A variant of the castor zinc finger 1 (CASZ1) gene is differentially associated with the clinical classification of chronic venous disease

Abstract

Recent reports have suggested a reproducible association between the rs11121615 SNP, located within an intron of the castor zinc finger 1 (CASZ1) gene, and varicose veins. This study aimed to determine if this variant is also differentially associated with the various clinical classifications of chronic venous disease (CVD). The rs11121615 SNP was genotyped in two independent cohorts from New Zealand (n = 1876 controls /1606 CVD cases) and the Netherlands (n = 1626/2966). Participants were clinically assessed using well-established CVD criteria. The association between the rs11121615 C-allele and varicose veins was validated in both cohorts. This was strongest in those with higher clinical severity classes and was not significant in those with non-varicose vein CVD. Functional analysis of the rs11121615 variant demonstrated that the risk allele was associated with increased enhancer activity. This study demonstrates that the CASZ1 gene associated C-allele of rs11121615 has a significant, reproducible, association with CVD (CEAP C ≥ 2 meta-odds ratio 1.31, 95% CI 1.27–1.34, P = 1 × 10−98, PHet = 0.25), but not with non-varicose vein (CEAP C1, telangiectasia or reticular veins) forms of venous disease. The effect size of this association therefore appears to be susceptible to influence by phenotypic heterogeneity, particularly if a cohort includes a large number of cases with lower severity CVD.

Mutations in EPHB4 cause human venous valve aplasia

“…(11,57,58) Delineating the roles of the various genes implicated in VV pathogenesis is important and may lead to novel therapies, which could be targeted towards patients at risk of deterioration to chronic ulceration. (59) In this study we have identified a striking 'boundary' in the endothelial expression of Efnb2 at the site of developing VVs (meaning a demarcation between ephrinB2 lo upstream cells and ephrinB2 hi VFCs and cells immediately downstream), and that both ephrinB2 and EphB4 are required for normal organization of VFCs at this critical stage of development in mice. Since ephrinB2 remains the only known ligand for EphB4, this leads us to speculate that an ephrinB2-EphB4 interaction within venous endothelia regulates VV formation.…”

“…The extent of overlap of the genetic causes of VV failure and varicose veins is unclear since regulation of VVs is understudied, but some important indications of similarity have already emerged, including the identification of PPP3R1 and PIEZO1 in genome-wide association studies of varicose veins, and in mice as critical regulators of VV development ( 11 , 57 , 58 ). Delineating the roles of the various genes implicated in VV pathogenesis is important and may lead to novel therapies, which could be targeted toward patients at risk of deterioration to chronic ulceration ( 59 )…”

Genome-wide association study of varicose veins identifies a protective missense variant in GJD3 enriched in the Finnish population

“…Yet the fact that rs11121615-T ( CASZ1 lead SNP) is the most significantly associated variant in the FinnGen data, indicates that the VV cases are not at least substantially confounded by the least severe form of VV, i.e. telangiectasia or reticular veins (C1 on the CEAP classification system 65 ), as earlier studies have observed this CASZ1 variant is not associated with these forms of venous disease 66 . The average age at the end of follow-up for VV controls was 12.2 and 10.7 years higher than the sex-specific VV diagnosis age for females and males (Supplementary Data 9 ).…”

Role of the CASZ1 transcription factor in tissue development and disease

“…CASZ1 and its related genes may promote the occurrence of stroke, which is of great significance for the treatment and prevention of stroke [90]. There is a reproducible association between rs11121615 SNP, located within an intron of CASZ1 gene, and chronic venous disease (CVD) [91][92][93]. In addition, the mutation frequency of SNPs rs10511083 of CASZ1 gene was significantly correlated with psoriasis [94].…”