Accepted_test

Polymorphic variants of autophagy-regulating genes: polygenic and survival analysis of pathological and healthy phenotypes in the advanced age
by Erdman Vera | Institute of Biochemistry and Genetics – Subdivision of the Ufa Federal Research Centre of the Russian Academy of Sciences
Abstract ID: 188
Event: BGRS-abstracts
Sections: Section “Genetics and systems biology of aging”

Achieving the advanced age during the age-associated diseases suggests the presents of adaptive endogenous mechanisms. The aging-critical autophagy process is regulated under oxidative stress conditions and provided by the dynamic system of mitochondria and endoplasmic reticulum membranes. The aim was to search for combined polymorphic profile of genes involved in regulation of autophagy process, in physiological aging and age-related pathology.
In total sample of 2806 unrelated individuals in age from 18 to 114 years the polygenic and survival analysis was performed. The functional polymorphic loci of the autophagy-regulating genes were genotyped by a TaqMan real-time PCR assay.
We have identified the single and multilocus predictors of survival under the certain clinical phenotypes in the advanced age, as well as longevity genetic markers. The most significant combinations were the CAT*T+MSRA*TT+GPXI*T, HIF1A*C+MSRA*T+SOD1*AA, MSRA*T+SOD1*AA, GSTP1*A+SOD1*A+SOD2*CT, and GSTP1*A+GSR*G (OR > 3, pFDR < 0.01); and the NQO1*C+GSR*T+SOD2*T, and AKT1*G+HIF1A*C+GSTP1*GG (OR < 0.15, pFDR < 0.01).
The survival analysis has revealed the elements that are core meaningful for longevity status. The cancer mortality was associated with the CAT rs1001179*TT and SOD1 rs2070424*AG genotypes (HR > 1.5, p = 0.05). The PONI*G+MSRA*C+NQO1*T+SOD1*G allele combination was associated with the highest risk of all-causes mortality among men (HR = 29.56, p = 9.47×10-4). The AKT1*GG+HIF1A*T+SIRT1*T pattern had a protective effect on survival status (HR = 0.71, p = 0.014).
Probably, these gene networks are involved in a highly adaptive phenotype that allows to minimize the negative effects of the age-related pathologies and to reach the longevity.