**6. Genetic polymorphism other location than HLA alleles and PLA2R1 antigens**

In addition to the previously mentioned HLA alleles and PLA2R1 polymorphism, many other genes were discovered to be linked with primary membranous nephropathy. It has been shown that TH2 cells are predominant in primary membranous nephropathy due to the presence of IgG4, which belongs to type 2 immune response [43]. TH2 cells are responsible for the secretion of IL4, IL 10, and TNF **α** as major cytokines. These cytokines can enhance the expression of the HLA molecule and lead to disease pathogenesis.

In a case–control study, TNF**α** and TNFd genotypes belonging to MHC class III were associated with primary membranous nephropathy [44]. It was noted in this study that for that association to occur, the underlying HLA was B8/DR3/DQ2. The influence of TNF **α** gene polymorphism on disease progression was not present for either of the TNF genotypes separately or in combination. The importance of TNF in clinical practice was examined in a small study of 10 patients who did not respond to maximum RAS blockade. Pentoxifylline is a phosphodiesterase inhibitor that is capable of lowering TNF **α** levels were used, and patients were followed up for 6 months. 9 out of 10 patients achieved remission with TNF **α** levels trending down in both plasma and urine [45].

Another study showed an association between specific IL4 and IL10 genotypes and membranous nephropathy [46]. This raises a particular question for future studies using interleukin inhibitors in membranous nephropathy.
