ABCMdb

PMID: 18523221

Frikke-Schmidt R, Nordestgaard BG, Stene MC, Sethi AA, Remaley AT, Schnohr P, Grande P, Tybjaerg-Hansen A
Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischemic heart disease.
JAMA. 2008 Jun 4;299(21):2524-32., [PubMed]

Sentences

No. Mutations Sentence Comment

12 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 25 ABCA1 p.Asn1800His ABCA1 p.Lys776Asn ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Ser364Cys ABCA1 p.Thr774Pro ABCA1 p.Pro1065Ser 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 26 ABCA1 p.Asn1800His ABCA1 p.Lys776Asn ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Ser364Cys ABCA1 p.Thr774Pro ABCA1 p.Pro1065Ser 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 38 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 39 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 47 ABCA1 p.Asn1800His When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment 48 ABCA1 p.Asn1800His ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Pro1065Ser 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 52 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 54 ABCA1 p.Lys776Asn ABCA1 p.Ser364Cys ABCA1 p.Thr774Pro LOSS-OF-FUNCTION MUTATIONS IN THE ABCA1 GENE AND RISK OF ISCHEMIC HEART DISEASE 2528 reductions in levels of HDL cholesterol in plasma in heterozygotes vs noncarriers in the CCHS as well as in the CGPS, while were not (S364C, T774P, K776N). Login to comment 56 ABCA1 p.Asn1800His 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 58 ABCA1 p.Asn1800His Unadjusted plasma levels of HDL cholesterol were reduced by, respectively, 17 mg/dL in heterozygotes overall and 16 mg/dL in N1800H heterozygotes alone (Pb0d;.001); the corresponding reductions for apolipoprotein A-I were 40 mg/dL and 34 mg/dL (to convert to g/L, multiply by 0.01) (Pb0d;.001). Login to comment 60 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 62 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 65 ABCA1 p.Asn1800His Characteristics of Individuals Heterozygous for Missense or Nonsense Mutations in ABCA1 and Cardiovascular Risk Factors Among 9022 Participants in the Copenhagen City Heart Studya Characteristic Noncarriers (n = 8994) Heterozygotes N1800H (n = 22) Rare Mutations (n = 6)b All Mutations (n = 28)c Age, median (IQR), y 60 (48-70) 64 (58-78)d 61 (54-74) 64 (57-77)d Sex, No. Login to comment 69 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 70 ABCA1 p.Lys776Asn ABCA1 p.Ser364Cys ABCA1 p.Thr774Pro reductions in levels of HDL cholesterol in plasma in heterozygotes vs noncarriers in the CCHS as well as in the CGPS, while 3 were not (S364C, T774P, K776N). Login to comment 72 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 73 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment 74 ABCA1 p.Asn1800His Unadjusted plasma levels of HDL cholesterol were reduced by, respectively, 17 mg/dL in heterozygotes overall and 16 mg/dL in N1800H heterozygotes alone (PϽ.001); the corresponding reductions for apolipoprotein A-I were 40 mg/dL and 34 mg/dL (to convert to g/L, multiply by 0.01) (PϽ.001). Login to comment 78 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 81 ABCA1 p.Asn1800His Characteristics of Individuals Heterozygous for Missense or Nonsense Mutations in ABCA1 and Cardiovascular Risk Factors Among 9022 Participants in the Copenhagen City Heart Studya Characteristic Noncarriers (n = 8994) Heterozygotes N1800H (n = 22) Rare Mutations (n = 6)b All Mutations (n = 28)c Age, median (IQR), y 60 (48-70) 64 (58-78)d 61 (54-74) 64 (57-77)d Sex, No. Login to comment 84 ABCA1 p.Asn1800His When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment 85 ABCA1 p.Asn1800His When the number of IHD events/cases and controls from all 3 studies were combined to achieve the maximal statistical power (n=41 961; n=6666 cases; 109 heterozygotes), the corresponding OR for IHD inheterozygotesvsnoncarrierswas0.93 (95% CI, 0.53-1.62); with 80% statistical power to exclude an OR of 1.77 or more. 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. COMMENT The principal finding of this study is that heterozygosity for loss-of-function mutations in ABCA1 associated with substantial, lifelong lowering of plasma levels of HDL cholesterol, but not with corresponding higher levels of plasma triglycerides or atherogenic remnant lipoproteins, did not predict an increased risk of IHD. Login to comment 88 ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser bProbands heterozygous for P1065S, G1216V, or R2144X. Login to comment 89 ABCA1 p.Asn1800His ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser ABCA1 p.Pro1065Ser cProbands heterozygous for P1065S, G1216V, R2144X, or N1800H. Login to comment 98 ABCA1 p.Asn1800His ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* When restricting the analyses to N1800H heterozygotes, the corresponding values were an HR of 0.50 (95% CI, 0.16-1.56), an OR of 0.87 (95% CI, 0.36-2.10), and an OR of 0.51 (95% CI, 0.15-1.80). Login to comment 100 ABCA1 p.Asn1800His ABCA1 p.Pro1065Ser 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 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 117 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Arg2144* Plasma High-Density Lipoprotein (HDL) Cholesterol and Apolipoprotein A-I Levels for Heterozygous Carriers of ABCA1 Mutations in the Copenhagen General Population 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 240 140 160 120 180 200 220 100 80 0 20 40 60 80 100 Women Age, y 240 160 140 180 200 220 120 100 80 60 0 20 40 60 80 100 Men Age, y Apolipoprotein A-I 95th 50th 5th 95th 50th 5th 95th 50th 5th 95th 50th 5th G1216V N1800H R2144X Mutation Age, y Age, y 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=31 241). Login to comment 119 ABCA1 p.Pro1065Ser P1065S was not identified in the Copenhagen General Population Study. Login to comment 120 ABCA1 p.Asn1800His ABCA1 p.Asn1800His 1741 2427 2498 6666 HR (95% CI) OR (95% CI) Age-and sex-adjusted All mutations 0.65 (0.27-1.56) 0.96 (0.41-2.26) 0.73 (0.29-1.86) 0.84 (0.48-1.45) N1800H 0.47 (0.15-1.46) 1.04 (0.44-2.47) 0.46 (0.14-1.51) 0.69 (0.37-1.29) Multifactorially adjustedb All mutations 0.67 (0.28-1.61) 0.82 (0.34-1.96) 0.86 (0.32-2.32) 0.93 (0.53-1.62) N1800H 0.50 (0.16-1.56) 0.87 (0.36-2.10) 0.51 (0.15-1.80) 0.77 (0.41-1.45) Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study; HR, hazard ratio; OR, odds ratio. Login to comment 137 ABCA1 p.Asn1800His ABCA1 p.Asn1800His 1741 2427 2498 6666 HR (95% CI) OR (95% CI) Age-and sex-adjusted All mutations 0.65 (0.27-1.56) 0.96 (0.41-2.26) 0.73 (0.29-1.86) 0.84 (0.48-1.45) N1800H 0.47 (0.15-1.46) 1.04 (0.44-2.47) 0.46 (0.14-1.51) 0.69 (0.37-1.29) Multifactorially adjustedb All mutations 0.67 (0.28-1.61) 0.82 (0.34-1.96) 0.86 (0.32-2.32) 0.93 (0.53-1.62) N1800H 0.50 (0.16-1.56) 0.87 (0.36-2.10) 0.51 (0.15-1.80) 0.77 (0.41-1.45) Abbreviations: CCHS, Copenhagen City Heart Study; CGPS, Copenhagen General Population Study; CIHDS, Copenhagen Ischemic Heart Disease Study; HR, hazard ratio; OR, odds ratio. Login to comment