ABCMdb

PMID: 16725228

Sundar PD, Feingold E, Minster RL, DeKosky ST, Kamboh MI
Gender-specific association of ATP-binding cassette transporter 1 (ABCA1) polymorphisms with the risk of late-onset Alzheimer's disease.
Neurobiol Aging. 2007 Jun;28(6):856-62. Epub 2006 May 24., [PubMed]

Sentences

No. Mutations Sentence Comment

4 ABCA1 p.Arg219Lys In the present study, we examined the role of two ABCA1 polymorphisms, R219K (rs2230806) and G-17C (rs2740483) in modifying the risk of late-onset AD (LOAD) in a large American white cohort of 992 AD cases and 699 controls. Login to comment 5 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys We observed significant gender × R219K interaction (p = 0.00008). Login to comment 8 ABCA1 p.Arg219Lys The risk associated with the R219K polymorphism was independent of the recently reported significant association in the ubiquilin (UBQLN1) gene in this region on chromosome 9q. Login to comment 9 ABCA1 p.Arg219Lys Our data suggest a gender-specific and APOE and UBQLN1 independent association between the ABCA1/R219K polymorphism and LOAD. Login to comment 31 ABCA1 p.Arg219Lys In the present case-control association study, we examined the role of two ABCA1 polymorphisms: R219K (rs2230806) located in exon 7 resulting in a G to A nucleotide change at position 1051 and G-17C (rs2740483) located in the promoter region with LOAD risk. Login to comment 32 ABCA1 p.Arg219Lys Previously R219K has been found to be associated with HDL-C levels and coronary artery disease (CAD) risk [5,8] but has shown inconsistent association with AD [17,22,32]. Login to comment 43 ABCA1 p.Arg219Lys The R219K and G-17C genotypes were determined by pyrosequencing on the PSQTM HS 96 system (Biotage, Uppsala, Sweden). Login to comment 44 ABCA1 p.Arg219Lys Duplex pyrosequencing assay was performed using the following PCR (F, R) and sequencing (S) primers for R219K: F-5 -/5Bio/TGCAAGGCTACCAGTT- ACATT-3 ; R-5 -TAGGCTTCAGGATGTCCATGTT-3 ; S-5 -GCAGCCAGTTTCTCC-3 and G-17C: F-5 -CGTG- CTTTCTGCTGAGTGACTG-3 ; R-5 -/5Bio/CGAGCGCA- GAGGTTACTATC-3 ; S-5 -ACAGAGGCCGGGA-3 according to the previously described procedure [7]. Login to comment 53 ABCA1 p.Arg219Lys For the simultaneous analysis of ABCA1 and UBQLN1, we included the ABCA1/R219K SNP and three UBQLN1 SNPs (intron 6 A → C, intron 8 T → C and intron 9 A → G). Login to comment 58 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Associations between ABCA1 polymorphisms and late-onset AD We genotyped 1691 subjects for the R219K SNP (992 cases and 699 controls) and 1379 subjects for the G-17C Table 1 Distribution of ABCA1 polymorphisms in American white LOAD cases and controls Genotype Total Female Male AD Controls AD Controls AD Controls n (%) n (%) n (%) n (%) n (%) n (%) R219K RR 489 49.3 374 53.5 306 46.4 249 57.64a 183 55.0 125 46.82b RK 424 42.7 274 39.2 296 44.9 151 35.0 128 38.4 123 46.1 KK 79 8.0 51 7.3 57 8.7 32 7.4 22 6.6 19 7.1 Total 992 699 659 432 333 267 Allele frequency R/K 70.7/29.3 73.1/26.9 68.9/31.1 75.1/24.9c 74.2/25.8 69.9/30.1 G-17C GG 422 50.4 291 53.8 280 50.0 174 52.4 142 51.1 117 56.0 CG 319 38.1 203 37.5 216 38.6 125 37.7 103 37.1 78 37.3 CC 97 11.6 47 8.7 64 11.4 33 9.9 33 11.9 14 6.7 Total 838 541 560 332 278 209 Allele frequency G/C 69.4/30.6 72.6/27.4 69.3/30.7 71.2/28.8 69.6/30.4 74.6/25.4 a Significantly different between female AD cases and controls (RR vs. RK + KK; p = 0.0003). Login to comment 62 ABCA1 p.Arg219Lys The genotype distributions of the R219K polymorphism followed HWE in both AD cases and controls. Login to comment 65 ABCA1 p.Arg219Lys The genotype and allele frequencies for the R219K and G-17C polymorphisms were comparable between AD cases and controls in the total sample (Table 1). Login to comment 67 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Since the (gender × R219K) interaction term in the regression model was highly significant (p = 0.00008), we further examined the data stratified by gender. Login to comment 71 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys To exclude the possibility if the additional 312 individuals that were genotyped for the R219K SNP but not for the G-17C SNP could have impacted the result of the R219K SNP, we reanalyzed the data on 1370 individuals having genotypes for both SNPs. Login to comment 72 ABCA1 p.Arg219Lys The results for the R219K SNP were essentially the same as shown in Table 1. Login to comment 73 ABCA1 p.Arg219Lys Both AD and controls were in HWE for the R219K SNP. Login to comment 76 ABCA1 p.Arg219Lys Estimated haplotypes and late-onset AD risk The R219K and G-17C polymorphisms were not in linkage disequilibrium with each other (D = 0.084; p = 0.43). Login to comment 85 ABCA1 p.Arg219Lys We fit a logistic regression model with the following independent variables: age, Table 2 Estimated haplotype frequencies among American white LOAD cases and controls Subjects Haplotype SNPs Haplotype frequency (%) p-Value R219K G-17C Total AD C Total n = 1370 n = 833 n = 537 1 R C 19.9 20.7 18.7 2 R G 52.0 50.3 54.7 3 K C 9.3 9.8 8.6 4 K G 18.7 19.2 18.0 ln(L) -2524.12 -1554.79 -966.69 0.15a Female n = 884 n = 555 n = 329 1 R C 20.2 20.1 20.3 2 R G 51.7 49.2 55.8 3 K C 9.6 10.5 8.1 4 K G 18.5 20.1 15.8 ln(L) -1636.2 -1042.6 -588.48 0.017a Male n = 486 n = 278 n = 208 1 R C 19.5 21.9 16.0 2 R G 52.6 52.4 53.2 3 K C 8.8 8.5 9.5 4 K G 19.0 17.2 21.3 ln(L) -887.54 -509.96 -374.35 0.09a a Calculated from the T5 statistic: 2[ln(L)case + ln(L)control - ln(L)case + control]; d.f. = 3. gender, APOE*4, ABCA1, UBQLN1 joint genotype at three sites (intron 6, intron 8 and intron 9), gender × ABCA1 interaction, and UBQLN1 × ABCA1 interaction (see Section 2 for precise definitions of these variables). Login to comment 92 ABCA1 p.Arg219Lys Initial stud- Table 3 Logistic regression results for UBQLN1 3-site joint genotypes (Intron 6, Intron 8, Intron 9) and ABCA1/R219K OR 95% CI p-Value Baselinea 1.00 Sex 1.05 0.72-1.53 0.813 APOE*4 carriers 5.00 3.79-6.61 <0.0001 UBQLN1/haplotype H5 carriers 0.22 0.06-0.81 0.023 UBQLN1/one copy of haplotype H4 1.36 1.01-1.82 0.040 UBQLN1/two copies of haplotype H4 6.45 2.05-20.26 0.0014 ABCA1 1.57 1.13-2.19 0.0077 Sex × ABCA1 0.0135 a Female non-APOE*4, ABCA1/RR, UBQLN1/haplotypes non-H4 and H5-UBQLN1 haplotype H4 and haplotype H5 are described in Kamboh et al. [16]. Login to comment 100 ABCA1 p.Arg219Lys In the current study, we examined the role of two ABCA1 polymorphisms, R219K and G-17C, with the risk of AD in a large case-control cohort of American whites. Login to comment 101 ABCA1 p.Arg219Lys We found a significant interaction with the R219K polymorphism and gender (p = 0.00008). Login to comment 103 ABCA1 p.Arg219Lys The R219K association was confirmed in the two-site haplotype analysis, where the overall haplotype distribution was significant in females only (p = 0.017). Login to comment 105 ABCA1 p.Arg219Lys Intriguingly, male AD cases and controls showed an opposite trend in R219K allele and haplotype frequency distribution compared to females. Login to comment 106 ABCA1 p.Arg219Lys The underlying mechanism for the gender-specific differences in frequency and effect on AD risk for the R219K polymorphism in our study is unclear. Login to comment 107 ABCA1 p.Arg219Lys Although both male and female controls in our study appeared to be in HWE for the R219K polymorphism, it needs to be taken into account that theirR219Kfrequenciesmaynotberepresentativeofthegen- eral population at large because this control group selectively included older, non-demented individuals. Login to comment 113 ABCA1 p.Arg219Lys We do not know if different frequencies of the R219K SNP between our older normal males and females represent a survival effect because reported AD case-control studies have not presented gender-stratified genotype data for comparison. Login to comment 114 ABCA1 p.Arg219Lys Most of the earlier studies with the R219K SNP were carried out in relation to CAD risk and with the exception of one study all other studies presented gender-combined data. Login to comment 123 ABCA1 p.Arg219Lys Previous studies have not investigated the gender-specific effect of the R219K polymorphism on AD risk. Login to comment 124 ABCA1 p.Arg219Lys Wollmer et al. [32] did not observe any effect of either the R219K SNP or another ABCA1 SNP, rs2230808 (R1587K), on LOAD risk, but reported a significant association of the 219K allele in delaying the AAO of AD. Login to comment 127 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys In contrast to our findings, Katzov et al. [17] found a significantly higher frequency of the R219K/KK genotype among 185 Swedish controls compared to 390 LOAD subjects (p = 0.014), however, the controls in their study were not in HWE showing an unusually inflated frequency of the R219K/KK genotype. Login to comment 128 ABCA1 p.Arg219Lys While Li et al. [22] did not observe any effect of R219K on LOAD, the rs2230808 SNP was associated with significant protective effect against LOAD. Login to comment 131 ABCA1 p.Arg219Lys The obvious difference between our study and those reported previously is that we used a very large LOAD case-control cohort from a single geographical location (1691 subjects) that is more than double than the previously reported largest LOAD case-control series of 796 individuals for the R219K SNP [22]. Login to comment 132 ABCA1 p.Arg219Lys Similar to the previous studies, the R219K SNP in our study did not show significant difference between cases and controls in the gender-combined total sample. Login to comment 133 ABCA1 p.Arg219Lys The other difference between our study and other studies is that we analyzed gender-specific effect of the R219K SNP in our large case-control cohort and found opposite association of the same allele in males and females. Login to comment 136 ABCA1 p.Arg219Lys To our knowledge, the functional significance of the R219K SNP has not been evaluated. Login to comment 137 ABCA1 p.Arg219Lys However, a recent study by Katzov et al. [18] has shown that the R219K SNP could affect the Abeta metabolism in an allele-specific manner such that the 219K allele carriers were associated with significantly higher CSF Abeta42 levels than the RR homozygotes (p = 0.0007). Login to comment 150 ABCA1 p.Arg219Lys In summary, we report a significant association for the ABCA1/R219K polymorphism with LOAD risk in American white subjects, with a more pronounced effect in females. Login to comment