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. 2017 May 18;2017:3937893. doi: 10.1155/2017/3937893

Genetic Epidemiology of Type 2 Diabetes in Mexican Mestizos

Eiralí Guadalupe García-Chapa 1, Evelia Leal-Ugarte 1, Valeria Peralta-Leal 1, Jorge Durán-González 1, Juan Pablo Meza-Espinoza 1,*
PMCID: PMC5451767  PMID: 28607931

Abstract

There are currently about 415 million people with diabetes worldwide, a figure likely to increase to 642 million by 2040. In 2015, Mexico was the second Latin American country and sixth in the world in prevalence of this disorder with nearly 11.5 million of patients. Type 2 diabetes (T2D) is the main kind of diabetes and its etiology is complex with environmental and genetic factors involved. Indeed, polymorphisms in several genes have been associated with this disease worldwide. To estimate the genetic epidemiology of T2D in Mexican mestizos a systematic bibliographic search of published articles through PubMed, Scopus, Google Scholar, and Web of Science was conducted. Just case-control studies of candidate genes about T2D in Mexican mestizo inhabitants were included. Nineteen studies that met the inclusion criteria were found. In total, 68 polymorphisms of 41 genes were assessed; 26 of them were associated with T2D risk, which were located in ABCA1, ADRB3, CAPN10, CDC123/CAMK1D, CDKAL1, CDKN2A/2B, CRP, ELMO1, FTO, HHEX, IGF2BP2, IRS1, JAZF1, KCNQ1, LOC387761, LTA, NXPH1, SIRT1, SLC30A8, TCF7L2, and TNF-α genes. Overall, 21 of the 41 analyzed genes were associated with T2D in Mexican mestizos. Such a genetic heterogeneity compares with findings in other ethnic groups.

1. Introduction

Type 2 diabetes (T2D) is a metabolic disorder characterized by impaired glucose uptake in muscle and fat, altered glucose-induced insulin secretion, and increased hepatic glucose production, which lead to hyperglycemia. It is the most common type of diabetes and generally occurs in adults [1]. According to the International Diabetes Federation there are currently around 415 million people with diabetes worldwide, a figure likely to increase to 642 million by 2040 [2]. This disorder accounts for high morbidity and mortality due to complications like renal failure, blindness, amputations, cardiovascular disease, and cerebrovascular events [1]. In 2015 there were approximately 5.0 million deaths by diabetes worldwide [2]. With about 7.3 million patients in 2010 [3], our country was second in Latin America and tenth in the world in prevalence of this disorder [4]. Five years later, the number of diabetic patients was estimated to be 11.5 million and our country ranked sixth in the world [2]. In 2011 most frequent morbidities by T2D were renal failure (24.2%) and peripheral circulatory complications (17.3%), and the mortality rate was 70/100,000 inhabitants (http://fmdiabetes.org/wp-content/uploads/2014/11/diabetes2013INEGI.pdf). The complex etiology of T2D includes factors that influence the risk and evolution of the disease, such as ethnicity, poor alimentation, sedentary lifestyle, obesity, dyslipidemia, and family history [1, 5]. Regarding genetics, worldwide researches have shown association of this disease with numerous allelic variants of nearly 80 candidate genes [6]. The aim of this study is to carry out a literature review about genetic researches conducted in Mexican mestizos for a better understanding of the genetic epidemiology of T2D in our population.

2. Methods

A systematic search was done through PubMed, Scopus, Google Scholar, and Web of Science for genetic studies conducted in Mexican mestizo inhabitants with T2D. Key words derived from the phrase “Genetic polymorphisms associated with Diabetes Mellitus type 2 in Mexico, Mexican patients and/or Mexican mestizo” were used. Related terms such as “variants”, “alleles”, and “SNP associated with diabetes, T2DM, or T2D” complemented our search. Just case-control studies of candidate genes performed in Mexican mestizos resident in the country were included. Researches conducted in Mexican native populations were excluded, as well as those done in patients with metabolic syndrome. In surveys that included both patients with metabolic syndrome and patients with T2D, only cases with T2D were registered. Although in the selected studies different models of genotype analyses were used (recessive, dominant, or codominant), solely comparisons between allele frequencies were considered in our review. In studies without described odds ratio (OR), unadjusted OR were estimated from the reported allele or genotype frequencies. Allele comparisons were performed by 2 × 2 contingency tables [Yates' correction chi-square test (http://vassarstats.net/odds2x2.html)] and genotypes were contrasted by chi-square test (https://ihg.gsf.de/cgi-bin/hw/hwa2.pl). In both comparisons, OR were estimated using 95% confidence intervals (95% CI). A p ≤ 0.05 defined a significant association.

Whenever a polymorphism was analyzed in different studies, data were combined and unadjusted OR for alleles were calculated using a 2 × 2 contingency table (Yates' correction chi-square test). However, studies with suspicion of overlapping of patients were not included in this analysis.

3. Results

In total, 19 case-control studies on the possible association of genetic polymorphisms with T2D in Mexican mestizos resident in the country were included [7–25]. Altogether, 68 polymorphisms of 41 genes were assessed (Table 1). Of them, 25 were associated with an increased risk for T2D and they were located in 20 genes, namely, ABCA1, ADRB3, CAPN10, CDC123/CAMK1D, CDKN2A/2B, CRP, ELMO1, FTO, HHEX, IGF2BP2, IRS1, JAZF1, KCNQ1, LOC387761, LTA, NXPH1, SIRT1, SLC30A8, TCF7L2, and TNF-α. Among the variants that showed association there were 4/20 amino acid substitutions, 13/30 intronic sites, 6/10 of promoter region or 5′-flanking region or upstream of gene, 1/2 intergenic regions, and 2/6 of 3′-untranslated or 3′-flanking region of gene. On the other hand, 12 polymorphisms were analyzed by different authors, and concordance was observed in most of them, except for rs3842570 (CAPN10) [11, 13, 14], rs13266634 (SLC30A4) [8, 17], rs7903146 (TCF7L2) [8, 10, 12, 22], and rs1800629 (TNF-α) [20, 24, 25]. Eleven of these polymorphisms were pooled and analyzed as shown in Table 2. Note that rs4994 (ADRB3) was discarded of this analysis (suspicion of overlap of [9, 10]). Similarly, data by Cruz et al. [10] for rs7903146 and rs12255372 of TCF7L2 were not considered (possible overlapping with the study by Martínez-Gómez et al. [12]). Thus, the 3R allele of rs3842570, which was associated with T2D in a small sample, did not seemingly confer susceptibility to the disease; in contrast, the C allele of rs7754840 (CDKAL1), which evidenced no risk in independent studies, showed association with T2D. Including this allele, a total of 26 polymorphisms and 21 genes were associated with T2D in Mexican mestizos.

Table 1.

Analyzed genes in studies about type 2 diabetes conducted in Mexican mestizos.

Gene Chrom dbSNP loc Change Effect n a; nb OR (95% CI) p Reference
ABCA1 9q31 rs9282541 C/T R/C 244; 202 2.50 (1.48–4.24) 0.001 [7]
rs2000069 C/T Intronic 244; 202 1.08 (0.82–1.42)c 0.58 [7]
rs2230806 G/A R/K 244; 202 1.17 (0.89–1.55)c 0.27 [7]
rs2487037 C/T Intronic 244; 202 1.06 (0.79–1.43)c 0.71 [7]
rs3818689 G/C Intronic 244; 202 0.94 (0.52–1.68)c 0.82 [7]
ADAMTS9 3p14 rs4607103 C/T Intronic 1027; 990 1.05 (0.91–1.20)d 0.521 [8]
ADRB1 10q25 rs1801253 C/G R/G 501; 552 0.79 (0.61–1.02)c 0.07 [9]
ADRB3 8p11 rs4994 C/T W/R 519; 547 1.69 (1.37–2.09) c 0.0001 [10]
rs4994 C/T W/R 501; 552 1.34 (1.10–1.64) c 0.004 [9]
ARHGEF11 1q21 rs945508 G/A R/H 868; 504 0.91 (0.76–1.09)e 0.319 [8]
CAPN10 2q37 rs3792267 G/A Intronic 132; 112 0.97 (0.66–1.42)c 0.86 [11]
rs3792267 G/A Intronic 719; 746 1.11 (0.95–1.29)c,f 0.20 [12]
rs3792267 G/A Intronic 211; 152 0.91 (0.66–1.26) 0.56 [13]
rs3842570 2R/3R Intronic 132; 112 0.97 (0.68–1.40)c 0.89 [11]
rs3842570 2R/3R Intronic 43; 64 1.81 (1.03–3.18) c 0.038 [14]
rs3842570 2R/3R Intronic 211; 152 0.75 (0.55–1.02) 0.06 [13]
rs5030952 C/T Intronic 132; 113 0.85 (0.56–1.29)c 0.45 [11]
rs5030952 C/T Intronic 211; 152 1.35 (0.89–2.06) 0.16 [13]
rs2975760 T/C Intronic 134; 113 2.72 (1.16–6.35) 0.017 [11]
CAPN10 2q37  rs7607759 A/G T/A 127; 110 2.27 (0.98–5.25)c 0.051 [11]
CDC123/CAMK1D 10p13 rs12779790 A/G Intergenic 1027; 990 1.24 (1.05–1.47) d 0.013 [8]
CDKAL1 6p22 rs10946398 A/C Intronic 519; 547 1.09 (0.91–1.32)c 0.337 [10]
rs9465871 C/T Intronic 519; 547 1.04 (0.85–1.26)c 0.718 [10]
rs7754840 C/G Intronic 519; 547 1.08 (0.89–1.29)c 0.438 [10]
rs7754840 C/G Intronic 1027; 990 1.13 (0.98–1.30)d,g 0.081 [8]
CDKN2A/2B 9p21 rs10811661 C/T Upstream 1027; 990 1.42 (1.15–1.75) d 0.001 [8]
CRP 1q23 rs1130864 C/T 3′-UTR 166; 130 1.59 (1.15–2.22) c,h,i 0.005 [15]
rs1205 G/A 3′-UTR 166; 130 0.82 (0.59–1.14)c,h,i 0.24 [15]
rs2794521 A/G 5′-flanking 166; 130 1.97 (1.15–3.38) c,h,i 0.012 [15]
rs3093062 G/A Promoter 166; 130 3.49 (0.98–12.4) c,h,i 0.039 [15]
ELMO1 7p14 rs1345365 A/G Intronic 148; 269 1.37 (1.02–1.84) c,h,i 0.035 [16]
ENPP1 6q23 rs1044498 A/C K/Q 519; 547 0.94 (0.76–1.16)c 0.577 [10]
EXT2 11p11 rs3740878 A/G Intronic 455; 234 0.83 (0.65–1.05) 0.054 [17]
FTO 16q12 rs8050136 A/C Intronic 868; 504 0.90 (0.74–1.09)e 0.278 [8]
rs9939609 A/T Intronic 519; 547 1.25 (1.02–1.54) c 0.027 [10]
HHEX 10q23 rs5015480 C/T Upstream 519; 547 0.96 (0.80–1.14)c 0.631 [10]
rs1111875 C/T 3′-flanking 1027; 990 1.01 (0.89–1.16)d 0.859 [8]
rs1111875 C/T 3′-flanking 455; 234 1.12 (0.88–1.44) 0.27 [17]
HHEX 10q23 rs7923837 A/G 3′-flanking 868; 504 1.21 (1.02–1.44) k 0.025 [8]
HMOX1 22q12 rs2071749 A/G Promoter 614; 956 0.98 (0.84–1.14)c 0.76 [18]
IGF2BP2 3q27 rs4402960 G/T Intronic 868; 504 1.24 (1.01–1.53) j 0.042 [8]
IRS1 2q36 rs1801278 G/A G/R 719; 746 2.04 (1.41–2.96) c,f <0.001 [12]
rs1801278 G/A G/R 444; 444 3.22 (1.99–5.20) 0.001 [19]
rs1801276 C/G P/A 444; 444 0.98 (0.72–1.32) 0.83 [19]
rs3731594 G/A N/D 444; 444 0.83 (0.42–1.66) 0.47 [19]
rs1801108 G/C R/P 444; 444 1.07 (0.85–1.34) 0.40 [19]
JAZF1 7p15 rs864745 T/C Intronic 868; 504 1.24 (1.04–1.47) k 0.015 [8]
KCNJ11 11p15 rs5215 C/T V/I 519; 547 1.03 (0.87–1.23)c 0.729 [10]
rs5210 A/G 3′-UTR 519; 547 1.03 (0.86–1.23)c 0.764 [10]
rs5219 C/T E/K 1027; 990 1.10 (0.96–1.26)d 0.154 [8]
KCNQ1 11p15 rs2237892 C/T Intronic 868; 504 1.36 (1.13–1.64) k 0.001 [8]
LEPR 1p31 rs1137100 A/G K/R 519; 547 1.00 (0.84–1.21)c 0.92 [10]
LOC387761 11p12 rs7480010 A/G Intronic 455; 234 1.43 (1.05–1.94) 0.006 [17]
LTA 6p21 rs909253 A/G Intronic 51; 48 1.98 (1.02–3.8) c 0.041 [20]
MGEA5 10q24 MGEA5-14 A/T Intronic 271; 244 1.60 (0.52–4.86) 0.404 [21]
NOTCH2 1p11 rs10923931 G/T Intronic 1027; 990 1.04 (0.82–1.32)d 0.731 [8]
NQO1 16q22 rs1800566 C/T P/S 623; 993 0.98 (0.85–1.13)c 0.76 [18]
NRF2 2q31 rs2364723 C/G Intronic 625; 992 0.91 (0.79–1.05)c 0.18 [18]
NRF2 2q31 rs6721961 C/A Promoter 623; 989 0.89 (0.74–1.06)c 0.18 [8]
NXPH1 7p22 rs757705 A/G Intronic 868; 504 1.25 (1.05–1.48) k 0.01 [8]
PPARG 3p25 rs1801282 C/G P/A 719; 746 1.00 (0.81–1.24)c,f 1.00 [12]
rs1801282 C/G P/A 1027; 990 1.10 (0.90–1.34)d 0.342 [8]
rs17793693 A/C Intronic 519; 547 1.09 (0.91–1.31)c 0.329 [10]
RALGPS2 1q25 rs2773080 A/G Intronic 868; 504 0.90 (0.74–1.10)e 0.315 [8]
RORA 15q22 rs7164773 C/T Intronic 868; 504 1.08 (0.91–1.28)e 0.357 [8]
SIRT1 10q21 rs3758391 C/T Upstream 519; 547 1.29 (1.08–1.54) c 0.004 [10]
SLC30A4 8q24 rs13266634 C/T R/W 455; 234 1.01 (0.76–1.33) 0.92 [17]
rs13266634 C/T R/W 1027; 990 1.22 (1.05–1.41) d 0.009 [8]
TCF7L2 10q25 rs7903146 C/T Intronic 868; 504 1.04 (0.84–1.28)e,l 0.735 [8]
rs7903146 C/T Intronic 200; 200 1.84 (1.05–3.20) c,m 0.04 [12]
rs7903146 C/T Intronic 519; 547 1.48 (1.18–1.86) c 0.0007 [10]
rs7903146 C/T Intronic 283; 271 1.25 (0.92–1.70) 0.16 [22]
rs12255372 G/T Intronic 200; 200 1.83 (1.21–2.76) c,m 0.006 [12]
rs12255372 G/T Intronic 281; 268 1.78 (1.11–2.88) 0.017 [22]
rs12255372 G/T Intronic 519; 547 1.37 (1.06–1.76) c 0.014 [10]
DG10S478 STR CACA Intronic 282; 274 1.62 (1.02–2.57) 0.041 [22]
TLR2 4q32 rs5743708 G/A R/Q 321; 538 0.41 (0.04–3.7) 0.40 [23]
TLR4 9q33 rs4986790 A/G D/G 321; 538 1.39 (0.42–4.56) 0.58 [23]
rs4986791 C/T T/I 321; 538 1.01 (0.32–3.18) 0.98 [23]
TNF-α 6p21 rs1800629 -308G/A Upstream 51; 48 0.76 (0.31–1.85)c,n 0.55 [20]
rs1800629 -308G/A Upstream 95; 87 4.66 (1.73–12.5) c 0.001 [24]
rs1800629 -308G/A Upstream 259; 645 1.25 (0.83–1.87) 0.29 [25]
rs361525 -238G/A Upstream 259; 645 1.57 (1.07–2.29) 0.018 [25]
TSPAN8/LGR5 12q14–q21 rs7961581 C/T Intergenic 868; 504 0.93 (0.73–1.17)e 0.516 [8]
TXNIP 1q21 rs7211 C/T 3′ UTR 623; 969 0.97 (0.82–1.14) 0.67 [18]
UBQLNL 11p15 rs979752 C/T Upstream 868; 504 1.04 (0.84–1.30)e 0.70 [8]
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Chrom: chromosome. Risk alleles are marked in bold. na; nb. Sample for cases and controls, respectively. cConventional OR (unadjusted) was assessed by us from allele or genotype frequencies reported. dLargest n was registered. eTest without ancestry correction was considered. fCombined datasets were registered. gRisk was only observed in nonobese T2D patients (OR = 1.25; p = 0.009). hOnly Genotypes of T2D patients and healthy controls were used in our analysis. iAssessment derived from the sum of T2D patients (obese and nonobese). jThe authors reported a protector effect for the A allele (OR = 0.65; p < 0.001), but in our estimation we took as reference the A allele, since it is the most common. kSignificant analysis with ancestry correction was taken. lAssociation was only found in early-onset T2D (OR = 1.39; p = 0.024). mJust the population of Guerrero was recorded due to possible overlapping of the patients from the Mexico City with [10]. nThe G allele was assessed as risk by the authors; but in our analysis we took the A allele, the same as that in previous studies.

Table 2.

Analysis of SNPs studied by two or more groups in Mexican mestizos.

Gene dbSNP loc Cases
(allele)		 Controls
(allele)		 Risk allele frequency
(%) 		OR (95% CI) p ∗ value Reference
Cases Controls
CAPN10 rs3792267 1086 928 29.5 28.7 1.06 (0.87–1.29) 0.56 [11–13]
CAPN10 rs3842570 772 656 61.7 62.5 0.96 (0.78–1.20) 0.74 [11, 13, 14]
CAPN10 rs5030952 686 530 19.0 18.3 1.04 (0.78–1.40) 0.78 [11, 13]
CDKAL1 rs7754840 3092 3074 31.4 29.1 1.12 (1.00–1.25) 0.044 [8, 10]
HHEX rs1111875 2974 2448 62.8 61.7 1.05 (0.94–1.17) 0.43 [8, 17]
IRS1 rs1801278 2326 2380 6.6 2.8 2.45 (1.83–3.28) <0.0001 [12, 19]
PPARG rs1801282 3492 3472 87.3 86.7 1.05 (0.91–1.21) 0.51 [8, 12]
SLC30A4 rs13266634 2964 2448 76.3 73.0 1.19 (1.05–1.35) 0.005 [8, 17]
TCF7L2 rs7903146 3740 3042 17.8 14.1 1.32 (1.16–1.50) <0.0001 [8, 12, 22]
TCF7L2 rs12255372 2476 2586 18.3 11.6 1.40 (1.19–1.65) <0.0001 [12, 22]
TNF-α rs1800629 810 1560 11.5 6.2 1.96 (1.45–2.64) <0.0001 [20, 24, 25]
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∗Yates' correction chi-square test.

4. Discussion

This review about genetics of T2D in Mexican mestizo subjects shows that 26 polymorphisms distributed in 21 genes are associated with this disease, so T2D has a high heterogeneity in our population, the same as that in other ethnic groups. Therefore, in some individuals alleles of certain genes are involved, while in others subjects are implicated variants of different genes. A previous conclusion that T2D in Mexican mestizos is genetically homogeneous was based on an analysis of three genetic markers [26] and here appears untenable. Though the Mexican mestizo population has a European genetic ancestry near 30% [27], not all the alleles conferring diabetes risk in Europeans are associated with T2D in our population [8]. These variations could be related to genetic background, differences in clinical classifications, sample size, selection and analysis criteria, and environmental factors such as obesity, lifestyle, and diet. On the other hand, researches in several ethnic groups have shown association of T2D with genes not yet analyzed in Mexican population [5, 6, 28–32]. It would be important to carry out the analysis of such genes to determine whether these variants are also associated with T2D in Mexican patients and increase the knowledge about the genetic epidemiology of this disorder in our country.

Regarding Mexican studies, an increased risk was detected when analysis was performed adjusting covariates. For instance, Cruz et al. observed an additive effect in the T2D risk when they considered variables such as age, education, sex, body mass index, and ancestry [10]. Gamboa-Meléndez et al. reported association with T2D for the polymorphisms rs7923837 (HHEX), rs4402960 (IGF2BP2), and rs2237892 (KCNQ1) only when ancestry was adjusted [8]. For the polymorphisms rs864745 (JAZF1) and rs757705 (NXPH1), the analysis stratified by ancestry did not show significant differences, whereas an association was observed in the comparison without such an adjustment. In addition, they found association for rs7903146 (TCF7L2) and rs7754840 (CDKAL1) just in early-onset T2D [OR = 1.39 (1.04–1.85), p = 0.024] and in nonobese T2D patients [OR = 1.25 (1.06–1.49), p = 0.009], respectively. Another study found a lower OR when the analysis was adjusted by sex, body mass index, and family history of T2D for three polymorphisms of IRS1 in a dominant model [19].

The reported association of rs3842570 (CAPN10) [14], rs909253 (LTA) [20], and rs1800629 (TNF-α) [24] with T2D should be interpreted with caution given the small sample sizes and poor statistical power. With respect to the rs1345365 polymorphism (ELMO1), the authors reported a protector effect for the A allele [OR = 0.65 (0.55–0.78), p < 0.001] [16]. But in our analysis we took as reference the A allele, as it is the most common; thus, the G allele showed association with T2D [OR = 1.37 (1.02 to 1.84), p = 0.035].

Since T2D is a complex disorder and several genes are implicated in its etiology and evolution, the identification of risk alleles could be useful, because if the involved genes and their function are known, it is more probable to achieve prevention, treatment, prognosis, and/or cure of the disease. Complications could also be prevented or treated better [29, 33]. However, published studies demonstrate that genetic screening for the prediction of T2D in high risk subjects is currently of little value in clinical practice. Actually, genetic risks are difficult to calculate because several alleles could contribute to an additive effect to T2D susceptibility [34], not to mention the diverse environmental factors involved. Although some of these genes are implicated in the glucose and fat metabolism, β-cell function, and sensitivity and secretion of insulin [29, 35], how some of their variants increase the T2D risk remains to be elucidated [29]. Anyway, it is fundamental to analyze the genetic epidemiology of this disease in each population because of the underlying differences in genetic background and lifestyle among ethnic groups. So, it is possible that polymorphisms associated with T2D in some races do not show association in others. Genome-wide association studies will ultimately precise the genetic landscape.

Acknowledgments

The authors thank Dr. Horacio Rivera for his support and critical review of the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest concerning the publication of this paper.

Authors' Contributions

Eiralí Guadalupe García-Chapa and Juan Pablo Meza-Espinoza contributed equally to this work. All the authors participated in drafting and review of this paper.

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