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Published online November 14, 2007
Diabetes 57:509-513, 2008
DOI: 10.2337/db07-0484
© 2008 by the American Diabetes Association
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Brief Report

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

M. Teresa Villarreal-Molina1, M. Teresa Flores-Dorantes1, Olimpia Arellano-Campos2, Marisela Villalobos-Comparan1, Maricela Rodríguez-Cruz3, Angel Miliar-García4, Adriana Huertas-Vazquez1, Marta Menjivar5, Sandra Romero-Hidalgo6, Niels H. Wacher7, M. Teresa Tusie-Luna1, Miguel Cruz7, Carlos A. Aguilar-Salinas2, Samuel Canizales-Quinteros1, and the Metabolic Study Group

1 Unit of Molecular Biology and Genomic Medicine, Salvador Zubiran National Institute of Medical Sciences and Nutrition (INCMNSZ), Institute of Biomedical Research, National Autonomous University of Mexico, Mexico City, Mexico
2 Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico
3 Unit of Medical Research in Nutrition, Pediatrics Hospital, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico City, Mexic
4 Postgraduate Studies and Research Section, Postgraduate Studies and Research Section, School of Medicine, National Polytechnic Institute, Mexico City, Mexico
5 Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico, Mexico City, Mexico
6 National Coordination of Genetic Medicine, Institute of Social Security and Services for Government Employees, Mexico City, Mexico
7 Units of Medical Research in Clinical Epidemiology and Biochemistry, Specialties Hospital, National Medical Center XXI Century, Mexican Institute of Social Security, Mexico City, Mexico

Address correspondence and reprint requests to Samuel Canizales-Quinteros, PhD, Unidad de Biología Molecular y Medicina Genómica, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga #15 Colonia Sección 16, Tlalpan 14000, México D.F. E-mail: cani{at}servidor.unam.mx

Key Words: ABCA1, ATP-binding cassette transporter A1 • AIM, ancestry informative marker • Apo A-I, apolipoprotein A-I • LD, linkage disequilibrium • SNP, single nucleotide polymorphism


   ABSTRACT
TOP
 ABSTRACT
RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
OBJECTIVE—The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic β-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population.

RESEARCH DESIGN AND METHODS—The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20–69 years (121 with onset ≤45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics.

RESULTS—R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis ≤45 years) (OR 3.776, P = 3.3 x 10–6). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 x 10–6, respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 x 10–6 and 9.4 x 10–8, respectively).

CONCLUSIONS—The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.

The identification of ATP-binding cassette transporter A1 (ABCA1) as the defective gene in Tangier disease has contributed substantially to the understanding of its role as a key transporter of cholesterol and phospholipids across cell membranes to acceptor molecules such as apolipoprotein (Apo) A-I (1–3). While the role of ABCA1 in HDL formation is well known, it may have multiple and diverse functions in other tissues (4,5). ABCA1 is expressed in pancreatic β-cells and is regulated by a transcriptional regulatory network including several proteins and drugs involved in lipid and glucose metabolism (6,7). Moreover, insulin downregulates ABCA1 expression in vitro, while glucose upregulates ABCA1 expression in leukocytes in vivo (8,9). Very recently, mice with specific inactivation of ABCA1 in β-cells showed accumulation of cellular cholesterol, marked insulin secretion reduction in vivo, and progressive glucose tolerance impairment, establishing a pivotal role for ABCA1 in pancreatic β-cell function (10).

Although there is solid evidence of the role of ABCA1 in glucose metabolism, the association of ABCA1 with type 2 diabetes in humans has not been thoroughly studied. Daimon et al. (11) reported an ABCA1 diplotype associated with type 2 diabetes in the Japanese population, suggesting this gene may have influence on the pathophysiology of type 2 diabetes independently of serum HDL cholesterol levels. In a previous study, we found an apparently functional ABCA1 variant significantly associated not only with low HDL cholesterol levels, but also with obesity and the metabolic syndrome, that is apparently exclusive to Amerindian and Amerindian-derived populations such as Mexican-Mestizos. We also observed an association of this variant with type 2 diabetes in a reduced number of diabetic individuals recruited from general population (12). Based on this evidence, we sought to confirm and further investigate the role of the ABCA1 R230C variant in type 2 diabetes in this population.


   RESEARCH DESIGN AND METHODS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 
Subjects.
The initial study group included 244 unrelated Mexican-Mestizo diabetic patients attending three different reference centers in Mexico City, diagnosed between the ages 20 and 80 years. Type 2 diabetes was diagnosed according to World Health Organization criteria (13). To reduce the probability of including control individuals who may develop type 2 diabetes in later life, a group of 202 unrelated nondiabetic subjects with no family history of diabetes aged 50–80 years made up the control group: 68 control subjects from a previous study (12), and 134 additional control subjects who met the same criteria. Absence of diabetes was defined as no medical history of diabetes and fasting glucose levels ≤5.5 mmol/l. Only individuals born in Mexico whose parents and grandparents identified themselves as Mexican-Mestizos were included.

The association test was replicated in an independent group of type 2 diabetic patients (n = 242) and control subjects (n = 225, aged 45–65 years) recruited from the Siglo XXI Medical Center of the Mexican Institute of Social Security (IMSS) in Mexico City, as described previously (14). The project was approved by the Institutional Committee of Biomedical Research in Humans of the Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) and Ethics Committee of the Siglo XXI Medical Center. All individuals gave written informed consent before their inclusion in the study. Descriptive characteristics of the replication group are given in online Appendix Table 1 (available online at http://dx.doi.org/10.2337/db07-0484). The biochemical measurements are described in supplementary information that is also available online.


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  		TABLE 1 Clinical and biochemical parameters of the initial study group

 
Single nucleotide polymorphisms genotyping.
R230C and four additional single nucleotide polymorphisms (SNPs) (rs3818689, rs2487037, rs2000069 and rs2230806) contained in three haplotype blocks within the ABCA1 gene were genotyped using Taqman assays (ABI Prism 7900HT Sequence Detection System, Applied Biosystems). Genotyping call exceeded 95% per SNP, and no discordant genotypes were observed in 36 duplicate samples. Deviation from Hardy-Weinberg equilibrium was not observed for any SNP. In addition, a panel of 10 ancestry informative markers (AIMs) was used to evaluate whether the association analysis was confounded by population stratification (12) (see online supplementary information).

Statistical analyses.
Student's t test was used to compare phenotypic differences between case and control individuals. Although associations were tested under dominant, recessive, or additive models, because the number of C230C homozygotes was reduced, the dominant model (R230C/C230C vs. R230R) was considered the most appropriate. Covariance analysis was used to construct a model for quantitative traits where age, sex, and BMI were included as covariates (when appropriate) and genotype was included as a fixed factor (GLM Univariate). Since fasting serum insulin/triglyceride levels and HOMA indices were not normally distributed, they were log transformed for analysis. Logistic regression analysis with adjustment for age, sex, and BMI was used to test for associations between genotype and type 2 diabetes (SPSS Version 10.0, Chicago, IL). The ADMIXMAP program (15) was used to test the possible effect of population stratification on associations with type 2 diabetes as previously described (12). Pairwise linkage disequilibrium between SNPs was calculated by direct correlation (r2), and haplotypes were inferred for each individual using Haploview (version 3.2) (16).


   RESULTS
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
DISCUSSION
 APPENDIX
 REFERENCES
 
Table 1 compares anthropometric and biochemical measurements in diabetic and control individuals of the initial study group. Significantly lower fasting insulin and higher A1C levels were observed in R230C/C230C than in R230R diabetic subjects (P = 0.011 and 0.015, respectively; adjusted by age, sex, BMI, duration of diabetes, and treatment); however, differences in insulin levels according to genotype were not observed in nondiabetic subjects.

Overall, R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%, OR 2.501, 95% CI 1.476–4.238, P = 0.001) (Table 2), even after adjusting for admixture (P = 0.0008). Interestingly, age at diagnosis was significantly lower in R230C/C230C than in R230R diabetic individuals (42.6 ± 9.3 years vs. 47.0 ± 10.9 years, respectively; P = 0.005, adjusted by sex and BMI) (Table 1). We then tested the association of R230C with early-onset type 2 diabetes (≤45 years, n = 121), based on the average age of diagnosis of R230C/C230C individuals and on the previous use of 45 years as the cutoff age in linkage and association studies for type 2 diabetes (17,18). While the association of R230C/C230C with late-onset type 2 diabetes (>45 years, n = 123) was not significant (P = 0.149), its association with early-onset type 2 diabetes was highly significant (OR 3.776, 95% CI 2.121–6.748, P = 3.3 x 10–6) even after adjusting for admixture (8.1 x 10–6) (Table 2).


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  		TABLE 2 R230C genotype frequencies in type 2 diabetic patients and nondiabetic control subjects stratified according to age of onset of type 2 diabetes

 
Figure 1 shows the approximate genomic locations of the four additional SNPs tested and linkage disequilibrium (LD) estimates in the initial study group. There was no evidence for LD between R230C and the other four SNPs. Individually, all SNPs other than R230C failed to show association with type 2 diabetes (P > 0.311, Table 3). Moreover, of the five most frequent haplotypes (>3%), only that including the 230C allele was associated with type 2 diabetes (P = 0.0004, P = 0.002 after Bonferroni correction) (online appendix Table 2), which is very similar to the association for the individual 230C allele (P = 0.0002, P = 0.001 after Bonferroni correction).


Figure 1
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  		FIG. 1. Pairwise LD among five SNPs within the ABCA1 gene. Drawing is not to scale. Exons are represented by boxes. Figure depicts the measured r2 between SNP pairs, represented by box shade intensity. There is no evidence for LD between the R230C variant and the other four SNPs. However, SNPs rs2230806 (R219K) and r2487037 were in high LD (r2 >0.8).

 

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  		TABLE 3 Allelic association analyses results of individual SNPs in the ABCA1 gene in case-control samples of the initial study group

 
To further test this association, we analyzed an independent group of Mexican type 2 diabetic case and control subjects. The results were very similar, as 24.8% of type 2 diabetic individuals and 13.8% of control subjects had R230C/C230C genotypes (OR 2.098, 95% CI 1.255–3.507, P = 0.005). However, although R230C remained significantly associated with early-onset type 2 diabetes (OR 2.190, 95% CI 1.258–3.732, P = 0.004), the improvement in significance was less evident than that observed in the initial study group. We were not able to test the association of R230C with fasting insulin levels and A1C in the replication group, as this information was not available.

R230C/C230C type 2 diabetic individuals had a significantly lower age at diagnosis (44.1 ± 9.2 years vs. 46.56 ± 10.9 years, P = 0.028), and higher BMI (29.1 ± 4.2 vs. 28.3 ± 4.2 kg/m2, P = 0.047) than in R230R type 2 diabetes subjects in both study populations (data not shown). The combined analysis of both groups revealed a highly significant association of R230C with type 2 diabetes (OR 2.097, 95% CI 1.483–2.960, P = 7.6 x 10–6), particularly with early-onset type 2 diabetes (OR 2.757, 95% CI 1.869–3.917, P = 9.4 x 10–8). Interestingly, all 10 C230C homozygotes identified had type 2 diabetes (8 were obese and 2 were overweight). To test whether the association of the R230C variant with type 2 diabetes is independent of its previously reported association with obesity (12), we tested the association including only obese individuals. R230C/C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals (P = 0.001).


   DISCUSSION
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
APPENDIX
 REFERENCES
 
The ABCA1 R230C variant was significantly associated with type 2 diabetes in the Mexican population. Because the association remained significant after adjusting for admixture, it is unlikely that population stratification confounded our analysis. Moreover, R230C was not in LD with any other SNP tested in neighboring haplotype blocks within the ABCA1 gene, suggesting that the R230C variant is functional and is a significant risk allele for type 2 diabetes in the Mexican population. Interestingly, the association with type 2 diabetes was highly significant in the early-onset group. This is epidemiologically relevant in the Mexican population because type 2 diabetes is highly prevalent (8.2%) (19), ~15% are diagnosed before age 40 years (20), and early onset leads to longer exposure to risk factors related to complications of diabetes (21).

It is important to point out that this study was conducted based on a previous observation in a reduced group of diabetic individuals who showed a very high frequency of R230C/C230C genotypes (41.2%) (12). These individuals were recruited from the general population, and most were unaware of their condition when interviewed. In contrast, the 486 diabetic individuals analyzed here were attending specialized clinics and were significantly older than the previously published group of diabetic individuals (mean age 54.0 ± 11.7 vs. 49.6 ± 11.8 years, P = 0.03). This age difference or other population stratification factors may explain the higher R230C/C230C genotype frequency reported in first group.

Obesity is known to lead to insulin resistance and is implicated as one of the main determinants of type 2 diabetes (22). Because R230C was previously found to be associated with obesity and obesity-related comorbidities (12), it could be speculated that it confers susceptibility to type 2 diabetes through obesity and insulin resistance. However, 10–40% of diabetic individuals are not insulin resistant (23). Aguilar-Salinas et al. (24) reported a high frequency of insulin secretion deficiency (85%) coexisting with insulin resistance in 35% of the cases in a group of early-onset type 2 diabetic Mexican individuals. Even though the mechanisms by which ABCA1 deficiency could lead to type 2 diabetes in humans have not been studied, Brunham et al. (10) recently reported that cholesterol accumulation in the pancreatic β-cell leads to insulin secretion failure in the mouse model, which may be an important component of lipotoxicity in pancreatic islets. They also found that selective loss of ABCA1 in pancreatic β-cells leads to age-related progressive impairment in glucose tolerance even in heterozygous mice. Moreover, Hao et al. (25) found that excess cholesterol inhibits insulin secretion, opening a novel set of mechanisms that may contribute to β-cell dysfunction and the onset of diabetes in obese patients. Detailed in vivo studies of the β-cell function are required to assess the effect of this variant on β-cell function.

In addition to its effect on insulin secretion, R230C may also be associated with type 2 diabetes through an increased risk of obesity. However, the R230C/C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals, suggesting that both associations may be independent. Thus, the consequences of this probably functional variant on pancreatic β-cell and adipocyte function could lead to increased risk of type 2 diabetes by more than one mechanism remaining to be elucidated.

In conclusion, our findings suggest there is an association of the R230C variant with early-onset type 2 diabetes in Mexican-Mestizos, which is in accordance with recent findings on β-cell physiology and the effects of cholesterol lipotoxicity on insulin secretion. This variant is epidemiologically relevant because of its high frequency and its association with type 2 diabetes. Functional analyses are required to further elucidate the role of ABCA1 variation in the pathogenesis of type 2 diabetes.


   APPENDIX
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
REFERENCES
 
The Metabolic Study Group includes the following:

From the Unit of Molecular Biology and Genomic Medicine, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ), Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Mexico City, Mexico: Salvador Ramírez-Jimenez, Leonor Jacobo, Margarita Zavala.

From the Department of Endocrinology and Metabolism, INCMNSZ, Mexico City, Mexico: Ivette Cruz-Bautista, Daniela Riaño, Cristina García-Ulloa, Lorena Robles, Francisco J. Gómez-Pérez.

From the Subdirección Médica, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico: Rubén Ramírez-Campuzano, Rebeca Sandoval-Silva.

From the Laboratory of Endocrinology, Unit of Investigation, Hospital Juárez de México, Mexico City, Mexico: Guadalupe Ortíz-López, María de los Ángeles Granados.

From the Unit of Medical Research in Human Genetics, Hospital de Pediatría, Centro Médico Nacional, Siglo XXI-IMSS, Mexico City, Mexico: Ramon Coral-Vazquez.

From the Unit of Medical Research in Clinical Epidemiology, Hospital de Especialidades No.2, CMNNO, Ciudad Obregón, Sonora, Mexico: Olga Brito-Zurita.

From the Laboratory of Reproductive Biology, Centro de Investigaciones Regionales Dr. Hideyo Noguchi, Universidad Autónoma de Yucatán, Yucatán, Mexico: Thelma Canto-de Cetina.

From the Unidades de Investigación Médica en Epidemiología Clínica y Bioquímica, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Mexico City. Mexico: Catarina Munguia and Maria Elena Sánchez Contreras.


   ACKNOWLEDGMENTS
 
This research was supported by grant 47414 from the Consejo Nacional de Ciencia y Tecnología (CONACyT) and was partially supported by grant IN227007 from DGAPA. The authors wish to thank Rosa María Cerezo, Maribel Rodriguez, Olga Gaja, and Luz E. Guillén-Pineda for their technical assistance and Dr. Graeme I. Bell for the critical review of the manuscript.

Electronic database information: Kbiosciences (http://www.kbioscience.co.uk), ADMIXMAP (http://www.ucd.ie/genepi/software.html).


   FOOTNOTES
 
M.T.V.-M. is currently affiliated with the National Institute of Genomic Medicine.

Published ahead of print at http://diabetes.diabetesjournals.org on 14 November 2007. DOI: 10.2337/db07-0484.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0484.

M.T.V.-M. and M.T.F.-D. contributed equally to this work.

A complete list of individuals and institutions participating in the Metabolic Study Group appears in the APPENDIX.

Received for publication April 6, 2007 and accepted in revised form November 7, 2007


   REFERENCES
TOP
 ABSTRACT
 RESEARCH DESIGN AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX
 REFERENCES
 

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