ABCMdb

PMID: 16372134

Katzov H, Bennet AM, Hoglund K, Wiman B, Lutjohann D, Brookes AJ, Andreasen N, Blennow K, De Faire U, Prince JA
Quantitative trait loci in ABCA1 modify cerebrospinal fluid amyloid-beta 1-42 and plasma apolipoprotein levels.
J Hum Genet. 2006;51(3):171-9. Epub 2005 Dec 22., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCA1 p.Arg219Lys Here, genetic association of the common R219K variant of ABCA1 is shown with cerebrospinal fluid (CSF) Ab1-42 levels, reinforcing emerging evidence of a connection between lipid and Ab metabolism. Login to comment 6 ABCA1 p.Arg219Lys No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Login to comment 7 ABCA1 p.Arg219Lys No other genetic markers in ABCA1 exhibit effects as large as R219K, although a modest independent effect of R1587K was observed. Login to comment 39 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Genotyping Information on the R219K, I883M, and R1587K variants [representing cDNA (GenBank accession number NM_005502.2) rs2230806, c.658 G>A; rs4149313, c.2650 A>G; rs2230808, c.4762 G>A, respectively] may be found at dbSNP (http://www.ncbi.nlm.nih.gov/ SNP/). Login to comment 40 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys Genotyping Information on the R219K, I883M, and R1587K variants [representing cDNA (GenBank accession number NM_005502.2) rs2230806, c.658 G>A; rs4149313, c.2650 A>G; rs2230808, c.4762 G>A, respectively] may be found at dbSNP (http://www.ncbi.nlm.nih.gov/ SNP/). Login to comment 70 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys We focussed on the R219K, I883M, and R1587K variants since these give rise to amino acid changes and because they are common in European populations (Clee et al. 2001). Login to comment 72 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys A significant effect of the R219K variant on CSF Ab1-42 levels was observed whereby RK heterozygotes had the highest trait levels (547±19.2, n=141; 658±35.1, n=71; 443±60.6, n=4; F2,212=6.2, P=0.0024, for RR, RK, and KK genotype classes, respectively; pg/ ml ±SEM). Login to comment 74 ABCA1 p.Arg219Lys A significant effect of the R219K variant on CSF Ab1-42 levels was observed whereby RK heterozygotes had the highest trait levels (547&#b1;19.2, n=141; 658&#b1;35.1, n=71; 443&#b1;60.6, n=4; F2,212=6.2, P=0.0024, for RR, RK, and KK genotype classes, respectively; pg/ ml &#b1;SEM). Login to comment 88 ABCA1 p.Arg219Lys In an initial screen, we tested the R219K variant using ANOVA for effects upon these selected traits in the entire set of samples. Login to comment 90 ABCA1 p.Arg219Lys In an initial screen, we tested the R219K variant using ANOVA for effects upon these selected traits in the entire set of samples. Login to comment 96 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys To begin exploring this latter possibility in the CVD sample (since it affords the most power to detect such effects), genotyping of the I883M and R1587K variants was performed, and ANOVA used to model the potential independent main effects in a joint analysis of all three markers (including R219K). Login to comment 98 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys In smokers, the main effect for R219K improved when adjusting for the other sites from F2,943=8.4, P=0.00024 in isolation to F2,898=9.9, P=0.000055 when all three markers were included. Login to comment 100 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys The I883M variant was not associated with the APOB trait either in isolation or in the full model. Login to comment 102 ABCA1 p.Ile883Met The I883M variant was not associated with the APOB trait either in isolation or in the full model. Login to comment 111 ABCA1 p.Ile883Met We also tested the R219K, I883M, and R1587K markers for association with MI risk in the whole sample and in smokers and non-smokers. Login to comment 113 ABCA1 p.Ile883Met We also tested the R219K, I883M, and R1587K markers for association with MI risk in the whole sample and in smokers and non-smokers. Login to comment 122 ABCA1 p.Arg219Lys To explore the possible functional effects of ABCA1 variants, we used the PolyPhen tool (http://www.bor Table 1 Quantitative trait analyses for the R219K variant. Login to comment 124 ABCA1 p.Arg219Lys To explore the possible functional effects of ABCA1 variants, we used the PolyPhen tool (http://www.bor Table 1 Quantitative trait analyses for the R219K variant. Login to comment 126 ABCA1 p.Arg219Lys HDL-C High density lipoprotein cholesterol, LDL-C low density lipoprotein cholesterol, TC total cholesterol, TG triglycerides Table 2 Phenotypic effects of the R219K variant in smokers and non-smokers ApoB KK RK RR F value P value Non-smokers 1.56±0.04 (102) 1.51±0.02 (573) 1.50±0.01 (878) 1.1 0.32 Smokers 1.80±0.06 (53) 1.56±0.02 (366) 1.62±0.02 (527) 8.4 0.00024 TC Non-smokers 6.06±0.11 (102) 5.97±0.04 (574) 5.93±0.04 (879) 0.84 0.43 Smokers 6.62±0.16 (53) 6.14±0.06 (367) 6.15±0.05 (526) 4.0 0.019 LDL-C Non-smokers 4.14±0.10 (102) 4.03±0.04 (568) 3.99±0.03 (868) 1.34 0.26 Smokers 4.54±0.16 (50) 4.13±0.05 (355) 4.17±0.05 (516) 3.5 0.031 Values are the mean ± SEM according to R219K genotype. Login to comment 127 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met The number of individuals in each category is shown in parenthesis. Comparisons were performed by ANOVATC total cholesterol, LDL-C low density lipoprotein cholesterol Traits KK RK RR F value P value APOA1a (g/l) 1.46±0.02 (157) 1.48±0.01 (966) 1.47±0.01 (1,439) 0.23 0.79 APOB (g/l) 1.64±0.03 (157) 1.53±0.01 (966) 1.55±0.01 (1,439) 5.4 0.0046 HDL-C (mmol/l) 1.16±0.26 (156) 1.20±0.01 (961) 1.20±0.01 (1,427) 1.1 0.34 LDL-C (mmol/l) 4.26±0.86 (154) 4.08±0.03 (951) 4.05±0.03 (1,415) 0.26 0.038 TC (mmol/l) 6.24±0.09 (157) 6.04±0.04 (969) 6.01±0.03 (1,439) 3.02 0.049 TGa (mmol/l) 1.87±0.11 (157) 1.71±0.04 (969) 1.72±0.03 (1,441) 1.38 0.25 a Log-transformed traits k.embl-heidelberg.de/PolyPhen/) (Ramensky et al. 2002) for five coding SNPs (cSNPs) in ABCA1 (R219K rs2230806; V771M rs2066718; V825I rs4149312; I883M rs2066714; R1587K rs2230808) (Frikke-Schmidt et al. 2004). Login to comment 128 ABCA1 p.Arg219Lys ABCA1 p.Arg130Cys As a control we also tested the APOE-e4 (R130C rs428358) variant. Login to comment 129 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met The number of individuals in each category is shown in parenthesis. Comparisons were performed by ANOVATC total cholesterol, LDL-C low density lipoprotein cholesterol Traits KK RK RR F value P value APOA1a (g/l) 1.46&#b1;0.02 (157) 1.48&#b1;0.01 (966) 1.47&#b1;0.01 (1,439) 0.23 0.79 APOB (g/l) 1.64&#b1;0.03 (157) 1.53&#b1;0.01 (966) 1.55&#b1;0.01 (1,439) 5.4 0.0046 HDL-C (mmol/l) 1.16&#b1;0.26 (156) 1.20&#b1;0.01 (961) 1.20&#b1;0.01 (1,427) 1.1 0.34 LDL-C (mmol/l) 4.26&#b1;0.86 (154) 4.08&#b1;0.03 (951) 4.05&#b1;0.03 (1,415) 0.26 0.038 TC (mmol/l) 6.24&#b1;0.09 (157) 6.04&#b1;0.04 (969) 6.01&#b1;0.03 (1,439) 3.02 0.049 TGa (mmol/l) 1.87&#b1;0.11 (157) 1.71&#b1;0.04 (969) 1.72&#b1;0.03 (1,441) 1.38 0.25 a Log-transformed traits k.embl-heidelberg.de/PolyPhen/) (Ramensky et al. 2002) for five coding SNPs (cSNPs) in ABCA1 (R219K rs2230806; V771M rs2066718; V825I rs4149312; I883M rs2066714; R1587K rs2230808) (Frikke-Schmidt et al. 2004). Login to comment 130 ABCA1 p.Arg130Cys As a control we also tested the APOE-e4 (R130C rs428358) variant. Login to comment 153 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys MI Myocardial infarction R219K (rs2230806) KK RK RR P value Smokers MI 29 (0.05) 205 (0.39) 293 (0.56) 0.98 Controls 24 (0.06) 162 (0.38) 236 (0.56) Non-smokers MI 35 (0.06) 198 (0.36) 314 (0.57) 0.87 Controls 67 (0.67) 377 (0.37) 566 (0.56) I883M (rs4149313) II IM MM Smokers MI 418 (0.76) 127 (0.23) 4 (0.01) 0.14 Controls 349 (0.81) 77 (0.18) 3 (0.01) Non-smokers MI 445 (0.78) 115 (0.2) 12(.02) 0.31 Controls 843 (0.81) 184 (0.18) 16 (0.02) R1587K (rs2230808) (rs2230808) KK RK RR Smokers MI 29 (0.05) 160 (0.30) 342 (0.64) 0.025 Controls 14 (0.03) 159 (0.38) 250 (0.59) Non-smokers MI 25 (0.04) 182 (0.33) 346 (0.62) 0.66 Controls 57 (0.05) 329 (0.32) 650 (0.63) also serve as a point to revisit in large published studies, such as that of Frikke-Schmidt et al. (2004). Login to comment 155 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys MI Myocardial infarction R219K (rs2230806) KK RK RR P value Smokers MI 29 (0.05) 205 (0.39) 293 (0.56) 0.98 Controls 24 (0.06) 162 (0.38) 236 (0.56) Non-smokers MI 35 (0.06) 198 (0.36) 314 (0.57) 0.87 Controls 67 (0.67) 377 (0.37) 566 (0.56) I883M (rs4149313) II IM MM Smokers MI 418 (0.76) 127 (0.23) 4 (0.01) 0.14 Controls 349 (0.81) 77 (0.18) 3 (0.01) Non-smokers MI 445 (0.78) 115 (0.2) 12(.02) 0.31 Controls 843 (0.81) 184 (0.18) 16 (0.02) R1587K (rs2230808) (rs2230808) KK RK RR Smokers MI 29 (0.05) 160 (0.30) 342 (0.64) 0.025 Controls 14 (0.03) 159 (0.38) 250 (0.59) Non-smokers MI 25 (0.04) 182 (0.33) 346 (0.62) 0.66 Controls 57 (0.05) 329 (0.32) 650 (0.63) also serve as a point to revisit in large published studies, such as that of Frikke-Schmidt et al. (2004). Login to comment 159 ABCA1 p.Arg219Lys Fig. 2 Diplotype analysis of quantitative traits considering the joint contributions of the R219K and R1587K variants. Login to comment 160 ABCA1 p.Arg219Lys Categories represent the diplotype configurations of each individual from among four possible haplotypes (RR, KK, RK, and KR, where R219K is at the first position). Login to comment 161 ABCA1 p.Arg219Lys Fig. 2 Diplotype analysis of quantitative traits considering the joint contributions of the R219K and R1587K variants. Login to comment 162 ABCA1 p.Arg219Lys Categories represent the diplotype configurations of each individual from among four possible haplotypes (RR, KK, RK, and KR, where R219K is at the first position). Login to comment 164 ABCA1 p.Arg219Lys The highest trait levels occur in individuals that are homozygous for the K variant of R219K and homozygous for the R variant of R1587K. Login to comment 166 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Among discovered and examined variable sites, the best evidence for potentially functional polymorphism is for the commonly studied R219K and R1587K variants (Tregouet et al. 2004). Login to comment 168 ABCA1 p.Arg219Lys Among discovered and examined variable sites, the best evidence for potentially functional polymorphism is for the commonly studied R219K and R1587K variants (Tregouet et al. 2004). Login to comment