**8. Genetic polymorphism on TLR, MYH9, NF-**κ**B, and IRF4**

The toll-like receptor expressed on the surface of the macrophage plays an important role in the link between innate immunity and adaptive immunity. TLR recognizes microbes leading to activation of downstream signals that result in the production of INF gamma. It is speculated that the association of TLR9 in membranous nephropathy might explain why and how infections can trigger the occurrence of membranous nephropathy. In a previous study, overexpression of TLR in the renal tissues was confirmed in lupus nephritis [51]. The same idea was tested in an Asian study to identify the link between TLR9 and the incidence of membranous nephropathy. Genotyping for TLR9 found a statistically significant difference between AA and GG genotypes on two specific SNPs loci on TLR9 when compared to controls [52]. Although the incidence of tubulointerstitial fibrosis was higher in the A-G haplotype when compared to the non-A-G haplotype, survival did not differ between the two groups. Another study investigated the association between membranous nephropathy and TLR4 specific gene polymorphism and found a statistically significant difference between A/G TLR4 genotype in membranous nephropathy and control, and no difference in haplotype frequency [53]. These observations suggest a possible association between membranous nephropathy and TLR4/9.

Myosin heavy chain 9 (MYH9) is expressed on most of the tissues that participate in the process of cell division and migration. Mutation in MYH9 was found to be associated with many renal diseases [54]. A difference in specific gene pleomorphism on MYH9 between membranous nephropathy and control was found [55]. On haplotype frequency, C-A was the common haplotype in membranous nephropathy and that was significantly different from controls.

NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a complex protein that controls cytokine production and plays a key role in regulating the immune response to infection.

The most abundant SNP (rs230540) found on the NKFB1 locus was predicted to have a functional impact on specific immune cells. Investigators have found that the previously mentioned SNP locus is associated with higher mRNA expression of NFKB1 in whole blood [34, 56]. Coinciding with the NFKB1 pro-inflammatory effect, another UK study has found that membranous nephropathy risk haplotype at this same locus has shown a higher leucocyte signal [57]. Another SNP locus (rs9405192) on IRF4 has shown a major role in innate immunity activation. IRF4 IS A lymphocytic gene that regulates toll-like receptor activation signaling, which is under the control of NFKB1 complex [58]. This highlights that certain loci on NFKB1 and IRF4 play a crucial role in the underlying membranous nephropathy pathophysiology at the cellular pathway level.

#### **9. Conclusion**

The heterogenicity of clinical phenotypes and outcomes in membranous nephropathy could be related to the underlying complex molecular, cellular, and biological pathways. Both genomic and proteomic analysis are becoming widely available tools to interrogate these possibilities. Membranous nephropathy being

#### *Unraveling Primary Membranous Nephropathy Using Proteogenomic Studies DOI: http://dx.doi.org/10.5772/intechopen.97622*

an autoimmune condition, requires identification of potential antigenic peptides at the podocyte, glomerular capillaries, and basement membrane levels. The proteogenomic analysis will help reveal downstream pathways that arise from the interaction between these genes, which can occur either at the glomerular level or in the immune system pathway. Hence, understanding the pathophysiology and the close interaction between various arms of the immune system and ancillary pathways is crucial for future targeted therapy in membranous nephropathy.

Laser microdissection and mass spectrometry will likely be crucial in revealing the link between the antibody subtypes and newly discovered glomerular antigens, and the three different complement pathways. Even though the classical pathway does not play a major role, some evidence has shed the light on its involvement. Thus, further investigations into types of complement activation with targets at the molecular level should be an area for future research.

The advent of proteogenomic analysis has shown a link between HLA and PLA2R antigen, but evidence for the link with THSD7A and other antigens is yet to be discovered. Also, the correlation between HLA and disease outcome is another area of interest that might further aid our future choice for immunosuppression treatment. A well-designed trial is required to correlate that link with disease outcome and treatment response.

Identifying certain high-risk alleles in patients with urokinase plasminogen activator gene polymorphism and plasminogen inhibitor activator 1 pleomorphism, has shown a probable association with cancers, thrombosis, disease progression, and remission response. This might pave the way for future discovery of certain genes that can identify cancer as a trigger for membranous nephropathy even if it would occur years after diagnosis. Also, can help with identifying patients who are more prone to venous thromboembolism and would benefit from anticoagulation. Moreover, patients who are more liable for disease progression can benefit from early immunosuppression treatment without the need for a period of watchful wait on RASS inhibition compared to other patients who might attain complete remission without the need for aggressive immunosuppression therapy.

Hence, the proteogenomic analysis is the way forward for identifying targeted immunosuppression therapy for membranous nephropathy in the era of precision medicine.

### **Author details**

Omar Ragy\*, Patrick Hamilton and Durga Kanigicherla Manchester Royal infirmary, Manchester, UK

\*Address all correspondence to: omarragy85@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
