Immunogenetics of systemic lupus erythematosus: A comprehensive review

Abstract

Summary Our understanding of the genetic basis of systemic lupus erythematosus has progressed rapidly in recent years. While many genetic polymorphisms have been associated with disease susceptibility, the next major step involves integrating these genetic polymorphisms into the molecular mechanisms and cellular immunology of the human disease. In this review, we summarize some recent work in this area, including the genetics of the type I IFN response in SLE, including polygenic and monogenic factors, as well as epigenetic influences. Contributions of both HLA and non-HLA polymorphisms to the complex genetics of SLE are reviewed. We also review recent reports of specific gene deficits leading to monogenic SLE-like syndromes. The molecular functions of common SLE-risk variants are reviewed in depth, including regulatory variations in promoter and enhancer elements and coding-change polymorphisms, and studies which are beginning to define the molecular and cellular functions of these polymorphisms in the immune system. We discuss epigenetic influences on lupus, with an emphasis on micro-RNA expression and binding, as well as epigenetic modifications that regulate the expression levels of various genes involved in SLE pathogenesis and the ways epigenetic marks modify SLE susceptibility genes. The work summarized in this review provides a fascinating window into the biology and molecular mechanisms of human SLE. Understanding the functional mechanisms of causal genetic variants underlying the human disease greatly facilitates our ability to translate genetic associations toward personalized care, and may identify new therapeutic targets relevant to human SLE disease mechanisms.

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

“…3,4,7,8 Furthermore, an increase in type I interferon (IFN) activity was documented in family members of SLE patients, suggesting a key role in its pathogenesis. 9,10 Based on the similarities and differences in phenotypes and immunopathogenesis of numerous monogenic autoinflammatory disorders, including CANDLE syndrome and monogenic form SLE, recent suggestion argues for grouping these disorders as interferonopathies. 11,12 This work demonstrates the heterogeneity of phenotypic and genotypic features of the first three cases of CANDLE syndrome in an Arab population and the overlap with some features of monogenic form of SLE, namely C1q deficient SLE.…”

The epigenetics of PBC: The link between genetic susceptibility and environment

“…Besides that, some mechanisms remain largely unknown, such as causal nucleotide changes, rare genetic variants or the missing heritability sequencing [19][20][21]. Indeed, the use of GWAS have been very disappointing, i.e., it is likely that there are loci that have not been identified due to a lack of statistical significance; this is true not only of PBC, but also for a variety of other AIDs, many of which have been recently reviewed [22][23][24][25][26][27][28][29][30][31][32][33]. As a consequence, progress towards understanding disease mechanisms has been limited by difficulties in assigning a molecular function to the vast majority of GWAS hits that do not affect protein-coding sequences.…”

Association of polymorphic variants of PTPN22, TNF and VDR systems in children with lupus nephritis: a study in trios of Colombian families

“…En reportes previos, se ha demostrado el papel de algunas variantes genéticas presentes en los genes PTPN22 (10,11), VDR (12,13), TNF (14,15), y HLA (16,17), entre otros (18), como factores de riesgo o de protección en los diferentes endotipos de lupus eritematoso sistémico, incluida la nefritis lúpica. La mayoría de estos estudios emplean un diseño de asociación genética de casos y controles para la detección de factores genéticos asociados a una enfermedad en particular (19,20).…”