Biomedical subjects

L Adrienne Cupples

Publications and source records attributed to L Adrienne Cupples.

At least 19 recordsLinked to original sources

PubMed2006

Dietary intake of n-6 fatty acids modulates effect of apolipoprotein A5 gene on plasma fasting triglycerides, remnant lipoprotein concentrations, and lipoprotein particle size: the Framingham Heart Study.

BACKGROUND: Apolipoprotein A5 gene (APOA5) variation is associated with plasma triglycerides (TGs). However, little is known about whether dietary fat modulates this association. METHODS AND RESULTS: We investigated the interaction between APOA5 gene variation and dietary fat in determining plasma fasting TGs, remnant-like particle (RLP) concentrations, and lipoprotein particle size in 1001 men and 1147 women who were Framingham Heart Study participants. Polymorphisms -1131T>C and 56C>G, representing 2 independent haplotypes, were analyzed. Significant gene-diet interactions between the -1131T>C polymorphism and polyunsaturated fatty acid (PUFA) intake were found (P<0.001) in determining fasting TGs, RLP concentrations, and particle size, but these interactions were not found for the 56C>G polymorphism. The -1131C allele was associated with higher fasting TGs and RLP concentrations (P<0.01) in only the subjects consuming a high-PUFA diet (>6% of total energy). No heterogeneity by sex was found. These interactions showed a dose-response effect when PUFA intake was considered as a continuous variable (P<0.01). Similar interactions were found for the sizes of VLDL and LDL particles. Only in carriers of the -1131C allele did the size of these particles increase (VLDL) or decrease (LDL) as PUFA intake increased (P<0.01). We further analyzed the effects of n-6 and n-3 fatty acids and found that the PUFA-APOA5 interactions were specific for dietary n-6 fatty acids. CONCLUSIONS: Higher n-6 (but not n-3) PUFA intake increased fasting TGs, RLP concentrations, and VLDL size and decreased LDL size in APOA5 -1131C carriers, suggesting that n-6 PUFA-rich diets are related to a more atherogenic lipid profile in these subjects.

Adult↗

PubMed2006

Non-contrast-enhanced computerized tomography and analgesic-related kidney disease: report of the national analgesic nephropathy study.

Previous studies suggested that the non-contrast-enhanced computerized tomography (CT) scan is a highly reliable tool for the diagnosis of analgesic-associated renal disease. However, this issue has not been addressed in the US population. A total of 221 incident patients with ESRD from different regions of the United States underwent a helical CT scan and detailed questioning about drug history. Specific renal anatomic criteria were developed to determine whether a constellation of CT findings (small indented calcified kidneys [SICK]) is linked to analgesic ingestion. For approximating use before the onset of renal disease, only analgesic ingestion at least 9 yr before starting dialysis was considered relevant. Fifteen patients met the criteria for SICK. This represented 7% of the enrolled patients and approximately 1% of the total ESRD population. There was a significant increase in the estimated risk among patients with a history of heavy aspirin ingestion (odds ratio [OR] 7.4 [95% confidence interval (CI) 1.2 to 43] for > or =1 kg lifetime; OR 8.8 [95% CI 1.2 to 66] for > or =0.3 kg/yr). Total analgesic ingestion of > or =0.3 kg/yr also was significantly associated with SICK (OR 8.2; 95% CI 1.5 to 45). These findings were accounted for largely by combination products that contained aspirin and phenacetin (used by three patients with SICK), which are no longer available. In addition, the CT finding of SICK was present only in a minority of heavy analgesic users, yielding a sensitivity of 5 to 26%. Findings of SICK are infrequent in the US ESRD population and do not occur among a sufficient proportion of heavy analgesic users to render the non-contrast-enhanced CT scan a sensitive tool to detect analgesic-associated kidney injury.

Adult↗

PubMed2006

Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts.

Understanding the mechanisms by which estrogens affect cardiovascular disease risk, including the role of variation in the gene for estrogen receptor alpha (ESR1), may be key to new treatment strategies. We investigated whether the CC genotype at ESR1 c.454-397T>C is associated with increased risk among men. Study of more than 7000 whites in 5 cohorts from 4 countries provided evidence that genotype CC, present in roughly 20% of individuals, is a risk factor for nonfatal acute myocardial infarction (odds ratio=1.44; P<0.0001), after adjustment for established cardiovascular risk factors. After exclusion of younger subjects from 2 cohorts, because of age interaction, the odds ratio increased (to 1.63).

Adult↗

PubMed2006

Variants at the APOA5 locus, association with carotid atherosclerosis, and modification by obesity: the Framingham Study.

Genetic variation at the apolipoprotein A5 gene (APOA5) is associated with increased triglyceride concentrations, a risk factor for atherosclerosis. Carotid intimal medial thickness (IMT) is a surrogate measure of atherosclerosis burden. We sought to determine the association of common APOA5 genetic variants with carotid IMT and stenosis. A total of 2,273 Framingham Offspring Study participants underwent carotid ultrasound and had data on at least one of the five APOA5 variants (-1131T>C, -3A>G, 56C>G, IVS3+476G >A, and 1259T>C). Although none of the individual variants was significantly associated with carotid measures, the haplotype defined by the presence of the rare allele of the 56C>G variant was associated with a higher common carotid artery (CCA) IMT compared with the wild-type haplotype (0.75 vs. 0.73 mm; P < 0.05). The rare allele of each of the -1131T >C, -3A>G, IVS3+476G>A, and 1259T>C variants and the haplotype defined by the presence of the rare alleles in these four variants were each significantly associated with CCA IMT in obese participants. These associations remained significant even after adjustment for triglycerides. APOA5 variants were associated with CCA IMT, particularly in obese participants. The mechanism of these associations and the effect modification by obesity are independent of fasting triglyceride levels.

Apolipoprotein A-V↗

PubMed2006

Sex and age specific effects of chromosomal regions linked to body mass index in the Framingham Study.

BACKGROUND: Previously, we reported significant linkage of body mass index (BMI) to chromosomes 6 and 11 across six examinations, covering 28 years, of the Framingham Heart Study. These results were on all individuals available at each exam, thus the sample size varied from exam to exam. To remove any effect of sample size variation we have now constructed six subsets; for each exam individuals were only included if they were measured at every exam, i.e. for each exam, included individuals comprise the intersection of the original six exams. This strategy preferentially removed older individuals who died before reaching the sixth exam, thus the intersection datasets are smaller (n = 1114) and significantly younger than the full datasets. We performed variance components linkage analysis on these intersection datasets and on their sex-specific subsets. RESULTS: Results from the sex-specific genome scans revealed 11 regions in which a sex-specific maximum lodscore was at least 2.0 for at least one dataset. Randomization tests indicated that all 11 regions had significant (p < 0.05) differences in sex-specific maximum lodscores for at least three datasets. The strongest sex-specific linkage was for men on chromosome 16 with maximum lodscores 2.70, 3.00, 3.42, 3.61, 2.56 and 1.93 for datasets 1-6 respectively. Results from the full genome scans revealed that linked regions on chromosomes 6 and 11 remained significantly and consistently linked in the intersection datasets. Surprisingly, the maximum lodscore on chromosome 10 for dataset 1 increased from 0.97 in the older original dataset to 4.23 in the younger smaller intersection dataset. This difference in maximum lodscores was highly significant (p < 0.0001), implying that the effect of this chromosome may vary with age. Age effects may also exist for the linked regions on chromosomes 6 and 11. CONCLUSION: Sex specific effects of chromosomal regions on BMI are common in the Framingham study. Some evidence also exists for age-specific effects of chromosomal regions.

Adult↗

PubMed2006

Association between well-characterized lipoprotein-related genetic variants and carotid intimal medial thickness and stenosis: The Framingham Heart Study.

OBJECTIVE: To determine the association of well-characterized lipoprotein-related genetic variants with carotid intimal medial thickness (IMT) and stenosis. METHODS: 3380 men and women from the Framingham Offspring Study underwent carotid ultrasound to determine carotid IMT and stenosis>/=25%. We genotyped 12 variants in 10 lipoprotein-related genes known to be associated with significant differences in lipoprotein levels. RESULTS: For most of the variants, there was no association with carotid IMT. In multivariable, sex-specific analyses, the rare allele of the cholesterol ester transfer protein (CETP) TaqIB variant was associated with lower ICA IMT in men. Hypertension was associated with higher ICA IMT only in male carriers of the rare allele of the APOCIII Sst-1 variant (p for the interaction=0.041). In analyses of carotid stenosis in male, carriers of the lipoprotein lipase (LPL) N291S rare variant showed a higher risk of carotid stenosis (OR=2.59, 95% confidence interval: 1.11-6.02, p=0.028) compared to NN genotype. CONCLUSIONS: While there is no evidence for a significant association of several common lipoprotein-related genetic variants with carotid IMT, our results are consistent with the previously reported role of CETP and LPL genetic variants in cardiovascular risk and the possible modulation of the association between hypertension and carotid IMT by APOCIII Sst-1 variant.

Adolescent↗

PubMed2006

The relationship between aldosterone, oxidative stress, and inflammation in chronic, stable human heart failure.

BACKGROUND: Aldosterone antagonists reduce morbidity and mortality in patients with severe heart failure, but the mechanisms responsible are not fully understood. Observations in animal models suggest that elevated levels of aldosterone promote oxidative stress and inflammation in the myocardium. It is unknown if these findings are relevant to heart failure patients who may have much lower aldosterone levels. METHODS AND RESULTS: We therefore examined the relationship of plasma aldosterone levels to markers of oxidative stress, inflammation and matrix turnover in 58 patients with chronic, stable heart failure from systolic dysfunction (LV ejection fraction <0.40) who were not receiving aldosterone antagonists. Chronic, stable heart failure patients had modestly elevated levels of aldosterone. Additionally, these patients had elevated levels of 8-isoprostaglandin F(2alpha), C-reactive protein, soluble intercellular adhesion molecule-1, osteopontin, brain natriuretic peptide, procollagen type III aminoterminal peptide, and tissue inhibitor of metalloproteinase-1. Among these patients with heart failure, aldosterone levels correlated with 8-iso-PGF(2alpha) (P = .003), ICAM-1 (P = .008), and TIMP-1 (P = .006) after adjustment for age, gender, race, diabetes, smoking, heart rate, left ventricular mass, and body mass index. CONCLUSION: In chronic, stable heart failure patients on standard therapy, higher aldosterone levels are associated with systemic evidence of oxidative stress, inflammation, and matrix turnover.

Aldosterone↗

PubMed2005

Comparisons of case-selection approaches based on allele sharing and/or disease severity index: application to the GAW14 simulated data.

For mapping complex disease traits, linkage studies are often followed by a case-control association strategy in order to identify disease-associated genes/single-nucleotide polymorphisms (SNPs). Substantial efforts are required in selecting the most informative cases from a large collection of affected individuals in order to maximize the power of the study, while taking into consideration study cost. In this article, we applied and extended three case-selection strategies that use allele-sharing information method for families with multiple affected offspring to select most informative cases using additional information on disease severity. Our results revealed that most significant associations, as measured by the lowest p-values, were obtained from a strategy that selected a case with the most allele sharing with other affected sibs from linked families ("linked-best"), despite reduction in sample size resulting from discarding unlinked families. Moreover, information on disease severity appears to be useful to improve the ability to detect associations between markers and disease loci.

Alleles↗

PubMed2005

Power and type I error rate of false discovery rate approaches in genome-wide association studies.

In genome-wide genetic studies with a large number of markers, balancing the type I error rate and power is a challenging issue. Recently proposed false discovery rate (FDR) approaches are promising solutions to this problem. Using the 100 simulated datasets of a genome-wide marker map spaced about 3 cM and phenotypes from the Genetic Analysis Workshop 14, we studied the type I error rate and power of Storey's FDR approach, and compared it to the traditional Bonferroni procedure. We confirmed that Storey's FDR approach had a strong control of FDR. We found that Storey's FDR approach only provided weak control of family-wise error rate (FWER). For these simulated datasets, Storey's FDR approach only had slightly higher power than the Bonferroni procedure. In conclusion, Storey's FDR approach is more powerful than the Bonferroni procedure if strong control of FDR or weak control of FWER is desired. Storey's FDR approach has little power advantage over the Bonferroni procedure if there is low linkage disequilibrium among the markers. Further evaluation of the type I error rate and power of the FDR approaches for higher linkage disequilibrium and for haplotype analyses is warranted.

False Positive Reactions↗

PubMed2005

Impact of non-ignorable missingness on genetic tests of linkage and/or association using case-parent trios.

The transmission/disequilibrium test was introduced to test for linkage disequilibrium between a marker and a putative disease locus using case-parent trios. However, parental genotypes may be incomplete in such a study. When parental information is non-randomly missing, due, for example, to death from the disease under study, the impact on type I error and power under dominant and recessive disease models has been reported. In this paper, we examine non-ignorable missingness by assigning missing values to the genotypes of affected parents. We used unrelated case-parent trios in the Genetic Analysis Workshop 14 simulated data for the Danacaa population. Our computer simulations revealed that the type I error of these tests using incomplete trios was not inflated over the nominal level under either recessive or dominant disease models. However, the power of these tests appears to be inflated over the complete information case due to an excess of heterozygous parents in dyads.

Genes, Dominant↗

PubMed2005

Allele imbalance, or loss of heterozygosity, in normal breast epithelium of sporadic breast cancer cases and BRCA1 gene mutation carriers is increased compared with reduction mammoplasty tissues.

PURPOSE: Normal-appearing breast epithelium can contain genetic abnormalities, including allele imbalance (AI), also referred to as loss of heterozygosity. Whether abnormalities are associated with cancer or cancer risk is unknown. PATIENTS AND METHODS: We performed a miniallelotype, using 20 microsatellites, on each of 460 histologically normal, microdissected breast terminal ducto-lobular units (TDLUs) from three groups of women: sporadic breast cancer patients (SP; n = 18), BRCA1 gene mutation carriers (BRCA1; n = 16), and controls undergoing reduction mammoplasty (RM; n = 18). We analyzed the results using Fisher's exact tests, logistic regression, and generalized estimating equations. RESULTS: AI was increased three-fold in SP and BRCA1 groups compared with RM. Both the number of TDLUs with AI increased (eight [5%] of 162 in the RM group compared with 24 [15%] of 162 in the SP and 22 [16%] of 136 in the BRCA1 groups; P = .0150), and the proportion of patients with AI increased (five [28%] of 18 in the RM group compared with 15 [83%] of 18 in the SP and 13 [81%] of 16 in the BRCA1 groups; P = .0007). The adjusted odds ratios (OR) for AI in TDLU increased in SP (OR = 15.5) and BRCA1 (OR = 13.7) patients compared with RM (P = .0025). This result was particularly evident on chromosome 17q (P = .0393), where more AI was seen in BRCA1 (OR = 12.4) than in SP (OR = 4.9) patients or RM controls. CONCLUSION: Increased prevalence of AI in normal-appearing epithelium is associated with breast cancer and increased breast cancer risk. The increased prevalence may reflect dysregulation, even in normal-appearing epithelium, of genomic processes contributing to cancer development. The clinical significance of genetic alterations in the subset of controls remains to be determined.

Adult↗

PubMed2005

Polymorphisms in the PON gene cluster are associated with Alzheimer disease.

Paraoxonase is an arylesterase enzyme that is expressed in the liver and found in the circulation in association with apoA1 and the high-density lipoprotein, and prevents the accumulation of oxidized lipids in low-density lipoproteins in vitro. Common polymorphisms in genes encoding paraoxonase are established risk factors in a variety of vascular disorders including coronary artery disease and carotid artery stenosis, but their association with Alzheimer disease (AD) is controversial. We tested the association of 29 SNPs in PON1, PON2 and PON3 with AD in 730 Caucasian and 467 African American participants of the MIRAGE Study, an ongoing multi-center family-based genetic epidemiology study of AD. Eight SNPs were associated with AD in the African American families (0.0001< or =P< or =0.04) and two SNPs were associated with AD in Caucasian families (0.01< or =P< or =0.04). Of note, the pattern of association for the PON1 promoter SNP -161[C/T] was the same in both ethnic groups (P=0.006). Haplotype analysis using sliding windows revealed 11 contiguous SNP combinations spanning the three PON genes with significant global test scores (0.006< or =P< or =0.04) in the two ethnic groups combined. The most significantly associated haplotype comprised SNPs in the region spanning the -161[C/T] SNP (P=0.00009). Our results demonstrate association between AD and variants in the PON gene cluster in Caucasians and African Americans.

Black or African American↗

PubMed2005

LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: We tested the hypothesis that concentrations of LpA-I and/or LpA-I:A-II HDL subclasses are significantly associated with CHD prevalence and recurrent cardiovascular events. METHODS: LpA-I levels were determined by differential electroimmunoassay in male participants with (n = 169) and without CHD (n = 850) from the Framingham Offspring Study (FOS) and in male participants with CHD from the placebo arm of the Veterans Affairs HDL Intervention Trial (VA-HIT) (n = 741). Data were analyzed cross-sectionally (FOS) and prospectively (VA-HIT) and were adjusted for established lipid and non-lipid CHD risk factors. RESULTS: We observed slightly but significantly higher LpA-I levels in CHD cases compared to all or to HDL-C-matched controls and slightly but significantly higher LpA-I:A-II levels in CHD cases compared to HDL-C-matched controls it the FOS. Neither LpA-I nor LpA-I:A-II levels were significantly different between groups with and without recurrent cardiovascular events in the VA-HIT. No significant differences were observed in LpA-I and LpA-I:A-II levels in low HDL-C (< or = 40 mg/dl) subjects with CHD (VA-HIT, n = 711) and without CHD (FOS, n = 373). Plasma LpA-I concentration had a positive correlation with the large LpA-I HDL particle (alpha-1) but no correlation with the small LpA-I HDL particle (prebeta-1). LpA-I:A-II concentration had a positive correlation with the large (alpha-2) and an inverse correlation with the small (alpha-3) LpA-I:A-II HDL particles. CONCLUSION: Our data do not support the hypothesis that CHD prevalence (FOS) or recurrence of cardiovascular events (VA-HIT) are associated with significant reductions in the concentrations of LpA-I and/or LpA-I:A-II HDL subclasses.

Cholesterol, HDL↗

PubMed2005

Sex-specific association between estrogen receptor-alpha gene variation and measures of adiposity: the Framingham Heart Study.

BACKGROUND: Polymorphisms in estrogen receptor-alpha (ESR1) may be associated with variation in body mass index and waist circumference. However, most prior studies have been limited by sample size and power. METHODS: DNA from 1763 unrelated men and women (mean age, 56 yr) from the Framingham Heart Study offspring cohort was genotyped for four ESR1 polymorphisms: T30C (rs2077647) in exon 1, PvuII (rs2234693), and XbaI (rs 9340799) in intron 1, and C1335G (rs 1801132) in exon 4. RESULTS: Men homozygous for the PvuII C allele (frequency, 0.45) had lower waist circumference (99.3 cm), compared with TT homozygous men (99.8 cm) and heterozygotes (100.6 cm) (P < 0.004). Similar results were obtained with XbaI, which lies in the same linkage disequilibrium block. C1335G also demonstrated a gender-specific association: men with CG or GG genotypes had lower mean body mass index, 27.7 and 27.9 kg/m2 respectively, compared with 28.6 kg/m2 among the CC homozygotes (P < 0.01). No significant associations were seen with T30C, nor were associations observed among women. CONCLUSIONS: Polymorphisms in ESR1 are associated with measures of adiposity in men. These associations further support the hypothesis that the intron 1 region of ESR1 influences phenotypes important for cardiovascular risk.

Adiposity↗

PubMed2005

Value of high-density lipoprotein (HDL) subpopulations in predicting recurrent cardiovascular events in the Veterans Affairs HDL Intervention Trial.

OBJECTIVE: To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). METHODS AND RESULTS: Apolipoprotein A-I (apoA-I)-containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (alpha-1, alpha-2, pre-alpha-1, and pre-alpha-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre-beta-1 and alpha-3) levels than subjects without such events. Multivariate analyses indicated that alpha-1 and alpha-2 particle levels were significant negative risk factors, whereas alpha-3 level was a significant positive risk factor for new CVD events. Pre-beta-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that alpha-1 was the most significant risk factor for recurrent CVD events among HDL particles. CONCLUSIONS: An altered HDL subpopulation profile marked with low alpha-1 and alpha-2 levels and a high alpha-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, alpha-1 and alpha-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.

Aged↗

PubMed2005

CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1) is a chemokine strongly implicated in promoting atherosclerosis in animal models, but human genetic evidence is contradictory. METHODS AND RESULTS: We analyzed the association of genetic variation in the MCP-1 gene (CCL2) with prevalent myocardial infarction and serum MCP-1 levels in the community-based Framingham Heart Study Offspring Cohort (50% women; mean age, 62 years). MCP-1 levels and CCL2 genotypes were determined in 3236 and 1797 individuals, respectively. Significant clinical correlates of MCP-1 levels were age, cigarette smoking, triglycerides, body mass index, and waist-to-hip ratio. The MCP-1-2578G allele located in the CCL2 regulatory region was significantly associated with both higher serum MCP-1 levels in a recessive genetic model (358+/-10 versus 328+/-3 pg/mL; P=0.002) and higher prevalence of myocardial infarction in a dominant genetic model (adjusted odds ratio, 2.0; 95% CI, 1.2 to 3.3; P=0.005). We also defined the linkage disequilibrium structure at the CCL2 locus and observed 6 common haplotypes in whites. We performed haplotype-based association analysis and found that only the most frequent haplotype, defined by the MCP-1-2578G allele, was associated with prevalent MI. CONCLUSIONS: Our data are consistent with the hypothesis that MCP-1 is involved in the pathogenesis of human atherosclerosis and myocardial infarction.

Aged↗

PubMed2005

Influence of alcohol dehydrogenase 1C polymorphism on the alcohol-cardiovascular disease association (from the Framingham Offspring Study).

Although moderate alcohol consumption is associated with a lower risk of cardiovascular disease (CVD), little is known of the effects of alcohol dehydrogenase 1C (ADH1C) polymorphism on the association between alcohol and CVD. We used data on 1,805 unrelated subjects in the Framingham Offspring Study to assess whether rs1693482 and rs698, 2 single nucleotide polymorphisms of the ADH1C gene, modify the relation between alcohol consumption and prevalent CVD. The 2 single nucleotide polymorphisms were in linkage disequilibrium (D' = 0.99, R(2) = 0.96). There was evidence for a U-shaped association between alcohol consumption and CVD in this population. Multivariable adjusted odds ratios for prevalent CVD were 0.63 (95% confidence interval 0.41 to 0.97) and 0.80 (95% confidence interval 0.46 to 1.41) for CT and TT genotypes of rs1693482 relative to CC genotype (model p <0.0001). Corresponding values for AG and GG genotypes of rs698 were 0.68 (95% confidence interval 0.45 to 1.04) and 0.84 (95% confidence interval 0.49 to 1.46), respectively, compared with the AA genotype (model p <0.0001). There were nonstatistically significant associations between rs693482 C-->T and rs698 A-->G mutations and prevalent CVD among current drinkers (lower CVD prevalence with minor allele) but not among nondrinkers in whom the minor allele was associated with a trend toward higher CVD prevalence (p values for interaction are 0.16 for rs1693482 and 0.52 for rs698). Alcohol consumption was associated with high-density lipoprotein cholesterol across all genotypes of the 2 single nucleotide polymorphisms in a dose-response fashion without evidence for interaction. In conclusion, these data suggest borderline interactions between genes and environment of ADH1C variation and alcohol intake on prevalent CVD. The interaction does not appear to be mediated through effects on high-density lipoprotein cholesterol.

Adult↗

PubMed2005

Tobacco smoking, estrogen receptor alpha gene variation and small low density lipoprotein level.

High levels of small low density lipoprotein (LDL) particles are a major risk factor for cardiovascular morbidity and mortality. Both estrogens and smoking, with known anti-estrogenic effects, alter the atherogenic lipid profile. We tested for a role of interaction between smoking and estrogen receptor alpha gene (ESR1) variation in association with plasma concentration of atherogenic small LDL particles and LDL particle size. We studied 1727 unrelated subjects, 854 women and 873 men, mean age 51 years (SD 10), from the population-based Framingham Heart Study. After covariate adjustment, women who smoked and had the common ESR1 c.454-397 TT genotype (in 30% of women, T was present on both chromosomes at position 397 prior to the start of exon 2) had >1.7-fold higher levels of small LDL particles than women with the alternative genotypes (P-value for smoking-genotype interaction was 0.001). Similar results were obtained for three other ESR1 variants including c.454-351A > G, in the same linkage disequilibrium block. A similar substantial gender-specific result was also evident with a fifth variant, in a separate linkage disequilibrium block, in exon 4 (P = 0.003). Women who smoked and had specific, common ESR1 genotypes had a substantially higher plasma concentration of atherogenic small LDL particles. Significant results revealed a dose-dependent effect of smoking and were evident in both pre- and postmenopausal women. The reported association has the potential to explain the risks associated with estrogen use in certain women and a recent report of association between an ESR1 haplotype comprised of c.454-397 T and c.454-351 A alleles with increased myocardial infarction and ischaemic heart disease, independent of the standard, established cardiovascular risk factors.

Estrogen Receptor alpha↗