Systemic lupus erythematosus as a genetic disease

Harley, Isaac T.W.; Sawalha, Amr H.

doi:10.1016/j.clim.2022.108953

Cited by 32 publications

(35 citation statements)

References 260 publications

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“…Decreased cost of genotyping and the increasing size of autoimmune disease genetic cohorts has led to a seemingly ever-increasing list of disease risk loci. Indeed, for several common autoimmune diseases, the number of risk genetic loci across the genome now exceeds 200 ( 117 ). Each of these loci makes at most a modest contribution to relative risk of disease (odd ratio < 1.2) ( 117 ) and most are favored to act by regulating target causal genes ( 118 – 120 ).…”

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

“…Indeed, for several common autoimmune diseases, the number of risk genetic loci across the genome now exceeds 200 ( 117 ). Each of these loci makes at most a modest contribution to relative risk of disease (odd ratio < 1.2) ( 117 ) and most are favored to act by regulating target causal genes ( 118 – 120 ). Together these risk alleles are thought to set a liability threshold that allows the development of autoimmune pathology in certain circumstances.…”

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

“…In terms of genetic structure, SLE is most commonly polygenic ( 117 ), but numerous monogenic forms of SLE have been described, 51 of which we are aware ( 124 – 196 ). Monogenic SLE presents more commonly with childhood onset and a severe disease phenotype ( 117 , 124 – 126 ). It appears that in addition a minority of childhood onset cases, currently estimated at approximately 15% exhibit a probable mix of monogenic and polygenic genetic etiologies ( 197 , 198 ).…”

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

“…However, the extent to which such mutations contribute to SLE risk is still being defined ( 199 ). To synthesize what is known about polygenic causes of SLE, we applied a previously described approach to published SLE risk variants in the NHGRI-EBI GWAS catalog ( 117 ). First, we grouped SLE risk variants listed in the GWAS catalog ( 200 ) into loci/regions, then integrated published results the from Open Targets Genetics ( 201 ) Locus to Gene (L2G) ( 202 ) algorithm.…”

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

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Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

2022

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Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor via a process termed anergy. Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal (especially murine) models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.

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Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

Section: Genetic Structure: the Usual Structure Of Human Autoimmune D...mentioning

confidence: 99%

See 3 more Smart Citations

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

2022

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Phenotype Risk Score but Not Genetic Risk Score Aids in Identifying Individuals With Systemic Lupus Erythematosus in the Electronic Health Record

Barnado

Wheless

Camai

et al. 2023

Arthritis & Rheumatology

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ObjectiveSystemic lupus erythematosus (SLE) poses diagnostic challenges. We undertook this study to evaluate the utility of a phenotype risk score (PheRS) and a genetic risk score (GRS) to identify SLE individuals in a real‐world setting.MethodsUsing a de‐identified electronic health record (EHR) database with an associated DNA biobank, we identified 789 SLE cases and 2,261 controls with available MEGAEX genotyping. A PheRS for SLE was developed using billing codes that captured American College of Rheumatology SLE criteria. We developed a GRS with 58 SLE risk single‐nucleotide polymorphisms (SNPs).ResultsSLE cases had a significantly higher PheRS (mean ± SD 7.7 ± 8.0 versus 0.8 ± 2.0 in controls; P < 0.001) and GRS (mean ± SD 12.2 ± 2.3 versus 11.0 ± 2.0 in controls; P < 0.001). Black individuals with SLE had a higher PheRS compared to White individuals (mean ± SD 10.0 ± 10.1 versus 7.1 ± 7.2, respectively; P = 0.002) but a lower GRS (mean ± SD 9.0 ± 1.4 versus 12.3 ± 1.7, respectively; P < 0.001). Models predicting SLE that used only the PheRS had an area under the curve (AUC) of 0.87. Adding the GRS to the PheRS resulted in a minimal difference with an AUC of 0.89. On chart review, controls with the highest PheRS and GRS had undiagnosed SLE.ConclusionWe developed a SLE PheRS to identify established and undiagnosed SLE individuals. A SLE GRS using known risk SNPs did not add value beyond the PheRS and was of limited utility in Black individuals with SLE. More work is needed to understand the genetic risks of SLE in diverse populations.

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Unique Interplay Between Antinuclear Antibodies and Nuclear Molecules in the Pathogenesis of Systemic Lupus Erythematosus

Pisetsky

2024

Arthritis & Rheumatology

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that primarily affects young women and causes a wide range of inflammatory manifestations. The hallmark of SLE is the production of antibodies to components of the cell nucleus (antinuclear antibodies or ANAs). These antibodies can bind to DNA, RNA and protein complexes with nucleic acids. Among ANAs, antibodies to DNA (anti‐DNA) are markers for classification and disease activity, waxing and waning in many patients. In the blood, anti‐DNA antibodies can bind DNA to form immune complexes with two distinct roles in pathogenesis: renal deposition to provoke nephritis and stimulation of cytokine production following uptake into innate immune cells and interaction with internal nucleic acid sensors. These sensors are part of an internal host defense system in the cell cytoplasm that can respond to DNA from infecting organisms; during cell stress, DNA from nuclear and mitochondrial sources can also trigger these sensors. The formation of immune complexes requires a source of extracellular DNA in an immunologically accessible form. As shown in in vivo and in vitro systems, extracellular DNA can emerge from dead and dying cells in both a free and particulate form. Neutrophils undergoing the process of NETosis can release DNA in mesh‐like structures called NETs (neutrophil extracellular traps). In SLE, therefore, the combination of ANAs and immunologically active DNA can create new structures which can promote inflammation throughout the body as well as drive organ inflammation and damage.

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Systemic lupus erythematosus as a genetic disease

Cited by 32 publications

References 260 publications

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

Polygenic autoimmune disease risk alleles impacting B cell tolerance act in concert across shared molecular networks in mouse and in humans

Phenotype Risk Score but Not Genetic Risk Score Aids in Identifying Individuals With Systemic Lupus Erythematosus in the Electronic Health Record

Unique Interplay Between Antinuclear Antibodies and Nuclear Molecules in the Pathogenesis of Systemic Lupus Erythematosus

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