ABCMdb

PMID: 12624133

Cenarro A, Artieda M, Castillo S, Mozas P, Reyes G, Tejedor D, Alonso R, Mata P, Pocovi M, Civeira F
A common variant in the ABCA1 gene is associated with a lower risk for premature coronary heart disease in familial hypercholesterolaemia.
J Med Genet. 2003 Mar;40(3):163-8., [PubMed]

Sentences

No. Mutations Sentence Comment

128 ABCA1 p.Arg219Lys In order to know if the presence of the R219K variant in the ABCA1 gene could be a protective factor for premature CHD in FH, we have determined the presence of this genetic variant by amplification by PCR and restriction analysis in a group of 374 FH subjects, with and without premature CHD. Login to comment 129 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys The K allele of the R219K variant was significantly more frequent in FH subjects without premature CHD (0.32, 95% CI 0.27 to 0.37) than in FH subjects with premature CHD (0.25, 95% CI 0.21 to 0.29) (p<0.05), suggesting that the genetic variant R219K in ABCA1 could influence the development and progression of atherosclerosis in FH subjects. Login to comment 130 ABCA1 p.Arg219Lys Moreover, the K allele of the R219K polymorphism seems to modify CHD risk without important modification of plasma HDL-C levels, and it appears to be more protective for smokers than non-smokers. Login to comment 137 ABCA1 p.Arg219Lys In order to discover if the presence of the R219K polymorphism in the ABCA1 gene plays a protective role for premature CHD in FH, we have analysed this genetic variant in a group of FH subjects. Login to comment 138 ABCA1 p.Arg219Lys In this work, we report that the common variant R219K in the ABCA1 gene is significantly more frequent in FH subjects without premature CHD than in FH subjects with premature CHD, suggesting that genetic variation in ABCA1 influences the atherosclerosis process in FH subjects. Login to comment 195 ABCA1 p.Arg219Lys R219K polymorphism analysis Genomic DNA from peripheral blood was isolated using a previously described method, with minor modifications.27 A 166 bp fragment of exon 7 of the ABCA1 gene involving nucleotide 1051 of the cDNA sequence28 was amplified by polymerase chain reaction (PCR), using the following primers: R219Ks: 5'-GCAAGGCTACCAGTTACATTTGACAAG-3' and R219Kas: 5'- GATTGGCTTCAGGATGTCCATGTTGG-3'. Login to comment 206 ABCA1 p.Arg219Lys Associations between R219K polymorphism and lipid data were analysed by multivariate ANOVA adjusted by age, gender, and BMI. Login to comment 219 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys The R219K polymorphism is the result of a nucleotide change G→A at position 1051 of the cDNA sequence, and it results in the substitution of lysine for arginine at amino acid 219 of the ABCA1 protein. Login to comment 222 ABCA1 p.Arg219Lys The R219K polymorphism was in Hardy-Weinberg equilibrium in the control and premature CHD groups. Login to comment 223 ABCA1 p.Arg219Lys The genotype frequency distribution for the R219K polymorphism is shown in table 2. Login to comment 226 ABCA1 p.Arg219Lys The allelic frequencies for the minor K allele of the R219K polymorphism were 0.32 (95% CI 0.27 to 0.37) and 0.25 (95% CI 0.21 to 0.29) for control and premature CHD groups, respectively (p<0.05). Login to comment 227 ABCA1 p.Arg219Lys The presence of the K allele of the R219K polymorphism reduced the coronary event risk in the FH studied population (odds ratio 0.63, 95% CI 0.42 to 0.95). Login to comment 228 ABCA1 p.Arg219Lys The clinical and biochemical characteristics of carriers and non-carriers of the K allele for the R219K variant in the ABCA1 Table 1 Clinical and biochemical characteristics of the FH subjects included in this study Male p Female p Control PCHD Control PCHD No 66 144 92 72 Age (years) 64.3 (6.6) 51.1 (10.4) <0.001 70.5 (5.6) 57.8 (10.5) <0.001 BMI (kg/m2 ) 27.2 (3.0) 27.0 (3.5) NS 27.0 (4.3) 28.2 (4.6) NS TC (mmol/l) 10.7 (1.8) 10.8 (1.9) NS 11.1 (1.9) 11.2 (2.2) NS LDL-C (mmol/l) 8.7 (1.8) 8.9 (1.9) NS 9.0 (1.9) 9.2 (2.4) NS TG (mmol/l) 1.55 (0.71) 1.57 (0.73) NS 1.42 (0.66) 1.39 (0.60) NS HDL-C (mmol/l) 1.24 (0.36) 1.14 (0.30) NS 1.45 (0.36) 1.42 (0.44) NS Lp(a) (µmol/l) 1.50 (1.52) 2.11 (2.01) 0.049 2.11 (2.07) 1.96 (2.16) NS Xanthomas 46.0% 41.1% NS 28.9% 33.8% NS Arcus cornealis 77.8% 55.4% 0.002 63.3% 40.0% 0.003 Hypertension 27.9% 18.0% NS 36.1% 39.3% NS Smoking 61.7% 79.7% 0.008 2.4% 14.8% 0.006 DM-2 11.9% 2.3% 0.006 7.3% 5.2% NS Values are mean (SD) for quantitative variables, and percentages for qualitative variables. Login to comment 231 ABCA1 p.Arg219Lys Male subjects with the RR genotype had higher LDL-C levels than K allele carriers of the R219K polymorphism (p=0.04). Login to comment 233 ABCA1 p.Arg219Lys On the other hand, subjects not carrying the K allele of the R219K polymorphism had more xanthomas than subjects with the RK or KK genotypes (p=0.04). Login to comment 235 ABCA1 p.Arg219Lys The remaining variables, age, BMI, lipid and lipoprotein levels, and presence of arcus cornealis, did not show differences between carriers and non-carriers of the K allele of the R219K polymorphism. Login to comment 236 ABCA1 p.Arg219Lys To assess whether the presence of the K allele of the R219K variant has an effect on the age of onset of the first coronary event in the premature CHD group, we analysed the distribution of carriers and non-carriers of the K allele in subjects who suffered their first coronary event before 40 years old (first quartile) (PCHD<40 group, n=53), in subjects who suffered their first coronary event after 40 years old (PCHD>40 group, n=163), and in the control group. Login to comment 238 ABCA1 p.Arg219Lys A different distribution was observed, with fewer carriers of the K allele of the R219K polymorphism in the PCHD<40 group than in the PCHD>40 and fewer than in the control group. Login to comment 244 ABCA1 p.Arg219Lys The effect of the K allele of the R219K polymorphism on a premature event of CHD (before 40 years) was analysed in smokers and non-smokers separately. Login to comment 247 ABCA1 p.Arg219Lys In subjects with premature CHD before 40 years old, the odds ratio of carrying the K allele in smokers v non-smokers was 0.35 (95% Figure 1 Determination of the R219K genotype by PCR amplification and restriction analysis. Login to comment 252 ABCA1 p.Arg219Lys Table 2 Genotype and allele frequencies distribution for the R219K polymorphism in the control and premature coronary heart disease groups of FH subjects studied Genotype frequencies Allele frequencies RR RK KK p RR RK+KK p R K p Control 45.6% 44.9% 9.5% 0.037 45.6% 54.4% 0.029 0.68 0.32 0.036 PCHD 56.9% 36.1% 6.9% 56.9% 43.1% 0.75 0.25 PCHD, premature coronary heart disease. Login to comment 254 ABCA1 p.Arg219Lys These results would suggest that the protective effect of the K allele of the R219K variant on premature CHD risk is more pronounced in smokers. Login to comment 257 ABCA1 p.Arg219Lys Specifically, the R219K polymorphism has been shown to be associated with decreased TG levels and a decreased severity of CHD, these effects being compatible with a net increase in ABCA1 function and accelerated reverse cholesterol transport.21 This polymorphism could influence the phenotype of FH in such a way that subjects carrying the protective allele have a slower progression of atherosclerosis and a delayed onset of CHD. Login to comment 258 ABCA1 p.Arg219Lys Previous studies have reported a carrier frequency of the R219K polymorphism of 46% in the European population,21 which is similar (47.8%) to that found in our FH patients. Login to comment 260 ABCA1 p.Arg219Lys In the present work, we have found that the frequency of the K allele of the R219K variant is significantly higher in the group of FH subjects without premature CHD than in the group of FH subjects with premature CHD. Login to comment 261 ABCA1 p.Arg219Lys The presence of the K allele of the R219K polymorphism seems to be protective against onset of premature CHD in FH subjects. Login to comment 262 ABCA1 p.Arg219Lys One result of our study is that the K allele of the R219K variant seems to modify CHD risk without important modification of plasma HDL-C concentration. Login to comment 266 ABCA1 p.Arg219Lys It is possible that the R219K variant increases the activity of ABCA1 in a similar way, although the precise mechanism underlying the functional effect of this variant will require further analyses. Login to comment 267 ABCA1 p.Arg219Lys In this series of FH patients studied, we have observed a correlation between the presence of the K allele of the R219K variant and the age of onset of the first coronary event. Login to comment 269 ABCA1 p.Arg219Lys Comparison of the odds ratio of the control v the PCHD<40 group (OR=0.51) with the odds ratio of the control v the premature CHD total group (OR=0.63) suggests that younger subjects lacking the K allele of the R219K variant have a higher coronary risk. Login to comment 270 ABCA1 p.Arg219Lys This observation confirms the protective effect of the K allele, as subjects lacking the K allele of the R219K variant develop CHD at an earlier age than subjects carrying this allele. Login to comment 271 ABCA1 p.Arg219Lys Another observation of our study is that the R219K variant appears to be more protective for smokers and ex-smokers than non-smokers in the PCHD<40 group. Login to comment 274 ABCA1 p.Arg219Lys Similarly, in our series of FH patients, smoking increases the risk of CHD in all subjects, but particularly in those subjects lacking the K allele of the R219K polymorphism in ABCA1. Login to comment 275 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Smoking increases the rate of oxidation of lipoprotein particles, and it might be possible that this oxidative stress would be alleviated in part through the ABCA1 pathway, since ABCA1 has been reported to mediate the cellular secretion of α tocopherol, the active form of vitamin E with antioxidant properties.37 Thus, it might be possible that Table 3 Clinical and biochemical characteristics of non-carriers and carriers of the K allele of the R219K polymorphism in FH subjects studied Male Female All RR RK+KK p RR RK+KK p RR RK+KK p No 120 90 75 89 195 179 Age (years) 55.4 (10.8) 55.1 (11.7) NS 63.6 (10.3) 66.1 (10.2) NS 58.5 (11.3) 60.6 (12.3) NS BMI (kg/m2 ) 27.2 (3.4) 26.9 (3.2) NS 27.1 (4.4) 27.9 (4.6) NS 27.2 (3.8) 27.4 (3.9) NS TC (mmol/l) 10.9 (2.0) 10.5 (1.7) NS 11.2 (2.3) 11.1 (1.9) NS 11.1 (2.1) 10.8 (1.8) NS LDL-C (mmol/l) 9.1 (2.0) 8.6 (1.8) 0.04 9.1 (2.4) 9.1 (1.9) NS 9.1 (2.1) 8.8 (1.9) NS TG (mmol/l) 1.53 (0.65) 1.60 (0.81) NS 1.46 (0.64) 1.38 (0.63) NS 1.49 (0.64) 1.49 (0.73) NS HDL-C (mmol/l) 1.17 (0.32) 1.19 (0.33) NS 1.42 (0.38) 1.45 (0.41) NS 1.27 (0.36) 1.32 (0.40) NS Lp(a) (µmol/l) 1.93 (1.70) 1.96 (2.12) NS 2.00 (2.17) 2.07 (2.05) NS 1.96 (1.90) 2.00 (2.08) NS Xanthomas 47.4% 36.4% NS 34.2% 28.4% NS 42.3% 32.4% 0.04 Arcus cornealis 57.9% 68.2% NS 52.8% 53.4% NS 55.9% 60.8% NS Values are mean (SD) for quantitative variables, and percentages for qualitative variables. Login to comment 277 ABCA1 p.Arg219Lys Figure 2 Percentage of non-carriers and carriers of the K allele of the R219K polymorphism in each of the three groups of FH subjects analysed: free of premature coronary heart disease (controls), premature coronary heart disease with first coronary event after 40 years old (PCHD>40), and premature coronary heart disease with first coronary event before 40 years old (PCHD<40); p indicates the difference between the control and PCHD<40 groups. Login to comment 278 ABCA1 p.Arg219Lys subjects carrying the K allele of the R219K variant would be more protected against lipoprotein oxidation and subsequent risk of atherosclerosis. Login to comment 280 ABCA1 p.Arg219Lys In this work we show that the R219K variant of ABCA1 influences premature CHD frequency in subjects with heterozygous familial hypercholesterolaemia. Login to comment 281 ABCA1 p.Arg219Lys FH subjects are a very high cardiovascular risk owing to their high LDL-C levels as a consequence of a mutation in the LDLR gene, but other genetic and/or environmental factors modify the disease expression18 and it is possible that one of them could be the variant R219K in ABCA1. Login to comment 283 ABCA1 p.Arg219Lys Although the ABCA1 locus, and specifically the polymorphism R219K, influences the early onset of CHD in FH, other different loci are also implicated with small and/or large contributions, the disease expression being the result of the interaction of these loci.16 Further studies to that effect will help to identify FH subjects at high risk of premature CHD, which will be helpful for better prevention and management of cardiovascular disease in familial hypercholesterolaemia. Login to comment