Genetic association analysis of the cardiovascular biomarker: N-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP)

BACKGROUND: NT-proBNP is a biomarker of cardiovascular disease (CVD). Little is known about the heritability and genetic variants associated with NT-proBNP. Therefore, we estimated the heritability of and examined genetic associations of SNPs in the BNP gene region with circulating NT-proBNP and prevalent CVD in 4,331 participants from the Long Life Family Study (LLFS). METHODS AND RESULTS: Genotypes of 10 SNPs from the NPPB and NPPA regions that encode BNP and A-type natriuretic peptide, respectively, were tested for association with NT-proBNP and prevalent cardiovascular disease and risk factors. We performed analyses using the Sequential Oligogenic Linkage Analysis (SOLAR) program to account for family relatedness, and adjusted all models for age, sex, and field center. The mean age of the LLFS was 69.8 years (range 24-110) with 55.4% females. NT-proBNP was significantly heritable (h2 = 0.21; P = 4x10-14), and the minor alleles of rs632793 (p\u3c0.001) and rs41300100 (p = 0.05) were independently associated with higher serum NT-proBNP levels. Additionally, the minor allele of rs632793 was significantly and consistently associated with lower prevalent CVD, including blood pressures, independent of NT-proBNP level (all P\u3c0.05). Results for prevalent CVD, but not NT-proBNP levels, showed significant interaction by familial generation. CONCLUSION: In this family-based study of subjects with exceptional longevity, we identified several allelic variants in the BNP gene region associated with NT-pro-BNP levels and prevalent CVD

Mechanisms underlying familial aggregation of exceptional health and survival: A three-generation cohort study

The familial resemblance in length of adult life is very modest. Studies of parent-offspring and twins suggest that exceptional health and survival have a stronger genetic component than lifespan generally. To shed light on the underlying mechanisms, we collected information on Danish long-lived siblings (born 1886-1938) from 659 families, their 5379 offspring (born 1917-1982), and 10,398 grandchildren (born 1950-2010) and matched background population controls through the Danish 1916 Census, the Civil Registration System, the National Patient Register, and the Register of Causes of Death. Comparison with the background, population revealed consistently lower occurrence of almost all disease groups and causes of death in the offspring and the grandchildren. The expected incidence of hospitalization for mental and behavioral disorders was reduced by half in the offspring (hazard ratio 0.53, 95% confidence interval 0.45-0.62) and by one-third in the grandchildren (0.69, 0.61-0.78), while the numbers for tobacco-related cancer were 0.60 (0.51-0.70) and 0.71 (0.48-1.05), respectively. Within-family analyses showed a general, as opposed to specific, lowering of disease risk. Early parenthood and divorce were markedly less frequent in the longevity-enriched families, while economic and educational differences were small to moderate. The longevity-enriched families in this study have a general health advantage spanning three generations. The particularly low occurrence of mental and behavioral disorders and tobacco-related cancers together with indicators of family stability and only modest socioeconomic advantage implicate behavior as a key mechanism underlying familial aggregation of exceptional health and survival

A Growth Curve Model with Fractional Polynomials for Analysing Incomplete Time-Course Data in Microarray Gene Expression Studies

Identifying the various gene expression response patterns is a challenging issue in expression microarray time-course experiments. Due to heterogeneity in the regulatory reaction among thousands of genes tested, it is impossible to manually characterize a parametric form for each of the time-course pattern in a gene by gene manner. We introduce a growth curve model with fractional polynomials to automatically capture the various time-dependent expression patterns and meanwhile efficiently handle missing values due to incomplete observations. For each gene, our procedure compares the performances among fractional polynomial models with power terms from a set of fixed values that offer a wide range of curve shapes and suggests a best fitting model. After a limited simulation study, the model has been applied to our human in vivo irritated epidermis data with missing observations to investigate time-dependent transcriptional responses to a chemical irritant. Our method was able to identify the various nonlinear time-course expression trajectories. The integration of growth curves with fractional polynomials provides a flexible way to model different time-course patterns together with model selection and significant gene identification strategies that can be applied in microarray-based time-course gene expression experiments with missing observations

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

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

Association of leukocyte telomere length with perceived physical fatigability

BACKGROUND: Leukocyte telomere length (LTL) is a potential genomic marker of biological aging, but its relation to fatigability, a prognostic indicator of phenotypic aging (e.g., functional decline) is unknown. We hypothesized shorter LTL would predict greater perceived physical fatigability, but that this association would be attenuated by adjusting for chronological age. METHODS: Two generations of participants (N = 1997; 309 probands, 1688 offspring) were from the Long Life Family Study (age = 73.7 ± 10.4, range 60-108, 54.4 % women), a longitudinal cohort study of aging. LTL was assayed at baseline. Perceived physical fatigability was measured 8.0 ± 1.1 years later using the validated, self-administered 10-item Pittsburgh Fatigability Scale (PFS, 0-50, higher scores = greater fatigability). Generalized estimating equations were generated to model the association between LTL and PFS Physical scores. RESULTS: Prevalence of greater physical fatigability (PFS scores≥15) was 41.9 %. Using generalized estimating equations, a one kilobase pair shorter LTL was associated with higher PFS Physical scores (β = 1.8, p \u3c .0001), accounting for family structure, and adjusting for field center, follow-up time, sex, and follow-up body mass index, physical activity, and chronic health conditions. When age was included as a covariate, the association was fully attenuated (β = 0.1, p = .78). CONCLUSION: LTL may provide an alternative method for estimating an individual\u27s lifetime exposure to chronic stressors, but does not appear to provide additional information not captured by chronological age. Further research is needed to characterize the interaction between age, LTL, and perceived fatigability, and develop a method of identifying individuals at risk for deleterious aging

The APOE ε4 allele is associated with a reduction in FEV1/FVC in women: A cross-sectional analysis of the Long Life Family Study

Introduction Murine studies have shown that apolipoprotein E modulates pulmonary function during development, aging, and allergen-induced airway disease. It is not known whether the polymorphic human APOE gene influences pulmonary function. Objectives We assessed whether an association exists between the polymorphic human APOE ε2, ε3, and ε4 alleles and pulmonary function among participants in the Long Life Family Study. Methods Data from 4,468 Caucasian subjects who had genotyping performed for the APOE ε2, ε3, and ε4 alleles were analyzed, with and without stratification by sex. Statistical models were fitted considering the effects of the ε2 allele, defined as ε2/2 or ε2/3 genotypes, and the ε4 allele, defined as ε3/4 or ε4/4 genotypes, which were compared to the ε3/3 genotype. Results The mean FEV1/FVC ratio (the forced expiratory volume in one second divided by the forced vital capacity) was lower among women with the ε4 allele as compared to women with the ε3/3 genotype or the ε2 allele. Carriage of the APOE ε4 allele was associated with FEV1/FVC, which implied lower values. Further analysis showed that the association primarily reflected women without lung disease who were older than 70 years. The association was not mediated by lipid levels, smoking status, body mass index, or cardiovascular disease. Conclusions This study for the first time identifies that the APOE gene is associated with modified lung physiology in women. This suggests that a link may exist between the APOE ε4 allele, female sex, and a reduction in the FEV1/FVC ratio in older individuals

Perceived physical fatigability predicts all-cause mortality in older adults

BACKGROUND: Perceived physical fatigability is highly prevalent in older adults and associated with mobility decline and other health consequences. We examined the prognostic value of perceived physical fatigability as an independent predictor of risk of death among older adults. METHODS: Participants (N = 2 906), mean age 73.5 [SD, 10.4] years, 54.2% women, 99.7% white enrolled in the Long Life Family Study, were assessed at Visit 2 (2014-2017) with 2.7 [SD, 1.0] years follow-up. The Pittsburgh Fatigability Scale (PFS), a 10-item, self-administered validated questionnaire (score range 0-50, higher = greater fatigability) measured perceived physical fatigability at Visit 2. Deaths post-Visit 2 through December 31, 2019 were identified by family members notifying field centers, reporting during another family member\u27s annual phone follow-up, an obituary, or Civil Registration System (Denmark). We censored all other participants at their last contact. Cox proportional hazard models predicted mortality by fatigability severity, adjusted for family relatedness and other covariates. RESULTS: Age-adjusted PFS Physical scores were higher for those who died (19.1 [SE, 0.8]) compared with alive (12.2, [SE, 0.4]) overall, as well as across age strata (p \u3c .001), except for those 60-69 years (p = .79). Participants with the most severe fatigability (PFS Physical scores ≥ 25) were over twice as likely to die (hazard ratio, 2.33 [95% CI, 1.65-3.28]) compared with those who had less severe fatigability (PFS Physical scores \u3c 25) after adjustment. CONCLUSIONS: Our work underscores the utility of the PFS as a novel patient-reported prognostic indicator of phenotypic aging that captures both overt and underlying disease burden that predicts death