Mariya Smetanina

Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins

Heredity plays an important role in the etiology of varicose veins (VVs). However, the genetic basis underlying this condition remains poorly understood. Our aim was to replicate top association signals from genome‐wide association studies (GWASs) for VVs of lower extremities using 2 independent datasets—our sample of ethnic Russian individuals (709 cases and 278 controls) and a large cohort of British residents from UK Biobank (10 861 cases and 397 594 controls). Associations of polymorphisms rs11121615, rs6712038, rs507666, rs966562, rs7111987, rs6062618, and rs6905288 were validated in the UK Biobank individuals at a Bonferroni‐corrected significance level. In Russian cohort, only rs11121615 reached a nominal significance level of P < .05. Results of original GWAS and replication studies were combined by a meta‐analysis, and polymorphisms listed above as well as rs111434909 and rs4463578 passed a genome‐wide significant threshold. Notably, the majority of these polymorphisms were located within or near genes involved in vascular development and remodeling, and regulation of inflammatory response. Our results confirm the role of these polymorphisms in genetic susceptibility to VVs and indicate the revealed genomic regions as good candidates for further fine‐mapping studies and functional analysis. Moreover, our findings implicate inflammation and abnormal vascular architecture in VVs pathogenesis.

Association of polymorphisms near the FOXC2 gene with the risk of varicose veins in ethnic Russians.

Objective To investigate the association of polymorphisms located near the FOXC2 gene with the risk of varicose veins in ethnic Russians. Methods Allele, genotype, and haplotype frequencies were determined in the sample of 474 patients with primary varicose veins and in the control group of 478 individuals without a history of chronic venous disease. Results Polymorphisms rs7189489, rs4633732, and rs1035550 showed the association with the increased risk of varicose veins, but none of the observed associations remained significant after correction for multiple testing. Haplotype analysis revealed the association of haplotype rs7189489 C–rs4633732 T–rs34221221 C–rs1035550 C–rs34152738 T–rs12711457 G with the increased risk of varicose veins (OR = 2.67, P = 0.01). Conclusions Our results provide evidence that the studied polymorphisms do not play a major role in susceptibility to varicose veins development in the Russian population.

Allele rs2010963 C of the VEGFA gene is associated with the decreased risk of primary varicose veins in ethnic Russians

Objective To study the association of polymorphisms rs699947, rs2010963, rs3025039 in the VEGFA gene region and rs1870377, rs2305949, rs2071559 in the VEGFR2 gene region with the risk of primary varicose veins in ethnic Russians. Methods Genotypes were determined by real-time PCR allelic discrimination. The case group consisted of 448 patients with primary varicose veins and the control group comprised 609 individuals without a history of chronic venous disease. Association was studied by logistic regression analysis. Results Allele rs2010963 C was associated with the decreased risk of varicose veins (additive model of inheritance: odds ratio = 0.73, 95% confidence interval = 0.59–0.91, P = 0.004). Conclusions Our results provide evidence that polymorphism rs2010963 located in the 5′ untranslated region of the VEGFA gene can influence genetic susceptibility to primary varicose veins in Russians. Otherwise, it can be in linkage disequilibrium with another functional single nucleotide polymorphism that can alter the level of vascular endothelial growth factor A protein.

Polymorphisms in inflammation-related genes and the risk of primary varicose veins in ethnic Russians

Inflammation was shown to be activated in varicose veins, although its role in the development of vein wall transformation remains inconclusive. We aimed to investigate the influence of 13 inflammation-related single nucleotide polymorphisms (SNPs) TNF rs1800629 and rs3093661, IL1A rs1800587, IL1RN rs4251961, IL6 rs1800795 and rs1800796, IFNG rs2430561, IL10 rs1800896, TGFB1 rs1800469, HIF1A rs11549465, NFKB1 rs28362491, and rs4648068 on the risk of primary varicose veins (PVVs) in ethnic Russians. We genotyped 709 patients with PVVs and 278 individuals without a history of chronic venous disease and performed a single SNP and a haplotype analysis. Several associations with P < 0.05 were revealed in our study. Variant allele HIF1A rs11549465 T, TNF rs3093661 A, and NFKB1 rs28362491 ATTG deletion showed the reverse association with PVV risk, and allele IL6 rs1800795 C was associated with the increased risk of the studied pathology. Haplotype analysis revealed associations of TNF haplotypes rs3093661 A-rs1800629 G and IL6 rs1800795 C-rs1800796 G with the decreased and the increased risk of PVVs, correspondingly. However, all the observed associations failed to reach statistical significance after the correction for multiple testing, which was set at a level of 10−3 due to many tests performed. Our study therefore provides evidence that investigated polymorphisms do not play a major role in susceptibility to PVVs.

Genome-wide association study in ethnic Russians suggests an association of the MHC class III genomic region with the risk of primary varicose veins

Heredity is a well-known risk factor for varicose veins, but genetic basis of this condition remains poorly studied. Our aim was to conduct a large-scale genetic association study for primary varicose veins (PVVs) in the population of ethnic Russians. An initial scan using Illumina HumanExome-12 v1.0 BeadChip was performed for 273 patients with PVVs and 250 controls without a history of chronic venous disease and other venous disorders. After quality control and removal of monomorphic markers, 25,424 common and 48,232 rare variants were included in the analysis. 42 single nucleotide polymorphisms (SNPs) were genotyped in the independent replication cohort of 447 PVVs patients and 443 controls. Association of common variants with PVVs was investigated by logistic regression, and the impact of rare variants was analyzed using sequence kernel association test. No effect of low frequency alleles has been revealed in our study. Common variant analysis identified a promising signal at chromosome 6 within classical major histocompatibility complex (MHC) class III subregion. The most strongly associated SNP in a combined analysis that reached a suggestive significance level of 3.2e-05 was polymorphism rs4151657 in the complement factor B gene. Testing for potential pleiotropy with other traits indicated that the same causal variant in this region increases the risk of rheumatoid arthritis and has a negative impact on human height. Our results provide suggestive evidence for the involvement of the MHC class III genes in the pathogenesis of PVVs. Further independent studies are needed to confirm our pilot findings.

Correction to: Polymorphisms of genes involved in inflammation and blood vessel development influence the risk of varicose veins

Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Theoretical and Applied Functional Genomics Laboratory, Novosibirsk State University, Novosibirsk, Russia Laboratory of Recombination and Segregation Analysis, Institute of Cytology and Genetics, Theoretical and Applied Functional Genomics Laboratory, Novosibirsk State University, Novosibirsk, Russia Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Department of Fundamental Medicine, Novosibirsk State University, Novosibirsk, Russia Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Department of Natural Sciences, Novosibirsk State University, Novosibirsk, Russia Department of Faculty Surgery, Pirogov Russian National Research Medical University, Moscow, Russia Private Surgery Center “Medalp”, Saint Petersburg, Russia Department of Faculty Surgery, Pirogov Russian National Research Medical University, Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russia Correspondence: Alexandra Shadrina, Laboratory of Pharmacogenomics, Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentjev Avenue, Novosibirsk 630090, Russia. Email: weiner.alexserg@gmail.com Funding information Russian Science Foundation

Polymorphisms in the MTHFR and MTR genes and the risk of varicose veins in ethnical Russians.

Abstract Objectives: The objective of this study was to study the association of polymorphisms MTHFR C677T (rs1801133) and MTR A2756G (rs1805087) with the risk of varicose veins in ethnical Russians. Methods: We genotyped 475 patients with varicose veins, 168 individual without chronic venous disease, and the population-based group of 896 subjects. Association was studied using logistic regression analysis adopting co-dominant, additive, recessive, and dominant models of inheritance. Results: None of the polymorphisms showed a statistically significant association with the risk of varicose veins. Conclusions: Our results provide evidence that the studied polymorphisms do not contribute to genetic susceptibility to varicose veins in ethnical Russians.