Suggestions from Geroscience for the genetics of age-related diseases

Autor: Konstantin G. Arbeev, Alexander M. Kulminski, Liang He, Svetlana V. Ukraintseva, Deqing Wu, Fang Fang, Yelena Kernogitski, Mikhail Kovtun, Matt Duan, Olivia Bagley, Irina Culminskaya, Elena Loiko, Arseniy P. Yashkin, Anatoliy I. Yashin, Liubov Arbeeva, Yury Loika
Rok vydání: 2016
Předmět:
0301 basic medicine
Cancer Research
Genome-wide association study
Bioinformatics
Vascular Medicine
Biochemistry
Diabetes mellitus genetics
Endocrinology
Mathematical and Statistical Techniques
0302 clinical medicine
Framingham Heart Study
Medicine and Health Sciences
Coronary Heart Disease
Genetics (clinical)
Genetics
Neurodegenerative Diseases
Genetic Pleiotropy
3. Good health
Stroke
Neurology
Physical Sciences
Statistics (Mathematics)
Research Article
lcsh:QH426-470
Endocrine Disorders
Cerebrovascular Diseases
Cardiology
Locus (genetics)
Biology
Research and Analysis Methods
03 medical and health sciences
Alzheimer Disease
Mental Health and Psychiatry
Diabetes Mellitus
Genetic predisposition
Humans
Genetic Predisposition to Disease
Statistical Methods
Mortality
Allele
Molecular Biology
Alleles
Ecology
Evolution
Behavior and Systematics
Heart Failure
Biology and Life Sciences
Minor allele frequency
lcsh:Genetics
030104 developmental biology
Metabolic Disorders
Genetics of Disease
Dementia
Mathematics
Biomarkers
030217 neurology & neurosurgery
Meta-Analysis
Zdroj: PLoS Genetics
PLoS Genetics, Vol 12, Iss 11, p e1006314 (2016)
ISSN: 1553-7404
DOI: 10.1371/journal.pgen.1006314
Popis: Gaining insights into genetic predisposition to age-related diseases and lifespan is a challenging task complicated by the elusive role of evolution in these phenotypes. To gain more insights, we combined methods of genome-wide and candidate-gene studies. Genome-wide scan in the Atherosclerosis Risk in Communities (ARIC) Study (N = 9,573) was used to pre-select promising loci. Candidate-gene methods were used to comprehensively analyze associations of novel uncommon variants in Caucasians (minor allele frequency~2.5%) located in band 2q22.3 with risks of coronary heart disease (CHD), heart failure (HF), stroke, diabetes, cancer, neurodegenerative diseases (ND), and mortality in the ARIC study, the Framingham Heart Study (N = 4,434), and the Health and Retirement Study (N = 9,676). We leveraged the analyses of pleiotropy, age-related heterogeneity, and causal inferences. Meta-analysis of the results from these comprehensive analyses shows that the minor allele increases risks of death by about 50% (p = 4.6×10−9), CHD by 35% (p = 8.9×10−6), HF by 55% (p = 9.7×10−5), stroke by 25% (p = 4.0×10−2), and ND by 100% (p = 1.3×10−3). This allele also significantly influences each of two diseases, diabetes and cancer, in antagonistic fashion in different populations. Combined significance of the pleiotropic effects was p = 6.6×10−21. Causal mediation analyses show that endophenotypes explained only small fractions of these effects. This locus harbors an evolutionary conserved gene-desert region with non-coding intergenic sequences likely involved in regulation of protein-coding flanking genes ZEB2 and ACVR2A. This region is intensively studied for mutations causing severe developmental/genetic disorders. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.
Author Summary Biomedical research and medical care are traditionally focused on individual health conditions in order to postpone, ameliorate, or prevent the accumulation of morbidities in late life. An attractive idea is to find factors, which could reduce burden of not just one disease but a major subset of them to efficiently extend healthy lifespan. Here we focus on the analyses of genetic predisposition to risks of major human age-related diseases and mortality. The analyses highlight a locus in band 2q22.3 associated with risks of coronary heart disease, heart failure, stroke, diabetes, cancer, neurodegenerative diseases, and death. Our analyses indicate a promising target region for interventions aimed to reduce risks of many major human diseases and mortality.
Databáze: OpenAIRE
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