Framingham Heart Study 100K Project: genome-wide associations for blood pressure and arterial stiffness

Background

Genes implicated in common complex disorders such as obesity, type 2 diabetes mellitus (T2DM) or cardiovascular diseases are not disease specific, since clinically related disorders also share genetic components. Cysteine protease Calpain 10 (CAPN10) has been associated with T2DM, hypertension, hypercholesterolemia, increased body mass index (BMI) and polycystic ovary syndrome (PCOS), a reproductive disorder of women in which isunlin resistance seems to play a pathogenic role. The calpain 5 gene (CAPN5) encodes a protein homologue of CAPN10. CAPN5 has been previously associated with PCOS by our group. In this new study, we have analysed the association of four CAPN5 gene variants(rs948976A>G, rs4945140G>A, rs2233546C>T and rs2233549G>A) with several cardiovascular risk factors related to metabolic syndrome in general population.

Methods

Anthropometric measurements, blood pressure, insulin, glucose and lipid profiles were determined in 606 individuals randomly chosen from a cross-sectional population-based epidemiological survey in the province of Segovia in Central Spain (Castille), recruited to investigate the prevalence of anthropometric and physiological parameters related to obesity and other components of the metabolic syndrome. Genotypes at the four polymorphic loci in CAPN5 gene were detected by polymerase chain reaction (PCR).

Results

Genotype association analysis was significant for BMI (p ≤ 0.041), diastolic blood pressure (p = 0.015) and HDL-cholesterol levels (p = 0.025). Different CAPN5 haplotypes were also associated with diastolic blood pressure (DBP) (0.0005 ≤ p ≤ 0.006) and total cholesterol levels (0.001 ≤ p ≤ 0.029). In addition, the AACA haplotype, over-represented in obese individuals, is also more frequent in individuals with metabolic syndrome defined by ATPIII criteria (p = 0.029).

Conclusion

As its homologue CAPN10, CAPN5 seems to influence traits related to increased risk for cardiovascular diseases. Our results also may suggest CAPN5 as a candidate gene for metabolic syndrome.     

Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

Background

The TPH2 gene encodes the enzyme responsible for serotonin (5-HT) synthesis in the Central Nervous System (CNS). Stereotypic and repetitive behaviors are influenced by 5-HT, and initial studies report an association of TPH2 alleles with childhood-onset obsessive-compulsive disorder (OCD) and with autism. GLO1 encodes glyoxalase I, the enzyme which detoxifies α-oxoaldehydes such as methylglyoxal in all living cells. The A111E GLO1 protein variant, encoded by SNP C419A, was identifed in autopsied autistic brains and proposed to act as an autism susceptibility factor. Hyperserotoninemia, macrocephaly, and peptiduria represent some of the best-characterized endophenotypes in autism research.

Methods

Family-based and case-control association studies were performed on clinical samples drawn from 312 simplex and 29 multiplex families including 371 non-syndromic autistic patients and 156 unaffected siblings, as well as on 171 controls. TPH2 SNPs rs4570625 and rs4565946 were genotyped using the TaqMan assay; GLO1 SNP C419A was genotyped by PCR and allele-specific restriction digest. Family-based association analyses were performed by TDT and FBAT, case-control by χ², endophenotypic analyses for 5-HT blood levels, cranial circumference and urinary peptide excretion rates by ANOVA and FBAT.

Results

TPH2 alleles and haplotypes are not significantly associated in our sample with autism (rs4570625: TDT P = 0.27, and FBAT P = 0.35; rs4565946: TDT P = 0.45, and FBAT P = 0.55; haplotype P = 0.84), with any endophenotype, or with the presence/absence of prominent repetitive and stereotyped behaviors (motor stereotypies: P = 0.81 and 0.84, verbal stereotypies: P = 0.38 and 0.73 for rs4570625 and rs4565946, respectively). Also GLO1 alleles display no association with autism (191 patients vs 171 controls, P = 0.36; TDT P = 0.79, and FBAT P = 0.37), but unaffected siblings seemingly carry a protective gene variant marked by the A419 allele (TDT P < 0.05; patients vs unaffected siblings TDT and FBAT P < 0.00001).

Conclusion

TPH2 gene variants are unlikely to contribute to autism or to the presence/absence of prominent repetitive behaviors in our sample, although an influence on the intensity of these behaviors in autism cannot be excluded. GLO1 gene variants do not confer autism vulnerability in this sample, but allele A419 apparently carries a protective effect, spurring interest into functional correlates of the C419A SNP.     

Framingham Heart Study 100K project: genome-wide associations for cardiovascular disease outcomes

Background

Cardiovascular disease (CVD) and its most common manifestations – including coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) – are major causes of morbidity and mortality. In many industrialized countries, cardiovascular disease (CVD) claims more lives each year than any other disease. Heart disease and stroke are the first and third leading causes of death in the United States. Prior investigations have reported several single gene variants associated with CHD, stroke, HF, and AF. We report a community-based genome-wide association study of major CVD outcomes.

Methods

In 1345 Framingham Heart Study participants from the largest 310 pedigrees (54% women, mean age 33 years at entry), we analyzed associations of 70,987 qualifying SNPs (Affymetrix 100K GeneChip) to four major CVD outcomes: major atherosclerotic CVD (n = 142; myocardial infarction, stroke, CHD death), major CHD (n = 118; myocardial infarction, CHD death), AF (n = 151), and HF (n = 73). Participants free of the condition at entry were included in proportional hazards models. We analyzed model-based deviance residuals using generalized estimating equations to test associations between SNP genotypes and traits in additive genetic models restricted to autosomal SNPs with minor allele frequency ≥0.10, genotype call rate ≥0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001.

Results

Six associations yielded p < 10^-5. The lowest p-values for each CVD trait were as follows: major CVD, rs499818, p = 6.6 × 10^-6; major CHD, rs2549513, p = 9.7 × 10^-6; AF, rs958546, p = 4.8 × 10^-6; HF: rs740363, p = 8.8 × 10^-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 – 1.9 × 10^-5) and major CHD (p 2.5 – 3.5 × 10^-4) that confirm associations with CHD in two recently reported genome-wide association studies. Also, rs10501920 in CNTN5 was associated with AF (p = 9.4 × 10^-6) and HF (p = 1.2 × 10^-4). Complete results for these phenotypes can be found at the dbgap website http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

No association attained genome-wide significance, but several intriguing findings emerged. Notably, we replicated associations of chromosome 9p21 with major CVD. Additional studies are needed to validate these results. Finding genetic variants associated with CVD may point to novel disease pathways and identify potential targeted preventive therapies.

     

A genome-wide association study for blood lipid phenotypes in the Framingham Heart Study

Background

Blood lipid levels including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are highly heritable. Genome-wide association is a promising approach to map genetic loci related to these heritable phenotypes.

Methods

In 1087 Framingham Heart Study Offspring cohort participants (mean age 47 years, 52% women), we conducted genome-wide analyses (Affymetrix 100K GeneChip) for fasting blood lipid traits. Total cholesterol, HDL-C, and TG were measured by standard enzymatic methods and LDL-C was calculated using the Friedewald formula. The long-term averages of up to seven measurements of LDL-C, HDL-C, and TG over a ~30 year span were the primary phenotypes. We used generalized estimating equations (GEE), family-based association tests (FBAT) and variance components linkage to investigate the relationships between SNPs (on autosomes, with minor allele frequency ≥10%, genotypic call rate ≥80%, and Hardy-Weinberg equilibrium p ≥ 0.001) and multivariable-adjusted residuals. We pursued a three-stage replication strategy of the GEE association results with 287 SNPs (P < 0.001 in Stage I) tested in Stage II (n ~1450 individuals) and 40 SNPs (P < 0.001 in joint analysis of Stages I and II) tested in Stage III (n~6650 individuals).

Results

Long-term averages of LDL-C, HDL-C, and TG were highly heritable (h² = 0.66, 0.69, 0.58, respectively; each P < 0.0001). Of 70,987 tests for each of the phenotypes, two SNPs had p < 10^-5 in GEE results for LDL-C, four for HDL-C, and one for TG. For each multivariable-adjusted phenotype, the number of SNPs with association p < 10^-4 ranged from 13 to 18 and with p < 10^-3, from 94 to 149. Some results confirmed previously reported associations with candidate genes including variation in the lipoprotein lipase gene (LPL) and HDL-C and TG (rs7007797; P = 0.0005 for HDL-C and 0.002 for TG). The full set of GEE, FBAT and linkage results are posted at the database of Genotype and Phenotype (dbGaP). After three stages of replication, there was no convincing statistical evidence for association (i.e., combined P < 10^-5 across all three stages) between any of the tested SNPs and lipid phenotypes.

Conclusion

Using a 100K genome-wide scan, we have generated a set of putative associations for common sequence variants and lipid phenotypes. Validation of selected hypotheses in additional samples did not identify any new loci underlying variability in blood lipids. Lack of replication may be due to inadequate statistical power to detect modest quantitative trait locus effects (i.e., <1% of trait variance explained) or reduced genomic coverage of the 100K array. GWAS in FHS using a denser genome-wide genotyping platform and a better-powered replication strategy may identify novel loci underlying blood lipids.

     

Framingham Heart Study genome-wide association: results for pulmonary function measures

Background

Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study.

Methods

Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV₁), forced vital capacity (FVC), forced expiratory flow from the 25^th to 75^th percentile (FEF_25–75), the FEV₁/FVC ratio, and the FEF_25–75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years.

Results

Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency ≥ 10%, genotype call rate ≥ 80%, and Hardy-Weinberg equilibrium p-value ≥ 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF_25–75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV₁ and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes.

Conclusion

GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

     

Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project

Background

Obesity is related to multiple cardiovascular disease (CVD) risk factors as well as CVD and has a strong familial component. We tested for association between SNPs on the Affymetrix 100K SNP GeneChip and measures of adiposity in the Framingham Heart Study.

Methods

A total of 1341 Framingham Heart Study participants in 310 families genotyped with the Affymetrix 100K SNP GeneChip had adiposity traits measured over 30 years of follow up. Body mass index (BMI), waist circumference (WC), weight change, height, and radiographic measures of adiposity (subcutaneous adipose tissue, visceral adipose tissue, waist circumference, sagittal height) were measured at multiple examination cycles. Multivariable-adjusted residuals, adjusting for age, age-squared, sex, smoking, and menopausal status, were evaluated in association with the genotype data using additive Generalized Estimating Equations (GEE) and Family Based Association Test (FBAT) models. We prioritized mean BMI over offspring examinations (1–7) and cohort examinations (10, 16, 18, 20, 22, 24, 26) and mean WC over offspring examinations (4–7) for presentation. We evaluated associations with 70,987 SNPs on autosomes with minor allele frequencies of at least 0.10, Hardy-Weinberg equilibrium p ≥ 0.001, and call rates of at least 80%.

Results

The top SNPs to be associated with mean BMI and mean WC by GEE were rs110683 (p-value 1.22*10^-7) and rs4471028 (p-values 1.96*10^-7). Please see http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 for the complete set of results. We were able to validate SNPs in known genes that have been related to BMI or other adiposity traits, including the ESR1 Xba1 SNP, PPARG, and ADIPOQ.

Conclusion

Adiposity traits are associated with SNPs on the Affymetrix 100K SNP GeneChip. Replication of these initial findings is necessary. These data will serve as a resource for replication as more genes become identified with BMI and WC.

     

Genome-wide association to body mass index and waist circumference: the Framingham Heart Study 100K project

Background

The FABP2 gene encodes for the intestinal FABP (IFABP) protein, which is expressed only in intestinal enterocytes. A polymorphism at codon 54 in exon 2 of the FABP2 gene exchanges an Alanine (Ala), in the small helical region of the protein, for Threonine (Thr). Given the potential physiological role of the Ala54Thr FABP2 polymorphism, we assess in this study the local population frequency and analyze possible associations with five selected markers, i.e. glycemia, total cholesterol, body mass index (BMI), hypertension, and high Cardiovascular Risk Index (CVR index).

Methods

We studied 86 men and 116 women. DNA was extracted from a blood drop for genotype analysis. Allele frequencies were calculated by direct counting. Hardy Weinberg Equilibrium was evaluated using a Chi-square goodness of fit test. For the polymorphism association analysis, five markers were selected, i.e. blood pressure, Framingham Risk Index, total cholesterol, BMI, and glycemia. For each marker, the Odds Ratio (OR) was calculated by an online statistic tool.

Results

Our results reveal a similar population polymorphism frequency as in previous European studies, with q = 0.277 (95% confidence limits 0.234–0.323). No significant association was found with any of the tested markers in the context of our Argentine nutritional and cultural habits. We did, however, observe a tendency for increased Cholesterol and high BMI in Thr54 carriers.

Conclusion

This is the first study to look at the population frequency of the Thr54 allele in Argentina. The obtained result does not differ from previously reported frequencies in European populations. Moreover, we found no association between the Thr54 allele and any of the five selected markers. The observed tendency to increased total cholesterol and elevated BMI in Thr54 carriers, even though not significant for p < 0.1 could be worth of further investigation to establish whether the Thr54 variant should be taken into consideration in cardiovascular prevention strategies.     

A genome-wide association for kidney function and endocrine-related traits in the NHLBI's Framingham Heart Study

Background

Glomerular filtration rate (GFR) and urinary albumin excretion (UAE) are markers of kidney function that are known to be heritable. Many endocrine conditions have strong familial components. We tested for association between the Affymetrix GeneChip Human Mapping 100K single nucleotide polymorphism (SNP) set and measures of kidney function and endocrine traits.

Methods

Genotype information on the Affymetrix GeneChip Human Mapping 100K SNP set was available on 1345 participants. Serum creatinine and cystatin-C (cysC; n = 981) were measured at the seventh examination cycle (1998–2001); GFR (n = 1010) was estimated via the Modification of Diet in Renal Disease (MDRD) equation; UAE was measured on spot urine samples during the sixth examination cycle (1995–1998) and was indexed to urinary creatinine (n = 822). Thyroid stimulating hormone (TSH) was measured at the third and fourth examination cycles (1981–1984; 1984–1987) and mean value of the measurements were used (n = 810). Age-sex-adjusted and multivariable-adjusted residuals for these measurements were used in association with genotype data using generalized estimating equations (GEE) and family-based association tests (FBAT) models. We presented the results for association tests using additive allele model. We evaluated associations with 70,987 SNPs on autosomes with minor allele frequencies of at least 0.10, Hardy-Weinberg Equilibrium p-value ≥ 0.001, and call rates of at least 80%.

Results

The top SNPs associated with these traits using the GEE method were rs2839235 with GFR (p-value 1.6*10^-05), rs1158167 with cysC (p-value 8.5*10^-09), rs1712790 with UAE (p-value 1.9*10^-06), and rs6977660 with TSH (p-value 3.7*10^-06), respectively. The top SNPs associated with these traits using the FBAT method were rs6434804 with GFR(p-value 2.4*10^-5), rs563754 with cysC (p-value 4.7*10^-5), rs1243400 with UAE (p-value 4.8*10^-6), and rs4128956 with TSH (p-value 3.6*10^-5), respectively. Detailed association test results can be found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007. Four SNPs in or near the CST3 gene were highly associated with cysC levels (p-value 8.5*10^-09 to 0.007).

Conclusion

Kidney function traits and TSH are associated with SNPs on the Affymetrix GeneChip Human Mapping 100K SNP set. These data will serve as a valuable resource for replication as more SNPs associated with kidney function and endocrine traits are identified.

     

A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study

Background

Cutaneous Malignant Melanoma causes over 75% of skin cancer-related deaths, and it is clear that many factors may contribute to the outcome. Matrix Metalloproteinases (MMPs) play an important role in the degradation and remodeling of the extracellular matrix and basement membrane that, in turn, modulate cell division, migration and angiogenesis. Some polymorphisms are known to influence gene expression, protein activity, stability, and interactions, and they were shown to be associated with certain tumor phenotypes and cancer risk.

Methods

We tested seven polymorphisms within the MMP-9 gene in 1002 patients with melanoma in order to evaluate germline genetic variants and their association with progression and known risk factors of melanoma. The polymorphisms were selected based on previously published reports and their known or potential functional relevance using in-silico methods. Germline DNA was then genotyped using pyrosequencing, melting temperature profiles, heteroduplex analysis, and fragment size analysis.

Results

We found that reference alleles were present in higher frequency in patients who tend to sunburn, have family history of melanoma, higher melanoma stage, intransit metastasis and desmoplastic melanomas among others. However, after adjustment for age, sex, phenotypic index, moles, and freckles only Q279R, P574R and R668Q had significant associations with intransit metastasis, propensity to tan/sunburn and primary melanoma site.

Conclusion

This study does not provide strong evidence for further investigation into the role of the MMP-9 SNPs in melanoma progression.     

A genome-wide association study of breast and prostate cancer in the NHLBI's Framingham Heart Study

Background

Breast and prostate cancer are two commonly diagnosed cancers in the United States. Prior work suggests that cancer causing genes and cancer susceptibility genes can be identified.

Methods

We conducted a genome-wide association study (Affymetrix 100K SNP GeneChip) of cancer in the community-based Framingham Heart Study. We report on 2 cancer traits – prostate cancer and breast cancer – in up to 1335 participants from 330 families (54% women, mean entry age 33 years). Multivariable-adjusted residuals, computed using Cox proportional hazards models, were tested for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate ≥80%, minor allele frequency ≥10%, Hardy-Weinberg test p ≥ 0.001) using generalized estimating equations (GEE) models and family based association tests (FBAT).

Results

There were 58 women with breast cancer and 59 men with prostate cancer. No SNP associations attained genome-wide significance. The top SNP associations in GEE models for each trait were as follows: breast cancer, rs2075555, p = 8.0 × 10^-8 in COL1A1; and prostate cancer, rs9311171, p = 1.75 × 10^-6 in CTDSPL. In analysis of selected candidate cancer susceptibility genes, two MSR1 SNPs (rs9325782, GEE p = 0.008 and rs2410373, FBAT p = 0.021) were associated with prostate cancer and three ERBB4 SNPs (rs905883 GEE p = 0.0002, rs7564590 GEE p = 0.003, rs7558615 GEE p = 0.0078) were associated with breast cancer. The previously reported risk SNP for prostate cancer, rs1447295, was not included on the 100K chip. Results of cancer phenotype-genotype associations for all autosomal SNPs are web posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

Although no association attained genome-wide significance, several interesting associations emerged for breast and prostate cancer. These findings can serve as a resource for replication in other populations to identify novel biologic pathways contributing to cancer susceptibility.

     

Increased ambulatory arterial stiffness index and blood pressure load in normotensive obese patients

ObjectivesIt has been shown that blood pressure (BP) values measured in obese subjects are higher than the individuals with normal weight, even in normotensive limits. However, data concerning the Ambulatory Arterial Stiffness Index (AASI) and blood pressure load in normotensive obese subjects is lacking. This study was aimed to compare the ambulatory arterial stiffness index and blood pressure load in normotensive obese and healthy controls.MethodsOne hundred normotensive obese and one hundred normal weight subjects were included in this study. All subjects underwent 24-hour ambulatory blood pressure monitoring. Ambulatory arterial stiffness index was calculated from 24-hour ambulatory blood pressure monitoring records. Ambulatory arterial stiffness index was defined as one minus the regression slope of unedited 24-h diastolic on systolic blood pressures. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) load values were calculated from 24-hour ambulatory blood pressure monitoring analysis.ResultsAmbulatory arterial stiffness index of the obese subjects was significantly higher than the healthy controls (0.48±0.2 vs. 0.33±0.11, p<0.001). 24-hours systolic blood pressure and diastolic blood pressure loads were significantly higher in obese subjects. Logistic regression analysis revealed that body mass index (BMI) was an independent predictor for an abnormal ambulatory arterial stiffness ındex (≥0.50) (OR: 1.137, 95% CI: 0.915-1.001, p=0.004).ConclusionBlood pressure load and ambulatory arterial stiffness index are increased in normotensive obese patients. Moreover, body mass index is an independent predictor for an abnormal ambulatory arterial stiffness index. Our results indicate that obese subjects are at higher risk for future cardiovascular events despite normal office BP levels.     

Genome-wide association study for subclinical atherosclerosis in major arterial territories in the NHLBI's Framingham Heart Study

Introduction

Subclinical atherosclerosis (SCA) measures in multiple arterial beds are heritable phenotypes that are associated with increased incidence of cardiovascular disease. We conducted a genome-wide association study (GWAS) for SCA measurements in the community-based Framingham Heart Study.

Methods

Over 100,000 single nucleotide polymorphisms (SNPs) were genotyped (Human 100K GeneChip, Affymetrix) in 1345 subjects from 310 families. We calculated sex-specific age-adjusted and multivariable-adjusted residuals in subjects tested for quantitative SCA phenotypes, including ankle-brachial index, coronary artery calcification and abdominal aortic calcification using multi-detector computed tomography, and carotid intimal medial thickness (IMT) using carotid ultrasonography. We evaluated associations of these phenotypes with 70,987 autosomal SNPs with minor allele frequency ≥ 0.10, call rate ≥ 80%, and Hardy-Weinberg p-value ≥ 0.001 in samples ranging from 673 to 984 subjects, using linear regression with generalized estimating equations (GEE) methodology and family-based association testing (FBAT). Variance components LOD scores were also calculated.

Results

There was no association result meeting criteria for genome-wide significance, but our methods identified 11 SNPs with p < 10^-5 by GEE and five SNPs with p < 10^-5 by FBAT for multivariable-adjusted phenotypes. Among the associated variants were SNPs in or near genes that may be considered candidates for further study, such as rs1376877 (GEE p < 0.000001, located in ABI2) for maximum internal carotid artery IMT and rs4814615 (FBAT p = 0.000003, located in PCSK2) for maximum common carotid artery IMT. Modest significant associations were noted with various SCA phenotypes for variants in previously reported atherosclerosis candidate genes, including NOS3 and ESR1. Associations were also noted of a region on chromosome 9p21 with CAC phenotypes that confirm associations with coronary heart disease and CAC in two recently reported genome-wide association studies. In linkage analyses, several regions of genome-wide linkage were noted, confirming previously reported linkage of internal carotid artery IMT on chromosome 12. All GEE, FBAT and linkage results are provided as an open-access results resource at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007.

Conclusion

The results from this GWAS generate hypotheses regarding several SNPs that may be associated with SCA phenotypes in multiple arterial beds. Given the number of tests conducted, subsequent independent replication in a staged approach is essential to identify genetic variants that may be implicated in atherosclerosis.

     

Diurnal and obstructive sleep apnea influences on arterial stiffness and central blood pressure in men

STUDY OBJECTIVES: Nocturnal and early morning elevation of blood pressure are common acute manifestations of obstructive sleep apnea (OSA) that do not always carry over into a sustained daytime hypertension. Using pulse wave analysis, we examined the effect of OSA on arterial stiffness and central aortic blood pressure to assess whether each would be elevated independent of diurnal changes in peripheral blood pressure. DESIGN: Cross-sectional sleep laboratory cohort study. SETTING: Two university teaching hospitals. PATIENTS: 57 male nonsmokers referred for suspected OSA and free of known cardiovascular disease or blood-pressure and lipid-lowering medications. MEASUREMENTS AND RESULTS: The augmentation index, a quantification of augmentation of central aortic pressure due to the reflected component of the pulse pressure waveform, and brachial and aortic blood pressure were determined in the evening and early morning. The augmentation index consistently increased from evening to morning (P < .001) and was accompanied by an increase in central systolic blood pressure (P = .007) and a decrease in pulse pressure amplification (P < .001). However, these changes were unaccompanied by any changes in peripheral blood pressure. Overnight changes in mean blood pressure and heart rate were the only predictors of this effect, but they only accounted for a third of the variance (r2 = 0.339, P = .002). After adjustment for known confounders, the respiratory disturbance index was positively correlated with augmentation index at both time points (PM: P = .008, am: P = .016). The respiratory disturbance index did not correlate with any indexes of peripheral or central blood pressure. CONCLUSIONS: Systemic arterial stiffness is positively correlated with OSA severity and, in addition, is increased in magnitude in the early morning independent of OSA severity.     

外周血压和中心动脉压的差异性研究

目的中心动脉压比外周动脉压对心血管终点事件具有更好的预测价值,本研究的目的是分析高血压人群中心动脉压和肱动脉压的差异。方法研究对象为640名(46岁±8岁)无明显心血管病体检者,根据肱动脉压分为高血压组和非高血压组,计算两组人群的中心动脉压和肱动脉压的脉压比值,来描述两动脉压的差异,通过逐步多变量线性回归分析确定脉压比值的独立影响因子。结果年龄和高血压是脉压比值的独立影响因子。随着年龄的增加,脉压比值不断增大。与非高血压人群相比,高血压人群脉压比值显著增加(P0.05)。对研究人群按照肱动脉收缩压进行风险等级划分,不同风险等级之间中心动脉收缩压的分布存在大量的重叠。结论中心动脉压不能由肱动脉压完全代替,准确评估中心动脉压可能提高对心血管事件的识别,完善对高血压人群的健康管理。     

Magnetic sensor for arterial distension and blood pressure monitoring

A novel sensor for measuring arterial distension, pulse and pressure waveform is developed and evaluated. The system consists of a magnetic sensor which is applied and fixed to arterial vessels without any blood vessel constriction, hence avoiding stenosis. The measurement principle could be validated by in vitro experiments on silicone tubes, and by in vivo experiments in an animal model, thereby indicating the non-linear viscoelastic characteristics of real blood vessels. The sensor is capable to provide absolute measurements of the dynamically varying arterial diameter. By calibrating the sensor, a long-term monitoring system for continuously measuring blood pressure and other cardiovascular parameters could be developed based on the method described. This will improve diagnostics for high risk patients and enable a better, specific treatment.     

Nicotinic acetylcholine receptor subunit variants are associated with blood pressure; findings in the Old Order Amish and replication in the Framingham Heart Study

Background  

Systemic blood pressure, influenced by both genetic and environmental factors, is regulated via sympathetic nerve activity. We assessed the role of genetic variation in three subunits of the neuromuscular nicotinic acetylcholine receptor positioned on chromosome 2q, a region showing replicated evidence of linkage to blood pressure.