Data for GAW20: Genome-Wide DNA Sequence Variation and Epigenome-Wide DNA Methylation Before and After Fenofibrate Treatment in a Family Study of Metabolic Phenotypes

GAW20 provided participants with an opportunity to comprehensively examine genetic and epigenetic variation among related individuals in the context of drug treatment response. GAW20 used data from 188 families (N = 1105) participating in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study (clinicaltrials.gov identifier NCT00083369), which included CD4+ T-cell DNA methylation at 463,995 cytosine-phosphate-guanine (CpG) sites measured before and after a 3-week treatment with fenofibrate, single-nucleotide variation at 906,600 loci, metabolic syndrome components ascertained before and after the drug intervention, and relevant covariates. All GOLDN participants were of European descent, with an average age of 48 years. In addition, approximately half were women and approximately 40% met the diagnostic criteria for metabolic syndrome. Unique advantages of the GAW20data set included longitudinal (3 weeks apart) measurements of DNA methylation, the opportunity to explore the contributions of both genotype and DNA methylation to the interindividual variability in drug treatment response, and the familial relationships between study participants. The principal disadvantage of GAW20/GOLDN data was the spurious correlation between batch effects and fenofibrate effects on methylation, which arose because the pre- and posttreatment methylation data were generated and normalized separately, and any attempts to remove time-dependent technical artifacts would also remove biologically meaningful changes brought on by fenofibrate. Despite this limitation, the GAW20 data set offered informative, multilayered omics data collected in a large population-based study of common disease traits, which resulted in creative approaches to integration and analysis of inherited human variation

Trade-offs in the effects of the apolipoprotein E polymorphism on risks of diseases of the heart, cancer, and neurodegenerative disorders: Insights on mechanisms from the long life family study

The lack of evolutionary established mechanisms linking genes to age-related traits makes the problem of genetic susceptibility to health span inherently complex. One complicating factor is genetic trade-off. Here we focused on long-living participants of the Long Life Family Study (LLFS), their offspring, and spouses to: (1) Elucidate whether trade-offs in the effect of the apolipoprotein E e4 allele documented in the Framingham Heart Study (FHS) are a more general phenomenon, and (2) explore potential mechanisms generating age- and gender-specific trade-offs in the effect of the e4 allele on cancer, diseases of the heart, and neurodegenerative disorders assessed retrospectively in the LLFS populations. The e4 allele can diminish risks of cancer and diseases of the heart and confer risks of diseases of the heart in a sex-, age-, and LLFS-population-specific manner. A protective effect against cancer is seen in older long-living men and, potentially, their sons (>75 years, relative risk [RR](>75)=0.48, p=0.086), which resembles our findings in the FHS. The protective effect against diseases of the heart is limited to long-living older men (RR(>76)=0.50, p=0.016), as well. A detrimental effect against diseases of the heart is characteristic for a normal LLFS population of male spouses and is specific for myocardial infarction (RR=3.07, p=2.1×10(−3)). These trade-offs are likely associated with two inherently different mechanisms, including disease-specific (detrimental; characteristic for a normal male population) and systemic, aging-related (protective; characteristic for older long-living men) mechanisms. The e4 allele confers risks of neurological disorders in men and women (RR=1.98, p=0.046). The results highlight the complex role of the e4 allele in genetic susceptibility to health span

Epigenome-wide association study of triglyceride postprandial responses to a high-fat dietary challenge

Postprandial lipemia (PPL), the increased plasma TG concentration after consuming a high-fat meal, is an independent risk factor for CVD. Individual responses to a meal high in fat vary greatly, depending on genetic and lifestyle factors. However, only a few loci have been associated with TG-PPL response. Heritable epigenomic changes may be significant contributors to the unexplained inter-individual PPL variability. We conducted an epigenome-wide association study on 979 subjects with DNA methylation measured from CD4(+) T cells, who were challenged with a high-fat meal as a part of the Genetics of Lipid Lowering Drugs and Diet Network study. Eight methylation sites encompassing five genes, LPP, CPT1A, APOA5, SREBF1, and ABCG1, were significantly associated with PPL response at an epigenome-wide level (P < 1.1 × 10(−7)), but no methylation site reached epigenome-wide significance after adjusting for baseline TG levels. Higher methylation at LPP, APOA5, SREBF1, and ABCG1, and lower methylation at CPT1A methylation were correlated with an increased TG-PPL response. These PPL-associated methylation sites, also correlated with fasting TG, account for a substantially greater amount of phenotypic variance (14.9%) in PPL and fasting TG (16.3%) when compared with the genetic contribution of loci identified by our previous genome-wide association study (4.5%). In summary, the epigenome is a large contributor to the variation in PPL, and this has the potential to be used to modulate PPL and reduce CVD

Offspring's leukocyte telomere length, paternal age, and telomere elongation in sperm.

PublishedJournal ArticleResearch Support, N.I.H., ExtramuralResearch Support, Non-U.S. Gov'tThis is the final version of the article. Available from Public Library of Science via the DOI in this record.Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18-94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.Supported by NIH grants R01-AG021593, R01-AG020132, and P01-AG0876. Support was also provided by NIH contract NOHC25195, the NHLBI cooperative agreement grants U01 HL 67893, U01 HL67894, U01 HL67895, U01 HL67896, U01 HL67897, U01 HL67898, U01 HL67899, U01 HL67900, U01 HL67901, U01 HL67902, U01 HL56563, U01 HL56564, U01 HL56565, U01 HL56566, U01 HL56567, U01 HL56568, and U01 HL56569. Also funded in part by the Wellcome Trust grant (ref 074951)

NIA Long Life Family Study: Objectives, design, and heritability of cross-sectional and longitudinal phenotypes

The NIA Long Life Family Study (LLFS) is a longitudinal, multicenter, multinational, population-based multigenerational family study of the genetic and nongenetic determinants of exceptional longevity and healthy aging. The Visit 1 in-person evaluation (2006-2009) recruited 4 953 individuals from 539 two-generation families, selected from the upper 1% tail of the Family Longevity Selection Score (FLoSS, which quantifies the degree of familial clustering of longevity). Demographic, anthropometric, cognitive, activities of daily living, ankle-brachial index, blood pressure, physical performance, and pulmonary function, along with serum, plasma, lymphocytes, red cells, and DNA, were collected. A Genome Wide Association Scan (GWAS) (Ilumina Omni 2.5M chip) followed by imputation was conducted. Visit 2 (2014-2017) repeated all Visit 1 protocols and added carotid ultrasonography of atherosclerotic plaque and wall thickness, additional cognitive testing, and perceived fatigability. On average, LLFS families show healthier aging profiles than reference populations, such as the Framingham Heart Study, at all age/sex groups, for many critical healthy aging phenotypes. However, participants are not uniformly protected. There is considerable heterogeneity among the pedigrees, with some showing exceptional cognition, others showing exceptional grip strength, others exceptional pulmonary function, etc. with little overlap in these families. There is strong heritability for key healthy aging phenotypes, both cross-sectionally and longitudinally, suggesting that at least some of this protection may be genetic. Little of the variance in these heritable phenotypes is explained by the common genome (GWAS + Imputation), which may indicate that rare protective variants for specific phenotypes may be running in selected families

Exogenous exposures shape genetic predisposition to lipids, Alzheimer\u27s, and coronary heart disease in the MLXIPL gene locus

Associations of single nucleotide polymorphisms (SNPs) of th

Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease, and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4,114 subjects of European descent (480 families) were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13) associated with an increase of HDL levels at genome-wide significant level (p< 5.0E-08). Additionally, several CETP (16q21) and ZNF259-APOA5-A4-C3-A1 (11q23.3) variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly LLFS subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in ENCODE; however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1) interacts with SREBP-1a (17p11) which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region

Genome- and CD4\u3csup\u3e+\u3c/sup\u3e T-Cell Methylome-Wide Association Study of Circulating Trimethylamine-N-Oxide in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN)

Background: Trimethylamine-N-oxide (TMAO), an atherogenic metabolite species, has emerged as a possible new risk factor for cardiovascular disease. Animal studies have shown that circulating TMAO levels are regulated by genetic and environmental factors. However, large-scale human studies have failed to replicate the observed genetic associations, and epigenetic factors such as DNA methylation have never been examined in relation to TMAO levels. Methods and results: We used data from the family-based Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to investigate the heritable determinants of plasma TMAO in humans. TMAO was not associated with other plasma markers of cardiovascular disease, e.g. lipids or inflammatory cytokines. We first estimated TMAO heritability at 27%, indicating a moderate genetic influence. We used 1000 Genomes imputed data (n = 626) to estimate genome-wide associations with TMAO levels, adjusting for age, sex, family relationships, and study site. The genome-wide study yielded one significant hit at the genome-wide level, located in an intergenic region on chromosome 4. We subsequently quantified epigenome-wide DNA methylation using the Illumina Infinium array on CD4þ Tcells. We tested for association of methylation loci with circulating TMAO (n = 847), adjusting for age, sex, family relationships, and study site as the genome-wide study plus principal components capturing CD4þ T-cell purity. Upon adjusting for multiple testing, none of the epigenetic findings were statistically significant. Conclusions: Our findings contribute to the growing body of evidence suggesting that neither genetic nor epigenetic factors play a critical role in establishing circulating TMAO levels in humans

Aromatase Gene Polymorphisms Are Associated with Survival among Patients with Cardiovascular Disease in a Sex-Specific Manner

CYP19A1 encodes aromatase, the enzyme responsible for the conversion of androgens to estrogens, and may play a role in variation in outcomes among men and women with cardiovascular disease. We sought to examine genetic variation in CYP19A1 for its potential role in sex differences in cardiovascular disease outcomes.Caucasian individuals from two independent populations were assessed: 1) a prospective cohort of patients with acute coronary syndromes with 3-year mortality follow-up (n = 568) and 2) a nested case-control study from a randomized, controlled trial of hypertension patients with stable coronary disease in which the primary outcome was death, nonfatal myocardial infarction (MI) or nonfatal stroke (n = 619). Six CYP19A1 SNPs were genotyped (-81371 C>T, -45965 G>C, M201T, R264C, 80 A>G, and +32226 G>A). The sex*genotype interaction term was assessed for the primary outcome and compared by genotype in men and women when a significant interaction term was identified.We identified a significant interaction between -81371 C>T and sex (p = 0.025) in the ACS population. The variant allele was associated with a 78% increase in mortality in men (HR 1.78, 95% confidence interval [CI] 1.08-2.94) and a nonsignificant 42% decrease in mortality among women (HR 0.58, 95% CI 0.22-1.54). We identified a similar association in the hypertensive CAD group, the -81371 C>T*sex interaction term was p<0.0001, with an associated 65% increase in death, MI, or stroke (HR 1.65, 95% CI 1.00-2.73) in men and a 69% decrease (HR 0.31, 95% CI 0.16-0.6) in women.Using two independent populations, this study is the first to document a significant interaction between CYP19A1 genotype and sex on cardiovascular outcomes. These findings could illuminate potential mechanisms of sex differences in cardiovascular disease outcomes

Short-term geriatric assessment units: 30 years later

<p>Abstract</p> <p>Background</p> <p>The increasing number of hospitalized elderly persons has greatly challenged decision makers to reorganize services so as to meet the needs of this clientele. Established progressively over the last 30 years, the short-term Geriatric Assessment Unit (GAU) is a specialized care program, now implemented in all the general hospital centres in Quebec. Within the scope of a broader reflection upon the appropriate care delivery for elderly patients in our demographic context, there is a need to revisit the role of GAU within the hospital and the continuum of care. The objective of this project is to describe the range of activities offered by Quebec GAU and the resources available to them.</p> <p>Methods</p> <p>In 2004, 64 managers of 71 GAU answered a mail questionnaire which included 119 items covering their unit's operation and resources in 2002-2003. The clinical and administrative characteristics of the clientele admitted during this period were obtained from the provincial database Med-Echo. The results were presented according to the geographical location of GAU, their size, their university academic affiliation, the composition of their medical staff, and their clinical care profile.</p> <p>Results</p> <p>Overall, GAU programs admitted 9% of all patients aged 65 years and older in the surveyed year. GAU patients presented one or more geriatric syndromes, including dementia. Based on their clientele, three distinct clinical care profiles of GAU were identified. Only 19% of GAU were focused on geriatric assessment and acute care management; 23% mainly offered rehabilitation care, and the others offered a mix of both types. Thus, there was a significant heterogeneity in GAU's operation.</p> <p>Conclusions</p> <p>The GAU is at the cutting edge of geriatric services in hospital centres. Given the scarcity of these resources, it would be appropriate to better target the clientele that may benefit from them. Standardizing and promoting GAU's primary role in acute care must be reinforced. In order to meet the needs of the frail elderly not admitted in GAU, alternative care models centered on prevention of functional decline must be applied throughout all hospital wards.</p