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ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment.

ABSTRACT: Our goals were to examine the relationships of a specific ATP-binding cassette transporter A1 (ABCA1) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial.The ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Of these subjects 47.6% carried the variant, with 40.0% carrying one allele, and 7.6% carrying both alleles. No effects on baseline LDL-C levels were noted, but mean HDL-C increased modestly according to the number of variant alleles being present (1.27 vs 1.28 vs 1.30 mmol/L, p = 0.024). No relationships between the presence or absence of this variant and statin induced LDL-C lowering response or CHD at baseline were noted. However within trial those with the variant as compared to those without the variant, the overall adjusted hazard ratio for new cardiovascular disease (fatal CHD, non-fatal myocardial infarction, or fatal or non-fatal stroke) was 1.22 (95% CI 1.06-1.40, p = 0.006), while for those in the pravastatin group it was 1.41 (1.15-1.73, p = 0.001), and for those in the placebo group it was 1.08 (0.89-1.30, p = 0.447) (p for interaction 0.058).Our data indicate that subjects with the ABCA1 R219K variant may get significantly less heart disease risk reduction from pravastatin treatment than those without the variant.

SUBMITTER: Akao H

PROVIDER: S-EPMC4556353 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment.

Akao Hironobu H Polisecki Eliana E Schaefer Ernst J EJ Trompet Stella S Robertson Michele M Ford Ian I Jukema J Wouter JW de Craen Anton J M AJ Packard Christopher C Buckley Brendan M BM Kajinami Kouji K

Atherosclerosis 20140508 1

<h4>Aims</h4>Our goals were to examine the relationships of a specific ATP-binding cassette transporter A1 (ABCA1) variant, rs2230806 (R219K), on baseline lipids, low-density lipoprotein cholesterol (LDL-C) lowering due to pravastatin, baseline heart disease, and cardiac endpoints on trial.<h4>Methods and results</h4>The ABCA1 R219K variant was assessed in 5414 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to prav ...[more]

PMID: 24854628

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Project description:BackgroundVenous thromboembolic events (VTE), including deep venous thrombosis and pulmonary embolism, are common in older age. It has been suggested that statins might reduce the risk of VTE however positive results from studies of middle aged subjects may not be generalisable to elderly people. We aimed to determine the effect of pravastatin on incident VTE in older people; we also studied the impact of clinical and plasma risk variables.MethodsThis study was an analysis of incident VTE using data from the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), a randomized, double-blind, placebo-controlled trial of pravastatin in men and women aged 70-82. Mean follow-up was 3.2 years. Risk for VTE was examined in non-warfarin treated pravastatin (n = 2834) and placebo (n = 2865) patients using a Cox's proportional hazard model, and the impact of other risk factors assessed in a multivariate forward stepwise regression analysis. Baseline clinical characteristics, blood biochemistry and hematology variables, plasma levels of lipids and lipoproteins, and plasma markers of inflammation and adiposity were compared. Plasma markers of thrombosis and hemostasis were assessed in a nested case (n = 48) control (n = 93) study where the cohort was those participants, not on warfarin, for whom data were available.ResultsThere were 28 definite cases (1.0%) of incident VTE in the pravastatin group recipients and 20 cases (0.70%) in placebo recipients. Pravastatin did not reduce VTE in PROSPER compared to placebo [unadjusted hazard ratio (95% confidence interval) 1.42 (0.80, 2.52) p = 0.23]. Higher body mass index (BMI) [1.09 (1.02, 1.15) p = 0.0075], country [Scotland vs Netherlands 4.26 (1.00, 18.21) p = 0.050 and Ireland vs Netherlands 6.16 (1.46, 26.00) p = 0.013], lower systolic blood pressure [1.35 (1.03, 1.75) p = 0.027] and lower baseline Mini Mental State Examination (MMSE) score [1.19 (1.01, 1.41) p = 0.034] were associated with an increased risk of VTE, however only BMI, country and systolic blood pressure remained significant on multivariate analysis. In a nested case control study of definite VTE, plasma Factor VIII levels were associated with VTE [1.52 (1.01, 2.28), p = 0.044]. However no other measure of thrombosis and haemostasis was associated with increased risk of VTE.ConclusionsPravastatin does not prevent VTE in elderly people at risk of vascular disease. Blood markers of haemostasis and inflammation are not strongly predictive of VTE in older age however BMI, country and lower systolic blood pressure are independently associated with VTE risk.Trial registrationNot applicable when study undertaken.

Project description:Background Single nucleotide polymorphisms (SNPs) in the EPHX2 gene have been implicated in susceptibility to cardiovascular diseases, including coronary heart disease (CHD). EPHX2 encodes for soluble epoxide hydrolase, an important enzyme involved in the metabolic breakdown of arachidonic acid-derived vasoactive and anti-inflammatory eicosanoids referred to as epoxyeicosatrienoic acids to their corresponding diols. Our pilot study aimed to investigate whether common SNPs such as rs751141, rs4149253, and rs1042064 of the EPHX2 gene are associated with susceptibility to CHD in Russian population. Methods A total of 1,183 unrelated Russian subjects comprising 602 patients with angiographically diagnosed CHD and 581 age- and sex-matched healthy subjects were recruited and their DNA samples were genotyped for the selected SNPs using a high-throughput Mass-ARRAY genotyping platform. Results No significant associations were found between the investigated SNPs and CHD risk (P>0.05). A polymorphism rs751141 (amino acid substitution, R287Q) displayed a trend towards association with CHD (odds ratio adjusted by sex and age was 3.02, 95% CI: 0.97–9.43, P correction =0.16). SNP-smoking interaction analyses did not identify synergic effects of the studied SNPs and cigarette smoking on the disease risk (P>0.05). A linkage disequilibrium was found between SNPs rs751141 and rs4149253 (D’ =0.995), rs751141 and rs1042064 (D’ =0.967), rs4149253 and rs1042064 (D’ =0.965). Four common haplotypes G-G-T (73%), A-G-C (10%), G-G-C (9%) and G-A-C (7%) have been identified, however, none of them showed a significant association with the risk of CHD in the studied population (P>0.05). Conclusions The investigated polymorphisms do not contribute to CHD susceptibility in our population. Nevertheless, because of a limited number of SNPs was investigated in this study, definitive conclusions yet to be made in further studies on the contribution of the EPHX2 gene to the development of CHD in Russians.

Dataset Information

ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment.

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ABCA1 gene variation and heart disease risk reduction in the elderly during pravastatin treatment.

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