Browsing by Author "Yashkin, Arseniy"

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    How the effects of aging and stresses of life are integrated in mortality rates: insights for genetic studies of human health and longevity.
    (Biogerontology, 2016-02) Yashin, Anatoliy I; Arbeev, Konstantin G; Arbeeva, Liubov S; Wu, Deqing; Akushevich, Igor; Kovtun, Mikhail; Yashkin, Arseniy; Kulminski, Alexander; Culminskaya, Irina; Stallard, Eric; Li, Miaozhu; Ukraintseva, Svetlana V
    Increasing proportions of elderly individuals in developed countries combined with substantial increases in related medical expenditures make the improvement of the health of the elderly a high priority today. If the process of aging by individuals is a major cause of age related health declines then postponing aging could be an efficient strategy for improving the health of the elderly. Implementing this strategy requires a better understanding of genetic and non-genetic connections among aging, health, and longevity. We review progress and problems in research areas whose development may contribute to analyses of such connections. These include genetic studies of human aging and longevity, the heterogeneity of populations with respect to their susceptibility to disease and death, forces that shape age patterns of human mortality, secular trends in mortality decline, and integrative mortality modeling using longitudinal data. The dynamic involvement of genetic factors in (i) morbidity/mortality risks, (ii) responses to stresses of life, (iii) multi-morbidities of many elderly individuals, (iv) trade-offs for diseases, (v) genetic heterogeneity, and (vi) other relevant aging-related health declines, underscores the need for a comprehensive, integrated approach to analyze the genetic connections for all of the above aspects of aging-related changes. The dynamic relationships among aging, health, and longevity traits would be better understood if one linked several research fields within one conceptual framework that allowed for efficient analyses of available longitudinal data using the wealth of available knowledge about aging, health, and longevity already accumulated in the research field.
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    Pleiotropic Meta-Analyses of Longitudinal Studies Discover Novel Genetic Variants Associated with Age-Related Diseases.
    (Front Genet, 2016) He, Liang; Kernogitski, Yelena; Kulminskaya, Irina; Loika, Yury; Arbeev, Konstantin G; Loiko, Elena; Bagley, Olivia; Duan, Matt; Yashkin, Arseniy; Ukraintseva, Svetlana V; Kovtun, Mikhail; Yashin, Anatoliy I; Kulminski, Alexander M
    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.
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    Pure and Confounded Effects of Causal SNPs on Longevity: Insights for Proper Interpretation of Research Findings in GWAS of Populations with Different Genetic Structures.
    (Front Genet, 2016) Yashin, Anatoliy I; Zhbannikov, Ilya; Arbeeva, Liubov; Arbeev, Konstantin G; Wu, Deqing; Akushevich, Igor; Yashkin, Arseniy; Kovtun, Mikhail; Kulminski, Alexander M; Stallard, Eric; Kulminskaya, Irina; Ukraintseva, Svetlana
    This paper shows that the effects of causal SNPs on lifespan, estimated through GWAS, may be confounded and the genetic structure of the study population may be responsible for this effect. Simulation experiments show that levels of linkage disequilibrium (LD) and other parameters of the population structure describing connections between two causal SNPs may substantially influence separate estimates of the effect of the causal SNPs on lifespan. This study suggests that differences in LD levels between two causal SNP loci within two study populations may contribute to the failure to replicate previous GWAS findings. The results of this paper also show that successful replication of the results of genetic association studies does not necessarily guarantee proper interpretation of the effect of a causal SNP on lifespan.
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    Relation between BMI and diabetes mellitus and its complications among US older adults.
    (South Med J, 2015-01) Gray, Natallia; Picone, Gabriel; Sloan, Frank; Yashkin, Arseniy
    OBJECTIVES: This study examined relations between elevated body mass index (BMI) and time to diagnosis with type 2 diabetes mellitus and its complications among older adults in the United States. METHODS: Data came from the Medicare Current Beneficiary Survey, 1991-2010. A Cox proportional hazard model was used to assess relations between excess BMI at the first Medicare Current Beneficiary Survey interview and time to diabetes mellitus diagnosis, complications, and insulin dependence among Medicare beneficiaries, older than 65 years of age with no prior diabetes mellitus diagnosis, and who were not enrolled in Medicare Advantage (N = 14,657). RESULTS: Among individuals diagnosed as having diabetes mellitus, elevated BMIs were associated with a progressively higher risk of complications from diabetes mellitus. For women with a BMI ≥40, the risk of insulin dependence (hazard ratio [HR] 3.57; 95% confidence interval [CI] 2.36-5.39) was twice that for women with 25 ≤ BMI < 27.5 (HR 1.77; 95% CI 1.33-2.33). A similar pattern was observed in risk of cardiovascular (25 ≤ BMI < 27.5: HR 1.34; 95% CI 1.15-1.54; BMI ≥40: HR 2.45; 95% CI 1.92-3.11), cerebrovascular (25 ≤ BMI < 27.5: HR 1.30; 95% CI 1.06-1.57; BMI ≥40: HR 2.00; 95% CI 1.42-2.81), renal (25 ≤ BMI < 27.5: HR 1.31; 95% CI 1.04-1.63; BMI ≥40: HR 2.23; 95% CI 1.54-3.22), and lower extremity complications (25 ≤ BMI < 27.5: HR 1.41; 95% CI 1.22-1.61; BMI ≥40: HR 2.95; 95% CI 2.35-3.69). CONCLUSIONS: Any increase in BMI above normal weight levels is associated with an increased risk of being diagnosed as having complications of diabetes mellitus. For men, the increased risk of these complications occurred at higher BMI levels than in women. Ocular complications occurred at higher BMI levels than other complication types in both men and women.