Leiomyoma and the importance of genetic variation on genes related to the vasculature system - CβS, MTHFR, NOS3, CYBA, and ACE1

Objective: The link between the systemic vasculature system and tumor biology is here investigated by studying the contribution of CβS (844ins68), MTHFR (677C > T), NOS3 (4a/4b), CYBA (C242T), and ACE1 (I/D) genes to leiomyoma onset, uterus and leiomyoma volumes. Methods: DNA samples from 130 women with leiomyomas and 527 from healthy women were genotyped by PCR or PCR-RFLP. Qui-square (χ2) or Fisher's exact test were used to test associations. All the mentioned tests were performed in IBM® SPSS® Statistics Version 28. Statistical significance was defined as a p-value < 0.05. Results: Results revealed that CβS (in the codominant and allelic models, p = 0.044 and, p = 0.015, OR = 1.791 [1.114–2.879], respectively), MTHFR (in the codominant, allelic and dominant models, p = 0.009, p = 0.002, OR = 0.585 [0.416–0.824] and p = 0.003, OR = 0.527 [0.346–0.802], respectively) and ACE1 (dominant model, p = 0.045, OR = 0.639 [0.411–0.992]) genes are associated with leiomyoma onset. NOS3 4a4a genotype is associated with a lower uterus volume (p = 0.004). This study also uncovers intriguing epistatic interactions among some genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the CC genotype (MTHFR) and (+/+) (CβS; p = 0.003), 4b4b (NOS3; p = 0.006, OR = 2.050 [1.223–3.439]) or DD (ACE1; p < 0.001, OR = 2.362 [1.438–3.880]) were shown to be associated with the disease, while 4a presence (NOS3) in epistasis with I presence (ACE1), increased the effect protection having just the I allele presence (p = 0.029, OR = 0.446 [0.214–0.930]). Conclusions: We conclude that variation in genes related to the systemic vascular system can play a role in the onset and development of leiomyoma.