ABCMdb

PMID: 16226177

Frikke-Schmidt R, Nordestgaard BG, Schnohr P, Steffensen R, Tybjaerg-Hansen A
Mutation in ABCA1 predicted risk of ischemic heart disease in the Copenhagen City Heart Study Population.
J Am Coll Cardiol. 2005 Oct 18;46(8):1516-20. Epub 2005 Sep 23., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Mutation in ABCA1 Predicted Risk of Ischemic Heart Disease in the Copenhagen City Heart Study Population Ruth Frikke-Schmidt, MD, PHD,* Børge G. Nordestgaard, MD, DMSC,†‡ Peter Schnohr, MD,‡ Rolf Steffensen, MD,§ Anne Tybjærg-Hansen, MD, DMSC,‡ Copenhagen, Herlev, Bispebjerg, and Hillerød, Denmark OBJECTIVES We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population. Login to comment 5 ABCA1 p.Lys776Asn RESULTS The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p ϭ 0.005). Login to comment 6 ABCA1 p.Lys776Asn At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. Login to comment 7 ABCA1 p.Lys776Asn The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Login to comment 10 ABCA1 p.Lys776Asn CONCLUSIONS Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study. Login to comment 21 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn The K776N mutation is of particular interest because: 1) K776 is completely conserved between species; 2) the K Ͼ N amino acid substitution results in a change in side chain charge (basic to uncharged polar); 3) K776N is reported to be relatively frequent in Caucasians (3 per 1,000) (14); 4) disease-causing mutations have been identified in the corresponding region of a closely related gene, the cystic fibrosis transmembrane conductance regulator (CFTR or ABCC7) (15). Login to comment 22 ABCA1 p.Lys776Asn We tested the hypothesis that ABCA1 K776N genotype is associated with risk of IHD in the general population. Login to comment 44 ABCA1 p.Lys776Asn An ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, California) was used to genotype the K776N (nucleotide 2327G b0e; C) mutation. Login to comment 45 ABCA1 p.Lys776Asn An ABI PRISM 7900HT Sequence Detection System (Applied Biosystems, Foster City, California) was used to genotype the K776N (nucleotide 2327G Ͼ C) mutation. Login to comment 54 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Cox proportional hazards regression models estimated hazard ratios for IHD as a function of K776N genotype, and Kaplan-Meier plots and log-rank tests evaluated the cumulative incidence of IHD as a function of age and K776N genotype. Login to comment 55 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Cox proportional hazards regression models estimated hazard ratios for IHD as a function of K776N genotype, and Kaplan-Meier plots and log-rank tests evaluated the cumulative incidence of IHD as a function of age and K776N genotype. Login to comment 62 ABCA1 p.Lys776Asn RESULTS Among the 9,076 participants in The Copenhagen City Heart Study, 37 (frequency: 0.4%) were heterozygous and none were homozygous for K776N. Login to comment 63 ABCA1 p.Lys776Asn RESULTS Among the 9,076 participants in The Copenhagen City Heart Study, 37 (frequency: 0.4%) were heterozygous and none were homozygous for K776N. Login to comment 64 ABCA1 p.Lys776Asn Risk factors for IHD did not differ between non-carriers and K776N heterozygotes, except for levels of HDL-C in men (Table 1). Login to comment 65 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Risk factors for IHD did not differ between non-carriers and K776N heterozygotes, except for levels of HDL-C in men (Table 1). Login to comment 66 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log- Abbreviations and Acronyms apoAI ϭ apolipoprotein AI CFTR ϭ cystic fibrosis transmembrane conductance regulator HDL-C ϭ high-density lipoprotein cholesterol IHD ϭ ischemic heart disease rank test: p ϭ 0.005) (Fig. Login to comment 67 ABCA1 p.Lys776Asn The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5) (Table 2). Login to comment 68 ABCA1 p.Lys776Asn At the age of 80 years, about 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years (Table 2). Login to comment 69 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5) (Table 2). Login to comment 70 ABCA1 p.Lys776Asn Mean plasma HDL-C in non-carriers and K776N heterozygotes was 1.72 mmol/l and 1.82 mmol/l in women (p afd; 0.42), and 1.38 mmol/l and 1.18 mmol/l in men (p afd; 0.05). Login to comment 71 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Finally, in an independent case-control study comparing 562 patients with IHD with 3,103 healthy controls within the same age range, the odds ratio for IHD in K776N heterozygotes versus non-carriers was 2.8 (95% confidence interval 0.8 to 9.4) (Table 3). Login to comment 72 ABCA1 p.Lys776Asn Mean plasma HDL-C in non-carriers and K776N heterozygotes was 1.72 mmol/l and 1.82 mmol/l in women (p ϭ 0.42), and 1.38 mmol/l and 1.18 mmol/l in men (p ϭ 0.05). Login to comment 73 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Mean plasma apoAI levels in non-carriers and K776N heterozygotes were 151 mg/dl and 150 mg/dl in women (p ϭ 0.93), and 130 mg/dl and 117 mg/dl in men (p ϭ 0.03) (data not shown); HDL-C levels in the 37 individuals heterozygous for K776N ranged from 1.0 to 2.7 mmol/l in women, and from 0.5 to 2.0 mmol/l in men. Login to comment 77 ABCA1 p.Lys776Asn The frequency of IHD in K776N heterozygotes in the present study was 26% to 28% (women: 5 of 19; men: 5 of 18), comparable to the frequency in Tangier disease. Login to comment 79 ABCA1 p.Lys776Asn The frequency of IHD in K776N heterozygotes in the present study was 26% to 28% (women: 5 of 19; men: 5 of 18), comparable to the frequency in Tangier disease. Login to comment 84 ABCA1 p.Val771Met A rare single nucleotide polymorphism (SNP) (V771M, allele frequency 0.03) and a muta- Figure 1. Login to comment 85 ABCA1 p.Lys776Asn Cumulative incidence of ischemic heart disease (IHD) as a function of age and ABCA1 K776N genotype. Login to comment 86 ABCA1 p.Val771Met A rare single nucleotide polymorphism (SNP) (V771M, allele frequency 0.03) and a muta- Figure 1. Login to comment 87 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Cumulative incidence of ischemic heart disease (IHD) as a function of age and ABCA1 K776N genotype. Login to comment 89 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Characteristics of Individuals in the General Population by ABCA1 K776N Genotype Women Men Non-Carriers (n ‫؍‬ 5,003) K776N Heterozygotes (n ‫؍‬ 19) Non-Carriers (n ‫؍‬ 4,036) K776N Heterozygotes (n ‫؍‬ 18) Age at entry (yrs) 46 Ϯ 0.2 45 Ϯ 3.0 45 Ϯ 0.2 48 Ϯ 2.5 Cholesterol (mmol/l) 6.3 Ϯ 0.02 6.2 Ϯ 0.3 6.0 Ϯ 0.02 5.6 Ϯ 0.3 Apolipoprotein B (mg/dl) 86.4 Ϯ 0.3 83.8 Ϯ 5.3 86.2 Ϯ 0.3 85.1 Ϯ 6.2 HDL-C (mmol/l) 1.72 Ϯ 0.01 1.82 Ϯ 0.11 1.38 Ϯ 0.01 1.18 Ϯ 0.09* Triglycerides (mmol/l) 1.7 Ϯ 0.02 1.4 Ϯ 0.2 2.1 Ϯ 0.03 2.3 Ϯ 0.3 Body mass index (kg/m2 ) 25.2 Ϯ 0.07 25.0 Ϯ 1.0 26.1 Ϯ 0.06 24.7 Ϯ 1.1 Smoking (%) 73 89 84 88 Diabetes mellitus (%) 3 0 6 11 Hypertension (%) 51 37 59 56 Values are mean Ϯ SE, or percentages. Login to comment 92 ABCA1 p.Thr774Pro tion (T774P, allele frequency 0.004) situated, respectively, five and two amino acids N-terminal of the K776 residue, have been reported. Login to comment 93 ABCA1 p.Val771Met Although we have recently shown that V771M is associated with increased HDL-C levels (9), effects on risk of IHD have not been documented for either of these variants (14,28). Login to comment 94 ABCA1 p.Thr774Pro tion (T774P, allele frequency 0.004) situated, respectively, five and two amino acids N-terminal of the K776 residue, have been reported. Login to comment 95 ABCA1 p.Val771Met Although we have recently shown that V771M is associated with increased HDL-C levels (9), effects on risk of IHD have not been documented for either of these variants (14,28). Login to comment 96 ABCA1 p.Lys776Asn To our knowledge, no homozygotes for K776N have been described so far, and we also did not identify any. Login to comment 98 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn To our knowledge, no homozygotes for K776N have been described so far, and we also did not identify any. Login to comment 99 ABCA1 p.Lys776Asn However, as is the case for K776N in the present study, in Tangier disease there also does not seem to be a clear correlation between the reduction in plasma HDL-C levels and risk of IHD. Login to comment 100 ABCA1 p.Lys776Asn It is therefore unlikely that the majority of K776N homozygotes would express an HDL-C deficiency phenotype comparable to Tangier disease, where HDL-C levels are generally below 0.2 mmol/l. Login to comment 101 ABCA1 p.Lys776Asn However, as is the case for K776N in the present study, in Tangier disease there also does not seem to be a clear correlation between the reduction in plasma HDL-C levels and risk of IHD. Login to comment 103 ABCA1 p.Lys776Asn Although K776N is a relatively common mutation, it is not a common cause of IHD. Login to comment 104 ABCA1 p.Lys776Asn The population-attributable fraction of K776N to IHD is about 0.4% in the Copenhagen City Heart Study, or comparable to the risk of IHD attributed to low-density lipoprotein receptor mutations in the same study. Login to comment 105 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Although K776N is a relatively common mutation, it is not a common cause of IHD. Login to comment 106 ABCA1 p.Lys776Asn The population-attributable fraction of K776N to IHD is about 0.4% in the Copenhagen City Heart Study, or comparable to the risk of IHD attributed to low-density lipoprotein receptor mutations in the same study. Login to comment 107 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp However, at the individual level, K776N appears to have a marked impact on risk. Login to comment 108 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn When taking multiple testing into account, the log-rank test for the cumulative incidence of ischemic heart disease as a function of age and K776N genotype fulfilled a Bonferroni-corrected p value b0d;0.007 (0.05 of 7) on a two-sided test (seven different genetic variants tested including K776N). Login to comment 109 ABCC7 p.Arg347Pro ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Lys776Asn ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp However, several arguments favor a true observation: 1) the involved amino acid residue is completely conserved between species and relatively conserved between 12 ABCAs with very different transport functions; 2) the amino acid substitution changes the charge of the side-chain, potentially leading to structural alterations of the protein, and consequently to altered protein interactions or transport properties; 3) in the CFTR (or ABCC7), a disease-causing mutation (R347P) has been identified at a site that corresponds to residue 764 in ABCA1 (15), and thus in close vicinity to K776N; 4) the present study is of a large cohort, and therefore includes only incident cases, avoiding the normal pitfalls of case reports and case-control studies (30); 5) we observed a similar trend on risk of IHD in a separate case-control study; 6) we have previously determined effects on lipids and lipoproteins of all non-synonymous SNPs identified in ABCA1 (R219K, V771M, V825I, I883M, E1172D, R1587K). Login to comment 110 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn When taking multiple testing into account, the log-rank test for the cumulative incidence of ischemic heart disease as a function of age and K776N genotype fulfilled a Bonferroni-corrected p value Ͻ0.007 (0.05 of 7) on a two-sided test (seven different genetic variants tested including K776N). Login to comment 111 ABCA1 p.Lys776Asn However, the fact that K776N was in Hardy-Weinberg equilibrium suggested that no serious selection bias had occurred in the cohort during follow-up. Login to comment 112 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn If mortality rate from ischemic heart disease was higher among K776N heterozygotes and homozygotes than among non-carriers, our study would underestimate the association between ABCA1 K776N and risk of ischemic heart disease. Login to comment 113 ABCA1 p.Lys776Asn However, the fact that K776N was in Hardy-Weinberg equilibrium suggested that no serious selection bias had occurred in the cohort during follow-up. Login to comment 114 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Risk of Ischemic Heart Disease as a Function of ABCA1 K776N Genotype in the General Population Events Incidence Rate/10,000 Person-Years (95% CI) Hazard Ratio (95% CI) Observed Expected Age-Adjusted HDL-C-Adjusted Multifactorial-Adjusted Non-carriers 1,023 1,029 61 (58-65) 1 1 1 K776N heterozygotes 10 4 157 (76-290) 2.4 (1.3-4.5) 2.4 (1.3-4.5) 2.4 (1.3-4.5) In the Cox regression model (age-adjusted, HDL-C-adjusted, and multifactorial-adjusted), age is adjusted for by incorporating age in the baseline hazard function (left truncation). Login to comment 116 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Risk of Ischemic Heart Disease as a Function of ABCA1 K776N Genotype in the General Population Events Incidence Rate/10,000 Person-Years (95% CI) Hazard Ratio (95% CI) Observed Expected Age-Adjusted HDL-C-Adjusted Multifactorial-Adjusted Non-carriers 1,023 1,029 61 (58-65) 1 1 1 K776N heterozygotes 10 4 157 (76-290) 2.4 (1.3-4.5) 2.4 (1.3-4.5) 2.4 (1.3-4.5) In the Cox regression model (age-adjusted, HDL-C-adjusted, and multifactorial-adjusted), age is adjusted for by incorporating age in the baseline hazard function (left truncation). Login to comment 119 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Risk of Ischemic Heart Disease as a Function of ABCA1 K776N Genotype in the Case-Control Study Frequency Odds Ratio (95% CI) Age-Adjusted IHD Controls All Non-carriers 558 (99.3) 3,095 (99.7) 1 K776N heterozygotes 4 (0.7) 8 (0.3) 2.8 (0.8-9.4) A total of 562 45-to 64-year-old patients with ischemic heart disease (IHD) verified by coronary angiography were compared with 3,103 healthy controls within the same age range. Login to comment 121 ABCA1 p.Lys776Asn ABCA1 p.Lys776Asn Risk of Ischemic Heart Disease as a Function of ABCA1 K776N Genotype in the Case-Control Study Frequency Odds Ratio (95% CI) Age-AdjustedIHD Controls All Non-carriers 558 (99.3) 3,095 (99.7) 1 K776N heterozygotes 4 (0.7) 8 (0.3) 2.8 (0.8-9.4) A total of 562 45-to 64-year-old patients with ischemic heart disease (IHD) verified by coronary angiography were compared with 3,103 healthy controls within the same age range. Login to comment