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 [greater than or equal to]0.10, genotype call rate [greater than or equal to]0.80, and Hardy-Weinberg equilibrium p-value [greater than or equal to] 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 x 10-6; major CHD, rs2549513, p = 9.7 x 10-6; AF, rs958546, p = 4.8 x 10-6; HF: rs740363, p = 8.8 x 10-6. Of note, we found associations of a 13 Kb region on chromosome 9p21 with major CVD (p 1.7 - 1.9 x 10-5) and major CHD (p 2.5 - 3.5 x 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 x 10-6) and HF (p = 1.2 x 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.

Genetic correlates of longevity and selected age-related phenotypes: a genome-wide association study in the Framingham Study

BACKGROUND: Family studies and heritability estimates provide evidence for a genetic contribution to variation in the human life span. METHODS:We conducted a genome wide association study (Affymetrix 100K SNP GeneChip) for longevity-related traits in a community-based sample. We report on 5 longevity and aging traits in up to 1345 Framingham Study participants from 330 families. Multivariable-adjusted residuals were computed using appropriate models (Cox proportional hazards, logistic, or linear regression) and the residuals from these models were used to test for association with qualifying SNPs (70, 987 autosomal SNPs with genotypic call rate [greater than or equal to]80%, minor allele frequency [greater than or equal to]10%, Hardy-Weinberg test p [greater than or equal to] 0.001).RESULTS:In family-based association test (FBAT) models, 8 SNPs in two regions approximately 500 kb apart on chromosome 1 (physical positions 73,091,610 and 73, 527,652) were associated with age at death (p-value < 10-5). The two sets of SNPs were in high linkage disequilibrium (minimum r2 = 0.58). The top 30 SNPs for generalized estimating equation (GEE) tests of association with age at death included rs10507486 (p = 0.0001) and rs4943794 (p = 0.0002), SNPs intronic to FOXO1A, a gene implicated in lifespan extension in animal models. FBAT models identified 7 SNPs and GEE models identified 9 SNPs associated with both age at death and morbidity-free survival at age 65 including rs2374983 near PON1. In the analysis of selected candidate genes, SNP associations (FBAT or GEE p-value < 0.01) were identified for age at death in or near the following genes: FOXO1A, GAPDH, KL, LEPR, PON1, PSEN1, SOD2, and WRN. Top ranked SNP associations in the GEE model for age at natural menopause included rs6910534 (p = 0.00003) near FOXO3a and rs3751591 (p = 0.00006) in CYP19A1. Results of all longevity 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: Longevity and aging traits are associated with SNPs on the Affymetrix 100K GeneChip. None of the associations achieved genome-wide significance. These data generate hypotheses and serve as a resource for replication as more genes and biologic pathways are proposed as contributing to longevity and healthy aging.

Building Responsive Systems from Physically-correct Specifications

Predictability - the ability to foretell that an implementation will not violate a set of specified reliability and timeliness requirements - is a crucial, highly desirable property of responsive embedded systems. This paper overviews a development methodology for responsive systems, which enhances predictability by eliminating potential hazards resulting from physically-unsound specifications. The backbone of our methodology is the Time-constrained Reactive Automaton (TRA) formalism, which adopts a fundamental notion of space and time that restricts expressiveness in a way that allows the specification of only reactive, spontaneous, and causal computation. Using the TRA model, unrealistic systems - possessing properties such as clairvoyance, caprice, in finite capacity, or perfect timing - cannot even be specified. We argue that this "ounce of prevention" at the specification level is likely to spare a lot of time and energy in the development cycle of responsive systems - not to mention the elimination of potential hazards that would have gone, otherwise, unnoticed. The TRA model is presented to system developers through the CLEOPATRA programming language. CLEOPATRA features a C-like imperative syntax for the description of computation, which makes it easier to incorporate in applications already using C. It is event-driven, and thus appropriate for embedded process control applications. It is object-oriented and compositional, thus advocating modularity and reusability. CLEOPATRA is semantically sound; its objects can be transformed, mechanically and unambiguously, into formal TRA automata for verification purposes, which can be pursued using model-checking or theorem proving techniques. Since 1989, an ancestor of CLEOPATRA has been in use as a specification and simulation language for embedded time-critical robotic processes.

Timeliness via Speculation for Real-Time Databases

Various concurrency control algorithms differ in the time when conflicts are detected, and in the way they are resolved. In that respect, the Pessimistic and Optimistic Concurrency Control (PCC and OCC) alternatives represent two extremes. PCC locking protocols detect conflicts as soon as they occur and resolve them using blocking. OCC protocols detect conflicts at transaction commit time and resolve them using rollbacks (restarts). For real-time databases, blockages and rollbacks are hazards that increase the likelihood of transactions missing their deadlines. We propose a Speculative Concurrency Control (SCC) technique that minimizes the impact of blockages and rollbacks. SCC relies on the use of added system resources to speculate on potential serialization orders and to ensure that if such serialization orders materialize, the hazards of blockages and roll-backs are minimized. We present a number of SCC-based algorithms that differ in the level of speculation they introduce, and the amount of system resources (mainly memory) they require. We show the performance gains (in terms of number of satisfied timing constraints) to be expected when a representative SCC algorithm (SCC-2S) is adopted.

An Ounce of Prevention is Worth a Pound of Cure: Towards Physically-Correct Specifications of Embedded Real-Time Systems

Predictability — the ability to foretell that an implementation will not violate a set of specified reliability and timeliness requirements - is a crucial, highly desirable property of responsive embedded systems. This paper overviews a development methodology for responsive systems, which enhances predictability by eliminating potential hazards resulting from physically-unsound specifications. The backbone of our methodology is a formalism that restricts expressiveness in a way that allows the specification of only reactive, spontaneous, and causal computation. Unrealistic systems — possessing properties such as clairvoyance, caprice, infinite capacity, or perfect timing — cannot even be specified. We argue that this "ounce of prevention" at the specification level is likely to spare a lot of time and energy in the development cycle of responsive systems - not to mention the elimination of potential hazards that would have gone, otherwise, unnoticed.

OS Support for Portable Bulk Synchronous Parallel Programs

Predictability -- the ability to foretell that an implementation will not violate a set of specified reliability and timeliness requirements -- is a crucial, highly desirable property of responsive embedded systems. This paper overviews a development methodology for responsive systems, which enhances predictability by eliminating potential hazards resulting from physically-unsound specifications. The backbone of our methodology is the Time-constrained Reactive Automaton (TRA) formalism, which adopts a fundamental notion of space and time that restricts expressiveness in a way that allows the specification of only reactive, spontaneous, and causal computation. Using the TRA model, unrealistic systems – possessing properties such as clairvoyance, caprice, infinite capacity, or perfect timing -- cannot even be specified. We argue that this "ounce of prevention" at the specification level is likely to spare a lot of time and energy in the development cycle of responsive systems -- not to mention the elimination of potential hazards that would have gone, otherwise, unnoticed. The TRA model is presented to system developers through the Cleopatra programming language. Cleopatra features a C-like imperative syntax for the description of computation, which makes it easier to incorporate in applications already using C. It is event-driven, and thus appropriate for embedded process control applications. It is object-oriented and compositional, thus advocating modularity and reusability. Cleopatra is semantically sound; its objects can be transformed, mechanically and unambiguously, into formal TRA automata for verification purposes, which can be pursued using model-checking or theorem proving techniques. Since 1989, an ancestor of Cleopatra has been in use as a specification and simulation language for embedded time-critical robotic processes.