ABCMdb

PMID: 17372331

Soro-Paavonen A, Naukkarinen J, Lee-Rueckert M, Watanabe H, Rantala E, Soderlund S, Hiukka A, Kovanen PT, Jauhiainen M, Peltonen L, Taskinen MR
Common ABCA1 variants, HDL levels, and cellular cholesterol efflux in subjects with familial low HDL.
J Lipid Res. 2007 Jun;48(6):1409-16. Epub 2007 Mar 19., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCA1 p.Arg219Lys Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. Login to comment 136 ABCA1 p.Arg219Lys Three SNPs differed significantly between the low-HDL family members and control subjects [L158 (rs2230805), P 5 0.004; R219K (rs2230806), P 5 0.005; and rs2297409, P 5 0.006], so that the rare alleles of each of these SNPs were overrepresented among low-HDL subjects (Table 3). Login to comment 137 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Three SNPs differed significantly between the low-HDL family members and control subjects [L158 (rs2230805), P 5 0.004; R219K (rs2230806), P 5 0.005; and rs2297409, P 5 0.006], so that the rare alleles of each of these SNPs were overrepresented among low-HDL subjects (Table 3). Login to comment 138 ABCA1 p.Arg219Lys The variants L158 and R219K showed significant association with low HDL-C levels (P 5 0.009 and P 5 0.007, respectively), and T1427 showed association with high HDL-C (P 5 0.028). Login to comment 139 ABCA1 p.Arg219Lys We constructed allelic haplotypes of the three SNPs that showed association with either high or low HDL-C levels (L158, R219K, and T1427T) using PHASE version 2.0 software. Login to comment 140 ABCA1 p.Arg219Lys We constructed allelic haplotypes of the three SNPs that showed association with either high or low HDL-C levels (L158, R219K, and T1427T) using PHASE version 2.0 software. Login to comment 145 ABCA1 p.Arg219Lys Comparisons of the ABCA1 allele frequencies between 47 low-HDL family members (19 unaffected and 28 affected subjects) and 25 control subjects, and ABCA1 genotype effects on cholesterol efflux, HDL-C, and mean IMT in the pooled study group (n 5 72) Single-Nucleotide Polymorphism Identification Number Amino Acid Residue Allele Frequencies and P Value in Low-HDL Family Members Versus Control Subjectsa HDL-C Pb Mean IMT Pc rs2472459 - NS NS NS rs2246293 - NS NS NS rs2515616 - NS NS NS rs1800978 - NS NS NS rs2740492 - NS NS NS rs3858075 - NS NS NS rs1929842 - NS NS NS rs2230805 L158 (0.45 vs. 0.12) 0.004 0.009 NS rs2230806 R219K (0.40 vs. 0.08) 0.005 0.007 NS rs2487037 - NS NS NS rs2297409 - (0.30 vs. 0.04) 0.006 NS NS rs2066716 T1427 (0.11 vs. 0.32) 0.053 0.003 NS rs2230808 R1587K NS NS NS rs2066881 - NS NS NS rs4149341 - NS NS 0.025 a For statistically significant differences, the corresponding allele frequencies are given in parentheses (in low-HDL family members vs. control subjects), followed by Chi-square P value, with Fisher`s exact test for the differences in allele frequencies between low-HDL family members and control subjects. Login to comment 146 ABCA1 p.Arg219Lys Comparisons of the ABCA1 allele frequencies between 47 low-HDL family members (19 unaffected and 28 affected subjects) and 25 control subjects, and ABCA1 genotype effects on cholesterol efflux, HDL-C, and mean IMT in the pooled study group (n 5 72) Single-Nucleotide Polymorphism Identification Number Amino Acid Residue Allele Frequencies and P Value in Low-HDL Family Members Versus Control Subjectsa HDL-C Pb Mean IMT Pc rs2472459 - NS NS NS rs2246293 - NS NS NS rs2515616 - NS NS NS rs1800978 - NS NS NS rs2740492 - NS NS NS rs3858075 - NS NS NS rs1929842 - NS NS NS rs2230805 L158 (0.45 vs. 0.12) 0.004 0.009 NS rs2230806 R219K (0.40 vs. 0.08) 0.005 0.007 NS rs2487037 - NS NS NS rs2297409 - (0.30 vs. 0.04) 0.006 NS NS rs2066716 T1427 (0.11 vs. 0.32) 0.053 0.003 NS rs2230808 R1587K NS NS NS rs2066881 - NS NS NS rs4149341 - NS NS 0.025 a For statistically significant differences, the corresponding allele frequencies are given in parentheses (in low-HDL family members vs. control subjects), followed by Chi-square P value, with Fisher`s exact test for the differences in allele frequencies between low-HDL family members and control subjects. Login to comment 157 ABCA1 p.Arg219Lys Interestingly, the carrier status of the haplotype containing the R219K variant was not associated with the cholesterol efflux activity, implying that this particular variant does not result in the disturbed function of ABCA1 in macrophages but rather tags the allelic variant related to serum HDL-C level regulation, possibly at the hepatic level. Login to comment 158 ABCA1 p.Arg219Lys Interestingly, the carrier status of the haplotype containing the R219K variant was not associated with the cholesterol efflux activity, implying that this particular variant does not result in the disturbed function of ABCA1 in macrophages but rather tags the allelic variant related to serum HDL-C level regulation, possibly at the hepatic level. Login to comment 161 ABCA1 p.Arg219Lys The efflux (%) was not changed significantly between carriers and noncarriers of the rare alleles in R219K. Login to comment 162 ABCA1 p.Arg219Lys The efflux (%) was not changed significantly between carriers and noncarriers of the rare alleles in R219K. Login to comment 190 ABCA1 p.Arg219Lys In turn, in healthy subjects and CHD patients of European 1414 Journal of Lipid Research Volume 48, 2007 at SEMMELWEIS EGYETEM NET KORELET, on December , and French-Canadian origin, the common variant R219K was associated with increased levels of HDL, decreased TGs, and reduced severity of atherosclerosis (42, 43). Login to comment 191 ABCA1 p.Arg219Lys In turn, in healthy subjects and CHD patients of European 1414 Journal of Lipid Research Volume 48, 2007 atHealthScienceLibraryCB#7585,onSeptember24,2012www.jlr.orgDownloadedfrom 0.DC1.html and French-Canadian origin, the common variant R219K was associated with increased levels of HDL, decreased TGs, and reduced severity of atherosclerosis (42, 43). Login to comment 193 ABCA1 p.Arg219Lys Of these, T1427 gave corresponding results in both data sets, showing association with increased HDL-C. The variant R219K showed association with low serum HDL levels but not with the cholesterol efflux in our study sample. Login to comment 194 ABCA1 p.Arg219Lys Of these, T1427 gave corresponding results in both data sets, showing association with increased HDL-C. The variant R219K showed association with low serum HDL levels but not with the cholesterol efflux in our study sample. Login to comment 203 ABCA1 p.Arg219Lys In summary, based on our data, we conclude that 1) macrophages derived from Finnish subjects with familial low HDL displayed similar cholesterol-loading capacity but decreased cholesterol efflux to apoA-I via the ABCA1 pathway after loading; 2) familial low HDL in these families is not caused by rare mutations in ABCA1; rather, the common allelic variants are associated with HDL-C levels, as indicated by the dose-dependent contribution of the haplotype carrying the common R219K change in these subjects; and 3) relative ABCA1 mRNA expression in cholesterol-loaded macrophages was increased significantly in the low-HDL group. Login to comment 204 ABCA1 p.Arg219Lys In summary, based on our data, we conclude that 1) macrophages derived from Finnish subjects with familial low HDL displayed similar cholesterol-loading capacity but decreased cholesterol efflux to apoA-I via the ABCA1 pathway after loading; 2) familial low HDL in these families is not caused by rare mutations in ABCA1; rather, the common allelic variants are associated with HDL-C levels, as indicated by the dose-dependent contribution of the haplotype carrying the common R219K change in these subjects; and 3) relative ABCA1 mRNA expression in cholesterol-loaded macrophages was increased significantly in the low-HDL group. Login to comment