ABCMdb

PMID: 20185793

Delgado-Lista J, Perez-Martinez P, Perez-Jimenez F, Garcia-Rios A, Fuentes F, Marin C, Gomez-Luna P, Camargo A, Parnell LD, Ordovas JM, Lopez-Miranda J
ABCA1 gene variants regulate postprandial lipid metabolism in healthy men.
Arterioscler Thromb Vasc Biol. 2010 May;30(5):1051-7. Epub 2010 Feb 25., [PubMed]

Sentences

No. Mutations Sentence Comment

1 ABCA1 p.Arg219Lys Methods and Results-To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. Login to comment 7 ABCA1 p.Arg219Lys Methods and Results-To further characterize the effects of ABCA1 variants in human postprandial lipid metabolism, we studied the influence of 3 single nucleotide polymorphisms (i27943 [rs2575875]; i48168 [rs4149272]; R219K [rs2230806]) in the postprandial lipemia of 88 normolipidemic young men who were given a fatty meal. Login to comment 11 ABCA1 p.Arg219Lys One of the most studied ABCA1 variants is R219K (rs2230806). Login to comment 16 ABCA1 p.Arg219Lys E-mail jlopezmir@uco.es (c) 2010 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.109.202580 though a typically plausible underlying mechanism of this altered atherosclerosis was the change in HDL concentration, this has not been found in the majority of studies.14,15 Looking for additional physiological pathways underlying ABCA1 effects on lipid metabolism and atherosclerosis, we investigated and report here the effects of ABCA1 variants i27943, i48168, and R219K on postprandial lipid metabolism of healthy males. Login to comment 17 ABCA1 p.Arg219Lys One of the most studied ABCA1 variants is R219K (rs2230806). Login to comment 22 ABCA1 p.Arg219Lys E-mail jlopezmir@uco.es (c) 2010 American Heart Association, Inc. Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org DOI: 10.1161/ATVBAHA.109.202580 though a typically plausible underlying mechanism of this altered atherosclerosis was the change in HDL concentration, this has not been found in the majority of studies.14,15 Looking for additional physiological pathways underlying ABCA1 effects on lipid metabolism and atherosclerosis, we investigated and report here the effects of ABCA1 variants i27943, i48168, and R219K on postprandial lipid metabolism of healthy males. Login to comment 30 ABCA1 p.Arg219Lys Biochemical Determinations Single Nucleotide Polymorphisms Selection, DNA Amplification, and Genotyping R219K Gb0e;A is a well-characterized single nucleotide polymorphism (SNP) that has been extensively studied and is associated with cardiovascular disease; however, its influence on postprandial lipemia has not been tested.14 We have reported previously on other effects of SNP i27943Gb0e;A and i48168Gb0e;A.19 Computational analysis ascribed potential functional characteristics to each variant allele of these SNP.19 Additionally, for the i48168 Gb0e;A polymorphism, analysis by MAPPER indicated a potential allele-specific binding site for the cartilage paired-class homeoprotein 1 (CART1 or ALX1) transcription factor, with a motif that appears enriched in certain genes involved in cholesterol metabolism (Parnell and Ordovas, unpublished data). Login to comment 35 ABCA1 p.Arg219Lys Baseline Characteristics of the Study Participants CHOL, mg/dL TG, mg/dL HDL, mg/dL LDL, mg/dL apoA1, mg/dL apoB, mg/dL ABCA1 R219K (rs2230806) GG nafd;50 153.61afe;3.39 86.7afe;4.6 45.64afe;1.38 90.68afe;3.1 103.64afe;2.55 67.88afe;2.48 GA/AA nafd;34/4 150.48afe;3.61 72.90afe;5.5 47.01afe;1.83 88.84afe;3.46 109.36afe;3.58 67.72afe;2.53 P 0.537 0.056 0.545 0.695 0.184 0.965 ABCA1 i48168 (rs4149272) CC nafd;23 152.54afe;4.78 73.64afe;7.29 50.061afe;2.07* 88.05afe;4.07 116.43afe;4.04* 63.50afe;3.13 CT nafd;51 152.82afe;3.06 80.76afe;4.67 45.36afe;1.32 90.72afe;3.2 103.59afe;2.59 69.16afe;2.00 TT nafd;14 149.33afe;5.85 81.56afe;8.93 45.389afe;2.53 87.4afe;5.38 106.75afe;4.95 67.30afe;3.83 P 0.867 0.685 0.041 0.820 0.033 0.310 ABCA1 i27943 (rs2575875) GG nafd;21 152.12afe;5.00 75.63afe;7.67 49.36afe;2.21 85.36afe;5.74 115.78afe;4.28ߤ 63.88afe;3.29 GA nafd;52 153.347afe;2.99 79.88afe;4.59 45.89afe;1.32 91.39afe;3.02 104.00afe;2.56 69.06afe;1.97 AA nafd;15 147.86afe;5.83 81.17afe;8.93 46.12afe;2.57 87.46afe;4.44 107.89afe;4.98 66.38afe;3.82 P 0.707 0.867 0.395 0.574 0.039 0.385 CHOL indicates cholesterol; LDL, low-density lipoprotein. Login to comment 36 ABCA1 p.Arg219Lys Biochemical Determinations Single Nucleotide Polymorphisms Selection, DNA Amplification, and Genotyping R219K GϾA is a well-characterized single nucleotide polymorphism (SNP) that has been extensively studied and is associated with cardiovascular disease; however, its influence on postprandial lipemia has not been tested.14 We have reported previously on other effects of SNP i27943GϾA and i48168GϾA.19 Computational analysis ascribed potential functional characteristics to each variant allele of these SNP.19 Additionally, for the i48168 GϾA polymorphism, analysis by MAPPER indicated a potential allele-specific binding site for the cartilage paired-class homeoprotein 1 (CART1 or ALX1) transcription factor, with a motif that appears enriched in certain genes involved in cholesterol metabolism (Parnell and Ordovas, unpublished data). Login to comment 41 ABCA1 p.Arg219Lys Baseline Characteristics of the Study Participants CHOL, mg/dL TG, mg/dL HDL, mg/dL LDL, mg/dL apoA1, mg/dL apoB, mg/dL ABCA1 R219K (rs2230806) GG nϭ50 153.61Ϯ3.39 86.7Ϯ4.6 45.64Ϯ1.38 90.68Ϯ3.1 103.64Ϯ2.55 67.88Ϯ2.48 GA/AA nϭ34/4 150.48Ϯ3.61 72.90Ϯ5.5 47.01Ϯ1.83 88.84Ϯ3.46 109.36Ϯ3.58 67.72Ϯ2.53 P 0.537 0.056 0.545 0.695 0.184 0.965 ABCA1 i48168 (rs4149272) CC nϭ23 152.54Ϯ4.78 73.64Ϯ7.29 50.061Ϯ2.07* 88.05Ϯ4.07 116.43Ϯ4.04* 63.50Ϯ3.13 CT nϭ51 152.82Ϯ3.06 80.76Ϯ4.67 45.36Ϯ1.32 90.72Ϯ3.2 103.59Ϯ2.59 69.16Ϯ2.00 TT nϭ14 149.33Ϯ5.85 81.56Ϯ8.93 45.389Ϯ2.53 87.4Ϯ5.38 106.75Ϯ4.95 67.30Ϯ3.83 P 0.867 0.685 0.041 0.820 0.033 0.310 ABCA1 i27943 (rs2575875) GG nϭ21 152.12Ϯ5.00 75.63Ϯ7.67 49.36Ϯ2.21 85.36Ϯ5.74 115.78Ϯ4.28† 63.88Ϯ3.29 GA nϭ52 153.347Ϯ2.99 79.88Ϯ4.59 45.89Ϯ1.32 91.39Ϯ3.02 104.00Ϯ2.56 69.06Ϯ1.97 AA nϭ15 147.86Ϯ5.83 81.17Ϯ8.93 46.12Ϯ2.57 87.46Ϯ4.44 107.89Ϯ4.98 66.38Ϯ3.82 P 0.707 0.867 0.395 0.574 0.039 0.385 CHOL indicates cholesterol; LDL, low-density lipoprotein. Login to comment 63 ABCA1 p.Arg219Lys R219K was not in linkage disequilibrium with either of the other 2 SNP (r2 b0d;0.012; Pb0e;0.05). Login to comment 65 ABCA1 p.Arg219Lys R219K A statistical study is presented for a genotype-dominant effect based on previously published data.14 In parallel, an additive model was also performed but we did not observe any differences compared with the dominant model. Login to comment 70 ABCA1 p.Arg219Lys R219K was not in linkage disequilibrium with either of the other 2 SNP (r2 Ͻ0.012; PϾ0.05). Login to comment 72 ABCA1 p.Arg219Lys R219K A statistical study is presented for a genotype-dominant effect based on previously published data.14 In parallel, an additive model was also performed but we did not observe any differences compared with the dominant model. Login to comment 73 ABCA1 p.Arg219Lys AUC of Lipid Fractions in the Postprandial Study ABCA1 R219K ABCA1 i48168 ABCA1 i27943 Total TG GG 79.5afe;5.0 CC 56.6afe;7.3* GG 56.8afe;7.8ߥ GA/AA 70.9afe;5.9 CT 76.5afe;4.7 GA 76.4afe;4.7 TT 89.6afe;9.0 AA 87.1afe;9.1 CHOL GG 80.9afe;1.7 CC 79.9afe;2.7 GG 78.5afe;2.8 GA/AA 80.8afe;2.1 CT 81.1afe;1.7 GA 81.9afe;1.7 TT 79.9afe;2.7 AA 79.0afe;3.3 Large TRL TG GG 33.4afe;2.5 CC 20.9afe;3.5* GG 21.6afe;3.7ߥ GA/AA 28.7afe;3.0 CT 31.8afe;2.3 GA 31.3afe;2.3 TT 38.2afe;4.4 AA 37.3afe;4.5 Small TRL TG GG 23.7afe;2.0 CC 20.3afe;3.1 GG 20.1afe;3.2 GA/AA 23.4afe;2.4 CT 23.9afe;2.0 GA 24.1afe;2.0 TT 24.9afe;3.9 AA 24.2afe;3.9 Large TRL CHOL GG 4.7afe;0.3 CC 4.7afe;0.4 GG 4.8afe;0.4 GA/AA 4.8afe;0.3 CT 4.7afe;0.2 GA 4.7afe;0.3 TT 4.6afe;0.5 AA 4.7afe;0.5 Small TRL CHOL GG 6.3afe;0.4 CC 5.5afe;0.7 GG 5.7afe;0.7 GA/AA 6.0afe;0.5 CT 6.1afe;0.5 GA 5.9afe;0.4 TT 6.5afe;0.9 AA 6.9afe;0.9 apoA1 GG 54.0afe;1.3 CC 60.1afe;1.9ߤ GG 59.1afe;2.1&#a7; GA/AA 56.6afe;1.5 CT 53.6afe;1.2 GA 54.2afe;1.2 TT 55.9afe;2.4 AA 55.9afe;2.4 apoB GG 35.1afe;1.1 CC 32.6afe;1.7 GG 31.8afe;1.7&#a7; GA/AA 35.5afe;1.3 CT 36.2afe;1.1 GA 36.5afe;1.0 TT 34.8afe;2.1 AA 34.2afe;2.0 HDL GG 23.7afe;0.8 CC 26.0afe;1.2 GG 25.3afe;1.3 GA/AA 24.2afe;0.9 CT 23.5afe;0.7 GA 23.9afe;0.8 TT 23.8afe;1.4 AA 23.8afe;1.5 Univariate ANOVA using body mass index and age as covariates. Login to comment 80 ABCA1 p.Arg219Lys AUC of Lipid Fractions in the Postprandial Study ABCA1 R219K ABCA1 i48168 ABCA1 i27943 Total TG GG 79.5Ϯ5.0 CC 56.6Ϯ7.3* GG 56.8Ϯ7.8‡ GA/AA 70.9Ϯ5.9 CT 76.5Ϯ4.7 GA 76.4Ϯ4.7 TT 89.6Ϯ9.0 AA 87.1Ϯ9.1 CHOL GG 80.9Ϯ1.7 CC 79.9Ϯ2.7 GG 78.5Ϯ2.8 GA/AA 80.8Ϯ2.1 CT 81.1Ϯ1.7 GA 81.9Ϯ1.7 TT 79.9Ϯ2.7 AA 79.0Ϯ3.3 Large TRL TG GG 33.4Ϯ2.5 CC 20.9Ϯ3.5* GG 21.6Ϯ3.7‡ GA/AA 28.7Ϯ3.0 CT 31.8Ϯ2.3 GA 31.3Ϯ2.3 TT 38.2Ϯ4.4 AA 37.3Ϯ4.5 Small TRL TG GG 23.7Ϯ2.0 CC 20.3Ϯ3.1 GG 20.1Ϯ3.2 GA/AA 23.4Ϯ2.4 CT 23.9Ϯ2.0 GA 24.1Ϯ2.0 TT 24.9Ϯ3.9 AA 24.2Ϯ3.9 Large TRL CHOL GG 4.7Ϯ0.3 CC 4.7Ϯ0.4 GG 4.8Ϯ0.4 GA/AA 4.8Ϯ0.3 CT 4.7Ϯ0.2 GA 4.7Ϯ0.3 TT 4.6Ϯ0.5 AA 4.7Ϯ0.5 Small TRL CHOL GG 6.3Ϯ0.4 CC 5.5Ϯ0.7 GG 5.7Ϯ0.7 GA/AA 6.0Ϯ0.5 CT 6.1Ϯ0.5 GA 5.9Ϯ0.4 TT 6.5Ϯ0.9 AA 6.9Ϯ0.9 apoA1 GG 54.0Ϯ1.3 CC 60.1Ϯ1.9† GG 59.1Ϯ2.1§ GA/AA 56.6Ϯ1.5 CT 53.6Ϯ1.2 GA 54.2Ϯ1.2 TT 55.9Ϯ2.4 AA 55.9Ϯ2.4 apoB GG 35.1Ϯ1.1 CC 32.6Ϯ1.7 GG 31.8Ϯ1.7§ GA/AA 35.5Ϯ1.3 CT 36.2Ϯ1.1 GA 36.5Ϯ1.0 TT 34.8Ϯ2.1 AA 34.2Ϯ2.0 HDL GG 23.7Ϯ0.8 CC 26.0Ϯ1.2 GG 25.3Ϯ1.3 GA/AA 24.2Ϯ0.9 CT 23.5Ϯ0.7 GA 23.9Ϯ0.8 TT 23.8Ϯ1.4 AA 23.8Ϯ1.5 Univariate ANOVA using body mass index and age as covariates. Login to comment 102 ABCA1 p.Arg219Lys Furthermore, in a recent report of type 2 diabetic patients, the ABCA1 SNP associated with coronary heart disease (including R219K) were not associ- Figure 1. Login to comment 109 ABCA1 p.Arg219Lys Furthermore, in a recent report of type 2 diabetic patients, the ABCA1 SNP associated with coronary heart disease (including R219K) were not associ- Figure 1. Login to comment 113 ABCA1 p.Arg219Lys ߥPb0d;0.05 i27943 GG vs GA. Arterioscler Thromb Vasc Biol May 2010 ated with HDL, and those associated with HDL were not associated with coronary heart disease.35 The explanation for these contradictory findings has been set on the limited effects that gene variation can have on final HDL levels, gene-environment interactions, or the influence of ABCA1 gene variants on other lipid molecules and enzymes that secondarily can mildly influence HDL concentrations.17 The minor allele of R219K has been associated with limited atherosclerosis,15 reduced risk for myocardial infarction, or progression of coronary disease in various studies.16,36-42 Here, we noticed only a trend toward lower fasting TG (Pafd;0.059), according to previous studies.14 Currently, this variant is thought to affect lipids mildly, but gene-environment interactions are strong, with greater effects on lipid concentration when oxidative stress or inflammation is elevated in subjects.14,15,39,40 Such is not the case in our study. Login to comment 114 ABCA1 p.Arg219Lys However, marginal effects not reaching significance were found in our study for practically all lipid parameters toward a protective effect for the minor allele of R219K, which could become significant when the subject is exposed to the aforementioned stressors or even simply with increasing age. Login to comment 121 ABCA1 p.Arg219Lys ated with HDL, and those associated with HDL were not associated with coronary heart disease.35 The explanation for these contradictory findings has been set on the limited effects that gene variation can have on final HDL levels, gene-environment interactions, or the influence of ABCA1 gene variants on other lipid molecules and enzymes that secondarily can mildly influence HDL concentrations.17 The minor allele of R219K has been associated with limited atherosclerosis,15 reduced risk for myocardial infarction, or progression of coronary disease in various studies.16,36-42 Here, we noticed only a trend toward lower fasting TG (Pϭ0.059), according to previous studies.14 Currently, this variant is thought to affect lipids mildly, but gene-environment interactions are strong, with greater effects on lipid concentration when oxidative stress or inflammation is elevated in subjects.14,15,39,40 Such is not the case in our study. Login to comment 122 ABCA1 p.Arg219Lys However, marginal effects not reaching significance were found in our study for practically all lipid parameters toward a protective effect for the minor allele of R219K, which could become significant when the subject is exposed to the aforementioned stressors or even simply with increasing age. Login to comment