Forkhead box C2 promoter variant c.-512C>T is associated with increased susceptibility to chronic venous diseases
| Autor: | Kalpana S. Ramegowda, Ravikumar B. Lakkappa, Giridhar Kamalapurkar, Athira Girijamma, Sumi Surendran, Divya H. Nair, Chandrasekharan C Kartha, Jissa Vinoda Thulaseedharan, Radhakrishnan Nair |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Pathology lcsh:Medicine Cardiovascular Exon Molecular cell biology Gene Frequency Nucleic Acids Genotype Gene expression Genome Sequencing Promoter Regions Genetic lcsh:Science Peripheral Vascular Diseases Multidisciplinary Forkhead Transcription Factors Genomics Middle Aged Functional Genomics medicine.anatomical_structure Medicine Female Disease Susceptibility medicine.symptom FOXC2 Research Article Adult medicine.medical_specialty Adolescent Clinical Research Design DNA transcription Biology Veins Molecular Genetics Young Adult Vascular Biology Varicose veins medicine Genetics Humans Gene Regulation Vascular Diseases Vein HEY2 Gene Genetic Association Studies Polymorphism Genetic lcsh:R Genetic Variation Human Genetics DNA Molecular biology Case-Control Studies Genetics of Disease Chronic Disease biology.protein lcsh:Q Gene Function |
| Zdroj: | PLoS ONE, Vol 9, Iss 3, p e90682 (2014) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Chronic venous disease (CVD) is one of the most prevalent yet underrated disorders worldwide. High heritability estimates of CVD indicate prominent genetic components in its etiology and pathology. Mutations in human forkhead box C2 (FoxC2) gene are strongly associated with valve failure in saphenous and deep veins of lower extremities. We explored the association of genetic variants of FoxC2 as well as FoxC2 mRNA and protein expression levels with CVD of lower limbs. We systematically sequenced the single coding exon, 5′ and 3′ flanking regions of FoxC2 gene in 754 study subjects which includes 382 patients with CVD and 372 healthy subjects. Four novel and three reported polymorphisms were identified in our cohort. Three variants in 5′ flanking region and one in 3′ flanking region of FoxC2 gene were significantly associated with CVD risk. FoxC2 mRNA in vein tissues from 22 patients was 4±1.42 fold increased compared to saphenous veins from 20 normal subjects (pT (rs34221221: C>T) variant which is located in the FoxC2 putative promoter region was further analyzed. Functional analysis of c.-512C>T revealed increased mRNA and protein expression in patients with homozygous TT genotype compared to heterozygous CT and wild CC genotypes. Luciferase assay indicated higher transcriptional activity of mutant compared to wild genotype of this variant. These findings suggested that c.-512C>T variant of FoxC2 was strongly associated with susceptibility to CVD and also that this variant resulted in FoxC2 overexpression. To obtain a mechanistic insight into the role of upregulated FoxC2 in varicosities, we overexpressed FoxC2 in venous endothelial cells and observed elevated expression of arterial markers Dll4 and Hey2 and downregulation of venous marker COUP-TFII. Our study indicates altered FoxC2-Notch signaling in saphenous vein wall remodeling in patients with varicose veins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|