Biomedical subjects

L Adrienne Cupples

Publications and source records attributed to L Adrienne Cupples.

At least 19 recordsLinked to original sources

PubMed2007

The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.

The recycling of the amyloid precursor protein (APP) from the cell surface via the endocytic pathways plays a key role in the generation of amyloid beta peptide (Abeta) in Alzheimer disease. We report here that inherited variants in the SORL1 neuronal sorting receptor are associated with late-onset Alzheimer disease. These variants, which occur in at least two different clusters of intronic sequences within the SORL1 gene (also known as LR11 or SORLA) may regulate tissue-specific expression of SORL1. We also show that SORL1 directs trafficking of APP into recycling pathways and that when SORL1 is underexpressed, APP is sorted into Abeta-generating compartments. These data suggest that inherited or acquired changes in SORL1 expression or function are mechanistically involved in causing Alzheimer disease.

Age of Onset↗

PubMed2007

APOA5 gene variation modulates the effects of dietary fat intake on body mass index and obesity risk in the Framingham Heart Study.

Diet is an important environmental factor interacting with our genes to modulate the likelihood of developing lipid disorders and, consequently, cardiovascular disease risk. Our objective was to study whether dietary intake modulates the association between APOA5 gene variation and body weight in a large population-based study. Specifically, we have examined the interaction between the APOA5-1131T>C and 56C>G (S19W) polymorphisms and the macronutrient intake (total fat, carbohydrate, and protein) in their relation to the body mass index (BMI) and obesity risk in 1,073 men and 1,207 women participating in the Framingham Offspring Study. We found a consistent and statistically significant interaction between the -1131T>C single-nucleotide polymorphism (SNP; but not the 56C>G) and total fat intake for BMI. This interaction was dose-dependent, and no statistically significant heterogeneity by gender was detected. In subjects homozygous for the -1131T major allele, BMI increased as total fat intake increased. Conversely, this increase was not present in carriers of the -1131C minor allele. Accordingly, we found significant interactions in determining obesity and overweight risks. APOA5-1131C minor allele carriers had a lower obesity risk (OR, 0.61, 95%; CI, 0.39-0.98; P = 0.032) and overweight risk (OR, 0.63, 95%; CI, 0.41-0.96; P = 0.031) compared with TT subjects in the high fat intake group (>or=30% of energy ) but not when fat intake was low (OR, 1.16, 95%; CI, 0.77-1.74; P = 0.47 and OR = 1.15, 95%; CI, 0.77-1.71; P = 0.48) for obesity and overweight, respectively). When specific fatty acid groups were analyzed, monounsaturated fatty acids showed the highest statistical significance for these interactions. In conclusion, the APOA5-1131T>C SNP, which is present in approximately 13% of this population, modulates the effect of fat intake on BMI and obesity risk in both men and women.

Apolipoprotein A-V↗

PubMed2007

Evidence for linkage of red blood cell size and count: genome-wide scans in the Framingham Heart Study.

Red blood cell (RBC) count and size are major criteria for evaluating anemia and related hematology disease diagnoses. While environmental factors influence RBC count (RBCC) and size, mean corpuscular volume (MCV), and mean corpuscular hemoglobin (MCH), studies have indicated that each of these measures has a substantial genetic component. So far, no linkage analysis or genome scan has been reported. We carried out 10 cM genome-wide scans on RBCC, MCV, and MCH in a community-based Caucasian cohort, the Framingham Heart Study, using 325 pedigrees with 1,144 individuals genotyped and phenotyped. Using variance-component linkage methods, heritabilities were estimated as 56, 52, and 52% after covariate adjusted for RBCC, MCV, and MCH, respectively. For RBCC, we found a maximum LOD score of 3.2 on chromosome 19, 24 cM (7.0 Mbp). Near this region, there lie a few important candidate genes, including erythropoietin receptor and erythroid Krüppel-like factor. For linkage analyses for MCV and MCH, there were coinciding maximized LOD scores on chromosome 11, 9 cM (5.2 Mbp) with values of 3.8 and 3.6, respectively. Under the peak resides the hemoglobin beta cluster - several beta-like genes, which are important candidates for RBC size. In subsequent analyses, we excluded individuals with low MCV to assess the possible influence of beta-thalassemia carriers, and there continued to be evidence for linkage in the same region on chromosome 11p15 (LOD scores of 2.6 and 2.7 for MCV and MCH, respectively). For MCV, we also identified a new region on chromosome 6q24 with a LOD score of 2.9. These findings suggest that further studies are warranted to identify potential causal genetic variants for RBC size and count and related erythrocyte indices.

Adolescent↗

PubMed2007

Informative-transmission disequilibrium test (i-TDT): combined linkage and association mapping that includes unaffected offspring as well as affected offspring.

To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid chi-square test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506-516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886-1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol.

Apolipoproteins E↗

PubMed2007

Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass.

UNLABELLED: Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner. INTRODUCTION: BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied. MATERIALS AND METHODS: Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing. RESULTS: For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct. CONCLUSIONS: This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.

Bone Density↗

PubMed2006

Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men.

Polymorphisms in the LRP5 gene have been associated with bone mineral density (BMD) in men and/or women. However, the functional basis for this association remains obscure. We hypothesized that LRP5 alleles could modulate Wnt signaling and the relationship between physical activity and BMD. This genetic association study was performed in the population-based Framingham Study Offspring Cohort, and included a subset of 1797 unrelated individuals who provided blood samples for DNA and who had BMD measurements of the hip and spine. Ten single-nucleotide polymorphisms (SNPs) spanning the LRP5 gene were genotyped and used for association and interaction analyses with BMD by regression methods. LRP5 haplotypes were transiently co-expressed with Wnt3a, MesD and Dkk1 in HEK293 cells and their activity evaluated by the TCF-Lef reporter assay. Six out of ten SNPs in LRP5 were associated with one or more of the femur or spine BMDs in men or women after adjustment for covariates, and these associations differed between genders. In men< or =age 60 years, 3 SNPs were significantly associated with BMD: rs2306862 on Exon 10 with femoral neck BMD (p=0.01) and Ward's BMD (p=0.01); rs4988321/p. V667M with Ward's BMD (p=0.02); and intronic rs901825 with trochanter BMD (p=0.03). In women, 3 SNPs in intron 2 were significantly associated with BMD: rs4988330 for trochanter (p=0.01) and spine BMD (p=0.003); rs312778 with femoral neck BMD (p=0.05); and rs4988331 with spine BMD (p=0.04). For each additional rare allele, BMD changed by 3-5% in males and 2-4% in females. Moreover, there was a significant interaction between physical activity and rs2306862 in exon 10 (p for interaction=0.02) and rs3736228/p. A1330V in exon 18 (p for interaction=0.05) on spine BMD in men. In both cases, the TT genotype was associated with lower BMD in men with higher physical activity scores, conversely with higher BMD in men with lower physical activity scores. In vitro, TCF-Lef activity in presence of Wnt3a was significantly reduced in cells expressing LRP5 haplotypes carrying the T allele of exon 10 and 18 compared to the wild-type allele, whereas co-expression of Dkk1 completely inhibited Wnt3a response through all LRP5 haplotypes. In summary, genetic variation in exons 10 and 18 of the LRP5 gene modulates Wnt signaling and the relationship between physical activity and BMD in men. These observations suggest that Wnt-LRP5 may play a role in the adaptation of bone to mechanical load in humans, and may explain some gender-related differences in bone mass.

Aged↗

PubMed2006

In utero exposure to diethylstilbestrol (DES) does not increase genomic instability in normal or neoplastic breast epithelium.

BACKGROUND: In 1992, the National Cancer Institute (NCI) established the Continuation of Follow-Up of DES-Exposed Cohorts to study the long-term health effects of exposure to diethylstilbestrol (DES). Genetic effects on human breast tissue have not been examined. The authors investigated whether breast tissue of women exposed in utero to DES might exhibit the genetic abnormalities that characterize other DES-associated tumors. METHODS: Subjects enrolled in the NCI Cohort were queried about breast biopsies or breast cancer diagnoses. Available tissue blocks were obtained for invasive cancers (IC), in situ cancers (CIS), or atypical hyperplasia (AH). Exposure status was blinded, lesions were microdissected, and their DNA was analyzed for microsatellite instability (MI) and loss of heterozygosity (LOH), or allele imbalance (AI), at 20 markers on 9 chromosome arms. RESULTS: From 31 subjects (22 exposed, 9 unexposed), 273 samples were analyzed (167 normal epithelium, 16 AH, 30 CIS, 60 IC). Exposed and unexposed subjects exhibited no differences in breast cancer risk factors or demographic characteristics, except for age at diagnosis (exposed vs. unexposed: 43.2 vs. 48.8 years of age, P = .02). The authors found that MI was rare and that AI was common, with frequencies consistent with previous reports. The global age-adjusted relative rate (RR) of AI was 1.3, 95% CI = 0.8-2.4. No statistically significant associations were observed after adjustment for risk factors or after stratification by histology or by chromosome arm. CONCLUSIONS: In utero DES exposure does not appear to significantly increase genomic instability in breast epithelium, as measured by MI and AI. Breast tissue may respond differently from that of the reproductive tract to in utero DES exposure. Consequences of in utero DES exposure on the breast may be mediated by proliferative effects of estrogen.

Adult↗

PubMed2006

Predictors of improved left ventricular systolic function in an urban cardiomyopathy program.

After long-term therapy, some patients with systolic heart failure (HF) display improved left ventricular (LV) function over time, a response that is associated with improved long-term outcomes. To investigate predictors of improved LV function in an ethnically diverse HF cohort, we selected 71 patients with HF who had baseline ejection fractions (EF) <40%, follow-up EFs > or =50%, and >20% increases on follow-up echocardiography performed > or =6 months later. Their clinical features were compared with 142 age- and gender-matched control patients with baseline EFs <40% and no change or worse EFs on follow-up echocardiography. The baseline EFs were similar between patients and controls. Compared with controls, patients had a lower prevalence of diabetes mellitus (19.7% vs 36.6%, p = 0.01), a lower prevalence of an ischemic cause of disease (8.4% vs 35.2%, p <0.001), but a higher prevalence of a hypertensive cause of cardiomyopathy (29.6% vs 12%, p <0.001). Fewer patients than controls used aspirin (p = 0.04) or statins (p = 0.001) or had previous cardiac procedures (p = 0.009). In a multivariate conditional logistic regression model adjusting for age, gender, disease cause, statin use, cardiac procedures, change in heart rate, and follow-up time, hypertensive etiology was most strongly associated with improved LV function (adjusted odds ratio 9.73, 95% confidence interval 1.44 to 52.76, p = 0.02). In conclusion, patients with hypertensive causes of HF are more likely to demonstrate improved LV function over time than patients with ischemic causes of HF. Because long-term prognosis and indication for defibrillator implantation may be affected by changes in LV function, the present study provides additional support for the importance of evaluating the cause of HF to guide management.

Cardiomyopathies↗

PubMed2006

Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study.

BACKGROUND: Bilirubin is an antioxidant that suppresses lipid oxidation and retards atherosclerosis formation. An inverse association between serum bilirubin and coronary heart disease has been reported. Linkage studies have identified a major locus at the chromosome 2q telomere that affects bilirubin concentrations. A candidate gene in the linkage region encodes hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1). The insertion of a TA in the TATAA box of the gene, an allele designated UGT1A1*28, decreases gene transcription. Individuals homozygous for UGT1A1*28 (genotype 7/7) have increased serum bilirubin levels compared with carriers of the 6 allele. To date, no significant association between UGT1A1*28 and cardiovascular disease (CVD) events has been reported. We performed an association study in the Framingham Heart Study population to investigate whether UGT1A1*28 is associated with the risk of CVD events. METHODS AND RESULTS: The study population included 1780 unrelated individuals from the Offspring cohort (49% males, mean age 36 years at entry) who had been followed up for 24 years. Individuals with genotype 7/7 had significantly higher bilirubin levels (mean+/-SD 1.14+/-0.44 mg/dL) than those with genotypes 6/6 and 6/7 (mean+/-SD 0.69+/-0.27 mg/dL, P<0.01). Using the Cox proportional hazards model, we found significant associations between the UGT1A1*28 allele and decreased risk of CVD. Individuals with genotype 7/7 (population frequency of 11%) had approximately one third the risk for CVD and coronary heart disease as carriers of the 6 allele, which resulted in a hazard ratio (95% confidence interval) of 0.36 (0.18 to 0.74) and 0.30 (0.12 to 0.74), respectively. CONCLUSIONS: Homozygote UGT1A1*28 allele carriers with higher serum bilirubin concentrations exhibit a strong association with lower risk of CVD.

Adult↗

PubMed2006

Matrix Gla protein is associated with risk factors for atherosclerosis but not with coronary artery calcification.

OBJECTIVE: Atherosclerotic coronary artery calcification (CAC) is associated with increased coronary heart disease (CHD) risk. Matrix Gla protein (MGP) is an inhibitor of calcification in vivo. However, little is known regarding the distribution of circulating MGP and its associations with CHD risk factors or with CAC in humans. METHODS AND RESULTS: Serum MGP concentrations were determined in 2 independent populations of men and women free of clinically apparent cardiovascular disease: study A, n=316, mean age 58 years, and study B, n=452, mean age 68 years. CAC was determined by computed tomography. Mean MGP concentrations were 98.4 and 198 ng/mL in men, and 97.4 and 201 ng/mL in women, in study A and study B, respectively. In both cohorts, MGP levels were higher with increasing age. In age-adjusted analyses, there was an association of circulating MGP with increasing Framingham CHD risk score (in study A, P=0.003 in men and P=0.016 in women, respectively; in study B, a nonsignificant increase in men and P=0.05 in women, respectively). Significant associations of circulating MGP with high-density lipoprotein and other individual CHD risk factors were also noted in both cohorts. There were no consistent associations between MGP and CAC after adjustment for CHD risk score in the 2 cohorts. CONCLUSIONS: MGP is associated with individual CHD risk factors and the Framingham CHD risk score in men and women free of clinically apparent CHD. The relation of MGP with CAC deserves further study in larger populations.

Adult↗

PubMed2006

Genome-wide significance for a modifier of age at neurological onset in Huntington's disease at 6q23-24: the HD MAPS study.

BACKGROUND: Age at onset of Huntington's disease (HD) is correlated with the size of the abnormal CAG repeat expansion in the HD gene; however, several studies have indicated that other genetic factors also contribute to the variability in HD age at onset. To identify modifier genes, we recently reported a whole-genome scan in a sample of 629 affected sibling pairs from 295 pedigrees, in which six genomic regions provided suggestive evidence for quantitative trait loci (QTL), modifying age at onset in HD. METHODS: In order to test the replication of this finding, eighteen microsatellite markers, three from each of the six genomic regions, were genotyped in 102 newly recruited sibling pairs from 69 pedigrees, and data were analyzed, using a multipoint linkage variance component method, in the follow-up sample and the combined sample of 352 pedigrees with 753 sibling pairs. RESULTS: Suggestive evidence for linkage at 6q23-24 in the follow-up sample (LOD = 1.87, p = 0.002) increased to genome-wide significance for linkage in the combined sample (LOD = 4.05, p = 0.00001), while suggestive evidence for linkage was observed at 18q22, in both the follow-up sample (LOD = 0.79, p = 0.03) and the combined sample (LOD = 1.78, p = 0.002). Epistatic analysis indicated that there is no interaction between 6q23-24 and other loci. CONCLUSION: In this replication study, linkage for modifier of age at onset in HD was confirmed at 6q23-24. Evidence for linkage was also found at 18q22. The demonstration of statistically significant linkage to a potential modifier locus opens the path to location cloning of a gene capable of altering HD pathogenesis, which could provide a validated target for therapeutic development in the human patient.

Adolescent↗

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↗