ABCMdb

PMID: 12870173

Srinivasan SR, Li S, Chen W, Boerwinkle E, Berenson GS
R219K polymorphism of the ABCA1 gene and its modulation of the variations in serum high-density lipoprotein cholesterol and triglycerides related to age and adiposity in white versus black young adults. The Bogalusa heart study.
Metabolism. 2003 Jul;52(7):930-4., [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCA1 p.Arg219Lys R219K Polymorphism of the ABCA1 Gene and Its Modulation of the Variations in Serum High-Density Lipoprotein Cholesterol and Triglycerides Related to Age and Adiposity in White Versus Black Young Adults. Login to comment 2 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys However, information regarding the frequency of common variants, including Arg219Lys (R219K) within the coding region of the ABCA1 gene and their effect on these phenotypes in the general population is limited. Login to comment 3 ABCA1 p.Arg219Lys This study examined the frequency and phenotypic effect of R219K variant in a community-based sample of 887 white and 390 black young adults aged 20 to 38 years. Login to comment 10 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys SERUM HIGH-DENSITY lipoprotein (HDL) cholesterol is inversely related to coronary artery disease (CAD).1 This has been attributed, in part, to the key role HDL plays in the transport of cholesterol from peripheral tissues including the arterial wall to the liver, an antiatherogenic process known as reverse cholesterol transport.2 In addition, HDL is metabolically inversely related to triglyceride-rich lipoproteins,3,4 another strong risk factor for CAD.5 In the general population, factors such as age, race, sex, body fatness, variability in lipoprotein lipase, hepatic triglyceride lipase, and cholesteryl ester transfer protein activities and apolipoprotein (apo) A-I production rate influence HDL cholesterol levels.6-10 It has been known that familial disorders of HDL metabolism contribute to very low levels of HDL cholesterol.11 Mutations in the gene encoding adenosine triphosphate (ATP)- binding cassette transporter 1 (ABCA1) have been identified as the molecular basis of 2 familial HDL disorders, Tangier disease and familial hypoalphalipoproteinemia.12-14 As a cholesterol efflux regulatory protein, ABCA1 participates in the biogenesis of HDL by facilitating both translocation of cholesterol and phospholipid to the plasma membrane and efflux on to lipid poor apo A-I particles.15,16 Because mutations associated with severe functional impairment of ABCA1 are not common among individuals with low HDL cholesterol, research has been focused recently on common single nucleotide polymorphisms in the coding and promotor regions of ABCA1.17-20 The ABCA1 gene, localized on chromosome 9q31, contains 49 exons that range in size from 33 to 249 bp and is over 70 kb in length.21 A G to A transversion at nucleotide position 1051 in exon 7 results in the substitutions of a lysine for arginine at amino acid residue 219 (R219K). Login to comment 12 ABCA1 p.Arg219Lys As part of the Bogalusa Heart Study, a biracial (black-white) community-based investigation of early natural history of cardiovascular disease, the present study examines the 219K allele frequency and the effect of R219K polymorphism on serum HDL cholesterol and triglycerides in young adults. Login to comment 14 ABCA1 p.Arg219Lys Of these, 1,277 individuals (887 whites and 390 blacks) aged 20 to 38 years who had ABCA1 R219K genotype data formed the study sample for this report. Login to comment 30 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Genotyping of R219K Polymorphism Genotyping of the ABCA1 R219K variant was performed using the TaqMan assay (Applied Biosystems, Foster City, CA). Login to comment 35 ABCA1 p.Arg219Lys Based on the analysis of 67 pairs of blind duplicates, there was 98.5% concordance in R219K genotyping. Login to comment 41 ABCA1 p.Arg219Lys Multiple regression model was used to examine the independent effects of R219K polymorphism and the interaction effect between genotype and age, sex, or BMI (or subscapular skinfold) on levels of HDL cholesterol and triglycerides. Login to comment 42 ABCA1 p.Arg219Lys RESULTS The R219K genotype and allele frequencies by race are given in Table 1. Login to comment 45 ABCA1 p.Arg219Lys Genotype and Allele Frequencies for the R219K Polymorphism of ABCA1 Gene by Race: The Bogalusa Heart Study White (n ϭ 887) Count (%) Black (n ϭ 390) Count (%) Genotype* RR 495 (55.8) 63 (16.2) RK 320 (36.1) 190 (48.7) KK 72 (8.1) 137 (35.1) Allele* R 1,310 (73.8) 316 (40.5) K 464 (26.2) 464 (59.5) *Race difference, P Ͻ .001. Login to comment 47 ABCA1 p.Arg219Lys Levels of Serum HDL Cholesterol and Triglycerides in Whites and Blacks by R219K Genotype of ABCA1: The Bogalusa Heart Study K219 Allele PNoncarrier Carrier Whites No. Login to comment 66 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys DISCUSSION The present community-based study demonstrates that (1) the relative allele frequency of the R219K polymorphism of the ABCA1 gene differs markedly between blacks and whites and (2) the R219K variant significantly alters association of HDL cholesterol with age, and triglycerides with adiposity in whites, but not in blacks. Login to comment 70 ABCA1 p.Arg219Lys Heterozygotes for ABCA1 deficiency have decreased HDL cholesterol and increased triglycerides.24,25 In contrast, the phenotypic effects of the common variants, such as R219K and I823M located in the coding region of the ABCA1 gene, are found to be just opposite, suggesting these common variants are associated with an enhanced ABCA1 function.17,18 In the current study, no genotypic effects on HDL cholesterol and triglycerides were apparent in whites or blacks. However, when interaction terms of genotype with age, sex, or adiposity were included in the model, significant interaction effects of genotype and age on HDL cholesterol and genotype and adiposity on triglycerides were noted in whites, but not in blacks. Login to comment 72 ABCA1 p.Arg219Lys Effect of Interaction Between R219K Genotype of ABCA1 and Age, Sex or BMI on Levels of Serum HDL Cholesterol and Triglycerides by Race: The Bogalusa Heart Study Independent Variable White Black HDL Cholesterol Triglycerides* HDL Cholesterol Triglycerides* beta† P beta P beta P beta P Age -0.122 .240 0.010 .045 0.385 .303 0.004 .736 Sex 7.056 Ͻ.001 -0.055 .265 -1.604 .692 -0.264 .052 BMI -0.646 Ͻ.001 0.045 Ͻ.001 -0.899 Ͻ.001 0.016 .081 Genotype -0.449 .697 -0.061 .276 -2.260 .531 0.015 .906 Age* genotype 0.524 Ͻ.001 -0.006 .391 -0.484 .233 0.014 .305 Sex* genotype 0.744 .624 0.041 .576 3.891 .375 0.029 .844 BMI* genotype 0.019 .883 -0.014 .029 0.293 .311 -0.003 .779 NOTE. Login to comment 77 ABCA1 p.Arg219Lys Relationship of serum HDL cholesterol to age in whites by R219K genotype of ABCA1. Login to comment 81 ABCA1 p.Arg219Lys ABCA1 p.Arg219Lys Based on earlier findings that the expression and activity of P-glycoprotein, another ABC transporter, increases with age,26 it has been suggested that ABCA1 activity may normally increase with age, but this was blunted in ABCA1 heterozygotes.24 With respect to common R219K polymorphism, an earlier study found that the age-related increases in HDL cholesterol and cholesterol efflux in older age groups (median age, 56.7 years) were also blunted in carriers of the K219 allele, although homozygous carriers of this common variant displayed reduced severity of CAD, decreased progression of atherosclerosis, and a trend toward increased HDL cholesterol.17 It is not clear whether differences in age and preexisting CAD among subjects between studies may account for the conflicting finding regarding R219K variant. Login to comment 85 ABCA1 p.Arg219Lys The observed lack of phenotypic effects of R219K polymorphism and its interaction with age or adiposity in blacks suggests that other factors may play a dominant role in determining levels of HDL cholesterol and triglycerides in this group. Login to comment 87 ABCA1 p.Arg219Lys Further, obesity has relatively less impact on these variables in blacks.9,10 Studies, including our own, have shown that blacks versus whites have markedly higher lipoprotein lipase activity and lower hepatic triglyceride lipase activity,30-32 key parameters associated with metabolism and systemic levels of triglyceride-rich lipoproteins and HDL.33 Because these metabolic parameters favor a relatively higher HDL cholesterol and lower triglyceride trait in blacks, the phenotypic effects of the R219K variant per se may not be evident in this group. Login to comment