Margret Chandira Rajappa^*, Karthikeyan Muthumani, John Kennedy Mariya Soosai, Vignesh Vezhaventhan, Gracy Gladin Solomon , Sanjay Gnanamoorthi and Ranjithkumar Sivaji

Department of Pharmaceutics, Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation, (Deemed to be University) Yercaud main road, Salem

Corresponding Author e-mail: mchandira172@gmail.com

Abstract

Genetic testing has significantly changed our understanding and treatment of systemic lupus erythematosus (SLE), particularly its severe manifestation, lupus nephritis (LN). Nephrology faces great difficulty with LN, which is characterized by severe inflammation and kidney damage. To create individualized treatments, it is essential to identify the genetic variables that influence the LN susceptibility and progression. This review highlights the importance of genetic testing in diagnosing and managing LN, covering genetic predispositions, common markers, the role of ethnicity, specific renal genes, and epigenetic factors. Key genetic markers such as HLA-DRB1, ITGAM, FCGR2A, and IRF5 have been linked to LN, impacting immune regulation and disease progression. Asians, African Americans, and Hispanics have greater prevalence rates of genetic susceptibility than Caucasians, suggesting that ethnicity plays a major role in genetic vulnerability. Genes like APOL1, PDGFRA, and HAS2 play vital roles in renal function and fibrosis, affecting disease outcomes. New treatment targets are provided by epigenetic mechanisms that control gene expression in LN, such as DNA methylation and histone alterations. The progress made in genome-wide association studies (GWAS) has led to the discovery of new genetic loci linked to LN, which has improved our knowledge of its pathogenesis. This review highlights the critical role of genetic testing in LN, emphasizing its potential to improve diagnosis, treatment, and patient outcomes through personalized medicine.

Keywords

Autoimmune Disease; Genetic markers; Kidney Inflammation; Lupus Nephritis; Personalized Medicine; Targeted therapy

Copy the following to cite this article: Rajappa M. C, Muthumani K, Soosai J. K. M, Vezhaventhan V, Solomon G. G, Gnanamoorthi S, Sivaji R. Reviewing Genetic Testing for Lupus: Implications for Nephritis. Biomed Pharmacol J 2024;17(3).

Copy the following to cite this URL: Rajappa M. C, Muthumani K, Soosai J. K. M, Vezhaventhan V, Solomon G. G, Gnanamoorthi S, Sivaji R. Reviewing Genetic Testing for Lupus: Implications for Nephritis. Biomed Pharmacol J 2024;17(3). Available from: https://bit.ly/3XczLJh

Introduction

In recent years, genetic testing for lupus has emerged as a critical tool in understanding and managing this complex autoimmune disease, particularly in its severe form, lupus nephritis. Lupus nephritis, characterized by significant inflammation and damage to the kidneys, poses a considerable challenge in the field of rheumatology and nephrology. It is critical to identify the genetic components of the lupus susceptibility and development, especially the inherited lupus predisposition¹. This leap forward has not only enhanced our comprehension of the disease’s intricate nature but also opened new avenues for personalized treatment strategies, thereby shedding light on the profound implications that genetic insights hold for affected individuals.

This article delves into the critical role of genetic testing in the diagnosis and management of lupus nephritis. It will cover an array of pertinent topics, including an overview of lupus nephritis, genetic factors predisposing to this condition, common genetic markers, the impact of ethnicity on genetic predisposition, and specific genes related to renal function. Furthermore, the discussion will extend to epigenetic factors that influence the disease and the practical implications these genetic findings have for developing future therapeutic approaches². This paper attempts to provide important insights into how genetic testing for lupus has emerged as a key component in the battle against this severe illness and how it opens the door to novel treatments by giving a thorough overview of these fields of study.

Overview of Lupus Nephritis

An autoimmune condition called systemic lupus erythematosus (SLE), in which the body’s immune system targets its own cells and organs, may trigger lupus nephritis, a severe kind of kidney disease. As this illness worsens, it may eventually result in renal failure, which would require dialysis treatment or a kidney transplant to stay alive. The prevalence of kidney disease in individuals with lupus is significant. In adults diagnosed with lupus, up to 50% may develop kidney disease, and this figure rises to 80% among children with lupus. It is also more frequent in men than in women to have lupus nephritis³.

Symptoms of lupus nephritis can vary but often include foamy urine and edema-swelling typically in the legs, feet, or ankles due to excess fluid in the body. High blood pressure is another common symptom associated with the condition. The onset of kidney issues frequently coincides with other lupus symptoms such as joint pain, muscle pain, unexplained fever, and a distinctive red rash across the nose and cheeks, often referred to as a butterfly rash ⁴.

A kidney biopsy confirms the diagnosis of lupus nephritis, which is made by blood and urine testing. This biopsy helps determine the extent of the disease and guides the treatment plan. Treatment primarily focuses on suppressing the immune system to prevent it from attacking the kidneys. Medications used may include ACE inhibitors, ARBs, diuretics, beta blockers, and calcium channel blockers to manage blood pressure⁵.

Kidney failure is a tragic prospect for ten to thirty per cent of those with lupus nephritis. The most severe form, known as diffuse proliferative nephritis, can lead to permanent scarring in the kidneys, with kidney function declining as more scars form. Prompt diagnosis and treatment are essential for averting permanent harm. Patients with lupus nephritis also face a higher risk of developing other serious health issues, including cancer, particularly B-cell lymphoma, and cardiovascular problems. This highlights the importance of comprehensive management and monitoring of the condition to mitigate these risks ⁶.

Genetic Factors Predisposing to Lupus Nephritis

In Historical Perspective

Up to 74% of people with systemic lupus erythematosus develop lupus nephritis, a severe clinical consequence. This condition is notably prevalent among ethnic minorities and contributes to considerable morbidity and mortality. Research indicates a strong genetic component in the development of SLE and, consequently, LN. Studies involving monozygotic twins show a concordance rate for SLE between 24%-35%, starkly higher than the 2%-5% observed in dizygotic twins. Furthermore, compared to fewer than 1% of controls, 10%–12% of patients with SLE have first- or second-degree biological relatives who also have the condition, according to familial aggregation studies⁷. These findings highlight the genetic susceptibility to both LN and SLE, which is further supported by the fact that African Americans with LN have end-stage renal illness in families, as well as several linkage studies.

Historically, the research on LN genetics has lagged behind that of SLE. The lack of a large-scale genome-wide association study (GWAS) that focuses only on LN to date is a reflection of the pre-GWAS era’s emphasis and the variable strength of genetic connections between various studies and populations. But current initiatives seek to combine available genome-wide association data to do strong meta-analyses for both LN and SLE, which could yield important insights into the genetic foundations of both illnesses, particularly with regard to ethnic heterogeneity⁸.

Recent Discoveries

Recent advances in genetic research have begun to elucidate the specific genetic factors contributing to lupus nephritis. Significantly influencing the likelihood of getting LN are a number of new genetic loci that have been found by genome-wide association studies. These discoveries offer new insights into the pathogenesis of LN and highlight the polygenic nature of this autoimmune complication⁹.

Major Histocompatibility Complex (MHC) class II genes, such as HLA-DRB1, have been identified as key genetic indicators. These genes are highly linked to LN and SLE. The development of SLE and nephritis caused by lupus is also significantly influenced by deficits in C2 and C4, as well as complement genes such as C1Q, C1R, and C1S. Furthermore, Fcγ receptor genes, which mediate the binding of IgG-containing immune complexes to phagocytes, have variants like FcγRIIa and FcγRIIIa that are associated with the disease in specific ethnic groups.

The role of cytokine and apoptosis genes is also significant. Variants in the IL10 and TNFAIP3 genes affect the inflammatory response and the survival of autoreactive B cells, contributing to the disease’s progression. Moreover, polymorphisms in genes related to the clearance of apoptotic cells, such as DNASE1 and the autophagy-related ATG5, have been linked to lupus nephritis, influencing the body’s ability to manage cell debris and immune responses¹⁰.

These genetic insights are not only pivotal for understanding the disease mechanism but also for developing targeted therapies that could modulate these genetic pathways to treat or even prevent lupus nephritis in genetically predisposed individuals.

Common Genetic Markers in Lupus Nephritis

HLA-DR

The HLA-DR gene, particularly HLA-DRB1, is a crucial susceptibility gene in the pathogenesis of systemic lupus erythematosus and lupus nephritis. It has been found that alleles such as HLA-DRB1*04 are significantly associated with renal disorders in patients with SLE¹¹. The immune system’s reaction, especially the activation of CD4+ T cells, depends on the HLA Class II region, which comprises HLA-DR, HLA-DQ, and HLA-DP¹².

ITGAM

The ITGAM gene encodes for CD11b, a part of the integrin alpha M beta-2, which is crucial in mediating phagocytosis and adherence to the vascular endothelium. Genetic variants in ITGAM, like the non-synonymous SNP rs1143679, result in functional changes that can reduce phagocytosis efficiency and alter inflammatory responses, thus affecting susceptibility to SLE and LN¹³.

FCGR

The FCGR gene locus includes genes that encode for Fc gamma receptors, which are critical in clearing immune complexes from the body. Variants in these genes, such as FCGR2A and FCGR3A, have been associated with systemic lupus erythematosus and lupus nephritis. These variants can affect the binding and clearance of immune complexes, influencing disease progression¹⁴.

IRF5

A transcription factor known as IRF5 is important for controlling immune system and virus-mediated stimulation of interferon. IRF5 variants are specifically connected to severe types of lupus nephritis and have been linked to an increased risk of SLE. Type I interferon and other inflammatory mediators can be produced in response to changes in IRF5 expression levels¹⁵.

TNIP1

TNIP1 interacts with the ubiquitin-editing enzyme A20 to regulate inflammatory responses through NF-kappaB signaling pathways. Changes in TNIP1 levels can cause these pathways to be regulated differently, which can contribute to the pathophysiology of lupus nephritis and SLE. Polymorphisms in TNIP1 have been associated with different responses to inflammation and autoimmune activity¹⁶.

STAT4

The STAT4 gene is involved in mediating responses to cytokines and plays a role in inflammatory and autoimmune diseases. Variants in STAT4 have been linked to SLE and lupus nephritis, with associations found in multiple studies. These variants can influence the development of proliferative nephritis, a severe subtype of lupus nephritis¹⁷.

TNFSF4

The TNF Super Family 4 protein, which is encoded by TNFSF4, is essential for T cell activation and interaction with antigen-presenting cells. Genetic variants in TNFSF4 have been associated with lupus nephritis in multiple ethnic groups, influencing the immune response and disease severity¹⁸.

Table 1: Common Genetic Markers in Lupus Nephritis

Genetic Marker	Chromosome	Gene/ Region	Study Name	Year	Patient Population	Key Findings
HLA-DRB1	6p21	HLA Region	Genetic Risk Factors for Lupus Nephritis11,12	2019	Multi-ethnic	Strong association with lupus nephritis
ITGAM	16p11.2	ITGAM (CD11b)	Genetic Variants in SLE Susceptibility Loci13	2010	Chinese	Associated with increased risk of lupus nephritis
FCGR2A	1q23	FCGR2A	Genome-wide Association Study in SLE14	2016	European	Linked to susceptibility to lupus nephritis
STAT4	2q32.2	STAT4	GWAS Identifies New Risk Loci for SLE17	2021	European, African American	Associated with severe lupus nephritis
IRF5	7q32	IRF5	Genetic Risk Factors for Lupus Nephritis15	2019	Multi-ethnic	Significant association with lupus nephritis
TNFSF4	1q25	TNFSF4	Genome-wide Association Study in SLE18	2016	European	Correlated with a higher risk of developing lupus nephritis
BLK	8p23	BLK	GWAS Identifies New Risk Loci for SLE17	2021	European, African American	Linked to lupus nephritis susceptibility
PTPN22	1p13	PTPN22	Molecular Patterns in Lupus Nephritis19	2023	Global	Associated with increased risk of lupus nephritis
BANK1	4q24	BANK1	Molecular Patterns in Lupus Nephritis19	2023	Global	Linked to the severity of lupus nephritis
APOL1	22q12.3	APOL1	GWAS Identifies New Risk Loci for SLE17,20	2021	African American	Associated with higher risk and severity of nephritis

Ethnicity and Genetic Predisposition

African Ancestry

Compared to people of European heritage, African Americans, East Asians, and Hispanics with systemic lupus erythematosus are more prone to develop lupus nephritis. Genetic ancestry, which defines the original population groups from which an individual is derived, has an impact on this discrepancy. Studies have shown that African ancestry contributes to a higher risk of LN, while European ancestry tends to be protective. Genetic variations such as the H131R variant of FcγRIIa and the V158F variant of FcγRIIIa have been linked to an increased risk of LN and SLE, respectively, among African Americans²¹.

Hispanic Ancestry

Hispanic populations develop SLE and its severe manifestations, including LN, at a younger age compared to their European counterparts. Genetic studies have identified specific variants that may contribute to this enhanced risk. The development of Hispanics with LN to end-stage renal disease (ESRD) has been linked to the high-binding FCGR3A-V176 variant. Additionally, genetic factors like TTC34 have been specifically associated with LN in Hispanic populations²².

Asian Ancestry

Asian patients, particularly those from East Asian backgrounds, exhibit a higher incidence of LN compared to Caucasians. The severity of LN among East Asians is comparable to that seen in African Americans, with certain manifestations like haematuria being more prevalent. The variable vulnerability to illness across various ethnic groups has been highlighted by genetic research; novel loci involving transcription factors like ETS1 and IKZF1 have been found in populations like the Chinese Han²³.

European Ancestry

Individuals of European descent generally show a lower prevalence of LN. A 10% increase in European ancestry was linked to a 15% lower risk of developing kidney illness, according to research with people who varied in their proportion of European ancestry. Common risk alleles, socioeconomic level, and other genetic ancestries had no bearing on this protective effect²⁴. Moreover, sub-stratification into North and South European groups revealed that North Europeans had a distinct risk profile for certain SLE phenotypes compared to South Europeans.

These findings highlight the complex interplay between genetic factors and ethnicity in the predisposition and manifestation of lupus nephritis, underscoring the need for personalized approaches in the management and treatment of this condition based on genetic and ethnic backgrounds²⁵.

Specific Renal Function Genes

APOL1

The human chromosome 22 APOL1 gene produces the high-density lipoprotein (HDL) component apolipoprotein L-1, which is widely distributed in the kidneys and other organs. Historically, individuals with an APOL1 variant have shown higher efficacy in lysing Trypanosomes when compared to those without the variant, as evidenced by the serum apolipoprotein L-1 from those with the variant conferring protection against the African Trypanosoma brucei rhodesiense infection²⁶. The majority of people with these variations are African Americans, most likely as a result of evolutionary pressure from infections with T. b. rhodesiense. However, the same APOL1 gene variations are linked to a higher risk of developing end-stage renal disease (ESRD) in non-diabetic nephropathy and HIV-associated nephropathy, as well as focal segmental glomerulonephritis. Additionally, Freedman showed that there is a considerably increased risk of progression to end-stage renal disease (ESRD) for African Americans with lupus nephritis who inherit the G1/G2 APOL1 risk alleles ²⁷.

PDGFRA

The alpha polypeptide of platelet-derived growth factor receptor alpha (PDGFRA) is encoded by the PDGFRA gene, which is located on the human chromosome 4, and is essential for renal health. PDGFRA and its ligand, PDGF-BB, are vital for normal kidney development and are implicated in the progression of mesangial proliferative diseases and renal interstitial fibrosis²⁸. In lupus nephritis, increased PDGFRA mRNA expression has been observed in renal tissues, suggesting its involvement in the disease’s pathogenesis. A specific variant, rs1364989, located near PDGFRA, has been strongly associated with lupus nephritis in the European population, indicating its potential role in mediating disease progression²⁹.

HAS 2

Hyaluronan synthase 2, or HAS 2, is found on human chromosome 8 and is responsible for manufacturing hyaluronan (HA), an essential substance in fibrosis in a number of organs. HA is important for renal fibrosis in lupus nephritis, which leads to chronic kidney disease and ultimately end-stage renal disease (ESRD). Research has demonstrated that renal mesangial cells react to growth stimuli and cytokines like PDGF and IL-1 beta by upregulating HAS 2 and causing HA production³⁰. Renal biopsies from individuals with active lupus nephritis have shown elevated HA levels; these observations are confirmed by research showing that anti-DNA antibodies cause IL-1 beta, which in turn causes HAS2 overexpression to cause HA synthesis. Furthermore, lupus nephritis has been strongly linked to a mutation in the HAS2 gene called rs7834765, according to genetic association studies³¹.

Table 2: Specific Renal Function Genes Linked to Lupus Nephritis

Gene Symbol	Full Gene Name	Function	Role in Lupus Nephritis	Strength of Association (Grade)	Key Studies
HLA-DRB132	Major Histocompatibility Complex, Class II, DR Beta 1	Presents peptides to T cells, which plays a vital role in the immune system	Associated with increased susceptibility to lupus nephritis due to its role in immune response modulation	Grade A – Strong association*	Graham RR; Lauwerys BR
IRF533	Interferon Regulatory Factor 5	Transcription factor involved in the induction of type I interferons and inflammatory cytokines	Variants are linked to increased risk of SLE and lupus nephritis through promotion of pro-inflammatory pathways	Grade A – Strong association*	Sigurdsson S; Graham RR
ITGAM34	Integrin Alpha M	Encodes the alpha chain of integrin molecule CR3, involved in leukocyte adhesion and migration	Variants’ involvement in immune complex clearance is linked to an increased risk of lupus nephritis	Grade B – Moderate association*	Nath SK; Maiti AK
FCGR2A14	Fc Fragment of IgG Receptor II a	Encodes a receptor for the Fc portion of IgG, involved in phagocytosis and immune complex clearance	Polymorphisms are affiliated with lupus nephritis due to altered immune complex handling	Grade B – Moderate association*	Salmon JE; Kozyrev SV
TNFSF417	Tumor Necrosis Factor Superfamily Member 4	Encodes a costimulatory molecule important for T cell activation	Variants increase susceptibility to lupus nephritis by enhancing immune cell activation and inflammation	Grade B – Moderate association*	Graham RR; Lessard CJ
APOL126,27	Apolipoprotein L1	Involved in lipid transport and associated with kidney disease	Risk alleles are highly correlated with the development of renal illness in lupus nephritis, particularly in people who are African American.	Grade A – Strong association*	Kopp JB; Freedman BI
PTPN2230	Protein Tyrosine Phosphatase, Non-Receptor Type 22	Negatively regulates T cell receptor signaling	Due to their impact on immunological tolerance, variants are linked to an increased incidence of SLE and lupus nephritis.	Grade B – Moderate association*	Criswell LA; Santiago C
BLK20	B-Lymphoid Tyrosine Kinase	Involved in B cell receptor signaling	Genetic variations are linked to increased risk of lupus nephritis through dysregulation of B cell function	Grade B – Moderate association*	Hom G; Kozyrev SV
STAT430	Signal Transducer and Activator of Transcription 4	Transcription factor involved in mediating responses to cytokines	Polymorphisms are associated with increased risk of lupus nephritis due to enhanced inflammatory signaling	Grade A – Strong association*	Remmers EF; Taylor KE
TGFBR223	Transforming Growth Factor Beta Receptor II	Mediates signaling by TGF-beta, involved in immune regulation and fibrosis	Variants may contribute to susceptibility to lupus nephritis by affecting immune regulation and renal fibrosis	Grade C – Preliminary association*	Zhao J; Lopez P

*Grade A: Strong association supported by multiple high-quality studies with consistent findings.

*Grade B: Moderate association supported by several studies, though some inconsistencies may exist.

*Grade C: Preliminary association with limited studies or mixed results.

Epigenetic Factors and Lupus Nephritis

DNA Methylation

A methyl group is added to the fifth carbon of cytosine residues in DNA methylation, a crucial epigenetic process that results in 5-methylcytosine. DNA methyltransferases including DNMT1, DNMT3A, and DNMT3B mediate this process. In lupus nephritis (LN), altered DNA methylation patterns are observed, particularly in the T cells of patients. Hypomethylation in these cells can lead to the overexpression of genes like ITGAL and TNFSF7, which are linked to disease activity. Moreover, the methylation level of immune-related genes such as CD40LG, KIR2DL4, and PRF1 influences their expression, impacting the immune response in LN³⁵.

In systemic lupus erythematosus (SLE), reduced global DNA methylation in lymphocytes corresponds with enhanced disease activity, which impacts cytokine gene expression and contributes to tissue damage. Specific cytokine genes, including IL-4 and IL-17A, are hypomethylated, leading to their increased expression in CD4+ T cells. Additionally, methylation changes in interferon-associated genes like IRF7 and MX1 have been documented, which play a role in the immune response in LN³⁶.

Histone Modification

Histone modifications, including methylation, acetylation, and phosphorylation, play a significant role in regulating gene expression in LN. Autoantibodies in SLE are directed against histone proteins, and modifications such as acetylation and methylation are particularly relevant. For example, histone H4 acetylation at lysines 8, 12, and 16, and H3 trimethylation at lysine 27, are linked to apoptosis and gene regulation processes³⁷. These modifications increase during cell apoptosis, contributing to the inflammatory response in LN.

Autoantibodies against modified histone peptides, like H4pac and H2Bpac, are specific to SLE and positively related to disease activity. In LN, patients show a higher reactivity with modified histones, indicating a strong association with renal involvement. Furthermore, epigenetic alterations such as decreased acetylation of histone H3 and increased methylation of H3K9 are observed in the T cells of SLE patients, impacting the expression of autoimmune response-related genes.

These epigenetic mechanisms are crucial for understanding the pathophysiology of LN and may provide targets for therapeutic interventions aimed at modifying these epigenetic alterations to manage or treat LN effectively³⁸.

Practical Implications and Future Therapies

Genetic Testing Studies on Lupus Nephritis

There is a significant drive to use the information available regarding genetic variations and altered immunological pathways to inform specific therapy decisions for SLE patients, given the growing interest in customized, precision medicine. There are difficulties with this kind of patient care. For instance, in uncontrolled trials, using rituximab in conjunction with B-lymphocyte depleting treatment produced a good response in patients with refractory lymphoblast necrosis, even in the absence of cyclophosphamide or steroids. Rituximab treatment may be most beneficial for LN patients who contain genetic variations within B-lymphocyte activation pathways, as the drug predominantly functions by decreasing CD20-positive B-lymphocytes. Genetic research on potential therapeutic targets in LN, such as BLyS (encoded by TNFSF13B) and TWEAK (encoded by TNFSF12), may also be beneficial for personalized therapy ³⁹.

Table 3: Genetic Testing Studies on Lupus Nephritis

Study Name	Year	Authors	Journal	Study Focus	Patient Details
Genetic Variants in SLE Susceptibility Loci39	2010	Yang, W	PLOS Genetics	Association of SLE susceptibility loci with lupus nephritis	1,306 SLE patients (Chinese descent), subgroups with and without nephritis
Genome-wide Association Study in SLE40	2016	Langefeld, C.D.	Nature Communications	Identification of new loci associated with lupus nephritis	1,206 SLE patients (European descent), focus on nephritis subtypes
Genetic Risk Factors for Lupus Nephritis41	2019	Morris, D.L.	The American Journal of Human Genetics	Genome-wide association and meta-analysis for lupus nephritis	7,219 SLE patients (multi-ethnic), detailed nephritis classification
GWAS Identifies New Risk Loci for SLE42	2021	Molineros, J.E.	Arthritis & Rheumatology	Identification of risk loci specific to lupus nephritis	4,036 SLE patients (European and African American), focused on nephritis
Molecular Patterns in Lupus Nephritis43	2023	Smith, K.G.C; Clatworthy, M.R.	Nature Reviews Nephrology	Transcriptomic and genetic profiling in lupus nephritis	2,000 SLE patients (global), detailed nephritis phenotype and outcomes

 

Targeted Treatments

The previously accepted induction-maintenance treatment method is under criticism due to the encouraging results of the trials evaluating additional treatment using voclosporin, belimumab, or obinutuzumab. Vocofloxin is a novel calcineurin inhibitor (CNI) that has as good of a metabolic profile as tacrolimus or cyclosporine, but it doesn’t require you to check your trough levels to block T-cell activity⁴⁴. As part of a multitarget therapy that also comprised mycophenolate mofetil (MMF, 2 g/day) and a rapidly tapered low-dose oral corticosteroid, the phase II AURA study evaluated voclosporin (23.7 mg or 39.5 mg, twice daily)⁴⁵. At 24 and 48 weeks, the low-dose voclosporin regimen exhibited significantly greater complete renal response rates than the placebo arm. Voclosporin (23.7 mg, twice day) added to MMF and low-dose steroids improved the efficacy of the induction regimen, as demonstrated by the phase III AURORA trial’s favourable outcomes⁴⁶.

Although there was initially less excitement for CD20+ cell depletion, following the unfavourable outcomes of the LUNAR trial, humoral immune blocking gained traction with the excellent findings of belimumab and obinutuzumab studies in proliferative lung cancer. The suppressor B-cell activating factor is belimumab, a recombinant human IgG1λ monoclonal antibody. When administered intravenously once a month for 104 months, it demonstrated effectiveness and safety as a supplemental treatment when used in conjunction with steroids and either MMF or cyclophosphamide-azathioprine regimens⁴⁷. Obintuzumab is a humanized type II anti-CD20 monoclonal antibody that causes a greater depletion of B-cells than rituximab. When compared to a standard of treatment that included MMF and steroids, Obinutuzumab, which was administered intravenously on days 1 and 14, and again after 6 months, demonstrated superiority in attaining a full renal response in the phase II NOBILITY study⁴⁸.

A deeper comprehension of the chemical and genetic origins of lupus nephritis and SLE has opened the door to the development of more effective treatments for these individuals. It may be possible to improve the therapeutic and prognosis characterization of each patient by taking into account the many extrarenal and intrarenal mechanisms that contribute to kidney-specific autoimmunity and damage.

Conclusion

Through this comprehensive exploration, we have delved into the critical role of genetic testing and the intricate web of genetic, epigenetic, and ethnic factors that may influence lupus nephritis’s sensitivity, course, and management. The discovery of numerous genetic markers and the impact of specific genetic variants underline the complexity and the personalized nature of this autoimmune disease. These findings not only offer a more profound understanding of lupus nephritis but also guide the development of targeted therapeutic strategies, highlighting the transition towards personalized medicine in managing this condition.

As we look ahead, the integration of genetic insights into clinical practice promises to revolutionize the management and treatment of lupus nephritis. The potential for personalized therapy, informed by one’s genetic makeup, paves the way for more effective, tailored treatments that can mitigate the autoimmune assault on the kidneys and improve patient outcomes. This shift towards precision medicine underscores the significance of continued research and innovation in understanding and combating lupus nephritis, reaffirming the importance of genetic testing as a cornerstone in the quest to conquer this debilitating disease.

Acknowledgment

The authors are deeply grateful to the Vinayaka Mission’s College of Pharmacy, Vinayaka Mission’s Research Foundation, for giving us the support to accomplish this work.

Conflicts of Interest

The author(s) declares no conflict of interest

Funding Source

The author(s) received no financial support for the research, authorship, and/or publication of this article

References

1. Fanouriakis A, Tziolos N, Bertsias G, Boumpas DT. Update on the diagnosis and management of systemic lupus erythematosus. Ann Rheum Dis. 2021;80(1):14-25.
   CrossRef
2.  Yeoh SA, Dias SS, Isenberg DA. Advances in systemic lupus erythematosus. Medicine (Baltimore). 2018;46(2):84-92.
   CrossRef
3. Zharkova O, Celhar T, Cravens PD, Satterthwaite AB, Fairhurst AM, Davis LS. Pathways leading to an immunological disease: systemic lupus erythematosus. Rheumatology. 2017;56(suppl_1): i55-i66.
   CrossRef
4. Mouliou DS. John Cunningham virus and progressive multifocal leukoencephalopathy: A falsely played diagnosis. Diseases. 2024;12(5):100.
   CrossRef
5. Moroni, G., Depetri, F., Ponticelli, C. Lupus nephritis: when and how often to biopsy and what does it mean? J Autoimmun. 2016; 74:27-40.
   CrossRef
6. Chen Y, Sun J, Zou K, Yang Y, Liu G. Treatment for lupus nephritis: an overview of systematic reviews and meta-analyses. Rheumatol Int. 2017 Jul; 37:1089-1099.
   CrossRef
7. Anders HJ, Saxena R, Zhao MH, et al. Lupus nephritis. Nat Rev Dis Primers. 2020;6(1):7.
   CrossRef
8. Gasparotto M, Gatto M, Binda V, Doria A, Moroni G. Lupus nephritis: clinical presentations and outcomes in the 21st century. Rheumatology (Oxford). 2020 Dec 5;59(5):v39-v51.
   CrossRef
9. Lanata CM, Nititham J, Taylor KE, et al. Genetic contributions to lupus nephritis in a multi-ethnic cohort of systemic lupus erythematosus patients. PLOS One. 2018 Jun;13(6):e0199003.
   CrossRef
10. Chen L, Wang YF, Liu L, et al. Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity. Hum Mol Genet. 2020;29(10):1745-1756.
    CrossRef
11. Selvaraja M, Chin VK, Abdullah M, et al. HLA-DRB1*04 as a risk allele to systemic lupus erythematosus and lupus nephritis in the Malay population of Malaysia. Front Med (Lausanne). 2021; 7:598665.
    CrossRef
12. Javinani A, Ashraf-Ganjouei A, Aslani S, Jamshidi A, Mahmoudi M. Exploring the etiopathogenesis of systemic lupus erythematosus: a genetic perspective. Immunogenetics. 2019;71(4):283-297.
    CrossRef
13. Khan SQ, Khan I, Gupta V. CD11b activity modulates pathogenesis of lupus nephritis. Front Med (Lausanne). 2018; 5:52.
    CrossRef
14. Iwamoto T, Niewold TB. Genetics of human lupus nephritis. Clin Immunol. 2017; 185:32-39.
    CrossRef
15. Guiteras J, Ripoll É, Bolaños N, et al. The gene silencing of IRF5 and BLYSS effectively modulates the outcome of experimental lupus nephritis. Mol Ther Nucleic Acids. 2021; 24:807-821.
    CrossRef
16. Brady MP, Korte EA, Caster DJ, Powell DW. TNIP1/ABIN1 and lupus nephritis. Lupus Sci Med. 2020 Oct;7(1): e000437.
    CrossRef
17. Guga S, Wang Y, Graham DC, Vyse TJ. A review of genetic risk in systemic lupus erythematosus. Expert Rev Clin Immunol. 2023;19(10):1247-1258.
    CrossRef
18. Imgenberg-Kreuz J, Almlöf JC, Leonard D, Alexsson A, Nordmark G, Eloranta ML, et al. DNA methylation mapping identifies gene regulatory effects in patients with systemic lupus erythematosus. Ann Rheum Dis. 2018;77(5):736-743.
    CrossRef
19. Mohan C, Zhang T, Putterman C. Pathogenic cellular and molecular mediators in lupus nephritis. Nat Rev Nephrol. 2023;19(8):491-508.
    CrossRef
20. Vinuesa CG, Shen N, Ware T. Genetics of SLE: mechanistic insights from monogenic disease and disease-associated variants. Nat Rev Nephrol. 2023;19(9):558-572.
    CrossRef
21. Davidson A. What is damaging the kidney in lupus nephritis? Nat Rev Rheumatol. 2016;12(3):143-153.
    CrossRef
22. Maningding E, Dall’Era M, Trupin L, Murphy LB, Yazdany J. Racial and ethnic differences in the prevalence and time to onset of manifestations of systemic lupus erythematosus: the California Lupus Surveillance Project. Arthritis Care Res. 2020;72(5):622-629.
    CrossRef
23. Owen KA, Grammer AC, Lipsky PE. Deconvoluting the heterogeneity of SLE: the contribution of ancestry. J Allergy Clin Immunol. 2022;149(1):12-23.
    CrossRef
24. Rees F, Doherty M, Grainge MJ, et al. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford). 2017;56(11):1945-1961.
    CrossRef
25. Gergianaki I, Fanouriakis A, Repa A, et al. Epidemiology and burden of systemic lupus erythematosus in a Southern European population: data from the community-based lupus registry of Crete, Greece. Ann Rheum Dis. 2017;76(12):1992-2000.
    CrossRef
26. Scales SJ, Gupta N, De Mazière AM, et al. Apolipoprotein L1-specific antibodies detect endogenous APOL1 inside the endoplasmic reticulum and on the plasma membrane of podocytes. J Am Soc Nephrol. 2020;31(9):2044-2064.
    CrossRef
27. Freedman BI, Langefeld CD, Andringa KK, et al. End‐stage renal disease in African Americans with lupus nephritis is associated with APOL1. Arthritis & Rheumatol. 2014;66(2):390-396.
    CrossRef
28. Chung SA, Brown EE, Williams AH, et al. Lupus nephritis susceptibility loci in women with systemic lupus erythematosus. J Am Soc Nephrol. 2014;25(12):2859-2870.
    CrossRef
29. Maria NI, Davidson A. Protecting the kidney in systemic lupus erythematosus: from diagnosis to therapy. Nat Rev Rheumatol. 2020;16(5):255-267.
    CrossRef
30. Mohan C, Putterman C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol. 2015;11(6):329-341.
    CrossRef
31. Bethunaickan R, Berthier CC, Zhang W, et al. Identification of stage‐specific genes associated with lupus nephritis and response to remission induction in (NZB× NZW) F1 and NZM2410 mice. Arthritis Rheumatol. 2014;66(8):2246-2258.
    CrossRef
32. Parikh SV, Malvar A, Song H, et al. Molecular imaging of the kidney in lupus nephritis to characterize response to treatment. Transl Res. 2017 Apr; 182:1-13.
    CrossRef
33. Hammad A, Mossad YM, Nasef N, Eid R. Interferon regulatory factor 5 gene polymorphism in Egyptian children with systemic lupus erythematosus. Lupus. 2017;26(8):871-880.
    CrossRef
34. Lee YH, Bae SC. Association between the functional ITGAM rs1143679 G/A polymorphism and systemic lupus erythematosus/lupus nephritis or rheumatoid arthritis: an update meta-analysis. Rheumatol Int. 2015;35(5):815-823.
    CrossRef
35. Teruel M, Sawalha AH. Epigenetic variability in systemic lupus erythematosus: what we learned from genome-wide DNA methylation studies. Curr Rheumatol Rep. 2017;19(6):32.
    CrossRef
36. Wu H, Chang C, Lu Q. The epigenetics of lupus erythematosus. Adv Exp Med Biol. 2020; 1253:185-207.
    CrossRef
37. Choi SE, Park DJ, Kang JH, Lee SS. Significance of co-positivity for anti-dsDNA, -nucleosome, and -histone antibodies in patients with lupus nephritis. Annals of Medicine. 2023;55(1):1009-1017.
    CrossRef
38. Fasano S, Milone A, Nicoletti GF, Isenberg DA, Ciccia F. Precision medicine in systemic lupus erythematosus. Nat Rev Rheumatol. 2023;19(6):331-342.
    CrossRef
39. Caster DJ, Powell DW. Utilization of biomarkers in lupus nephritis. Adv Chronic Kidney Dis. 2019;26(5):351-359.
    CrossRef
40. Langefeld CD, Comeau ME, Ng MC, et al. Genome-wide association studies suggest that APOL1-environment interactions more likely trigger kidney disease in African Americans with nondiabetic nephropathy than strong APOL1–second gene interactions. Kidney Int. 2018;94(3):599-607.
    CrossRef
41. Reid S, Alexsson A, Frodlund M, et al. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Ann Rheum Dis. 2020;79(3):363-369.
    CrossRef
42. Webber D, Cao J, Dominguez D, Gladman DD, Knight A, Levy DM, et al. Genetics of osteonecrosis in children and adults with systemic lupus erythematosus. Rheumatology. 2023;62(9):3205-3212.
    CrossRef
43. Liu R, Wen X, Peng X, Zhao M, Mi L, Lei J, Xu K. Immune podocytes in the immune microenvironment of lupus nephritis. Mol Med Rep. 2023;28(5):1-11.
    CrossRef
44. Obrișcă B, Sorohan B, Tuță L, Ismail G. Advances in lupus nephritis pathogenesis: from bench to bedside. Int J Mol Sci. 2021;22(7):3766.
    CrossRef
45. Mejía-Vilet JM, Romero-Díaz J. Voclosporin: a novel calcineurin inhibitor for the management of lupus nephritis. Expert Rev Clin Immunol. 2021;17(9):937-945.
    CrossRef
46. Ponticelli C, Reggiani F, Moroni G. Old and new calcineurin inhibitors in lupus nephritis. J Clin Med. 2021;10(21):4832.
    CrossRef
47. Yap DY, Mok CC. Novel and emerging treatment strategies for lupus nephritis. Expert Rev Clin Pharmacol. 2022;15(11):1283-1292.
    CrossRef
48. Samotij D, Reich A. Biologics in the treatment of lupus erythematosus: a critical literature review. Biomed Res Int. 2019 Jul 18; 2019:8142368.
    CrossRef

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