Genome-wide association studies have linked several single nucleotide polymorphisms with type 2 diabetes mellitus (T2DM). The present case–control study explored the probable association between the rs10811661 CDKN2A/B gene polymorphism and the risk of T2DM in a Saudi Arabian population.
Patients and methods
The study included 526 T2DM patients and 567 healthy control participants. The CDKN2A/B (rs10811661) polymorphism was genotyped using the TaqMan allelic discrimination method.
Results
The results identified single nucleotide polymorphism rs10811661 of CDKN2A/B as a risk factor for T2DM (odds ratio = 1.9; 95% confidence interval: 1.57–2.30; P= 0.0001). Levels of fasting plasma glucose and 2-h postprandial plasma glucose were significantly higher in patients with normal glucose tolerance but carrying the rs10811661 (C/T) risk allele compared with noncarriers.
Conclusion
A significant association was observed between CDKN2A/B rs10811661 (C/T) and susceptibility to T2DM in the Saudi Arabian population. Furthermore, the T allele is associated with an increased risk in patients with T2DM. The findings show that T2DM may interact with CDKN2A/B rs10811661 (C/T), which increases the risk of T2DM.

Keywords: CDKN2A/B, Saudi population, single nucleotide polymorphism, type 2 diabetes mellitus


How to cite this article:
Ajabnoor MA, Elmgeed Ahmed AA, Hadi Al-Ama MN, Alshali KZ, Ajabnoor GM. The covariant CDKN2A/B rs10811661 (C/T) gene polymorphism is associated with increased risk of type 2 diabetes mellitus in a Saudi Arabian population. Middle East J Med Genet 2018;7:19-25

How to cite this URL:
Ajabnoor MA, Elmgeed Ahmed AA, Hadi Al-Ama MN, Alshali KZ, Ajabnoor GM. The covariant CDKN2A/B rs10811661 (C/T) gene polymorphism is associated with increased risk of type 2 diabetes mellitus in a Saudi Arabian population. Middle East J Med Genet [serial online] 2018 [cited 2024 Mar 29];7:19-25. Available from: http://www.mxe.eg.net/text.asp?2018/7/1/19/228078


  Introduction Top


Type 2 diabetes mellitus (T2DM) is a complex, chronic, polygenic congenital ailment involving elaborate interactions between gene variants and environmental factors – for example, smoking, coffee, obesity, stress, physical activity, inflammation, diet, exercise, and family history (van Hoek et al., 2008; Yan et al., 2017). Evidence supporting gene and lifestyle association in T2DM comes from the prevalence of diabetes across diverse environmental situations and ethnic groups, as well as family-based intervention studies that show that related individuals' response to interventions is more similar than that in unrelated individuals (Paul et al., 2013). Researchers have calculated that by 2030, ∼552 million individuals worldwide will have diabetes, with Asians becoming the most affected group (Chan et al., 2009; Whiting et al., 2011). As the prevalence of diabetes is generally high among the population of Saudi Arabia, the disease is a major clinical and public health issue in the country (Alqurashi et al., 2011; Bahijri et al., 2016).

T2DM is a degenerative condition caused by hereditary as well as environmental factors that cause tissues to become resistant to insulin and that impair β-cell function. Genetic linkage analyses and genome-wide association studies (GWAS) have identified variants in a number of genes that contribute toward the development of T2DM (e.g. TCF7L2, FTO, KCNJ11, SLC30A8, ADAMTS9, JAZF1, and CDC123), with different reproducibility related to a positive association between polymorphisms of these genes and T2DM across populations (Sanghera and Blackett, 2012; Prasad and Groop, 2015; Vosti et al., 2017). Other GWAS have identified many more T2DM susceptibility loci, with ∼ 187 T2DM-associated loci confirmed to date (Voight et al., 2010; Trevers and McCarthy, 2011; Lau et al., 2017). A particularly important T2DM-associated polymorphism is located on chromosome 9p (rs10811661), 125 kbp upstream of the CDKN2A/B genes, which encode p16INK4a and p15INK4b, respectively, tumor suppressor proteins that inhibit cyclin-dependent kinase (CDK) 4 and CDK6 (Hribal et al., 2011).

p16INK4a and p15INK4b proteins [Figure 1] regulate pancreatic β-cell replication (Rane et al., 1999; Moritani et al., 2005). Mice devoid of CDK4 develop insulin-deficient diabetes as a result of a decrease in the number of pancreatic β cells. Mice that express mutant CDK4 that cannot bind the cell cycle inhibitor p16INK4a develop pancreatic hyperplasia because of excessive replication of β cells (Rane et al., 1999; Kong et al., 2016). A murine model study showed that increased expression of p15INK4b is correlated with the development of hypoplasia of the endocrine and exocrine glands (Moritani et al., 2005). Collectively, these findings suggest that the rs10811661 polymorphism upstream of the CDKN2A/B genes increases the likelihood of T2DM development by causing dysfunction in β cells. Variants in CDKN2A/B have also been studied in relation to the occurrence of T2DM in numerous cultural groups (Hribal et al., 2011). In addition to examining the link between T2DM and ethnicity, lifestyle, and hereditary background, identify relevant gene polymorphisms prevailing in a specific ethnicity or a specific region of a country of mosaic ethnic backgrounds is worthwhile.
Figure 1: The human CDKN2A/B locus at 9p21, hold genes encoding proteins (p15INK4B, p14ARF, p16INK4A) and the IncRNA ANPRILL. p14ARF, p16INK4A proteins are encoded by CDKN2A. Polymorphisms affecting type 2 diabetes mellitus (T2DM), are physically distinct from the coronary artery disease (CAD) interval. Drawing not to scale.

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To elucidate the possible influence of a common CDKN2A/B variant, rs10811661 (C/T), on the development of T2DM, we investigated possible associations between this single nucleotide polymorphism (SNP) and the chromosome 9p21.3 locus in the Saudi Arabian population in Jeddah, Kingdom of Saudi Arabia.


  Patients and Methods Top


Patients

A total of 526 T2DM patients (342 males and 184 females) were enrolled in the study and assessed at the Diabetic Clinic of King Abdul Aziz University (KAU) Hospital, Jeddah, Saudi Arabia, between October 2013 and February 2017. Approval for the investigation was obtained from the ethical committee of the KAU Hospital. A total of 567 individuals were selected as the control group. These participants had normal glucose tolerance (confirmed by a 75-g oral glucose tolerance test) and no other clinical abnormalities, and were recruited while seeking routine health examinations at the same clinic at KAU. The healthy controls belonged to the same ethnic group as the study participants. The research was conducted according to the Declaration of Helsinki (2008), and written consent was obtained from all participants.

T2DM was diagnosed by authorized physicians on the basis of the World Health Organization (WHO) and American Diabetes Association guidelines. T2DM patients were selected on the basis of fasting and random blood glucose levels of at least 126 and at least 200 mg/dl, respectively, which are typically indicative of diabetes. Patients were also diagnosed based on blood glucose levels of at least 200 mg/dl after a 75-g, 2-h glucose tolerance test.

Individuals with a medical record of exocrine pancreatic ailment, ketoacidosis, metabolic disorders, renal dysfunction, or severe liver disease were excluded from the study. Both diabetic patients and nondiabetic controls were at least 35 years of age. None of the control participants had T2DM or having first degree relatives with T2DM. We also confirmed that none of the study controls and patients were biologically related.

Clinical and biochemical analyses

All participants were required to complete a disclosure of clinical history as well as family history, thorough physical examination, including age, sex, BMI (kg/m 2), and midsection or waist circumference at the narrowest point between the lowest ribs. Laboratory investigations were carried out after an overnight fast. Fasting plasma glucose (FPG) and 2-hours postprandial plasma glucose (PPPG) levels were measured using an Aptio automated system and auto analyzer (Dimension Vista 1500; Siemens AG, Erfurt, Germany).

Genotyping

Fasting venous blood was collected into 5-ml EDTA-treated tubes. Genomic DNA was extracted from peripheral blood leukocytes using a QIAamp DNA kit (Qiagen Inc., Hilden, Germany) and the samples were kept at − 80°C until use. Genotyping was carried out at the Molecular Biology Laboratory, King Fahd Center for Medical Research, KAU, Jeddah, Kingdom of Saudi Arabia. The rs10811661 polymorphism was genotyped using the allelic discrimination assay-by-design TaqMan method on a Step One PCR instrument (Applied Biosystems, Foster City, California, USA). The TaqMan Assay kit (Applied biosystems) included the forward target-specific polymerase chain reaction (PCR) primer and reverse primer. TaqMan MGB probes were labeled with two special dyes: FAM and VIC. The reaction components for genotyping were as follows: 10 ng of DNA, 5 μl of TaqMan Genotyping Master Mix (Applied Biosystems), 0.25 μl of assay mix (40×), and water to a total volume of 10 μl. The amplification conditions were 60°C for 3 min, 95°C for 10 min, followed by 40 cycles of 95°C for 15 s and 60°C for 1 min. Endpoint fluorescence was recorded using the Step One data collection feature. Automatic allele calling using default settings was carried out using Step One data collection and analysis software, version 2.2.2.

Statistical analysis

Experimental data for the healthy control and T2DM groups were compared using the unpaired Student's t-test. Clinical attributes of all participants are expressed as mean ± SD. Qualitative data were compared using the χ2-test. Allele and gene frequencies were compared between healthy controls and T2DM patients using contingency tables and the χ2-test. Odds ratios (ORs) and 95% confidence intervals (CIs) were determined to describe the degree of relationships. P values less than 0.05 were considered to be indicative of statistical significance. Statistical analyses were carried out using SPSS software, version 19.0 (IBM Corp., Chicago, Illinois, USA).


  Results Top


Baseline characteristics

The study involved 526 T2DM patients and 567 healthy controls, all of whom were residents of Jeddah, KSA. The clinical characteristics of both the T2DM and healthy control groups are shown in [Table 1]. The T2DM group had significantly greater waist circumference (P = 0.0001), BMI (P< 0001), FPG (P< 0.0001), and 2-h PPPG (P< 0.0001) for the CDKN2A/2B covariant in comparison with the healthy control group. The mean age was 57.33 years among the T2DM patients and 56.35 years among the controls.
Table 1: Demographic characteristics of the study population

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The CDKN2A/2B polymorphism exhibited a Hardy–Weinberg distribution in the T2DM group. The genotype distribution of the CDKN2A/2B rs10811661 (C/T) polymorphism and the frequency of C and T alleles in the T2DM and control groups are presented in [Table 2]. The genotype and allele distribution of the SNP rs10811661 differed markedly between the T2DM and healthy control groups.
Table 2: Distribution of the CDKN2A/2B rs10811661 (C/T) genotype and alleles

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The major allele T of the rs10811661 SNP of CDKN2A/2B (OR = 1.9; 95% CI: 1.57–2.30; P = 0.0001) exhibited a modest but significant effect size [Table 2], indicating that this variant is a risk factor for T2DM in the Saudi Arabian population in Jeddah. Our findings showed a link between rs10811661 of CDKN2A/2B in both the dominant model (OR = 2.11; 95% CI: 1.66–2.69; P = 0.0001) and the recessive model (OR = 2.50; 95% CI: 1.58–3.95; P = 0.0001) [Table 3]. [Table 4] and [Table 5] show the relationship between the CDKN2A/2B rs10811661 (C/T) genotype and FPG and 2-h PPPG for the control and T2DM groups, respectively. Normal glucose-tolerant participants carrying a risk allele (genotypes TT + CT) of the rs10811661 of CDKN2A/2B (C/T) polymorphism showed significantly higher levels of FPG and 2-h PPPG (P< 0.0001 and < 0.0449, respectively) in comparison with noncarriers (genotype CC) [Table 4].
Table 3: Comparison of dominant and recessive models for CDKN2A/2B

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Table 4: Correlation of the CDKN2A/2B rs10811661 (C/T) genotype with fasting plasma glucose and 2-h postprandial plasma glucose for the control group

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Table 5: Correlation of the CDKN2A/2B rs10811661 (C/T) genotype with fasting plasma glucose and 2-h postprandial plasma glucose for the type 2 diabetes mellitus group

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  Discussion Top


T2DM is a complex polygenic disease (Lyssenko and Laakso, 2013). The pervasiveness of obesity, inappropriate percent body fat, poor physical condition, and diabetes are almost endemic in Saudi Arabia (Al Dokhi and Shahid, 2013; Khlid et al., 2017). According to the WHO reports, worldwide, Saudi Arabia is ranked the seventh in the prevalence of diabetes. Among the 22 Saudi adult population there is 4 million T2DM patients and 1.5 million undiagnosed cases raising the national adult disease prevalence to 25% (IDF, 2017). The high rates of consanguineous marriages and specific genetic predisposition, combined with dramatic lifestyle changes associated with economic prosperity, have caused a sharp increase in the incidence of T2DM among Saudis over the last four decades (Elhadd et al., 2007). As research has shown that various SNPs are associated with T2DM (McCarthy, 2010; Nurgul et al., 2017), the present study was conducted to examine the risk associated with a specific SNP within a Saudi population.

Advances in genotyping technology applied to GWAS have enabled the identification of more than 65 genetic variants suspected of causing a 10–30% increase in the risk of T2DM (Lyssenko and Laakso, 2013; Talmud et al., 2015). Studies of a possible association between the rs 10811661 polymorphism and T2DM risk have been contradictory and thus inconclusive (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al., 2007; Grarup et al., 2007; Scott et al., 2007; Sladek et al., 2007; Zeggini et al., 2007; Cauchi et al., 2008; Duesing et al., 2008; Lee et al., 2008; Wu et al., 2008; Helgeland et al., 2015; Talmud et al., 2015). Initially, Niels' group reported a pooled T2DM OR of 1.16–1.38 for the rs10811661 allele (Cauchi et al., 2008). A subsequent meta-analysis of GWAS data obtained from studies of Northern Europeans linked the SNPs rs10811661 and rs564398 of the CDKN2A/2B region with T2DM susceptibility. However, the association of the former SNP with T2DM risk was markedly stronger than that of the latter SNP (Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al., 2007; Scott et al., 2007; Zeggini et al., 2007). GWAS of French Canadians found nominal association signals for proxies (r2 ≥ 0.9) of rs10811661 (rs2383208, P = 2 × 10-4) and rs564398 (rs1063192, P = 2 × 10-2) (Sladek et al., 2007). By contrast, rs10811661 was associated strongly with T2DM in French Europids (Duesing et al., 2008), Chinese (Wu et al., 2008; Hu et al., 2009), and Koreans (Lee et al., 2008; Xiao et al., 2016). In a study of 5970 healthy middle-aged Danes, variants of CDKN2A/2B were associated strongly with T2DM, with an OR of 1.30 per risk allele and a predisposing impairment of glucose-induced insulin release (Grarup et al., 2007). A study involving 5327 nondiabetic Finish men established a similar association for variants in KAL1, SLC30A8, HHEX, and EXT2 (Strancakova et al., 2009). However, only a modest association was reported among Asians. CDKN2A/2B variants did not show such associations among African Americans, Pima Indians (Rong et al., 2009), Lebanese (Nemr et al., 2012), or Czech–Slavonic populations (Hubáček et al., 2013). Ethnic differences could be the reason for such discrepancies. Similarly, the significant T2DM risk variants of KAL1, SLC30A8, HHEX, EXT2, IGF2BP2, and LOC387761 among Europids were not replicated in Pima Indians (Rong et al., 2009). In support, the low-risk CDKN2A/B locus CC genotype was linked with greater improvement in β-cell function in a diabetes prevention program (troglitazone and lifestyle modification for 1 year) compared with the high-risk TT genotype (Moore et al., 2008). Chauhan et al. (2010) reported similar results for CDKN2A/2B (rs10811661) in a population in northwestern India (OR, 1.3).

In our case–control study, the association between the CDKN2A/B (rs10811661) polymorphism and the risk of T2DM was analyzed in a sample of the Saudi population in Jeddah, Saudi Arabia, the first study of its kind in this ethnic group. We found a modest but significant effect size for the CDKN2A/B (rs10811661) variant on susceptibility to T2DM, with an OR of 1.9 (95% CI: 1.57–2.30; P = 0.0001). This finding is in agreement with previous studies covering other ethnicities, namely, Scott et al. (2007), the Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research et al. (2007), and the Wellcome Trust Case Control Consortium (2007). FBG and 2-h PPPG levels were significantly higher in normal glucose-tolerant individuals with the TT + CT genotype of CDKN2A/B rs10811661. The frequency of the T allele and the TT genotype was significantly higher in the T2DM group than the control group. These outcomes are in agreement with the findings of previous studies (Wellcome Trust Case Control Consortium, 2007; Hribal et al., 2011; Yan et al., 2017). We also examined whether the T allele of CDKN2A/B is a risk factor for T2DM in the targeted Saudi population. We found that T2DM patients carrying the TT genotype had impaired glucose tolerance because of impaired glucose-induced insulin release, suggesting that variations in CDKN2A/B rs10811661 contribute toward T2DM by affecting β-cell function.

There is Evidence that the risk of T2DM is related to polymorphism of CDKN2A/B genes through affecting beta cell mass and its rate of proliferation. Changes in CDKN2A/B proteins have relative metabolic implications namely age –dependently the expansion of β - cell is controlled by p16INK4A, CDK4 is required for the expansion of postnatal β-cell mass, hepatic gluconeogenesis is modulated by p16INK4A, p15INK4B, p16INK4A controls adipocyte differentiation and activation of macrophage and CDK4 controls mitochondrial activity in muscle (Cozar et al., 2006, Salas et al., 2014, Kong et al., 2016).

The SNP rs10811661 is located in the chromosome 9p21 region. Previous GWAS showed that this region is associated with an increased risk of T2DM (Sanghera and Blackett, 2012; Kong et al., 2016) as well as cardiovascular disease (Palomaki et al., 2010; Helgeland et al., 2015), various forms of cancer (Bishop et al., 2009), and neurodegenerative diseases (Koppers et al., 2013). The pathogenesis of these diseases differs and their relevant polymorphisms are independent of each other, despite shared pathologies (e.g., myocardial infarction and T2DM). Although most reported studies have indicated an association between the rs10811661 SNP and T2DM, they have not reported an association with cardiovascular disease. An explanation for the mechanisms underlying such associations was not provided. We hypothesize that interactions between multiple factors encoded in this region in conjunction with transcriptional regulatory mechanism(s) affect disease risk.


  Conclusion Top


This study showed a significant risk effect for the T allele of CDKN2A/B rs10811661 in T2DM patients from a population in Jeddah, Kingdom of Saudi Arabia. Our data showed impaired glucose-induced insulin release and impaired glucose tolerance in participating T2DM patients carrying the TT genotype, implicating the CDKN2A/B rs10811661 variation in the risk of T2DM because of impaired β-cell function. Our findings show that the presence of CDKN2A/B rs10811661 (C/T) in certain populations adds to the risk of T2DM. [49]

Acknowledgements

The authors extend their sincere appreciation to the Deanship of Business and Knowledge Creativity Professor Ahmed Bn Hamed Nkady, King Abdul Aziz University, for unlimited support.


  Author Contributions Top


Mohammad Ali M. Ajabnoor carried out supervision of the study and review of the manuscript; Ahmed A. Elmgeed Ahmed conducted study design, data analysis, supervision of molecular biology and clinical chemistry work, writing of the paper; Mohmd N.A. Hadi Al-Ama carried out supervision of recruiting study participants and reveiw of manuscript; Khalid Z. Alshal carried out supervision of recruiting and clinical management of the study participants and review of manuscript; Ghada M.A. Ajabnoor conducted review of manuscript and supervision of molecular biology, and clinical chemistry work.

This study was supported by a grant from the Siraj Said Kaky Chair (Genetic Polymorphisms in Cardiovascular Disease and Type 2 Diabetes; No. SRC-3-434), King Fahd Medical Research Center, King Abdul Aziz University.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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