Role of RAAS pathway gene polymorphisms in congenital uropathies

Abstract

Aims: To study the prevalence of gene polymorphisms of RAS pathway genes in children with Congenital Anomalies of kidney and urinary tract (CAKUT) and evaluate their role in the outcome. Material and Methods: A cross sectional study was done in 250 children (<14 yr) with CAKUT and 150 controls over a period of 3 years (2019–2021). Three diseases namely Posterior Urethral Valve (PUV), Vesicoureteric reflux (VUR) and Pelvic ureteric junction obstruction (PUJO) were selected. Polymorphism of 4 genes of RAAS pathway-AGT, AT2R, AT1R and ACE was assessed in blood samples of subjects. Polymorphism frequency was analysed with respect to clinical and radiological outcomes. Patients were followed over a period of 1 year to evaluate the role of gene polymorphisms in disease progression. Results: While comparing the polymorphism frequencies in cases and controls, we found that disease alleles of all 4 genes were over represented in the case group and significant association was seen with 2 genes-AT2R (p = 0.03) and AT1R (p = 0.02). Multivariate analysis showed that odds of getting CAKUT were higher with following genotypes namely ACE DD (+0.5 times), AT2R (+0.4 times), AT1R AC (+1.6 times) and AGT CC (=0.6 times). Progressive deteriorators formed 22% of the cases, more seen in PUV patients. Sub group analysis of progressive deteriorators showed that AT2R G allele and ACE DD allele increased the odds of progressive deterioration by 7 and 14 times respectively. Cumulative effect of pathogenic alleles of different RAS genes showed that co existence of DD alleles with other alleles had the most serious outcomes, thus raising the possibility of synergism like a ‘second hit’. Conclusion: Almost 1/4th of children with CAKUT deteriorated despite getting the adequate treatment. Our studies found significant association of ACE and AT2R gene polymorphisms with incidence and progression of congenital uropathies.