ABCMdb

PMID: 18003760

Villarreal-Molina MT, Flores-Dorantes MT, Arellano-Campos O, Villalobos-Comparan M, Rodriguez-Cruz M, Miliar-Garcia A, Huertas-Vazquez A, Menjivar M, Romero-Hidalgo S, Wacher NH, Tusie-Luna MT, Cruz M, Aguilar-Salinas CA, Canizales-Quinteros S
Association of the ATP-binding cassette transporter A1 R230C variant with early-onset type 2 diabetes in a Mexican population.
Diabetes. 2008 Feb;57(2):509-13. Epub 2007 Nov 14., [PubMed]

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0 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population M. Teresa Villarreal-Molina,1 M. Teresa Flores-Dorantes,1 Olimpia Arellano-Campos,2 Marisela Villalobos-Comparan,1 Maricela Rodrı´guez-Cruz,3 Angel Miliar-Garcı´a,4 Adriana Huertas-Vazquez,1 Marta Menjivar,5 Sandra Romero-Hidalgo,6 Niels H. Wacher,7 M. Teresa Tusie-Luna,1 Miguel Cruz,7 Carlos A. Aguilar-Salinas,2 Samuel Canizales-Quinteros,1 and the Metabolic Study Group 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. Login to comment 4 ABCA1 p.Arg230Cys 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 ϭ 0.001). Login to comment 7 ABCA1 p.Arg230Cys 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 ϭ 7.6 ϫ 10-6 and 9.4 ϫ 10-8 , respectively). Login to comment 8 ABCA1 p.Arg230Cys CONCLUSIONS-The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population. Login to comment 18 ABCA1 p.Arg230Cys 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. Login to comment 46 ABCA1 p.Arg230Cys 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). Login to comment 52 ABCA1 p.Arg230Cys 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. Login to comment 59 ABCA1 p.Arg230Cys Significantly lower fasting insulin and higher A1C levels were observed in R230C/C230C than in R230R diabetic subjects (P ϭ 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. Login to comment 60 ABCA1 p.Arg230Cys 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 ϭ 0.001) (Table 2), even after adjusting for admixture (P ϭ 0.0008). Login to comment 61 ABCA1 p.Arg230Cys Interestingly, age at diagnosis was significantly lower in R230C/C230C than in R230R diabetic individuals (42.6 Ϯ 9.3 years vs. 47.0 Ϯ 10.9 years, respectively; P ϭ 0.005, adjusted by sex and BMI) (Table 1). Login to comment 62 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys We then tested the association of R230C with early-onset type 2 diabetes (Յ45 years, n ϭ 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). Login to comment 63 ABCA1 p.Arg230Cys While the association of R230C/C230C with late-onset type 2 diabetes (Ͼ45 years, n ϭ 123) was not significant (P ϭ 0.149), its association with early-onset type 2 diabetes was highly significant (OR 3.776, 95% CI 2.121-6.748, P ϭ 3.3 ϫ 10-6 ) even after adjusting for admixture (8.1 ϫ 10-6 ) (Table 2). Login to comment 64 ABCA1 p.Arg230Cys TABLE 1 Clinical and biochemical parameters of the initial study group Type 2 diabetic patients Type 2 diabetic patients Nondiabetic control subjects R230R R230C/C230C n 244 202 184 60 Males (%) 31.6 30.2 29.9 36.7 Age (years) 53.9 Ϯ 12.6 60.5 Ϯ 9.4* 54.6 Ϯ 12.4 51.7 Ϯ 13.1 Age at diagnosis (years) 45.8 Ϯ 10.7 - 47.0 Ϯ 10.9 42.6 Ϯ 9.3§ BMI (kg/m2 ) 28.4 Ϯ 4.8 27.4 Ϯ 4.3† 28.3 Ϯ 4.8 28.9 Ϯ 4.7 Fasting glucose (mmol/l) 9.8 Ϯ 4.3 4.9 Ϯ 0.6* 9.8 Ϯ 4.3 9.8 Ϯ 4.5 Fasting insulin (pmol/l) 71.1 Ϯ 54.6 51.2 Ϯ 40.6* 75.2 Ϯ 59.0 58.3 Ϯ 35.3‡ A1C (%) (n ϭ 141) 8.9 Ϯ 2.3 ND 8.7 Ϯ 2.2 9.9 Ϯ 2.5‡ HOMA-IR 4.9 Ϯ 5.1 1.9 Ϯ 1.5* 5.5 Ϯ 5.9 4.3 Ϯ 2.9 HOMA-beta 60.9 Ϯ 53.2 140.3 Ϯ 161.9* 62.3 Ϯ 53.9 57.1 Ϯ 51.4 HDL cholesterol (mmol/l) 1.1 Ϯ 0.3 1.3 Ϯ 0.4* 1.1 Ϯ 0.3 1.0 Ϯ 0.3 Apo A-I (mg/dl) 132.7 Ϯ 25.8 147.4 Ϯ 22.9* 134 Ϯ 27.1 125 Ϯ 22.3 Treatment (%) - Not treated 27 (15.3) 18 (13.4) 9 (20.9) Diet plus exercise 8 (4.5) 7 (5.2) 1 (2.3) OHA 124 (70.8) 95 (70.1) 29 (67.4) OHA plus insulin 14 (8.2) 11 (8.2) 3 (6.9) Insulin 4 (2.3) 3 (2.2) 1 (2.3) Data are means Ϯ SD unless otherwise indicated. Login to comment 65 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys *P Ͻ 0.001, †P Ͻ 0.05 comparing type 2 diabetic patients with nondiabetic subjects; ‡P Ͻ 0.05, R230C/C230C vs. R230R, adjusted for age, sex, BMI, duration of diabetes, and treatment (patients with insulin treatment were excluded); §P Յ 0.005, adjusted for sex and BMI. Login to comment 68 ABCA1 p.Arg230Cys There was no evidence for LD between R230C and the other four SNPs. Login to comment 69 ABCA1 p.Arg230Cys Individually, all SNPs other than R230C failed to show association with type 2 diabetes (P Ͼ 0.311, Table 3). Login to comment 72 ABCA1 p.Arg230Cys 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 ϭ 0.005). Login to comment 73 ABCA1 p.Arg230Cys However, although R230C remained significantly associated with early-onset type 2 diabetes (OR 2.190, 95% CI 1.258-3.732, P ϭ 0.004), the improvement in significance was less evident than that observed in the initial study group. Login to comment 74 ABCA1 p.Arg230Cys 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. Login to comment 75 ABCA1 p.Arg230Cys R230C/C230C type 2 diabetic individuals had a significantly lower age at diagnosis (44.1 Ϯ 9.2 years vs. 46.56 Ϯ 10.9 years, P ϭ 0.028), and higher BMI (29.1 Ϯ 4.2 vs. 28.3 Ϯ 4.2 kg/m2 , P ϭ 0.047) than in R230R type 2 diabetes subjects in both study populations (data not shown). Login to comment 76 ABCA1 p.Arg230Cys 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 ϭ 7.6 ϫ 10-6 ), particularly with early-onset type 2 diabetes (OR 2.757, 95% CI 1.869-3.917, P ϭ 9.4 ϫ 10-8 ). Login to comment 78 ABCA1 p.Arg230Cys 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. Login to comment 79 ABCA1 p.Arg230Cys R230C/ C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals (P ϭ 0.001). Login to comment 80 ABCA1 p.Arg230Cys DISCUSSION The ABCA1 R230C variant was significantly associated with type 2 diabetes in the Mexican population. Login to comment 82 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys 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. Login to comment 84 ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys This is epidemiologically relevant in TABLE 2 R230C genotype frequencies in type 2 diabetic patients and nondiabetic control subjects stratified according to age of onset of type 2 diabetes Genotype ͓n (%)͔ OR P * vs. nondiabeticR230R R230C/C230C Initial study group Type 2 diabetic patients (n ϭ 244) 184 (75.4) 60 (24.6) 2.501 0.001 Early-onset type 2 diabetes (n ϭ 121) 81 (66.9) 40 (33.1) 3.776 3.3 ϫ 10-6 Late-onset type 2 diabetes (n ϭ 123) 103 (83.7) 20 (16.3) 1.619 0.149 Nondiabetic subjects (n ϭ 202) 179 (88.6) 23 (11.4) Replication group Type 2 diabetic patients (n ϭ 242) 182 (75.2) 60 (24.8) 2.098 0.005 Early-onset type 2 diabetes (n ϭ 119) 88 (73.9) 31 (26.1) 2.190 0.004 Late-onset type 2 diabetes (n ϭ 123) 94 (76.4) 29 (23.6) 1.935 0.032 Nondiabetic subjects (n ϭ 225) 194 (86.2) 31 (13.8) Combined analysis Type 2 diabetic patients (n ϭ 486) 366 (75.3) 120 (24.7) 2.097 7.6 ϫ 10-6 Early-onset type 2 diabetes (n ϭ 240) 169 (70.4) 71 (29.6) 2.757 9.4 ϫ 10-8 Late-onset type 2 diabetes (n ϭ 246) 197 (80.1) 49 (19.9) 1.826 0.010 Nondiabetic subjects (n ϭ 427) 373 (87.4) 54 (12.6) Data are n (%). Login to comment 85 ABCA1 p.Arg230Cys *P values and ORs calculated by a logistic regression analysis using a dominant model (R230C/C230C vs. R230R) with adjustment for sex and BMI. Login to comment 87 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg230Cys ABCA1 p.Arg230Cys TABLE 3 Allelic association analyses results of individual SNPs in the ABCA1 gene in case-control samples of the initial study group dbSNP ID Position* ABCA1 region Major/minor allele MAF Allele frequencies P† P‡ Type 2 diabetes Nondiabetic rs2000069 106675690 Intron 5 C/T 0.380 0.372 0.390 0.729 0.999 rs2230806 (R219K) 106660688 Exon 7 G/A 0.327 0.312 0.346 0.311 0.845 rs9282541 (R230C) 106660656 Exon 7 C/T 0.097 0.131 0.056 0.0002 0.001 rs2487037 106657158 Intron 7 C/T 0.261 0.256 0.267 0.585 0.998 rs3818689 106634837 Intron 18 G/C 0.054 0.056 0.052 0.772 0.999 *Position is in contiguous NT_008470.18; †P values for type 2 diabetes with respect to the minor allele; ‡P values after Bonferroni correction for the five different SNPs tested. Login to comment 90 ABCA1 p.Arg230Cys 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). Login to comment 93 ABCA1 p.Arg230Cys This age difference or other population stratification factors may explain the higher R230C/C230C genotype frequency reported in first group. Login to comment 95 ABCA1 p.Arg230Cys 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. Login to comment 102 ABCA1 p.Arg230Cys In addition to its effect on insulin secretion, R230C may also be associated with type 2 diabetes through an increased risk of obesity. Login to comment 103 ABCA1 p.Arg230Cys However, the R230C/C230C genotypes were significantly more frequent in obese diabetic than in obese nondiabetic individuals, suggesting that both associations may be independent. Login to comment 105 ABCA1 p.Arg230Cys 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 beta-cell physiology and the effects of cholesterol lipotoxicity on insulin secretion. Login to comment 124 ABCA1 p.Arg230Cys There is no evidence for LD between the R230C variant and the other four SNPs. Login to comment 125 ABCA1 p.Arg219Lys ABCA1 p.Arg230Cys However, SNPs rs2230806 (R219K) and r2487037 were in high LD (r2 >0.8). Login to comment 126 ABCA1 p.Arg219Lys However, SNPs rs2230806 (R219K) and r2487037 were in high LD (r2 >0.8). Login to comment