ABCMdb

PMID: 16446539

Andrikovics H, Pongracz E, Kalina E, Szilvasi A, Aslanidis C, Schmitz G, Tordai A
Decreased frequencies of ABCA1 polymorphisms R219K and V771M in Hungarian patients with cerebrovascular and cardiovascular diseases.
Cerebrovasc Dis. 2006;21(4):254-9. Epub 2006 Jan 27., [PubMed]

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No. Mutations Sentence Comment

0 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Original Paper Cerebrovasc Dis 2006;21:254-259 DOI: 10.1159/000091223 Decreased Frequencies of ABCA1 Polymorphisms R219K and V771M in Hungarian Patients with Cerebrovascular and Cardiovascular Diseases Hajnalka Andrikovicsa Endre Pongráczb Ákos Kalinac Anikó Szilvásia Charalampos Aslanidisd Gerd Schmitzd Attila Tordaia a Department of Molecular Genetics, National Medical Center, b Neurology Department, Central Hospital, Ministry of Interior, and c Hospital of the National Railways, Budapest, Hungary; d Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Germany and 0 8 1.6%, respectively) were decreased. Login to comment 1 ABCA1 p.Arg219Lys ABCA1 p.Val771Met V771M was almost exclusively (35/36) found in individuals carrying the R219K allele. Login to comment 2 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Conclusions: Our data confirm earlier observations that ABCA1 R219K and V771M polymorphisms may be associated with a protective role against CHD and extend those to another important pathologic condition, namely stroke. Login to comment 7 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met Methods: We investigated 244 unrelated, consecutively enrolled patients with ischemic stroke, 150 patients with coronary heart disease (CHD) and 193 blood donors for allele frequencies (AFs) of three common ABCA1 polymorphisms (R219K, V771M and I883M). Login to comment 8 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Results: Compared to controls (30.8 8 4.7 and 4.9 8 2.2%, respectively), decreased AFs were found in both patient groups for R219K and V771M (28.7 8 4.1 and 3.1 8 1.6% in stroke, and 25.7 8 5.0%; 1.3 8 1.3% in CHD patients, respectively). Login to comment 10 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Similarly, among CHD patients younger than 60, AFs of R219K and V771M (22.6 8 7.5 Received: July 25, 2005 Accepted: October 12, 2005 Published online: January 27, 2006 Attila Tordai Department of Molecular Genetics National Medical Center, Diószegi út 64 HU-1113 Budapest (Hungary) Tel./Fax +36 1 385 2255, E-Mail tordai@biomembrane.hu (c) 2006 S. Karger AG, Basel 1015-9770/06/0214-$23.50/0 Accessible online at: www.karger.com/ced To date, the ABCA1 gene proved to be highly polymorphic with large numbers of sequence variations leading to amino acid changes or affecting the putative promoter region [8] (see also http://www.abca1 mutants.all.at). Login to comment 28 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met DNA Isolation and Detection of ABCA1 R219K, V771M and I883M Alleles with LightCycler Hybridization Probe Technique DNA isolation was performed from anticoagulated peripheral blood with the standard 'salting-out` procedure. Login to comment 29 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met The following ABCA1sequencevariantswerestudied:R219K(exon7,c.969A]G, substitution of Arg219 by Lys); V771M (exon 16, c.2624G]A, substitution of Val771 by Met), and I883M (exon 18, c.2962A]G, substitution of Ile883 by Met). Login to comment 53 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met 2006;21:254-259256 Results Genotyping for R219K, V771M and I883M ABCA1 Allelic Variants Using genomic DNA samples, simultaneous genotyping was carried out in the control blood donor and the stroke- and CHD-affected patient groups by PCR and fluorescent allelic discrimination techniques. Login to comment 55 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val771Met In the control group, AF figures (30.8 8 4.7, 4.9 8 2.2 and 12.4 8 4.5%) were found in the expected range for R219K, V771M and I883M, respectively. Login to comment 56 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Decreased AFs were found in both patient groups for R219K and V771M variants (28.9 8 4.1 and 3.3 8 1.6% in stroke, and 25.7 8 5.0% and 1.3 8 1.3% in CHD, respectively). Login to comment 57 ABCA1 p.Val771Met In the CHD group, the decrease in V771M AF was significant (p = 0.009) by univariate analyses. Login to comment 59 ABCA1 p.Arg219Lys ABCA1 p.Val771Met In a subset of stroke patients with disease onset before 50 (n = 114), both variants occurred in significantly lower frequencies compared to the control group [R219K: 22.4 8 5.5%, p = 0.013, crude OR = 0.55 (0.34-0.88); V771M: 1.8 8 1.7%, p = 0.045, crude OR = 0.33 (0.111.00)]. Login to comment 60 ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met A similar tendency was observed in the CHD group in a subset of patients younger than 60 (n = 62) for R219K and V771M, but only the V771M AF decrease was significant [22.6 8 3.6%, p 1 0.05; and 0 8 1.6%, p = 0.005, crude OR = 0.07 (0.004-1.2)]. Login to comment 61 ABCA1 p.Ile883Met The AF of the third allelic variant, I883M, did not show significant differences in the patient groups (12.3 8 3.8% in CHD and 15.2 8 3.2% in stroke patients) and the subgroups of different ages at onset studied. Login to comment 62 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Figure 1 further illustrates the tendency of R219K and V771M AF decreases following stratification of the patient groups by age at onset. Login to comment 63 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met Multivariate analyses (logistic regression) also showed that the R219K and V771M variants are protective factors against stroke, independently from age and sex [R219K: p = 0.032, adjusted OR: 0.68 (0.48-0.97); V771M: p = 0.017, adjusted OR: 0.34 (0.14-0.82)]. Login to comment 64 ABCA1 p.Val771Met In the CHD group, only V771M proved to be a significant independent protective factor [p = 0.027, adjusted OR: 0.08 (0.01-0.75), table 1]. Login to comment 66 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Similarly to results of the entire stroke group, R219K AF reduction was 27.4 8 4.9%, p = 0.015, adjusted OR: 0.59 (0.39-0.91), and V771M AF reduction was 3.3 8 2.0%, p = 0.042, adjusted OR: 0.36 (0.13-0.97) compared to control. Login to comment 67 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met We also observed significant R219K and V771M AF reduction in patients with CT-proven ischemic stroke [n = 124; R219K: 24.6 8 5.5%, p = 0.049, adjusted OR: 0.64 (0.41-0.99), and V771M: 1.2 8 1.4%, p = 0.021, adjusted OR: 0.19 (0.05-0.78)] compared to control. Login to comment 70 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met Genotyping results and statistical analyses for three common ABCA1 polymorphisms (R219K, V771M and I883M) in the control and patient groups Polymorphism AF % (895% CI) Heterozygous individuals n (%) Homozygous individuals n (%) p value Adjusted OR (95% CI) R219K Controls (n = 193) 30.8 (4.7) 73 (37.8) 23 (11.9) Patients with stroke (n = 244) 28.9 (4.1) 84 (34.1) 29 (11.8) 0.032 0.68 (0.48-0.97) Patients with CHD (n = 150) 25.7 (5.0) 55 (36.7) 11 (7.3) NS NS V771M Controls (n = 193) 4.9 (2.2) 19 (9.8) 0 Patients with stroke (n = 244) 3.3 (1.6) 14 (5.7) 1 (0.4) 0.017 0.34 (0.14-0.82) Patients with CHD (n = 150) 1.3 (1.3) 4 (2.7) 0 0.027 0.08 (0.01-0.75) I883M Controls (n = 105) 12.4 (4.5) 24 (22.9) 1 (1.0) Patients with stroke (n = 244) 15.2 (3.2) 61 (24.8) 7 (2.9) NS NS Patients with CHD (n = 150) 12.3 (3.8) 29 (19.3) 4 (2.6) NS NS AF = Allele frequency; CI = confidence interval; NS = nonsignificant. Login to comment 72 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met showed that R219K and V771M variants also play a protective role against stroke independently from age and sex in the stroke patient subgroup without ischemic heart disease [R219K: p = 0.040, adjusted OR: 0.69 (0.48-0.98), and V771M: p = 0.034, adjusted OR: 0.39 (0.16-0.93)]. Login to comment 73 ABCA1 p.Arg219Lys ABCA1 p.Val771Met These results indicate that the protective role of R219K and V771M in the stroke group cannot be explained with the frequent coexistence of CHD. Login to comment 78 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met We observed lower R219K and V771M AFs in the low-risk group (R219K: 27.4 8 5.2 vs. 30.6 8 6.6%, and V771M: 2.1 8 1.7 vs. 4.6 8 3.0%, respectively), but the differences were not significant. Login to comment 81 ABCA1 p.Arg219Lys However, the genotype distribution of R219K showed a significant (p = 0.00465) alteration from HWE exclusively in the stroke-affected patient group. Login to comment 84 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met The V771M allele was almost exclusively found in individuals carrying the R219K allele (36/37 V771M carriers were positive for R219K). Login to comment 86 ABCA1 p.Arg219Lys ABCA1 p.Val771Met 0.0005 by the Arlequin software) was observed between V771M and R219K. Login to comment 87 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Moreover, a similar, non-random allelic association was observed between R219K and I883M variants (p ! Login to comment 89 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Combining all genotyping results, 94/135 (69.6%) of I883M carriers were also positive for R219K, while only 148/374 (39.6%) of I883M wild-type individuals were positive for R219K. Login to comment 90 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The distribution of double-positive (R219K and I883M carriers) and single-positive (only I883M carriers) individuals was similar in the control, in the stroke and in the CHD-affected groups. Login to comment 91 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys These results suggest that the R219K and I883M polymorphisms are also in linkage disequilibrium in our population, although the common occurrence of these variants in the same individual is not likely to be related to disease development. Login to comment 92 ABCA1 p.Ile883Met ABCA1 p.Val771Met No significant linkage disequilibrium was observed between V771M and I883M. Login to comment 94 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Comparisons of AFs of the ABCA1 R219K and V771M variants in the control and patient groups. Login to comment 96 ABCA1 p.Arg219Lys ABCA1 p.Val771Met AF values and 95% CIs (bars) are presented for the R219K (a) and V771M (b) variants. Login to comment 103 ABCA1 p.Val771Met However, V771M carriers of the stroke group (n = 9) had higher plasma HDL levels than non-carriers [n = 104; 1.00 (0.90-1.30) vs. 1.60 (1.05-1.80) mM; p = 0.053]. Login to comment 106 ABCA1 p.Arg219Lys The most common missense polymorphism in the coding region of the ABCA1 gene is R219K with an AF of the K allele of 25-46% in the Caucasian population. Login to comment 107 ABCA1 p.Arg219Lys Two large studies investigating 2,028 and 794 individuals came to contradictory conclusions about the possible role of R219K in arteriosclerosis. Login to comment 108 ABCA1 p.Arg219Lys Brousseau et al. [15] reported an elevated R219K AF in patients with CHD and a low HDL level compared to disease-free individuals, suggesting that the mutant allele may cause a decrease in the HDL level, subsequently promoting arteriosclerosis and the development of CHD. Login to comment 109 ABCA1 p.Arg219Lys In their study, no correlation between R219K genotypes and the plasma lipid parameters could be observed either in the control group (mean age: 53 years) or in the CHD patient group (mean age: 64 years). Login to comment 110 ABCA1 p.Arg219Lys In another study, primarily focusing on ABCA1 haplotype analyses, R219K was also found to be associated with an increased risk for myocardial infarction [16]. Login to comment 111 ABCA1 p.Arg219Lys In contrast, Clee et al. [9] found that R219K carrier patients have reduced severity of CHD, decreased focal and diffuse arteriosclerosis and fewer coronary events than wild-type CHD patients. Login to comment 112 ABCA1 p.Arg219Lys They showed decreased triglyceride and increased HDL levels in their R219K carrier patients, although this difference existed only in the individuals younger than 57 years. Login to comment 113 ABCA1 p.Arg219Lys They concluded that R219K alone is an independent protective factor against CHD. Login to comment 114 ABCA1 p.Arg219Lys Further studies also described a putative protective effect of the R219K variant [18-20]. Login to comment 116 ABCA1 p.Val771Met Although we could only demonstrate significant AF decreases for the V771M variant comparing the entire CHD-affected group to the blood donor group, a trend toward an AF decrease could be demonstrated for both SNPs in both patient groups. Login to comment 117 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Moreover, the mean age of R219K homozygous and heterozygous patients with stroke was significantly higher than the age of R219K wild-type patients (58.2 8 13.0, 55.4 8 13.8 vs. 51.2 8 14.9 years, respectively). Login to comment 118 ABCA1 p.Arg219Lys In our CHD patient group, the mean age of the patients with different R219K genotype did not differ significantly. Login to comment 119 ABCA1 p.Arg219Lys ABCA1 p.Val771Met However, upon subgroup analyses, among patients affected by both diseases with younger ages at onset, both variants R219K and V771M showed significantly decreased AFs (fig. 1). Login to comment 120 ABCA1 p.Val771Met Clee et al. [9] reported that the ABCA1 V771M variant also plays a protective role against CHD. Login to comment 121 ABCA1 p.Arg219Lys ABCA1 p.Val771Met They explained this observation with the linkage disequilibrium between the R219K and V771M variants. Login to comment 122 ABCA1 p.Arg219Lys ABCA1 p.Val771Met ABCA1 p.Val771Met In our study, the V771M variant, or compound heterozygosity for V771M and R219K, showed significant AF reduction in the patient groups, in spite of the fact that our controls were relatively younger than our patients with stroke or CHD. Login to comment 123 ABCA1 p.Ile883Met We found no correlation between ABCA1 I883M genotypes and CHD or stroke development. Login to comment 125 ABCA1 p.Ile883Met Clee et al. [9] reported that I883M carrier patients have more severe manifestation of CHD. Login to comment 126 ABCA1 p.Ile883Met Wang et al. [10] found that I883M homozygotes had significantly higher plasma HDL cholesterol compared to heterozygous and wild-type individuals [10]. Login to comment 127 ABCA1 p.Ile883Met The differences between I883M genotypes might have remained hidden in the Hungarian population because of the low number of heterozygous and homozygous individuals. Login to comment 128 ABCA1 p.Arg219Lys ABCA1 p.Val771Met Our data confirm earlier observations that ABCA1 R219K and V771M polymorphisms may play a protective role against CHD and extend those to another frequently occurring pathologic condition, namely stroke. Login to comment