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Clinical research

Association of common polymorphisms in the VEGFA and SIRT1 genes with type 2 diabetes-related traits in Mexicans

Armando Totomoch-Serra, Maria de Lourdes Muñoz, Juan Burgueño, Maria Cristina Revilla-Monsalve, Alvaro Diaz-Badillo

Arch Med Sci 2018; 14, 6: 1361–1373
Online publish date: 2018/03/28
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Introduction

Type 2 diabetes mellitus (T2D) is a complex disease that has a strong impact on populations with genetic predisposition [1, 2], suggesting that susceptibility genes are triggered by shifts in non-genetic factors [3], such as diet and sedentary lifestyles. The risk of developing T2D is 40% for individuals who have one parent with this disease and almost 70% if both parents are affected [4]. Different approaches to understanding the background of the genetic variability in this complex and polygenic disease have been conducted in the past, including the candidate gene approach, linkage analysis, and genome-wide association studies [5], identifying approximately 153 genetic loci associated with risk of T2D and 24 genetic loci related to glycaemic traits [6]. These loci, previously linked to complex traits, should be replicated by various groups around the world and different populations for validation and used as genetic markers in diagnosis, prevention and treatment of the disease. This approach is relevant for Mexican mestizos because of the relatively recent admixture approximately 500 years ago [7].
The polymorphism rs10811661 upstream of CDKN2A/B, which may confer increased risk for T2D by affecting -cell function, has been associated with T2D in Asian and European subjects in a meta-analysis [8]. PPARGC1A (rs8192678) has been associated with T2D in populations from Denmark and northern China [9, 10], and the UCP2 (rs659366) gene has been associated with T2D and diabetic retinopathy in Shanghai, China [11]. These 2 variants have not been included in association studies with T2D in any Mexican mestizo population. Furthermore, the VEGFA (rs2010963) gene variant has been suggested to play a major role in proliferative diabetic retinopathy in subjects from India [12] and in a Chinese population [13], although is not associated with T2D in a United Kingdom Caucasian population [14]; and the SIRT1 (rs7896005) gene variant had a reduced acute insulin response nominally associated with T2D in a Pima population [15]. Consequently, all five variants have the possibility to be associated with T2D in the Mexican mestizo population.
The aim of this study was to assess the association of metabolic traits with five single nucleotide polymorphisms (SNPs) (rs10811661, rs8192678, rs2010963, rs7896005 and rs659366) located in different genes (CDKN2A/B, PPARGC1A, VEGFA, SIRT1 and UCP2 respectively) in 415 unrelated Mexican mestizos from Mexico City with T2D.

Material and methods

Subjects

Unrelated Mexican mestizos with T2D (301 female and 114 male, with a median age of 56 years) referred to the Metabolic Diseases Research Unit between 2010 and 2014 with signed informed consent were enrolled in the study, which was previously approved by the institutional ethical and research committees of Centro Medico Nacional Siglo XXI of IMSS in Mexico City. A complete medical history of each patient was taken, including anthropometric measures, glucose levels, cholesterol, triglycerides, insulin and glycated haemoglobin (HbA1c). The diagnosis was confirmed according to the clinical criteria for T2D from the American Diabetes Association: fasting glucose greater than 126 mg/dl on more than one occasion, random glucose level higher than 200 mg/dl on at least two occasions or HbA1c greater than 6.5%. The diagnosis of hypertension was made when systolic blood pressure (SBP) was ≥ 140 mm Hg and/or diastolic blood pressure (DBP) ≥ 90 mm Hg [16]. All subjects were considered Mexican mestizos if they were born in Mexico City, as traced back to the third generation [17]. In addition, Mexican mestizos are defined as Mexicans who have a relatively recent admixture (approximately 500 years ago) and exhibit strong genetic components of Native and European origin and, to a lesser extent, Asian and African descent [17]. Recent studies have shown no significant stratification effect in diabetes [18] and cardiovascular [19] studies in Mexican mestizos from Mexico City.

Exclusion criteria

The following exclusion criteria were included in this study: a) presence of clinically significant renal, respiratory, haematological, gastrointestinal, hepatic, neurological or other inherited disorder different to T2D capable of altering the glucose metabolism; b) volunteers born in other states of the country, with less than three generations living in Mexico City; c) self-administration of insulin or another medication to treat diabetes before the T2D diagnosis; d) familial relationship between participants; e) presence of substance abuse or alcoholism; f) pregnant women; g) volunteers with significant incomplete values in demographic or phenotypic data that could affect the statistical analysis.

Anthropometric variables and biochemical assays

Height and waist and hip circumference were measured to the nearest centimetre with a measuring tape. Patients were weighed before breakfast, at the same hour each day, without shoes and in light clothing. Body mass index (BMI) was calculated with the following formula: weight (kg)/height2 (m2). The homeostasis model assessment of insulin resistance index (HOMA-IR) was evaluated according to the HOMA calculator (version 2.2.3 HOMA, Oxford, England). Triglycerides, cholesterol, glucose and high-density lipoprotein cholesterol (HDL-C) were determined using the Biotecnica Automatic Analyser BT3000 (Biotecnica Instruments S.p.A, Rome, Italy). Insulin was determined using the Monobind Human Insulin ELISA (enzyme-linked immunosorbent assay) Kit (Monobind, Inc., Lake Forest, California, USA). Samples from individuals included in this study were obtained before the patient received any medical treatment and all T2D patients were newly diagnosed.

DNA isolation and genotyping

DNA was isolated with the Qiagen Gentra Puregene Blood kit (Qiagen, Hilden, Germany) from human nucleated cells from 5 ml of whole blood and quantified by a NanoDrop 2000 Spectrophotometer (Thermo Fisher Scientific, Waltham, Massachusetts, USA); five polymorphisms (rs10811661, rs8192678, rs2010963, rs7896005 and rs659366) located in five genes associated with diabetes or related traits in European and Asian populations (Table I) were selected and genotyped using 5 exonuclease TaqMan assay on a StepOnePlus System (Thermo Fisher Scientific, Waltham, Massachusetts, USA). Ten percent of DNA samples were genotyped twice to confirm concordance.

Statistical analysis

Statistical analyses were performed with IBM SPSS Statistics 24.0 (SPSS, Inc., Chicago, Illinois, USA). Baseline results were expressed as mean ± standard deviation (SD), and median (25th–75th percentiles) and genotype frequencies were calculated by direct counting. The 2 test for Hardy-Weinberg equilibrium was used to evaluate the deviation of equilibrium. Comparison of between-group differences in clinical and anthropometric variables was performed with ANOVA or the Kruskal-Wallis test, and categorical variables were analysed with the 2 or Fisher’s exact test.
Using the software Quanto 1.2.4 (University of Southern California, Los Angeles, California, USA) the main genetic effect (g) was calculated with a statistical power of 80% and  = 0.05, taking into account the global minor allelic frequency informed in the Single Nucleotide Polymorphism Database (dbSNP) of Nucleotide Sequence Variation (https://www.ncbi.nlm.nih.gov/snp/) and the mean and standard deviation for each trait after normalisation of the values, using the dominant, recessive and additive models of inheritance. Linear regression analysis was used to test the association of polymorphisms and diabetes traits under the three models of inheritance. Those variables with non-normal distribution were rank-based inverse normal transformed to avoid confounding factors due to the preponderance of one sex and obese patients, and the linear regression analysis was adjusted for age, sex, and BMI. Additionally, an association test among paired SNPs was performed, and an interaction analysis between candidate genes associated in the paired SNP analysis was performed with GeneMANIA software (www.genemania.org) [20]. Additionally, a power analysis was performed in the most unbalanced variable. A value of p between < 0.05 and > 0.01 was considered to have nominal significance, and in post-Bonferroni correction 0.05/5, p ≤ 0.01 was significant.

Results

Univariate analysis of risk factors for T2D in Mexican mestizos

The present analysis was performed to determine differences in the clinical, anthropometric and biochemical parameters of 415 (women = 301 and men = 114) unrelated Mexican mestizos with T2D. Table II shows the univariate analysis of the population divided by sex. Both groups (women and men) have a similar distribution in age, and there were no differences in SBP, DBP, glucose, triglycerides, cholesterol, insulin, HDL-C or HbA1c levels. Body mass index was significantly higher in women (29.13 ±7.19) than in men (26.95 ±3.85) with p < 0.001, and HOMA-IR was also substantially higher in women (2.65 (1.69–4.49)) than in men (2.26 (1.41–3.72)), with p < 0.001.

Comparison of allelic frequencies with HapMap and 1000 Genomes Project

The five analysed polymorphisms were in Hardy-Weinberg equilibrium. Allelic frequencies of the five polymorphisms are displayed in Table III and were compared to those reported in HapMap and the 1000 Genomes Project for Mexicans. The frequencies of rs10811661, rs8192678, rs659366, rs2010963 and rs7896005 agreed with these projects.

SNP association with T2D traits

Comparison of genotype frequencies with traits is displayed in Table IV and concerning obesity in Table V. Genotyping frequencies of polymorphisms in patients with T2D are not associated with obesity. These frequencies will be useful as a reference for future studies. Table II displays the results of the association analysis of genotype frequencies and for quantitative traits; nominal significance was identified for rs8192678 (PPARGC1A) with glucose (p = 0.023) and triglycerides (p = 0.013); rs2010963 (VEGFA) with DBP (p = 0.012) and cholesterol (p = 0.013) and a significant association with HDL-C (p = 0.0007); rs7896005 (SIRT1) with DBP (p = 0.012) and insulin (p = 0.01); and rs659366 (UCP2) with cholesterol (p = 0.034), glucose (p = 0.031) and triglycerides (p = 0.028).

SNP association with T2D traits by models of inheritance

All five polymorphisms were studied for association with several traits in linear regression under three models of inheritance (dominant, recessive and additive). Table VI shows the nominal and significant polymorphisms associated with the best model of inheritance after the Bonferroni correction for multiple testing: VEGFA polymorphism rs2010963 was significantly associated with HDL-C (p = 0.007) in the additive model, and with nominal significance with HbA1c (p = 0.020) in the dominant model, and DBP (p = 0.032) in the recessive model. The UCP2 polymorphism rs659366 was nominally significantly associated with SBP (p = 0.025) in the additive model, and polymorphism rs7896005 located in SIRT1 was significantly associated with DBP (p = 0.006) in the recessive model. All models were adjusted for age + sex + BMI, and they were designated following the best Akaike and Bayesian criteria.

SNP association with T2D traits by pairwise association test

Results of the association test among paired SNPs (Table VII) showed that all SNPs are independent of one another. Further, if the analysis is performed with all the SNPs independently of HOMA-IR, the results are the same, as SNPs are independent of one another. However, a significant value was found for the pair rs8192678 and rs10811661 (exact Pr ≥ 2 0.966). Finally, because arterial systemic hypertension displayed an unbalanced distribution with a high coefficient of variation, to determine its influence on the results, a power analysis was performed in the unbalanced distribution by dividing the variable of HBP (high blood pressure) into three subgroups (Table VIII and Figure 1). The results showed that a difference between means of around 0.10 times had an SD = 0.55, which can be detected as significant with a probability of 0.92. The genetic effect calculated (Tables IX and X) showed good power (0.80) with an accuracy of approximately 10% in most cases. We marked in bold the percentages greater than 10%.
The GeneMANIA bioinformatics analysis for interaction among CDKN2A/CDKN2B and SIRT1 with CDK6 and MCM10 genes are displayed in Figure 2. The results showed that CDKN2A, CDKN2B and SIRT1 interact with CDK6; and CDKN2A and SIRT1 interact with the MCM10 homologue gene (Figure 2).

Discussion

Diabetes is the third cause of death in Mexico. It is the leading cause of death in women and the second in men [21]. One of the efforts to counteract the impact of this disease has been to study the genetic influences in the Mexican mestizo population to establish primary prevention measures and improve treatment. Therefore, rs10811661, rs8192678, rs7896005, rs659366 and rs2010963, which have been associated with T2D in European, Chinese, Pima and Maya populations [8–15, 22–25], were selected to study their association with traits related to diabetes.
CDKN2A/B genes are expressed in adipocytes and pancreatic islets and play a role in -cell function and regeneration. The polymorphism rs10811661 located 125 kb upstream of these genes has been identified as a risk allele in a contemporaneous Mayan population [25] containing lower rates of dispersion and a high predisposition to obesity, diabetes and consanguineous marriage [26]. Our results showed no statistically significant difference in allele frequency of this variant compared to HapMap and the 1000 Genomes Project, or with any of the traits related to T2D. Future analysis of rs10811661 in multi-ethnic Mexican cohorts to elucidate its implications and impact on T2D is suggested.
PPARGC1A is a coactivator of nuclear receptors and other transcription factors that regulate mitochondrial biogenesis, respiration, hepatic gluconeogenesis and muscle fibre type switching [27, 28]. The frequencies obtained for rs8192678 had a difference of 2.2% compared with the 1000 Genomes Project and a difference of 10% with Mexicans from West Mexico (Jalisco State) [29]. The distribution difference obtained between these populations could represent different ancestry and migration history between central and western Mexico. Stratification of genotype frequencies resulted in significant nominal values for glucose (p = 0.023) and triglyceride levels (p = 0.013). This polymorphism has been associated with T2D in populations from China [9], and Denmark [10]; however, it has not been studied widely in Mexican populations for T2D related traits [30]. Consequently, association studies for this gene must be replicated.
Polymorphism rs2010963 in VEGFA has been associated with diseases, such as amyotrophic lateral sclerosis [31]. Allelic frequencies of this polymorphism in Mexicans reported in a case-control study with preeclampsia showed no evidence of an association of VEGFA alleles or haplotype frequencies with this disease [32]. However, diabetes complications, such as retinopathy with vascular implications, have been associated with rs2010963 in case-control studies [12, 13, 33]. Furthermore, metabolic traits analysed in T2D patients of this study showed a significant p-value for low HDL-C levels (Coef  (95% CI); –0.12 (‒0.20 – ‒0.03), p = 0.007) in the additive model and after correcting for multiple comparisons. The impact of the risk allele in the additive model could predispose people with T2D to cardiovascular diseases. A Slovenian group of 143 subjects with T2D and myocardial infarction (MI) was compared with 228 diabetic subjects without the disease, and the polymorphism rs2010963 was associated with MI [34]. These results are in agreement with our results, suggesting an impact of this polymorphism on low HDL-C levels and in the development of MI in patients with T2D. The present findings strengthen the contribution of VEGFA to variation in blood lipid levels, mainly for HDL-C. Additionally, a nominal association with HbA1c (p = 0.020; dominant model) and DBP (p = 0.032; recessive model) was also observed in our study. To the authors’ best knowledge, however, no information has become available on the association of polymorphism rs2010963 with HDL-C levels. These results support the association of rs2010963 in VEGFA with MI in patients with T2D [35]. The identification of genes sharing this covariance can be a target for future functional or clinical-intervention studies [36].
SIRT1 is a stress-response and chromatin-silencing factor, and in Pima Native American populations, rs7896005 has been associated with reduced acute insulin in response to an intravenous glucose bolus (adjusted p = 0.045) [15, 37]. This polymorphism displayed a significant association with DBP (Coef  (95% CI): –0.06 (–0.11 – –0.02), p = 0.006) in the recessive model, suggesting a protective role. This is the first study testing the association between rs7896005 and DBP in Mexicans. In mice, SIRT1 overexpression in vascular smooth muscle cells has been reported to reduce SBP [38], but not DBP.
UCP2 separates oxidative phosphorylation from ATP synthesis with energy dissipated as heat, also referred to as mitochondrial proton leak [39]. Allele frequencies displayed a difference of 3% with the reports from the international projects for Mexicans from Los Angeles, without significance. A recent meta-analysis using three cohorts from Europeans (20,242 individuals) showed that rs659366 was associated with liver dysfunction because -glutamyl transferase levels varied by genotype with an interaction with waist-to-hip ratio and body mass index [40]. However, in the present study no association with any of the T2D-related traits was found.
Diabesity is used to refer to a form of diabetes that typically develops due to obesity; however, only a fraction of people with obesity develop diabetes (< 10%) [41]. Previous studies have shown that rs10811661, rs8192678 and rs659366 were associated with obesity and T2D [8–11, 40], but our results did not show an association between these SNPs and obesity in this Mexican mestizo population. Furthermore, when the group of patients with T2D was divided and analysed by the binary variable obesity in the logistic regression, no association with SNPs was found (results not included). Association of the polymorphism rs10811661 at CDKN2A/2B with obesity and diabetes has been replicated in low-medium size samples. Therefore, the lack of association in this study may be due to the sample size or the stratification in the analysis. Nevertheless, some studies have shown that most obese, insulin-resistant individuals do not develop hyperglycaemia, maintaining a healthy -cell level despite obesity [42, 43]. Furthermore, only three loci have been found to share a strong association (FTO, MC4R and QPCTL/GIPR) and genetic correlation between T2D and obesity [44]; therefore, there remains a need to study traits as new sources of covariance for diabesity.
According to the results of the association test among paired SNPs, for rs8192678 and rs10811661 (0.9666 for exact Pr ≥ 2), a bioinformatics analysis for genetic interaction was performed to support these results. However, a direct interaction between these SNPs was not found, but identification of intermediary genes, such as the rich human -cell proliferation CDK6 [45] interaction with these two SNPs in SIRT1 and the CDKN2A/2B locus, was observed. CDK6 codes for a kinase regulated by cyclin D. A mutation in this kinase has been reported to reduce cell proliferation and impair cell motility and polarity (https://www.ncbi.nlm.nih.gov/gene/1021). A stronger interaction was observed between CDKN2A and CDK6 than between CDKN2B and CDK6 (Figure 2). A robust interaction was also observed between SIRT1 and CDKN2A with MCM10, which is required for both initiation and elongation during chromosomal DNA replication [46]. These interactions support a role of regulatory factors during -cell-cycle progression in the pathogenesis of T2D, and as a result, this may influence insulin synthesis and secretion.
The non-coding regulating polymorphisms in the CDKN2A and SIRT1 genes could affect -cell replication through the interaction with CDK6 and MCM10 and the regulation of the cell cycle in pancreatic cells. Consequently, additional bioinformatics analysis and functional studies in vitro and in vivo are needed to test this hypothesis.
In conclusion, our results indicated that VEGFA (rs2010963) and SIRT1 (rs7896005) gene polymorphisms are associated with the cardiometabolic traits HDL-C and DBP respectively in T2D patients. These findings may explain the susceptibility to develop cardiovascular complications and derived comorbidity as the main cause of death in Mexican patients with T2D. This association should be replicated in other Mexican populations to strengthen these findings.

Acknowledgments

We thank the study participants, CINVESTAV and CONACYT (scholarship number 382646, for their support to the Ph.D. studies of ATS) and CONACYT (grant number CB258103).

Conflict of interest

The authors declare no conflict of interest.

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