Genetics of human lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease characterized by immune complex formation with multi-organ manifestations. Lupus nephritis (LN) is one of the most severe types of organ damage in SLE, and it clearly contributes to increased morbidity and mortality due to SLE. LN occurs more frequently and is more severe in non-European ancestral backgrounds, although the cause of this disparity remains largely unknown. Genetic factors play an important role in the pathogenesis of SLE. Although many SLE susceptibility genes have been identified, the genetic basis of LN is not as well understood. While some of the established general SLE susceptibility genes are associated with LN, recent discoveries highlight a number of genes with renal functions that are specifically associated with LN. Some of these genes associated with LN help to explain the disparity in the prevalence of nephritis between individuals with SLE, and also partially explain differences in LN between ancestral backgrounds. Moreover, not only the gene mutations, but also post-translational modifications seem to play important roles in the pathogenesis of LN. Overall it seems likely that a combination of general SLE susceptibility genes cooperate with LN specific risk genes to result in the genetic propensity for LN. In this review, we will outline the genetic contribution to LN and describe possible roles of LN susceptibility genes.

High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus

“…Importantly however, the present study explores a GRS weighted by ORs for SLE rather than for renal manifestations. As there are several SNPs associated specifically with lupus nephritis,46 the method could be employed to design a nephritis-specific GRS with, plausibly, higher predictive accuracy.…”

Precision medicine in lupus nephritis: can biomarkers get us there?

“…The identified genetic risks for LN and their clinical application were thoroughly reviewed in 2015 by Munroe and James and in 2017 by Iwamoto and Niewold [152, 153]. The 2015 review lists over 50 disease susceptibility genes associated with LN and grouped them into five regulatory systems (program cell death, immune complex clearance, intrarenal pathogenesis, innate immunity, and adaptive immunity).…”

Defining Biological Subsets in Systemic Lupus Erythematosus: Progress Toward Personalized Therapy

“…For example, polymorphisms in integrin subunit alpha M (ITGAM), signal transducer and activator of transcription 4 (STAT4), apolipoprotein L1 (APOL1), platelet-derived growth factor receptor, alpha (PDGFRA), and hyaluronan synthase 2 (HAS2) have been associated with greater risk of nephritis in SLE patients [42–47]. While some of these polymorphisms such as ITGAM and STAT4 are also general SLE risk factors, APOL1, PDGFRA, and HAS2 are genes that seem to be specifically associated with risk of nephritis in SLE and are not general SLE-risk genes [48]. …”