Polygenic markers of survival and longevity in the antioxidant genes PON1, PON2, MTHFR, MSRA, SOD1, NQO1, and CAT in a 20-year follow-up study in the population from the Volga-Ural region.

BACKGROUND: Genetic background of healthy or pathological styles of aging and human lifespan is determined by joint gene interactions. Lucky combinations of antioxidant gene polymorphisms can result in a highly adaptive phenotype, providing a successful way to interact with external triggers. Our purpose was to identify the polygenic markers of survival and longevity in the antioxidant genes among elderly people with physiological and pathological aging. METHODS: In a 20-year follow-up study of 2350 individuals aged 18-114 years residing in the Volga-Ural region of Russia, sex-adjusted association analyses of MTHFR rs1801133, MSRA rs10098474, PON1 rs662, PON2 rs7493, SOD1 rs2070424, NQO1 rs1131341 and CAT rs1001179 polymorphic loci with longevity were carried out. Survival analysis was subsequently performed using the established single genes and gene-gene combinations as cofactors. RESULTS: The PON1 rs662*G allele was defined as the main longevity marker in women (OR = 1.44, p = 3E-04 in the log-additive model; HR = 0.77, p = 1.9E-04 in the Cox-survival model). The polymorphisms in the MTHFR, MSRA, PON2, SOD1, and CAT genes had an additive effect on longevity. A strong protective effect of combined MTHFR rs1801133*C, MSRA rs10098474*T, PON1 rs662*G, and PON2 rs7493*C alleles against mortality was obtained in women (HR = 0.81, p = 5E-03). The PON1 rs662*A allele had a meaningful impact on mortality for both long-lived men with cerebrovascular accidents (HR = 1.76, p = 0.027 for the PON1 rs662*AG genotype) and women with cardiovascular diseases (HR = 1.43, p = 0.002 for PON1 rs662*AA genotype). The MTHFR rs1801133*TT (HR = 1.91, p = 0.036), CAT rs1001179*TT (HR = 2.83, p = 0.031) and SOD1 rs2070424*AG (HR = 1.58, p = 0.018) genotypes were associated with the cancer mortality. CONCLUSION: In our longitudinal 20-year study, we found the combinations of functional polymorphisms in antioxidant genes involved in longevity and survival in certain clinical phenotypes in the advanced age.

Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity.

Longevity is a unique human phenomenon and a highly stable trait, characterized by polygenicity. The longevity phenotype occurs due to the ability to successfully withstand the age-related genomic instability triggered by Alu elements. The purpose of our cross-sectional study was to evaluate the combined contribution of ACE*Ya5ACE, CDH4*Yb8NBC516, COL13A1*Ya5ac1986, HECW1*Ya5NBC182, LAMA2*Ya5-MLS19, PLAT*TPA25, PKHD1L1*Yb8AC702, SEMA6A*Yb8NBC597, STK38L*Ya5ac2145 and TEAD1*Ya5ac2013 Alu elements to longevity. The study group included 2054 unrelated individuals aged from 18 to 113 years who are ethnic Tatars from Russia. We analyzed the dynamics of the allele and genotype frequencies of the studied Alu polymorphic loci in the age groups of young (18-44 years old), middle-aged (45-59 years old), elderly (60-74 years old), old seniors (75-89 years old) and long-livers (90-113 years old). Most significant changes in allele and genotype frequencies were observed between the long-livers and other groups. The search for polygenic predictors of longevity was performed using the APSampler program. Attaining longevity was associated with the combinations LAMA2*ID + CDH4*D (OR = 2.23, PBonf = 1.90 × 10-2) and CDH4*DD + LAMA2*ID + HECW1*D (OR = 4.58, PBonf = 9.00 × 10-3) among persons aged between 18 and 89 years, LAMA2*ID + CDH4*D + SEMA6A*I for individuals below 75 years of age (OR = 3.13, PBonf = 2.00 × 10-2), LAMA2*ID + HECW1*I for elderly people aged 60 and older (OR = 3.13, PBonf = 2.00 × 10-2) and CDH4*DD + LAMA2*D + HECW1*D (OR = 4.21, PBonf = 2.60 × 10-2) and CDH4*DD + LAMA2*D + ACE*I (OR = 3.68, PBonf = 1.90 × 10-2) among old seniors (75-89 years old). The key elements of combinations associated with longevity were the deletion alleles of CDH4 and LAMA2 genes. Our results point to the significance for human longevity of the Alu polymorphic loci in CDH4, LAMA2, HECW1, SEMA6A and ACE genes, involved in the integration systems.