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

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

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

Composite measure of physiological dysregulation as a predictor of mortality: The Long Life Family Study

Biological aging results in changes in an organism that accumulate over age in a complex fashion across different regulatory systems, and their cumulative effect manifests in increased physiological dysregulation (PD) and declining robustness and resilience that increase risks of health disorders and death. Several composite measures involving multiple biomarkers that capture complex effects of aging have been proposed. We applied one such approach, the Mahalanobis distance (

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

Pleiotropic Meta-Analysis of Age-Related Phenotypes Addressing Evolutionary Uncertainty in Their Molecular Mechanisms

Age-related phenotypes are characterized by genetic heterogeneity attributed to an uncertain role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic meta-analyses of 24 age-related phenotypes dealing with such evolutionary uncertainty and leveraging longitudinal information. Our analysis identified 237 novel single nucleotide polymorphisms (SNPs) in 199 loci with phenotype-specific (61 SNPs) and pleiotropic (176 SNPs) associations and replicated associations for 160 SNPs in 68 loci in a modest sample of 26,371 individuals from five longitudinal studies. Most pleiotropic associations (65.3%, 115 of 176 SNPs) were impacted by heterogeneity, with the natural-selection—free genetic heterogeneity as its inevitable component. This pleiotropic heterogeneity was dominated (93%, 107 of 115 SNPs) by antagonistic genetic heterogeneity, a phenomenon that is characterized by antagonistic directions of genetic effects for directly correlated phenotypes. Genetic association studies of age-related phenotypes addressing the evolutionary uncertainty in establishing their molecular mechanisms have power to substantially improve the efficiency of the analyses. A dominant form of heterogeneous pleiotropy, antagonistic genetic heterogeneity, provides unprecedented insight into the genetic origin of age-related phenotypes and side effects in medical care that is counter-intuitive in medical genetics but naturally expected when molecular mechanisms of age-related phenotypes are not due to direct evolutionary selection

Age, gender, and cancer but not neurodegenerative and cardiovascular diseases strongly modulate systemic effect of the Apolipoprotein E4 allele on lifespan

Enduring interest in the Apolipoprotein E (ApoE) polymorphism is ensured by its evolutionary-driven uniqueness in humans and its prominent role in geriatrics and gerontology. We use large samples of longitudinally followed populations from the Framingham Heart Study (FHS) original and offspring cohorts and the Long Life Family Study (LLFS) to investigate gender-specific effects of the ApoE4 allele on human survival in a wide range of ages from midlife to extreme old ages, and the sensitivity of these effects to cardiovascular disease (CVD), cancer, and neurodegenerative disorders (ND). The analyses show that women's lifespan is more sensitive to the e4 allele than men's in all these populations. A highly significant adverse effect of the e4 allele is limited to women with moderate lifespan of about 70 to 95 years in two FHS cohorts and the LLFS with relative risk of death RR = 1.48 (p = 3.6×10(−6)) in the FHS cohorts. Major human diseases including CVD, ND, and cancer, whose risks can be sensitive to the e4 allele, do not mediate the association of this allele with lifespan in large FHS samples. Non-skin cancer non-additively increases mortality of the FHS women with moderate lifespans increasing the risks of death of the e4 carriers with cancer two-fold compared to the non-e4 carriers, i.e., RR = 2.07 (p = 5.0×10(−7)). The results suggest a pivotal role of non-sex-specific cancer as a nonlinear modulator of survival in this sample that increases the risk of death of the ApoE4 carriers by 150% (p = 5.3×10(−8)) compared to the non-carriers. This risk explains the 4.2 year shorter life expectancy of the e4 carriers compared to the non-carriers in this sample. The analyses suggest the existence of age- and gender-sensitive systemic mechanisms linking the e4 allele to lifespan which can non-additively interfere with cancer-related mechanisms

How Well Does the Family Longevity Selection Score Work: A Validation Test Using the Utah Population Database

The Family Longevity Selection Score (FLoSS) was used to select families for the Long Life Family Study (LLFS) but has never been validated in other populations. The goal of this paper is to validate how well the FLoSS-based selection procedure works in an independent dataset. In this paper, we computed FLoSS using the lifespan data of 234,155 individuals from a large comprehensive genealogically-based resource, the Utah Population Database (UPDB), born between 1779 and 1910 with mortality follow-up through 2012–2013. Computations of FLoSS in a specific year (1980) confirmed the survival advantage of the “exceptional” sibships (defined by LLFS FLoSS threshold, FLoSS ≥ 7). We found that the subsample of the UPDB participants born after 1900 who were from the “exceptional” sibships had survival curves similar to that of the US participants from the LLFS probands' generation. Comparisons between the offspring of parents with “exceptional” and “ordinary” survival showed the survival advantage of the “exceptional” offspring. Investigators seeking to explain the extent genetics and environment contribute to exceptional survival will benefit from the use of exceptionally long-lived individuals and their relatives. Appropriate ranking of families by survival exceptionality and their availability for the purposes of providing genetic and phenotypic data is critical for selecting participants into such studies. This study validated the FLoSS as selection criteria in family longevity studies using UPDB