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

Alexandra Shadrina; Yakov Tsepilov; Ekaterina Sokolova; Mariya Smetanina; Elena Voronina; Eugene Pakhomov; Kseniya Sevost'ianova; Andrey Shevela; Evgeny Ilyukhin; Evgeny Seliverstov; Igor Zolotukhin; Maxim Filipenko

doi:10.1016/j.gene.2018.03.039

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

Gene. 2018 Jun 15:659:93-99. doi: 10.1016/j.gene.2018.03.039. Epub 2018 Mar 15.

Affiliations

¹ Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentjev Avenue, Novosibirsk 630090, Russia; Novosibirsk State University, 2 Pirogova street, Novosibirsk 630090, Russia. Electronic address: [email protected].
² Institute of Cytology and Genetics, 10 Lavrentjev Avenue, Novosibirsk 630090, Russia; Novosibirsk State University, 2 Pirogova street, Novosibirsk 630090, Russia.
³ Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentjev Avenue, Novosibirsk 630090, Russia; Novosibirsk State University, 2 Pirogova street, Novosibirsk 630090, Russia.
⁴ Novosibirsk State University, 2 Pirogova street, Novosibirsk 630090, Russia.
⁵ Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentjev Avenue, Novosibirsk 630090, Russia.
⁶ Private Surgery Center "Medalp", 54 Leningradskaya street, Saint Petersburg 197758, Russia.
⁷ Pirogov Russian National Research Medical University, 1 Ostrovitianova street, Moscow 117997, Russia.
⁸ Institute of Chemical Biology and Fundamental Medicine, 8 Lavrentjev Avenue, Novosibirsk 630090, Russia; Pirogov Russian National Research Medical University, 1 Ostrovitianova street, Moscow 117997, Russia.

PMID: 29551506
DOI: 10.1016/j.gene.2018.03.039

Abstract

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.

Keywords: Association; Genetics; Russians; Varicose veins.

MeSH terms

Adult
Aged
Aged, 80 and over
Case-Control Studies
Chromosomes, Human, Pair 6 / genetics*
Cohort Studies
Female
Genetic Predisposition to Disease
Genome-Wide Association Study / methods*
Humans
Logistic Models
Major Histocompatibility Complex*
Male
Middle Aged
Pilot Projects
Russia / ethnology
Sequence Analysis, DNA / methods*
Varicose Veins / genetics*
Young Adult