ABCMdb

PMID: 19596329

Frikke-Schmidt R
Genetic variation in the ABCA1 gene, HDL cholesterol, and risk of ischemic heart disease in the general population.
Atherosclerosis. 2010 Feb;208(2):305-16. Epub 2009 Jun 11., [PubMed]

Sentences

No. Mutations Sentence Comment

2337 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Pro1065Cys ABCA1 p.Arg2144* 4.2. Frequency of mutations in the general population Four of seven non-synonymous mutations (P1065C, G1216V, N1800H, R2144X), ranging in frequency from 0.1 to two per 1000, were associated with low levels of HDL cholesterol in the general population. Login to comment 2338 ABCA1 p.Lys776Asn ABCA1 p.Ser364Cys ABCA1 p.Thr774Pro The remaining non-synonymous mutations (S364C, T774P, and K776N), ranging in frequency from 0.1 to four per 1000, were not associated with low HDL cholesterol levels [65,66]. Login to comment 2340 ABCA1 p.Asn1800His These mutations were considered to be private mutations occurring only in individual families [30], until two studies of two different general population samples detected the well known Tangier disease mutation, N1800H [67], in three unrelated white individuals with low HDL cholesterol (below the 1st percentile) from the CCHS and in one white individual with low HDL cholesterol (below the 5th percentile) from the Dallas Heart Study [57,58]. Login to comment 2342 ABCA1 p.Asn1800His ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Gly1216Val ABCA1 p.Arg2144* ABCA1 p.Pro1065Ser 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 ABCA1 p.Asn1800His ABCA1 p.Gly1216Val ABCA1 p.Pro1065Ser 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 2344 ABCA1 p.Asn1800His The N1800H mutation accounted for the majority of HDL lowering mutations, 22 of 28 carriers in the CCHS, and 70 of 76 carriers in the CGPS [66]. Login to comment 2368 ABCA1 p.Lys776Asn Genetically increased IHD risk without low HDL cholesterol Another situation was observed with the identification of 37 heterozygous carriers of the K776N mutation in the CCHS [65]. Login to comment 2370 ABCA1 p.Lys776Asn Several arguments favor the functionality of the K776N mutation, among these that the involved amino acid residue is completely conserved between species, and relatively conserved between 12 human ABCAs with very different transport functions [57]. Login to comment 2371 ABCC7 p.Arg347Pro ABCA1 p.Lys776Asn Furthermore, a mutation (R347P) causing cystic fibrosis has been identified in the CFTR gene (=ABCC7, another full ABC transporter) at a site that corresponds to residue 764 in ABCA1 [73], i.e. in close vicinity to the K776N mutation. Login to comment 2372 ABCA1 p.Lys776Asn Also, the application of a substitution position-specific evolutionary conservation score (subPSEC score) [74], which considers site-specific variation among evolutionarily related proteins, predicted the K776N mutation to be deleterious [75]. Login to comment 2376 ABCA1 p.Lys776Asn Thus, it could be speculated that the membrane associated K776N mutation impairs the apoptotic machinery and consequently induces inflammation and atherogenesis without affecting the lipid efflux capacity and thus the level of HDL cholesterol in plasma. Login to comment 2377 ABCA1 p.Lys776Asn The K776N variant has been reported previously, but no association with IHD was observed [81], probably due to a low number of carriers in that study. Login to comment 2378 ABCA1 p.Lys776Asn Although, heterozygous men for the K776N mutation, had marginally lower levels of HDL cholesterol compared to non-carriers in the general population (Fig. 3, lower panel), the two- to three-fold increase in risk of IHD could not be explained by this effect on HDL cholesterol [65]. Login to comment 2380 ABCA1 p.Lys776Asn K776N heterozygotes, ischemic heart disease (IHD) and high-density lipoprotein (HDL) cholesterol levels. Login to comment 2381 ABCA1 p.Lys776Asn Cumulative incidence of IHD as a function of age and by K776N genotype (upper panel), and exact values of HDL cholesterol for the individual heterozygotes as a function of age (lower panels). Login to comment 2384 ABCA1 p.Lys776Asn Frikke-Schmidt et al. revealed four major findings: (1) approximately 10% of individuals with the lowest percentile of HDL cholesterol in the general population are heterozygous for mutations in ABCA1 [57], (2) the frequency of FHA caused by ABCA1 mutations in the general population is about three in 1000 [66], or considerably higher than previously assumed, (3) heterozygosity for a specific mutation, K776N, predicts a two- to three-fold risk of IHD, independent of HDL cholesterol levels [65], and (4) low plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 are not associated with an increased risk of IHD, supporting that a genetically lifelong reduction in plasma levels of HDL cholesterol per se does not predict an increased risk of IHD [66]. Login to comment 2385 ABCA1 p.Lys776Asn Frikke-Schmidt et al. revealed four major findings: (1) approximately 10% of individuals with the lowest percentile of HDL cholesterol in the general population are heterozygous for mutations in ABCA1 [57], (2) the frequency of FHA caused by ABCA1 mutations in the general population is about three in 1000 [66], or considerably higher than previously assumed, (3) heterozygosity for a specific mutation, K776N, predicts a two- to three-fold risk of IHD, independent of HDL cholesterol levels [65], and (4) low plasma levels of HDL cholesterol due to heterozygosity for loss-of-function mutations in ABCA1 are not associated with an increased risk of IHD, supporting that a genetically lifelong reduction in plasma levels of HDL cholesterol per se does not predict an increased risk of IHD [66]. Login to comment 2386 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Common ABCA1 variants in the general population 5.1. Frequency of common variants in the extreme tails of the HDL distribution Several resequencing studies have identified a number of common non-synonymous variations in ABCA1 [57,58,81-84]: R219K, V771M, V825I, I883M, E1172D and R1587K. Login to comment 2387 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Common ABCA1 variants in the general population 5.1. Frequency of common variants in the extreme tails of the HDL distribution Several resequencing studies have identified a number of common non-synonymous variations in ABCA1 [57,58,81-84]: R219K, V771M, V825I, I883M, E1172D and R1587K. Login to comment 2388 ABCA1 p.Val771Met In the largest resequencing study to date of Caucasians in the general population, two of the nonsynonymous SNPs (V771M and R1587K) and/or their haplotypes differed in frequency between the population extremes of HDL cholesterol levels [52,57]. Login to comment 2389 ABCA1 p.Val825Ile ABCA1 p.Val771Met In the largest resequencing study to date of Caucasians in the general population, two of the non-synonymous SNPs (V771M and R1587K) and/or their haplotypes differed in frequency between the population extremes of HDL cholesterol levels [52,57]. Login to comment 2390 ABCA1 p.Val825Ile Further, the frequency of V825I differed when women were considered separately. Login to comment 2394 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Frequencies of common variants and association with variation in lipid levels in the general population Frequencies for the most common non-synonymous ABCA1 SNPs (R219K, V825I, I883M, R1587K) are largely similar across studies that partly or as a whole represent general populations [57,58,81,82,86-88], whereas the less common SNPs (V771M, and E1172D) are reported in some [57,58,81,82,86,88], but not in all studies [58,87]. Login to comment 2395 ABCA1 p.Ile883Met ABCA1 p.Arg219Lys ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Frequencies of common variants and association with variation in lipid levels in the general population Frequencies for the most common non-synonymous ABCA1 SNPs (R219K, V825I, I883M, R1587K) are largely similar across studies that partly or as a whole represent general populations [57,58,81,82,86-88], whereas the less common SNPs (V771M, and E1172D) are reported in some [57,58,81,82,86,88], but not in all studies [58,87]. Login to comment 2397 ABCA1 p.Val825Ile ABCA1 p.Val771Met The V771M and V825I SNPs were associated with increases in HDL cholesterol in women, whereas the R1587K SNP was associated with decreased HDL cholesterol levels in both genders. Login to comment 2398 ABCA1 p.Val825Ile ABCA1 p.Val825Ile ABCA1 p.Val771Met ABCA1 p.Val771Met The V771M and V825I SNPs were associated with increases in HDL cholesterol in women, whereas the R1587K SNP was associated with decreased HDL cholesterol levels in both genders. Login to comment 2399 ABCA1 p.Val825Ile ABCA1 p.Val771Met This corresponded well with the findings from the initial screening where V771M and V825I (in women) were overrepresented in the high extreme, and R1587K was overrepresented in the low extreme of HDL cholesterol [57]. Login to comment 2401 ABCA1 p.Ile883Met ABCA1 p.Val825Ile ABCA1 p.Val771Met The HDL cholesterol and/or apoAI lowering effect of the rare allele of the very common R1587K SNP has now been observed in several different studies [57,81,82], whereas the HDL cholesterol increasing effect of the V771M and V825I/I883M SNPs appears to be confined to specific genders in different populations [57,58,87-89]. Login to comment 2402 ABCA1 p.Ile883Met ABCA1 p.Val825Ile ABCA1 p.Val771Met The HDL cholesterol and/or apoAI lowering effect of the rare allele of the very common R1587K SNP has now been observed in several different studies [57,81,82], whereas the HDL cholesterol increasing effect of the V771M and V825I/I883M SNPs appears to be confined to specific genders in different populations [57,58,87-89]. Login to comment 2403 ABCA1 p.Ile883Met ABCA1 p.Val825Ile The isolated single site analysis by Frikke-Schmidt et al. revealed that the V825I, and not the I883M SNP, was responsible for the HDL increments [57]. Login to comment 2404 ABCA1 p.Ile883Met ABCA1 p.Val825Ile The isolated single site analysis by Frikke-Schmidt et al. revealed that the V825I, and not the I883M SNP, was responsible for the HDL increments [57]. Login to comment 2409 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Frikke-Schmidt et al. showed for the first time in a large general population sample that three out of six non-synonymous SNPs (V771M, I883M, and E1172D) were independent predictors of IHD risk - risk increases that were not reflected in levels of HDL cholesterol [85]. Login to comment 2410 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp ABCA1 p.Glu1172Asp Frikke-Schmidt et al. showed for the first time in a large general population sample that three out of six non-synonymous SNPs (V771M, I883M, and E1172D) were independent predictors of IHD risk - risk increases that were not reflected in levels of HDL cholesterol [85]. Login to comment 2411 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp By stepwise regression, V771M and I883M were shown to be the best predictors in women, whereas I883M and E1172D were most informative in men. Login to comment 2412 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs with up to three-fold increases in risk for specific subsets of the genotypes (Fig. 4, lower panels) [85]. Login to comment 2413 ABCA1 p.Ile883Met ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp Additive effects on IHD risk were present for V771M/I883M and I883M/E1172D pairs with up to three-fold increases in risk for specific subsets of the genotypes (Fig. 4, lower panels) [85]. Login to comment 2440 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp For V771M, I883M, and E1172D as single sites, heterozygotes and homozygotes for the variant allele were pooled (heterozygotes and homozygotes in red, wildtype in green). Login to comment 2441 ABCA1 p.Ile883Met ABCA1 p.Val771Met ABCA1 p.Glu1172Asp For V771M, I883M, and E1172D as single sites, heterozygotes and homozygotes for the variant allele were pooled (heterozygotes and homozygotes in red, wildtype in green). Login to comment 2443 ABCA1 p.Ile883Met ABCA1 p.Glu1172Asp Cumulative incidence plots are shown for cells with significant hazard ratios except for the I883M/E1172D AGCC genotype in men, because only 2 incident events occurred in this group. Login to comment 2444 ABCA1 p.Ile883Met ABCA1 p.Glu1172Asp Cumulative incidence plots are shown for cells with significant hazard ratios except for the I883M/E1172D AGCC genotype in men, because only 2 incident events occurred in this group. Login to comment 2487 ABCA1 p.Asn1800His Left panel: Median decrease in HDL cholesterol levels for ABCA1 heterozygotes in the general population for all mutations (top), and for N1800H alone (bottom). Login to comment 2488 ABCA1 p.Asn1800His Left panel: Median decrease in HDL cholesterol levels for ABCA1 heterozygotes in the general population for all mutations (top), and for N1800H alone (bottom). Login to comment