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.

Multilocus evaluation of genetic predictors of multiple sclerosis.

BACKGROUND: Genome-wide association studies identified numerous susceptibility loci for multiple sclerosis in populations of European ancestry, but the associations are not always reproducible in other populations due to admixture and different linkage disequilibrium patterns obscuring true association signals. OBJECTIVE: Our aim was to identify genetic predictors of multiple sclerosis in three ethnically homogenous populations from the Volga-Ural region of Russian Federation. METHODS: In the largest to date study of multiple sclerosis in Russian population, involving 2048 participants from the Republic of Bashkortostan, Russian Federation (641 patients with multiple sclerosis and 1407 unaffected individuals), we performed replication analysis of previously identified genome-wide signals for multiple sclerosis. Associations were tested using logistic regression analysis under additive genetic model adjusted for sex. Meta-analysis of the study results in three populations was performed under fixed effects and random effects models. RESULTS: We demonstrate the association with multiple sclerosis of the five variants (INAVA rs7522462, EOMES rs11129295, C6orf10 rs3129934, CD86 rs9282641, and GPR65 rs2119704). The strongest association (OR = 2.16, CI:1.85-2.74, P = 2.53x10-13) was detected for rs3129934 polymorphism in the major histocompatibility region. Multilocus analysis has revealed 322 and 27 allelic patterns associated with multiple sclerosis in women and men, respectively. In women, the highest risk of MS was conferred by C6orf10 rs3129934*T/T + STAT3 rs744166*T combination (OR = 11.87), in men - by C6orf10 rs3129934*T + EOMES rs11129295*C + RPS6KB1 rs180515*C combination (OR = 3.25). CONCLUSION: We confirm five associations with multiple sclerosis previously reported in genome-wide scans in Europeans in three ethnic groups from the Volga-Ural region of Russia.

CXCL13 polymorphism is associated with essential hypertension in Tatars from Russia.

Essential arterial hypertension is a disease with distinct yet unexplored inflammatory component. Our aim was to assess the role of chemokine genes and their interaction in its development. Genotyping of polymorphic markers in six chemokine genes (CXCL13, CCL8, CCL16, CCL17, CCL18, and CCL23) was performed in the group of 522 men of Tatar ethnic origin from the Republic of Bashkortostan, Russia (213 patients with essential hypertension and 309 healthy individuals without history of cardiovascular disease). We found a strong association of CXCL13 rs355689*C allele with essential hypertension under additive (OR 0.56, PFDR = 0.008) and dominant (OR 0.41, PFDR 4.38 × 10- 4) genetic model. The analysis of gene-gene interactions revealed 12 allele/genotype combinations that remained significantly associated with essential hypertension after correction for multiple testing was applied, and each of these combinations included CXCL13 rs355689 polymorphism. Our results indicate that CXCL13 rs355689 polymorphism is strongly associated with essential hypertension in the ethnic group of Tatars, alone and in combination with polymorphic markers in other chemokine genes.

Genotype/allelic combinations as potential predictors of myocardial infarction.

In order to find new informative predictors of myocardial infarction, we performed an analysis of genotype frequencies of polymorphic markers of SELE (rs2076059, 3832T > C), SELP (rs6131, S290 N), SELL (rs1131498, F206L), ICAM1 (rs5498, K469E), VCAM1 (rs3917010, c.928 + 420A > C), PECAM1 (rs668, V125L), VEGFA (rs35569394, -2549(18)I/D), CCL2 (rs1024611, -2518A > G), NOS3 (rs1799983, E298D), and DDAH1 (rs669173, c.303 + 30998A > G) genes in the group of Russian men with myocardial infarction (N = 315) and the control group of corresponding ethnicity, gender, and age (N = 286). Using Markov chain Monte-Carlo method (APSampler), we found genotype combinations associated with increased and decreased risk of myocardial infarction. The most significant associations were detected for PECAM1*V/V + DDAH1*C (OR = 4.17 CI 1.56-11.15 Pperm = 0.005) SELE*C + VEGFA*I + CCL2*G + VCAM1*A + NOS3*D (OR = 2.74 CI 1.66-4.52 Pperm = 2.09 × 10(-5)), and VEGFA*D/D + CCL2*A + DDAH1*C (OR = 0.44 CI 0.28-0.7 Pperm = 7.89 × 10(-5)) genotype combinations.

Polymorphisms of inflammatory markers and risk of essential hypertension in Tatars from Russia.

Essential hypertension (EH) is a common disease with a clear genetic component. Inflammation and endothelial dysfunction play a prominent role in the development of persistent blood pressure elevation. The aim of the current study was to detect an association between EH and polymorphic markers in genes encoding for molecules involved in the control of intercellular interactions during the inflammation process. We analysed SNPs in SELE, SELP, SELL, ICAM1, VEGFA, IL1B, IL6, IL10 and IL12B genes in a group of 534 men of Tatar ethnicity (217 patients with EH and 317 controls). Using a Markov chain Monte-Carlo-based approach (APSampler), we found genotype and allelic combinations associated with EH. The most significant associations were observed for SELE rs2076059*C-SELP rs6131*A-VEGFA -2549*I-IL1B rs16944*C (p = 3.42 × 10(-5), FDR q = 0.035) and SELE rs2076059*C-SELP rs6131*A-IL12B rs3212227*C-IL1B rs16944*C (p = 323 × 10(-4), FDR q = 0.035).