**7. Genetic polymorphism and the risk of cancer and thrombosis**

Identifying PLA2R antibodies has not yet changed our approach for excluding secondary causes for membranous nephropathy. KDIGO recommendations include performing a secondary work up to rule out autoimmune conditions, infections, and malignancies [47]. Recently with the use of laser microdissection and mass spectrometry, NELL1 antigen has shown an association with cancers [14]. Genotyping by Polymerase chain reaction has shown an association between specific gene polymorphism and cancers, and progression to end-stage renal disease. In one study investigators sub-classified patients with urokinase plasminogen activator polymorphism (Gene 3'-UTR) into groups based on their allele distribution either C/C or C/T. Although the number of patients was significantly higher in the CC group, patients with T/C genotype had a better trend towards renal survival and lower cancer incidence [48]. It should be noted that this gene polymorphism was not different from the control group.

A plasminogen activator inhibitor 1 gene polymorphism was examined to assess for correlation with disease activity, treatment response, and long-term prognosis [49]. Patients carrying 5G/5G genotype were more likely to attain complete remission, whereas 4G/4G and 4G/5G were more likely to develop renal disease progression, and 4G/4G showing no signs of remission. Patients carrying the 4G allele (4G/4G or 4G/5G) were more likely to develop coronary artery disease and peripheral vascular disease in comparison to carriers of the 5G allele, which was in line with another meta-analysis that showed a high risk of myocardial infarction in plasminogen activator inhibitor 1 4G/5G carriers [50]. It should be noted that in the former study, gene polymorphism was not different between membranous nephropathy patients and controls. Moreover, the number of patients carrying 4G allele was almost double that for 5G allele. These studies are single-center studies

and need validation through well-designed multi-center trials to establish the relationship between polymorphism and disease outcomes. The framework of bio registries can help to validate the significance of these studies.
