ABCMdb

PMID: 17510946

Rodriguez-Rodriguez E, Mateo I, Llorca J, Sanchez-Quintana C, Infante J, Garcia-Gorostiaga I, Sanchez-Juan P, Berciano J, Combarros O
Association of genetic variants of ABCA1 with Alzheimer's disease risk.
Am J Med Genet B Neuropsychiatr Genet. 2007 Oct 5;144B(7):964-8., [PubMed]

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No. Mutations Sentence Comment

1 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys To evaluate the relationship between ABCA1 genetic variants and Alzheimer`s disease (AD), independently or in concert with the APOE e4 allele, we examined three ABCA1 polymorphisms located in the coding region (R219K, I883M, and R1587K) and two ABCA1 polymorphisms in the promoter region (CÀ14T and CÀ477T) in a group of 372 Spanish AD patients and 440 controls. Login to comment 16 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We focused on the ABCA1 I883M, R1587K, and R219K variants in the coding region since these give rise to amino acid changes [Singaraja et al., 2003], they are common in European populations [Singaraja et al., 2003], and have been reported to alter the susceptibility to AD [Katzov et al., 2004; Sundar et al., 2006]; in addition, we examined two potentially functional polymorphisms (CÀ14T and CÀ477T) in the promoter region of ABCA1 gene [Hodoglugil et al., 2005; Kyriakou et al., 2005]. Login to comment 35 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Genotyping of ABCA1 I883M (rs 4149313), ABCA1 R1587K (rs 2230808), ABCA1 R219K (rs 2230806), ABCA1 CÀ14T (rs 1800977), and ABCA1 CÀ477T (rs 2422493) polymorphisms was performed by a Taq-Man single-nucleotide-polymorphism assay (Applied Biosystems, Warrington, Cheshire, UK) and an ABI PRISM 7000 sequence detection system (Applied Biosystems). Login to comment 43 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys RESULTS Control groups for ABCA1 I883M (P ¼ 0.16), ABCA1 R1587K (P ¼ 0.47), ABCA1 R219K (P ¼ 0.29), ABCA1 CÀ14T (P ¼ 0.46), and ABCA1 CÀ477T (P ¼ 0.70) polymorphisms were within the range of Hardy-Weinberg equilibrium; the same occurred in case groups for ABCA1 I883M (P ¼ 0.74), ABCA1 R1587K (P ¼ 0.29), ABCA1 R219K (P ¼ 0.82), ABCA1 CÀ14T (P ¼ 0.82), and ABCA1 CÀ477T (P ¼ 0.26). Login to comment 44 ABCA1 p.Arg219Lys As shown in Table I, the distribution of the allele and genotype frequencies of the ABCA1 polymorphisms did not differ significantly between AD and control groups, except for ABCA1 R219K: when compared to 219RR genotype, the 219RK and KK genotypes were associated with AD (age, sex and APOE e4 status-adjusted OR ¼ 1.50; 95% CI ¼ 1.10-2.04; P ¼ 0.009). Login to comment 49 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 polymorphisms in the coding region were in linkage disequilibrium (LD): I883M and R1587K, D0 ¼ 0.2071, P ¼ 0.033; I883M and R219K, D0 ¼ 0.2616, P < 0.001; R1587K and R219K, D0 ¼ 0.2343, P < 0.001. Login to comment 62 ABCA1 p.Arg219Lys We performed a meta-analysis for ABCA1 R219K polymorphism, and we pooled 10 case-control series [Wollmer et al., 2003; Katzov et al., 2004; Li et al., 2004; Ko¨lsch et al., 2006; Sundar et al., 2006] including the present study; the combined total of 3,162 patients and 2,725 controls from these studies were included in the meta-analysis, and using a random-effects model, the pooled OR (estimated by Der Simonian-Laird method) for AD associated with ABCA1 219RK and KK genotypes was 1.07 (95% CI ¼ 0.95-1.20), showing no association with AD risk. Login to comment 67 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Distribution of ABCA1 Polymorphisms in Patients and Controls Stratified by APOE e4 Allele Polymorphism APOE e4 allele carriers APOE e4 allele noncarriers Total sample Patients Controls Patients Controls Patients Controls I883M II 121 (0.63) 47 (0.59) 117 (0.65) 237 (0.66) 238 (0.64) 284 (0.65) IM 64 (0.34) 33 (0.41) 57 (0.31) 110 (0.31) 121 (0.33) 143 (0.33) MM 6 (0.03) 0 (0.00) 7 (0.04) 11 (0.03) 13 (0.03) 11 (0.02) Total 191 80 181 358 372 438 Allele frequency I/M 0.80/0.20 0.79/0.21 0.80/0.20 0.82/0.18 0.80/0.20 0.81/0.19 R1587K RR 109 (0.58) 44 (0.57) 110 (0.63) 228 (0.65) 219 (0.60) 272 (0.64) RK 72 (0.38) 30 (0.39) 62 (0.35) 109 (0.31) 134 (0.36) 139 (0.32) KK 8 (0.04) 3 (0.04) 6 (0.02) 17 (0.04) 14 (0.04) 20 (0.04) Total 189 77 178 354 367 431 Allele frequency R/K 0.77/0.23 0.77/0.23 0.79/0.21 0.80/0.20 0.78/0.22 0.79/0.21 R219K RR 83 (0.43) 40 (0.51) 82 (0.45) 192 (0.54) 165 (0.44) 232 (0.53) RK 82 (0.43) 30 (0.38) 85(0.48) 136 (0.38) 167 (0.45) 166 (0.38) KK 26 (0.14) 9(0.11) 13 (0.07) 29 (0.08) 39 (0.11) 38 (0.09) Total 191 79 180 357 371 436 Allele frequency R/K 0.65/0.35 0.70/0.30 0.69/0.31 0.73/0.27 0.67/0.33 0.72/0.28 CÀ14T CC 81 (0.42) 34 (0.42) 67 (0.37) 147 (0.42) 148 (0.40) 181 (0.42) CT 79 (0.41) 42 (0.53) 96 (0.53) 161 (0.46) 175 (0.47) 203 (0.47) TT 31 (0.17) 4 (0.05) 18 (0.10) 44 (0.12) 49 (0.13) 48 (0.11) Total 191 80 181 352 372 432 Allele frequency C/T 0.63/0.37 0.69/0.31 0.64/0.36 0.65/0.35 0.63/0.37 0.65/0.35 CÀ477T CC 50 (0.26) 19 (0.24) 43 (0.24) 103 (0.29) 93 (0.25) 122 (0.28) CT 88 (0.46) 47 (0.59) 87 (0.48) 177 (0.49) 175 (0.47) 224 (0.51) TT 53 (0.28) 14 (0.17) 51 (0.28) 80 (0.22) 104 (0.28) 94 (0.21) Total 191 80 181 360 372 440 Allele frequency C/T 0.49/0.51 0.53/0.47 0.48/0.52 0.53/0.47 0.49/0.51 0.53/0.47 Figures in parentheses indicate frequencies; P > 0.05 for all comparisons except 219 RK and KK genotypes versus RR: age, sex and APOE e4 status-adjusted OR ¼ 1.50 (95% CI ¼ 1.10-2.04; P ¼ 0.009). Login to comment 76 ABCA1 p.Arg219Lys Similarly, in a family-based association study using a set of Caribbean Hispanics, a possible interaction was found between ABCA1 R1587K and R219K polymorphisms and APOE [Shibata et al., 2006]. Login to comment 81 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Distribution of ABCA1 Polymorphisms in Patients and Controls Stratified by Age Groups Polymorphism 72 yearsa >72 yearsa Patients Controls Patients Controls I883M II 123 (0.68) 47 (0.69) 115 (0.61) 237 (0.64) IM 52 (0.28) 18 (0.27) 69 (0.36) 125 (0.34) MM 7 (0.04) 3 (0.04) 6 (0.03) 8 (0.02) Total 182 68 190 370 Allele frequency I/M 0.82/0.18 0.82/0.18 0.79/0.21 0.81/0.19 R1587K RR 101 (0.57) 44 (0.65) 118 (0.63) 228 (0.63) RK 69 (0.39) 21 (0.31) 65 (0.34) 118 (0.32) KK 8 (0.04) 3 (0.04) 6 (0.03) 19 (0.05) Total 178 68 189 365 Allele frequency R/K 0.76/0.24 0.80/0.20 0.80/0.20 0.79/0.21 R219K RR 86 (0.47) 41 (0.60) 79 (0.42) 191 (0.52) RK 74 (0.41) 23 (0.34) 93 (0.49) 143 (0.39) KK 21 (0.12) 4 (0.06) 18 (0.09) 34 (0.09) Total 181 68 190 368 Allele frequency R/K 0.68/0.32 0.77/0.23 0.66/0.34 0.71/0.29 CÀ14T CC 65 (0.36) 31 (0.48) 83 (0.44) 150 (0.41) CT 96 (0.53) 28 (0.43) 79 (0.41) 175 (0.47) TT 21 (0.11) 6 (0.09) 28 (0.15) 43 (0.12) Total 182 65 190 368 Allele frequency C/T 0.62/0.38 0.69/0.31 0.64/0.36 0.65/0.35 CÀ477T CC 42 (0.23) 22 (0.32) 51 (0.27) 100 (0.27) CT 90 (0.49) 33 (0.49) 85 (0.45) 191 (0.51) TT 50 (0.28) 13 (0.19) 54 (0.28) 81 (0.22) Total 182 68 190 372 Allele frequency C/T 0.48/0.52 0.57/0.43 0.49/0.51 0.53/0.47 a Median age at AD onset (72 years) was set as cut-off; figures in parentheses indicate frequencies; P > 0.05 for all comparisons except 219 RK and KK genotypes versus RR: age, sex and APOE (4 status-adjusted OR ¼ 1.90 (95% CI ¼ 0.99-3.64; P ¼ 0.05) in the 72 years subgroup, and adjusted OR ¼ 1.51 (95% CI ¼ 1.02-2.23; P ¼ 0.04) in the >72 years subgroup. Login to comment 83 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Odds Ratios for Alzheimer`s Disease Risk According to the Haplotype Frequencies of the ABCA1 Gene Coding Region Polymorphisms Among Patients and Controls R219K I883M R1587K Frequency in AD patients (n ¼ 369) Frequency in controls (n ¼ 435) ORa (95% CI) P* R I R 0.4794 0.5218 1 (reference) K I R 0.1402 0.1100 1.78 (1.17-2.70) 0.0073 R I K 0.0939 0.0995 0.83 (0.52-1.33) 0.43 K I K 0.0887 0.0808 1.27 (0.79-2.05) 0.31 R M R 0.0743 0.0869 0.92 (0.52-1.62) 0.78 K M R 0.0859 0.0701 1.49 (0.92-2.41) 0.11 R M K 0.0238 0.0147 4.85 (0.83-28.49) 0.081 K M K 0.0139 0.0163 1.13 (0.24-5.26) 0.88 a Odds ratios adjusting by age, sex and APOE genotype. Login to comment