ABCMdb

ABCA1 p.Pro1065Ser

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Publications

PMID: 19596329 [PubMed] Frikke-Schmidt R et al: "Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population."

No. Sentence Comment

2342 Genotyping revealed 28 het- erozygous carriers of P1065S, G1216V, N1800H, and R2144X in the CCHS (n = 9022), and 76 heterozygous carriers of G1216V, N1800H, and R2144 in the Copenhagen General Population Study (CGPS) (n = 31,241) [66]. Login to comment
2343 By large-scale genotyping, and confirmed by in vitro cellular cholesterol efflux assays, Frikke-Schmidt et al. showed that the P1065S, G1216V, and N1800H were indeed loss-of-function mutations causing low HDL cholesterol levels in the general population. Login to comment

PMID: 18984885 [PubMed] Brunham LR et al: "ABCA1 gene mutations, HDL cholesterol levels, and risk of ischemic heart disease."

No. Sentence Comment

54 Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment
61 Third, our findings are consistent with our previous reports on the same cohort showing that polymorphisms and mutations in ABCA1 may or may not affect HDL levels, but that risk of IHD is independent of these HDL effects.2-4 Fourth, it is not correct that to state that heterozygosity for the 3 rare mutations in the CCHS (P1065S, G1216V, or R2144X; n=6) was associated with a 25% reduction in LDL cholesterol levels compared with noncarriers because this was not statistically significant. Login to comment

PMID: 18523221 [PubMed] Frikke-Schmidt R et al: "Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease."

No. Sentence Comment

12 Results Heterozygotes vs noncarriers for 4 ABCA1 mutations (P1065S, G1216V, N1800H, R2144X) had HDL cholesterol levels of 41 mg/dL (interquartile range, 31-50 mg/dL) vs 58 mg/dL (interquartile range, 46-73 mg/dL), corresponding to a reduction in HDL cholesterol of 17 mg/dL (PϽ.001). Login to comment
26 The 9022 individuals were genotyped for all non-synonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
39 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
48 HeLa cells were transfected (ExGen 500 in vitro transfection reagent, Fermentas Inc, Hanover, Maryland) with plasmids expressing the ABCA1 mutations (P1065S, G1216V, N1800H) created by site-directed mutagenesis (Quick- Change II XL Site-Directed Mutagenesis Kit, Stratagene Inc, La Jolla, California);R2144Xhaspreviouslybeenshown to cause reduced cholesterol efflux.7 Sequences of all plasmids were confirmed by direct sequencing (Applied Biosys- temsInc),andtransfectionefficiencywas examined by flow cytometry of transfected HeLa cells. Login to comment
60 On a continuous scale, a 17-mg/dL (to convert to mmol/L, multiply by 0.0259) lower HDL cholesterol level associated with a multifactorially adjusted HR for IHD of 1.70 (95% CI, 1.57-1.85), similar to that reported in other studies.1 ABCA1 Mutation Heterozygotes and Plasma HDL Cholesterol Four of 7 mutations (P1065S, G1216V, N1800H, R2144X) were associated with Figure 1. Login to comment
69 Number of Participants Heterozygous for Missense or Nonsense Mutations in ABCA1 in the Studied Populations Mutation CCHS (n = 9022) CGPS (n = 31 241) CIHDS (n = 2498) P1065S 1 0 0 G1216V 3 3 1 N1800H 22 70 3 R2144X 2 3 1 Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study. Login to comment
72 The overall heterozygote frequency in the general population was approximately 3:1000 in both the CCHS and the CGPS, the majority carrying the N1800H mutation. Login to comment
78 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
88 bProbands heterozygous for P1065S, G1216V, or R2144X. Login to comment
89 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment
100 When restricting the analyses to N1800H heterozygotes (n=95), the equivalent OR was 0.77 (95% CI, 0.41-1.45); with 80% statistical power to exclude an OR of 1.85 or more. Login to comment
111 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dLmg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
119 P1065S was not identified in the Copenhagen General Population Study. Login to comment
25 The 9022 individuals were genotyped for all nonsynonymous mutations (S364C, T774P, K776N, P1065S, G1216V, N1800H, R2144X [http://www.hgmd.cf.ac.uk/ac /index.php; http://www.mutdb.org]), which were previously identified by resequencing the promoter, coding region,andconsensussplicesitesofABCA1 in 190 individuals of Danish ancestry with high and low HDL cholesterol levels.13 All end points and data collection were recorded in the follow-up period of January 1, 1976, through July 9, 2007. Login to comment
38 Participants in the CIHDS were genotyped for the 4 mutations (P1065S, G1216V, N1800H, R2144X) associated with reduced HDL cholesterol levels in the CCHS and the CGPS. Login to comment
52 Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen City Heart Study 120 80 60 100 40 20 0 20 40 60 80 100 Women 120 80 60 100 40 20 0 20 40 60 80 100 Men HDL cholesterol 220 140 160 120 180 200 100 80 60 0 20 40 60 80 100 Women Age, y Age, y Age, y 200 160 140 180 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I Mutation P1065S G1216V N1800H R2144X 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th mg/dL mg/dL Exact values for each heterozygous mutation carrier are superimposed on the 5th, 50th, and 95th percentiles for age and sex as a whole (N=9022). Login to comment
62 ABCA1 Mutations and Cellular Cholesterol Efflux in Vitro In agreement with the observed lower plasma HDL cholesterol levels associated with these mutations in vivo, 4 mutations were associated with impaired cholesterol efflux in vitro: 79% (95% CI, 56%-103%) for P1065S, 74% (95% CI, 54%-95%) for G1216V, 49% (95% CI, 37%-60%) for N1800H, and 48%7 for R2144X compared with 100% in wild-type (P=.04 for all). Login to comment
73 cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment

PMID: 16704350 [PubMed] Brunham LR et al: "Variations on a gene: rare and common variants in ABCA1 and their impact on HDL cholesterol levels and atherosclerosis."

No. Sentence Comment

555 Since a complete loss of function allele would be expected to result in a 50% reduction in HDL levels, a greater than 50% reduction in HDL is most likely explained by a dominant negative allele, in which TABLE 3 Patient phenotypes associated with heterozygous ABCA1 mutations Mutation HDL (mmol/L) HDL (% of control) Number of patients M1091T 0.48 ± 0.5 30 ± 30 4 G1216V 0.50 40 1 R2144X 0.56 ± 0.2 41 ± 18 12 R282X 0.52 41 1 R909X 0.59 ± 0.3 42 ± 19 5 K776N 0.55 ± 0.1 47 ± 5 2 R587W 0.61 ± 0.1 47 ± 8 7 S364C 0.60 48 1 P1065S 0.80 51 1 c-ter deletion 0.75 53 1 N1800H - 56.5 33 P85L 0.72 ± 0.4 57 ± 33 5 Del693L 0.79 ± 0.2 57 ± 15 8 D1289N 0.80 ± 0.1 59 ± 12 4 R2081W 0.80 ± 0.1 59 ± 12 4 2203X 0.80 ± 0.2 59 ± 20 4 DelED1893,4 0.77 ± 0.2 59 ± 18 8 2145X 0.82 ± 0.1 59 ± 9 4 A1046D 0.70 ± 0.1 60 ± 8 2 Q597R 0.82 ± 0.1 60 ± 5 5 C1477R 0.82 ± 0.2 61 ± 15 9 IVS25 + 1G > C 0.78 ± 0.1 62 ± 12 4 D1099Y 0.83 ± 0.3 63 ± 21 5 1552X 1.00 64 1 F2009S 0.82 ± 0.2 64 ± 19 6 R587W 0.86 ± 0.1 65 ± 17 2 R1068H 0.90 ± 0.3 67 ± 26 9 N935S 1.00 ± 0.3 74 ± 16 7 T929I 1.01 ± 0.2 76 ± 7 8 1284X 1.11 ± 0.2 83 ± 14 5 A937V 1.15 ± 0.6 85 ± 28 2 R1680W 1.22 ± 0.2 87 ± 17 3 635X 1.24 ± 0.5 90 ± 32 7 W590S 1.32 ± 0.6 103 ± 46 15 the mutant protein actually interferes with the activity of the remaining wild-type protein. Login to comment

PMID: 24385509 [PubMed] Westerterp M et al: "ATP-binding cassette transporters, atherosclerosis, and inflammation."

No. Sentence Comment

59 In a Mendelian randomization approach in a prospective cohort comprising ࣈ9000 individuals, heterozygosity for the ABCA1 mutation K776N led to a 2-to-3 times higher risk of ischemic heart disease.105 Furthermore, 5 single-nucleotide polymorphisms (SNPs) inABCA1 (V771M,V825I, I883M, E1172D, R1587K) were shown to predict risk of ischemic heart disease in a cohort of 9259 individuals.106 However, the same group reported more recently that heterozygosity for 4 loss-of-function mutations (P1065S, G1216V, N1800H, R2144X) was not associated with a higher risk of ischemic heart disease in 3 prospective cohorts comprising 56ߙ886 individuals.107 It must be noted, however, that only small decreases in HDL, of ࣈ28% as opposed to ࣈ50% in previously reported ABCA1 heterozygotes, were observed.94,101-103,107 Also, the residual cholesterol efflux was substantial (74%-79% for P1065S and G1216V and 48%-49% for N1800H and R2144X for homozygous mutations compared with controls),107 whereas in patients with TD there was only 20% to 30% residual cholesterol efflux.108 In addition, LDL levels were reduced by ࣈ25%, probably offsetting the effects of reduced HDL on CVD.107 Thus, the conflicting results in these studies could be related to inclusion of relatively mild ABCA1 mutations as well as offsetting effects of reduced LDL cholesterol levels.109 In a meta-analysis of genome-wide association studies, SNPs near the ABCA1 gene have been associated with HDL and total cholesterol levels,110,111 but not with cardiovascular risk.112 Although these studies have the benefit of huge statistical power, some caution is merited in the interpretation of findings. Login to comment

PMID: 24844148 [PubMed] Koldamova R et al: "ATP-binding cassette transporter A1: from metabolism to neurodegeneration."

No. Sentence Comment

932 For example, some of the ABCA1 missense mutations (P1065S, G1216V, N1800H, R2144X) cause only a mild decrease of cholesterol efflux which in heterozygous state results in a relatively small reduction of HDL (less than 30% decrease compared to the normal values) explaining the lack of atherosclerosis (Frikke-Schmidt et al., 2008). Login to comment

PMID: 26616730 [PubMed] Murano T et al: "Subfraction analysis of circulating lipoproteins in a patient with Tangier disease due to a novel ABCA1 mutation."

No. Sentence Comment

124 The mutations, Pro1065Ser and Met1091Thr, have been shown to disturb the ATP-binding function; these mutations cause FHA [7,19,21, 26]. Login to comment