ABCMdb

PMID: 22377775

Sun YM, Li HL, Guo QH, Wu P, Hong Z, Lu CZ, Wu ZY
The polymorphism of the ATP-binding cassette transporter 1 gene modulates Alzheimer disease risk in Chinese Han ethnic population.
Am J Geriatr Psychiatry. 2012 Jul;20(7):603-11., [PubMed]

Sentences

No. Mutations Sentence Comment

3 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile Methods: We studied the role of R219K and V825I polymorphisms of ABCA1 in modulating the risk of AD in 321 AD patients and 349 comparisons of Chinese Han. Login to comment 4 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile Genotyping of R219K and V825I were performed by PCR-restriction fragment length polymorphism analysis. Login to comment 5 ABCA1 p.Arg219Lys Results: The genotype distribution of R219K was different with more RK in total AD group (χ2 = 8.705, df = 2, p = 0.013), late-onset AD (LOAD) group (χ2 = 10.636, df = 2, p = 0.005), APOE non-ε4ε4 group (χ2 = 9.900, df = 2, p = 0.007), and female AD group (χ2 = 8.369, df = 2, p = 0.015). Login to comment 8 ABCA1 p.Val825Ile However, no discrepancy was found in V825I. Login to comment 9 ABCA1 p.Arg219Lys In R219K, age at onset (AAO) was significantly lower by 4.9 years on average in patients of KK genotype than those of RK in APOE ε4 carrying group and higher by 5.5 years in patients of KK genotype than those of RR in APOE ε4 noncarrying group. Login to comment 10 ABCA1 p.Val825Ile In V825I, AAO was diseased by 4.3 years in II genotype compared with VV genotype in APOE ε4 noncarrying group and 3.4 years in APOE ε4ε4 noncarrying group. Login to comment 16 ABCA1 p.Arg219Lys C 2012 American Association for Geriatric Psychiatry DOI: 10.1097/JGP.0b013e3182423b6a of R219K may relate to the development of AD in the east of China. Login to comment 22 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile But clinical investigation of its relationship to AD has commenced in these years and the results were controversial.19 Also, the investigation in Chinese ethnic Han people is rare.20 Here, we examined two single nucleotide polymorphisms (SNPs) in the coding regions of ABCA1: R219K (rs2230806) located in exon 7 with a G to A nucleotide change, which is most popular SNP in both CAD and AD examinations; V825I (rs2066715) located in exon 17 with a G to A as well, which associated with HDL-C and played an important role in CAD but was rarely reported in AD patients.21,22 We conducted a case-control study to investigate the genetic association of these two SNPs with AD in a population of Chinese Han in eastern China. Login to comment 36 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile Genotyping of R219K, V825I, and APOE Genomic DNA was extracted from the sodium citrate treated blood samples of both AD patients and comparisons by TIANamp blood DNA Kit (TIAN- GEN). Login to comment 37 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile The genotypes of R219K and V825I were the same as the previous report.23 The APOE genotypes were determined as described by Donohoe et al.24 Statistical Analysis Statistical analyses were performed using SPSS version 12.0 (SPSS Inc., Chicago, IL). Login to comment 48 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile Genotype and Allele Frequency Distribution R219K and V825I were under Hardy-Weinberg equilibrium in both AD and comparison groups (p > 0.20) (see Table, Supplemental Digital Content 1, http://links.lww.com/AJGP/A26, which demonstrates Hardy-Weinberg equilibrium of the two SNPs inAD patientsandcomparisongroup). Login to comment 50 ABCA1 p.Arg219Lys The distribution of genotype in R219K was different in AD patients and comparisons (χ2 = 8.705, df = 2, p = 0.013). Login to comment 52 ABCA1 p.Arg219Lys There was difference in genotype of R219K inLOAD group(χ2 = 10.636, df = 2, p= 0.005) but no difference in EOAD group (χ2 = 0.598, df = 2, p = 0.741). Login to comment 59 ABCA1 p.Val825Ile As for V825I, no differences were found in either genotypes or allele frequencies though stratified by AAO, gender, APOE ε4 carrying status, or APOEε4ε4 carrying status (Table 2). Login to comment 60 ABCA1 p.Arg219Lys As shown in Table 3, logistic regression was used to further analyze the R219K genotype in total population, LOAD-comparison group, and APOE ε4ε4 noncarrying group. Login to comment 64 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile Influence of ABCA1 Polymorphisms on AAO and MMSE Score of AD As shown in Table 4, using ANOVA, we analyzed the effects of R219K and V825I genotypes on the AAO and MMSE scores of AD patients which were divided according to the onset age, gender, and APOE ε4 and ε4ε4 carrying status. Login to comment 65 ABCA1 p.Arg219Lys When further using the post-hoc LSD multiple comparisons, in the R219K, we found that AAO was significantly lower by 4.9 years in patients of KK genotype than those of RK in APOE ε4 carrying group and higher by 5.5 years on average in patients of KK genotype than those of RR in APOE ε4 noncarrying group. Login to comment 66 ABCA1 p.Val825Ile In the V825I, AAO was diseased by 4.3 years in II genotype compared with VV genotype in APOE ε4 noncarrying group and 3.4 years in APOE ε4ε4 noncarrying group. Login to comment 68 ABCA1 p.Arg219Lys R219K locates in the major extracellular loop in N-terminus of the ABCA1 protein, important for the cholesterol efflux. Login to comment 69 ABCA1 p.Val825Ile ABCA1 p.Val825Ile V825I locates in the middle part of the protein corresponding to the sixth transmembrane α-helix and is highly conserved.25 From our results, we did not find the apparent differences either in genotypes or in allele frequencies in V825I though stratified by AAO, gender, and APOE ε4 and ε4ε4 status. Login to comment 70 ABCA1 p.Val825Ile Katzov et al.26 obtained the same results after genotyping 390 LOAD and 185 controls of Swedish population, but in their subjects of EOAD, the V825I was monomorphic. Login to comment 71 ABCA1 p.Val825Ile V825I polymorphism was rarely reported in AD patients, whereas it was associated with increased clinical events and severity of atherosclerosis in CAD patients,27,28 and significantly increased HDL-C in women. Login to comment 72 ABCA1 p.Val825Ile Wang et al.23 found no association of V825I with lipids levels in Chinese Han ethnic stroke patients. Login to comment 73 ABCA1 p.Val825Ile This may imply that V825I is conservative and exerts minor influence on cholesterol efflux activity. Login to comment 74 ABCA1 p.Val825Ile One recent research demonstrated the V825I substitution on ABCA1 function in cells, which indicated 825I variant having higher activity in mediating cholesterol efflux than the wild type (825V).29 They also observed a trend toward higher symptom onset age in 825I allele carriers in CAD patients, and unfortunately the AAO between the groups of genotypes did not reach significance. Login to comment 76 ABCA1 p.Val825Ile So V825I might not be that conservative and might have some effect on AD pathogenesis. Login to comment 77 ABCA1 p.Arg219Lys The R219K has been one of the most studied SNPs in both CAD and AD in recent years. Login to comment 78 ABCA1 p.Arg219Lys In CAD, the 219K was depicted to associate with either increased HDL-C or reduced severity of atherosclerosis.30 However, the role of R219K polymorphism in AD remains controversial. Login to comment 80 ABCA1 p.Arg219Lys Rodr´ıguez-Rodr´ıguez et al.31 found that RK + KK in R219K was significantly associated with AD and conferred a risk of 1.78 (p = 0.007) in 372 Spanish AD patients and 440 controls, the same as our results, and they also demonstrated the RK + KK genotypes increased risk in both EOAD and LOAD. Login to comment 82 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile Genotypes and Allele Frequencies of R219K and V825I Polymorphisms in ABCA1 Gene in AD Patients and Comparison Group Comparison Comparison R219K AD (%) Group (%) V825I AD (%) Group (%) Total, n 321 349 321 349 RR 93 (29.0) 125 (35.8) VV 92 (28.7) 109 (31.2) RK 180 (56.1) 156 (44.7) VI 158 (49.2) 170 (48.7) KK 48 (15.0) 68 (19.5) II 71 (22.1) 70 (20.1) χ2 (p) 8.705 (0.013)a 0.715 (0.699) R frequency 366 (57.0) 407 (58.2) V frequency 342 (53.3) 388 (55.6) K frequency 276 (43.0) 293 (41.8) I frequency 300 (46.7) 310 (44.4) χ2 (p) 0.183 (0.669) 0.724 (0.395) EOAD, n 124 149 124 149 RR 42 (33.9) 53 (35.6) VV 31 (25.0) 50 (33.6) RK 66 (53.2) 73 (49.0) VI 62 (50.0) 66 (44.3) KK 16 (12.9) 23 (15.4) II 31 (25.0) 33 (22.1) χ2 (p) 0.598 (0.741) 2.375 (0.305) R frequency 150 (60.5) 179 (60.1) V frequency 124 (50.0) 166 (55.7) K frequency 98 (39.5) 119 (39.9) I frequency 124 (50.0) 132 (44.3) χ2 (p) 0.1 (0.921) 1.769 (0.184) LOAD, n 197 200 197 200 RR 51 (25.9) 72 (36.0) VV 61 (31.0) 59 (29.5) RK 114 (57.9) 83 (41.5) VI 96 (48.7) 104 (52.0) KK 32 (16.2) 45 (22.5) II 40 (20.3) 37 (18.5) χ2 (p) 10.636 (0.005)b 0.448 (0.799) R frequency 216 (54.8) 227 (56.8) V frequency 218 (55.3) 222 (55.5) K frequency 178 (45.2) 173 (43.2) I frequency 176 (44.7) 178 (44.5) χ2 (p) 0.229 (0.584) 0.002 (0.962) Male, n 123 125 123 125 RR 41 (33.3) 42 (33.6) VV 31 (25.2) 41 (32.8) RK 66 (53.7) 58 (46.4) VI 64 (52.0) 60 (48.0) KK 16 (13.0) 25 (20.0) II 28 (22.8) 24 (19.2) χ2 (p) 2.488 (0.288) 1.81 (0.405) R frequency 148 (60.2) 142 (56.8) V frequency 126 (51.2) 142 (56.8) K frequency 98 (39.8) 108 (43.2) I frequency 120 (48.8) 108 (43.2) χ2 (p) 0.577 (0.447) 1.555 (0.212) Female, n 198 224 198 224 RR 52 (26.3) 83 (37.1) VV 61 (30.8) 68 (30.4) RK 114 (57.6) 98 (43.8) VI 94 (47.5) 110 (49.1) KK 32 (16.2) 43 (19.2) II 43 (21.7) 46 (20.5) χ2 (p) 8.369 (0.015)a 0.134 (0.935) R frequency 218 (55.1) 264 (58.9) V frequency 216 (54.5) 246 (54.9) K frequency 178 (44.9) 184 (41.1) I frequency 180 (45.5) 202 (45.1) χ2 (p) 1.291 (0.256) 0.11 (0.915) APOE ε4 carrying, n 150 143 150 143 RR 48 (32.0) 52 (36.4) VV 37 (24.7) 44 (30.8) RK 82 (54.7) 62 (43.4) VI 78 (52.0) 74 (51.7) KK 20 (13.3) 29 (20.3) II 35 (23.3) 25 (17.5) χ2 (p) 4.426 (0.109) 2.211 (0.331) R frequency 178 (59.3) 166 (58.0) V frequency 152 (50.7) 162 (56.6) K frequency 122 (40.7) 120 (42.0) I frequency 148 (49.3) 124 (43.4) χ2 (p) 0.101 (0.751) 2.103 (0.147) APOE ε4 noncarrying, n 171 206 171 206 RR 45 (26.3) 73 (35.4) VV 55 (32.2) 65 (31.6) RK 98 (57.3) 94 (45.6) VI 80 (46.8) 96 (46.6) KK 28 (16.4) 39 (18.9) II 36 (21.1) 45 (21.8) χ2 (p) 5.33 (0.070) 0.039 (0.981) R frequency 188 (55.0) 240 (58.3) V frequency 190 (55.6) 226 (54.9) K frequency 154 (45.0) 172 (41.7) I frequency 152 (44.4) 186 (45.1) χ2 (p) 0.82 (0.365) 0.037 (0.847) APOE ε4ε4 carrying, n 35 3 35 3 RR 11 (31.4) 1 (33.3) VV 7 (20.0) 1 (33.3) RK 17 (48.6) 2 (66.7) VI 20 (57.1) 1 (33.3) KK 7 (20.0) 0 (0.0) II 8 (22.9) 1 (33.3) (Continued ) TABLE 2. Login to comment 83 ABCA1 p.Arg219Lys ABCA1 p.Val825Ile (Continued ) Comparison Comparison R219K AD (%) Group (%) V825I AD (%) Group (%) χ2 (p) 0.656 (1.000)c 1.321 (0.577)c R frequency 39 (55.7) 4 (66.7) V frequency 34 (48.6) 3 (50.0) K frequency 31 (44.3) 2 (33.3) I frequency 36 (51.4) 3 (50.0) χ2 (p) (0.692)c (1.000)c APOE ε4ε4 noncarrying, n 286 346 286 346 RR 82 (28.7) 124 (35.8) VV 85 (29.7) 108 (31.2) RK 163 (57.0) 154 (44.5) VI 138 (48.3) 169 (48.8) KK 41 (14.3) 68 (19.7) II 63 (22.0) 69 (19.9) χ2 (p) 9.9 (0.007)b 0.452 (0.798) R frequency 327 (57.2) 402 (58.1) V frequency 308 (53.8) 385 (55.6) K frequency 245 (42.8) 290 (41.9) I frequency 264 (46.2) 307 (44.4) χ2 (p) 0.11 (0.741) 0.405 (0.525) Notes: For all the χ2 of genotypes, df = 2; for all the χ2 of allele frequencies, df = 1. Login to comment 86 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Logistic Regression Analysis of R219K Polymorphism of ABCA1 Gene in AD Patients and Comparison Group R219K AD Comparison Group Wald p OR (95% CI) Total, n 321 (%) 349 (%) RR 93 (29.0) 125 (35.8) Reference RK 180 (56.1) 156 (44.7) 6.102 0.014a 1.546 (1.094-2.185) KK 48 (15.0) 68 (19.5) 0.062 0.804 0.943 (0.596-1.494) RK + KK 228 (71.1) 224 (64.2) 3.430 0.064 1.363 (0.982-1.892) LOAD, n 197 (%) 200 (%) RR 51 (25.9) 72 (36.0) Reference RK 114 (57.9) 83 (41.5) 7.746 0.005b 1.921 (1.213-3.041) KK 32 (16.2) 45 (22.5) 0.021 0.884 1.044 (0.583-1.871) RK + KK 146 (74.1) 128 (64.0) 4.750 0.029a 1.619 (1.050-2.497) APOE ε4ε4 noncarrying, n 286 (%) 346 (%) RR 82 (28.7) 124 (35.8) Reference RK 163 (57.0) 154 (44.5) 6.399 0.011a 1.586 (1.109-2.266) KK 41 (14.3) 68 (19.7) 0.175 0.675 0.903 (0.559-1.458) RK + KK 204 (71.3) 222 (64.2) 3.409 0.065 1.377 (0.981-1.933) Notes: For the Wald χ2 tests, df = 1. Login to comment 92 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val825Ile Effects of Two Single Nucleotide Polymorphisms (R219K and V825I) of ABCA1 Gene on AAO and MMSE Score in AD Patients R219K V825I RR (%) RK (%) KK (%) F (p) VV (%)g VI (%) II (%) F (p) Total, n 93 (29.0) 180 (56.1) 48 (15.0) 92 (28.7) 158 (49.2) 71 (22.1) AAO 65.4 ± 10.42 67.8 ± 9.46 67.3 ± 9.36 1.813 (0.165) 68.4 ± 9.34 66.8 ± 9.84 65.6 ± 10.01 1.764 (0.173) MMSE 14.1 ± 6.44 14.4 ± 6.00 14.5 ± 6.25 0.113 (0.893) 14.8 ± 5.87 14.0 ± 6.31 14.4 ± 5.87 0.545 (0.580) EOAD, n 42 (33.9) 66 (53.2) 16 (12.9) 31 (25.0) 62 (50.0) 31 (25.0) AAO 55.5 ± 5.33 57.0 ± 4.97 55.7 ± 4.92 1.222 (0.298) 57.0 ± 5.20 56.3 ± 5.04 55.7 ± 5.19 0.470 (0.626) MMSE 13.6 ± 6.84 13.0 ± 6.63 14.3 ± 8.62 0.237 (0.790) 13.9 ± 7.38 12.2 ± 6.92 15.2 ± 6.21a 2.119 (0.125) LOAD, n 51 (25.9) 114 (57.9) 32 (16.2) 61 (40.0) 96 (48.7) 40 (20.3) AAO 73.5 ± 5.23 74 ± 4.57 73.1 ± 4.1 0.523 (0.594) 74.2 ± 4.11 73.6 ± 4.99 73.2 ± 4.70 0.628 (0.535) MMSE 14.4 ± 6.14 15.2 ± 5.48 14.6 ± 4.81 0.427 (0.653) 15.3 ± 5.37 15.2 ± 5.63 13.7 ± 5.58 1.179 (0.310) Male, n 41 (33.3) 66 (53.7) 16 (13.0) 31 (25.2) 64 (52.0) 28 (22.8) AAO 65.1 ± 9.65 67.2 ± 9.38 67.9 ± 9.81 0.850 (0.430) 68.0 ± 10.50 66.8 ± 9.04 64.7 ± 9.51 0.887 (0.415) MMSE 15.2 ± 6.27 16.1 ± 6.21 15.0 ± 5.72 0.404 (0.668) 16.7 ± 5.67 14.9 ± 6.49 16.4 ± 5.77 1.110 (0.333) Female, n 52 (26.3) 114 (57.6) 32 (16.1) 61 (30.8) 94 (47.5) 43 (21.7) AAO 65.7 ± 11.80 68.1 ± 9.53 67.0 ± 9.27 1.036 (0.357) 68.7 ± 8.78 66.9 ± 10.39 66.2 ± 10.38 0.960 (0.385) MMSE 13.2 ± 6.50 13.4 ± 5.67 14.2 ± 6.57 0.301 (0.740) 13.9 ± 6.03 13.4 ± 6.15 13.1 ± 5.63 0.255 (0.775) APOE ε4 carrying, n 48 (32.0) 82 (54.7) 20 (13.3) 37 (24.7) 78 (52.0) 35 (23.3) AAO 65.7 ± 9.95 67.8 ± 8.64 62.7 ± 8.85b 2.798 (0.064) 67.9 ± 8.92 65.7 ± 9.41 66.7 ± 9.14 0.742 (0.478) MMSE 13.8 ± 6.04 14.8 ± 5.69 14.5 ± 7.13 0.369 (0.692) 15.3 ± 6.15 13.7 ± 6.32 15.2 ± 4.86 1.212 (0.301) APOE ε4 noncarrying, n 45 (26.3) 98 (57.3) 28 (16.4) 55 (32.2) 80 (46.8) 36 (21.1) AAO 65.1 ± 11.01 67.8 ± 10.14 70.6 ± 8.37c 2.627 (0.075) 68.8 ± 9.68 68.0 ± 10.16 64.5 ± 10.79d 2.160 (0.119) MMSE 14.3 ± 6.90 14.1 ± 6.27 14.5 ± 5.68 0.036 (0.964) 14.6 ± 6.13 14.3 ± 6.34 13.4 ± 6.69 0.252 (0.778) APOE ε4ε4 carrying, n 11 (31.4) 17 (48.6) 7 (20.0) 7 (20.0) 20 (57.1) 8 (22.9) AAO 64.8 ± 9.67 66.5 ± 6.79 67.6 ± 7.41 0.283 (0.756) 65.0 ± 8.37 66.0 ± 7.70 67.6 ± 8.16 0.215 (0.807) MMSE 14.9 ± 6.99 14.4 ± 4.70 13.4 ± 5.29 0.162 (0.851) 13.9 ± 4.41 14.5 ± 6.43 15.0 ± 4.03 0.077 (0.926) APOE ε4ε4 noncarrying, n 82 (28.7) 163 (57.0) 41 (14.3) 85 (29.7) 138 (48.3) 63 (22.0) AAO 65.5 ± 10.57 67.9 ± 9.70 67.2 ± 9.73 1.597 (0.204) 68.7 ± 9.41 67.0 ± 10.12 65.3 ± 10.24e 2.132 (0.121) MMSE 13.9 ± 6.40 14.4 ± 6.13 14.7 ± 6.44 0.206 (0.814) 14.9 ± 6.24 13.9 ± 6.31 14.3 ± 6.08 0.667 (0.514) Notes: MMSE score and AAO were analyzed by ANOVA and post-hoc LSD multiple comparisons and were expressed in mean ± SD. Login to comment 98 ABCA1 p.Arg219Lys If the function of R219K in ABCA1 is also related to age in the brain, the RR genotype may be assumed to become a protective factor in elder people. Login to comment 99 ABCA1 p.Arg219Lys We found that the impact of RK and RK + KK in R219K polymorphism on LOAD but not on EOAD, which may be explained by the assumption shown earlier. Login to comment 106 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Genotypes and allele frequencies of R219K showed no discrepancies in our study when stratified by APOE-ε4 allele carrying status, the same as the results of Wollmer et al.36 Other studies showed the association between R219K genotypes and the risk of AD in APOE-ε4 noncarriers,20,35 but seldom in APOE-ε4 carriers. Login to comment 107 ABCA1 p.Arg219Lys Wahrle et al.34 investigated R219K polymorphisms in 1225 AD cases and 1431 controls, which analyzed subgroups on the basis of APOE genotype according to the large number of sample. Login to comment 108 ABCA1 p.Arg219Lys They failed to show an effect of R219K SNP on risk of AD in either APOE ε4ε4 group or APOE non- ε4ε4 group.34 We did not find the difference in APOE ε4ε4 group and moreover the number of APOE ε4ε4 carrying subjects in our study was far smaller than theirs. Login to comment 109 ABCA1 p.Arg219Lys But in our APOE non-ε4ε4 carrying subjects, there were significant discrepancies in R219K genotypes with more RK genotype in AD group, which was not showed in APOE ε4ε4 carriers. Login to comment 110 ABCA1 p.Arg219Lys This may indicate the R219K RK genotype has a minor effect on AD than that of APOE ε4ε4 genotype. Login to comment 111 ABCA1 p.Arg219Lys Wollmer et al.36 found that R219K K allele was associated with delayed AAO by 1.7 years in their late-onset, sporadic AD patients. Login to comment 113 ABCA1 p.Arg219Lys The results indicated that R219K might affect the AD occurrence interacting with APOE ε4 allele, which needs further investigation. Login to comment 114 ABCA1 p.Arg219Lys In summary, our data revealed that the RK heterozygosis of R219K in ABCA1 increased the risk of AD in Chinese Han ethnic population, particularly in LOAD, APOE ε4ε4 noncarriers, and females. Login to comment 115 ABCA1 p.Val825Ile However, there was no association of V825I with AD in spite of stratification. Login to comment