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Background: MiRNA are multifunctional molecules involved in regulating posttranscriptional expression of genes. Several studies showed that miR‐107 influences expression of the BACE1 gene in the process of Aβ production. Extracellular accumulation of Aβ is well‐known hallmark of Alzheimer's disease (AD). The product NLRP3 gene is involved in inflammasome that induces neuroinflammation a pathological process accompanying AD. The role of miR‐107 in regulation of NRLP3 is unknown. Method: We used logistic regression model with the interaction term to test the hypothesis that interaction of SNPs from miR‐107 with SNPs from the NLRP3 gene is associated with AD. For this we used data on genotyped individuals collected in Framingham Health Study (FHS). The Cardiovascular Health Study (CHS) was used to replicate the research findings. Linkage Disequilibrium test and clumping procedure were used to reduce the number of tests and make Bonferroni correction less conservative. Result: In the analysis of FHS data we found that the association of the rs2926616 SNP from the miR‐107 miRNA with the rs10754557 SNP from the NLRP3 gene is positive and statistically significant. The effect size β = 0.356, p‐value 6.71E‐03. This value is smaller than the p‐value threshold calculated in accordance with Bonferroni correction 7.14E‐03. This result is replicated in the analysis of CHS data with β = 0.289, and p‐value 4.76E‐02. Using FHS data we also tested the role of interaction of SNPs from the miR‐107 with SNPs from the TLR2 gene in AD and found a pair of SNPs whose interaction has statistically significant association with AD. This finding was replicated in the analysis of the CHS data where an interaction of a pair of SNPs also showed significant association with AD. Detected SNPs from this pair were in linkage disequilibrium with the pair SNPs from the CHS data. Conclusion: The results of these analyses indicate that one miRNA may influence several components of AD pathological development. This property may have important implications for developing efficient medications against AD. More studies are needed to evaluate miRNA involvement in different pathways of AD regulation, as well as in identifying factors capable in affecting such miRNA. [ABSTRACT FROM AUTHOR]

Traditionally, genomewide association studies ( GWAS) have emphasized the benefits of large samples in the analyses of age-related traits rather than their specific properties. We adopted a realistic concept of genetic susceptibility to inherently heterogeneous, age-related traits driven by the elusive role of evolution in their properties. We analyzed in detail the associations of rs693 and rs562338 polymorphisms representing the Apolipoprotein B locus with endophenotypes (total cholesterol [ TC] and high-density lipoprotein cholesterol) and phenotypes (myocardial infarction [ MI] and survival) in four large-scale studies, which include 20 748 individuals with 2357 MI events. We showed that a strong, robust predisposition of rs693 and rs562338 to TC (β = 0.72, P = 7.7 × 10−30 for rs693 and β = −1.08, P = 9.8 × 10−42 for rs562338) is not translated into a predisposition to MI and survival. The rs693_A allele influences risks of MI and mortality after MI additively with lipids. This allele shows antagonistic effects-protecting against MI risks (β = −0.18, P = 1.1 × 10−5) or increasing MI risks (β = 0.15, P = 2.8 × 10−3) and mortality after MI, in different populations. Paradoxically, increased TC concentrations can be protective against MI for the rs693_A allele carriers. Our results uncouple the influences of the same alleles on endophenotypes and phenotypes despite potential causal relationships among the latter. Our strategy reveals virtually genomewide significance for the associations of rs693 with MI ( P = 5.5 × 10−8) that is contrasted with a weak estimate following the traditional, sample-size-centered GWAS strategy ( P = 0.16) in the same sample. These results caution against the use of the traditional GWAS strategy for gaining profound insights into genetic predisposition to healthspan and lifespan. [ABSTRACT FROM AUTHOR]

Age-related diseases may result from shared biological mechanisms in intrinsic processes of aging. Genetic effects on age-related diseases are often modulated by environmental factors due to their little contribution to fitness or are mediated through certain endophenotypes. Identification of genetic variants with pleiotropic effects on both common complex diseases and endophenotypes may reveal potential conflicting evolutionary pressures and deliver new insights into shared genetic contribution to healthspan and lifespan. Here, we performed pleiotropic meta-analyses of genetic variants using five NIH-funded datasets by integrating univariate summary statistics for age-related diseases and endophenotypes. We investigated three groups of traits: (1) endophenotypes such as blood glucose, blood pressure, lipids, hematocrit, and body mass index, (2) time-to-event outcomes such as the age-at-onset of diabetes mellitus (DM), cancer, cardiovascular diseases (CVDs) and neurodegenerative diseases (NDs), and (3) both combined. In addition to replicating previous findings, we identify seven novel genome-wide significant loci (<5e-08), out of which five are low-frequency variants. Specifically, from Group 2, we find rs7632505 on 3q21.1 in SEMA5B, rs460976 on 21q22.3 (1 kb from TMPRSS2) and rs12420422 on 11q24.1 predominantly associated with a variety of CVDs, rs4905014 in ITPK1 associated with stroke and heart failure, rs7081476 on 10p12.1 in ANKRD26 associated with multiple diseases including DM, CVDs, and NDs. From Group 3, we find rs8082812 on 18p11.22 and rs1869717 on 4q31.3 associated with both endophenotypes and CVDs. Our follow-up analyses show that rs7632505, rs4905014, and rs8082812 have age-dependent effects on coronary heart disease or stroke. Functional annotation suggests that most of these SNPs are within regulatory regions or DNase clusters and in linkage disequilibrium with expression quantitative trait loci, implying their potential regulatory influence on the expression of nearby genes. Our mediation analyses suggest that the effects of some SNPs are mediated by specific endophenotypes. In conclusion, these findings indicate that loci with pleiotropic effects on age-related disorders tend to be enriched in genes involved in underlying mechanisms potentially related to nervous, cardiovascular and immune system functions, stress resistance, inflammation, ion channels and hematopoiesis, supporting the hypothesis of shared pathological role of infection, and inflammation in chronic age-related diseases. [ABSTRACT FROM AUTHOR]

Despite evident success in clarifying many important features of Alzheimer's disease (AD) the efficient methods of its prevention and treatment are not yet available. The reasons are likely to be the fact that AD is a multifactorial and heterogeneous health disorder with multiple alternative pathways of disease development and progression. The availability of genetic data on individuals participated in longitudinal studies of aging health and longevity, as well as on participants of cross-sectional case-control studies allow for investigating genetic and non-genetic connections with AD and to link the results of these analyses with research findings obtained in clinical, experimental, and molecular biological studies of this health disorder. The objective of this paper is to perform GWAS of AD in several study populations and investigate possible roles of detected genetic factors in developing AD hallmarks and in other health disorders. The data collected in the Framingham Heart Study (FHS), Cardiovascular Health Study (CHS), Health and Retirement Study (HRS) and Late Onset Alzheimer's Disease Family Study (LOADFS) were used in these analyses. The logistic regression and Cox's regression were used as statistical models in GWAS. The results of analyses confirmed strong associations of genetic variants from well-known genes APOE, TOMM40, PVRL2 (NECTIN2), and APOC1 with AD. Possible roles of these genes in pathological mechanisms resulting in development of hallmarks of AD are described. Many genes whose connection with AD was detected in other studies showed nominally significant associations with this health disorder in our study. The evidence on genetic connections between AD and vulnerability to infection, as well as between AD and other health disorders, such as cancer and type 2 diabetes, were investigated. The progress in uncovering hidden heterogeneity in AD would be substantially facilitated if common mechanisms involved in development of AD, its hallmarks, and AD related chronic conditions were investigated in their mutual connection. [ABSTRACT FROM AUTHOR]