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    • Log linear analysis between genotype and complications indic

    2018-10-23

    Log-linear analysis between the full report and complications indicates that only c.1298A>C was significantly associated with congestive disease (CEAP C3–6, Fig. 2c, Suppl. Tables 3 and 7, p<0.01). No other significant associations between genotype and complications were recorded although visual inspection suggests a general relationship between mutant genotypes at both polymorphisms and complicated disease and in particular with recurrent disease (Fig. 2d, Suppl. Figs. 2–4). Notably, more patients with junctional type recurrence, mimicking trunk type morphology, presented with c.677C>T mutant genotype compared to those with perforator type recurrence predominantly presenting with mutant c.1298A>C (Suppl. Table 8). A further interaction between varicothrombosis and wildtype genotype, heterozygosity or homozygosity at c.677C>T was suggested (Fig. 2d, Suppl. Fig. 5). Finally, there appeared to be a significant association between recurrence and varicothrombosis (p=0.033), as well as between congestive disease and varicothrombosis (p=0.015) irrespective of genotype. The relationships and genotypes are summarized in Table 3.
    Discussion In this study, we differentially attributed varying morphological presentations and clinical phenotypes of primary varicose vein disorder to the genotypes at MTHFR polymorphisms c.677C>T and c.1298A>C. The axial trunk type morphology was almost exclusively associated with heterozygosity or homozygosity at c.677C>T, the perforator type morphology with heterozygosity or homozygosity at c.1298A>C and in particular double heterozygosity CTAC at c.677C>T and c.1298A>C with the combined trunk and perforator phenotypes. The association of mutant genotype at c.1298A>C (Table 2, Fig. 2c) with congestive disease was statistically highly significant. The visual association of junctional and perforator type recurrence with mutant genotypes at c.677C>T and c.1298A>C (Fig. 2d, Suppl. Fig. 3, Suppl. Table 8), respectively (although not statistically significant due to small sample size and combined consideration), further indicates a distinct genetic nature in recurrent disease. Finally, a comparable distribution of trunk varices among wildtype, heterozygous or homozygous genotypes at c.677C>T (Fig. 2d, Suppl. Fig. 5) suggests a stochastic origin of varicothrombosis in patients with trunk type morphology. The origin of complicated disease may thus be further linked to specific mutant genotypes at MTHFR (Suppl. Fig. 4; accordingly, however, not statistically significant too at combined consideration), but the detection of further statistically significant differences was precluded due to small sample size and constraints of the statistical methods used. The c.677C>T polymorphism leads to an alanine to valine substitution at codon position 222 (p.Ala222Val) in the presumed catalytic domain of the MTHFR protein, whereas the c.1298A>C polymorphism results in a glutamate to alanine in substitution at codon position 429 (p.Glu429Ala) within the predicted C-terminal regulatory domain of the MTHFR protein (Van der Put et al., 1998). Associations with the MTHFR polymorphisms c.677C>T and c.1298A>C have been reported in arterial occlusive disease (Ilhan et al., 2008), neural tube defects (Van der Put et al., 1998) and late occurrence of colon cancer (Fernández-Peralta et al., 2010). The molecular origins of these associations are unknown and possible associations with complicated phenotypes have not been described. The reduced enzyme activity of the MTHFR polymorphisms c.677C>T and c.1298A>C has been further linked to decreased DNA methylation (Castro et al., 2004) and hyperhomocysteinemia (Sam et al., 2003). Decreased DNA methylation may involve aberrant expression of structural and matrix proteins or reduced DNA integrity resulting in premature aging of venous tissue as essential step within the pathogenesis of primary varicose veins. The complete absence of individuals with a double homozygous TTCC genotype, however, supports a complementary role of both polymorphisms, c.677C>T and c.1298A>C, of MTHFR. Yet, we expect other genetic events to be involved in the pathogenesis of primary varicose veins.