Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen

Ghodke‐Puranik, Yogita; Imgruet, Molly; Dorschner, Jessica M.; Shrestha, Prakriti; McCoy, Kaci; Kelly, Jennifer A.; Marion, Miranda C.; Guthridge, Joel M.; Langefeld, Carl D.; Harley, John B.; James, Judith A.; Sivils, Kathy L.; Niewold, Timothy B.

doi:10.1016/j.cyto.2018.12.014

Cited by 21 publications

(15 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…22 The propensity to have high levels of type I IFN is stable over time and is associated with a number of genetic factors. 23,24 This supports the idea that elevated type I IFN marks a particular subgroup of patients with both genetic and molecular differences, that will likely be important in personalizing therapy. 21 Increased type I IFN has been associated with cutaneous and renal manifestations and the presence of autoantibodies, such as anti-Ro, anti-Smith (anti-Sm), anti-RNP, and anti-dsDNA antibodies.…”

Section: Type I Ifn Marks a Major Molecular Subset In Slesupporting

confidence: 56%

Lessons from precision medicine in rheumatology

et al. 2020

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are two common autoimmune rheumatic diseases that vary in severity, clinical presentation, and disease course between individuals. Molecular and genetic studies of both diseases have identified candidate genes and molecular pathways that are linked to various disease outcomes and treatment responses. Currently, patients can be grouped into molecular subsets in each disease, and these molecular categories should enable precision medicine approaches to be applied in rheumatic diseases. In this article, we will review key lessons learned about disease heterogeneity and molecular characterization in rheumatology, which we hope will lead to personalized therapeutic strategies.

show abstract

Section: Type I Ifn Marks a Major Molecular Subset In Slesupporting

confidence: 56%

Lessons from precision medicine in rheumatology

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Given that the effects are seen at many unlinked genes and given the unlikelihood of shared genetic variants at each of these unlinked genes among AA patients with SLE, the former hypothesis is more likely. To add confirmation to this hypothesis, we analyzed the P values for CpGs within genes with known AA‐specific SLE genetic associations and found a lack of association with methylation and SLE status for those sites . If known SLE‐related genetic risk factors were drivers of epigenetic effects, we would expect an overlap between these loci.…”

Section: Discussionmentioning

confidence: 98%

Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus

Breitbach

Ramaker

Roberts

et al. 2019

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective. To determine the stage of B cell development at which a systemic lupus erythematosus (SLE)associated DNA methylation signature originates in African American (AA) and European American (EA) subjects, and to assess whether epigenetic defects in B cell development patterns could be predictive of SLE status in individual and mixed immune cell populations.Methods. B cells from AA patients (n = 31) and EA patients (n = 49) with or without SLE were sorted using fluorescence-activated cell sorting into 5 B cell subsets. DNA methylation, measured at ~460,000 CpG sites, was interrogated in each subset. Enrichment analysis of transcription factor interaction at SLE-associated methylation sites was performed. A random forests algorithm was used to identify an epigenetic signature of SLE in the B cell subsets, which was then validated in an independent cohort of AA and EA patients and healthy controls.Results. Regression analysis across all B cell stages resulted in identification of 60 CpGs that reached genomewide significance for SLE-associated methylation differences (P ≤ 1.07 × 10 −7 ). Interrogation of ethnicity-specific CpGs associated with SLE revealed a hypomethylated pattern that was enriched for interferon (IFN)-regulated genes and binding of EBF1 in AA patients (each P < 0.001). AA patients with SLE could be distinguished from healthy controls when the predictive model developed with the transitional B cell subset was applied to other B cell subsets (mean receiver operating characteristic [ROC] area under the curve [AUC] 0.98), and when applied to CD19+ pan-B cells (mean ROC AUC 0.95) and CD4+ pan-T cells (mean ROC AUC 0.97) from the independent validation cohort.Conclusion. These results indicate that SLE-specific methylation patterns are ethnicity dependent. A pattern of epigenetic changes near IFN-regulated genes early in B cell development is a hallmark of SLE in AA female subjects. EBF1 binding sites are highly enriched for significant methylation changes, implying that this may be a potential regulator of SLE-associated epigenetic changes.

show abstract

“…One possibility could be that the levels of PPM1H increase with aging to counteract the parallel increase in Lrrk2 observed. Intriguingly, a recent study found a genetic association between PPM1H and INFα levels in systemic lupus erythematosus (SLE) patients [ 51 ]. As also LRRK2 can modulate the risk of inflammatory diseases such as SLE [ 52 , 53 ] and neuroinflammation is increased in 12-month old BAC G2019S mice ( Figure 5 ), future studies should be directed at exploring the possible link between LRRK2 and PPM1H in PD-related inflammation.…”

Section: Discussionmentioning

confidence: 99%

Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Iannotta

Biosa

Kluss

et al. 2020

Cells

View full text Add to dashboard Cite

Mutations in LRRK2 cause familial Parkinson’s disease and common variants increase disease risk. LRRK2 kinase activity and cellular localization are tightly regulated by phosphorylation of key residues, primarily Ser1292 and Ser935, which impacts downstream phosphorylation of its substrates, among which Rab10. A comprehensive characterization of LRRK2 activity and phosphorylation in brain as a function of age and mutations is missing. Here, we monitored Ser935 and Ser1292 phosphorylation in midbrain, striatum, and cortex of 1, 6, and 12 months-old mice carrying G2019S and R1441C mutations or murine bacterial artificial chromosome (BAC)-Lrrk2-G2019S. We observed that G2019S and, at a greater extent, R1441C brains display decreased phospho-Ser935, while Ser1292 autophosphorylation increased in G2019S but not in R1441C brain, lung, and kidney compared to wild-type. Further, Rab10 phosphorylation, is elevated in R1441C carrying mice, indicating that the effect of LRRK2 mutations on substrate phosphorylation is not generalizable. In BAC-Lrrk2-G2019S striatum and midbrain, Rab10 phosphorylation, but not Ser1292 autophosphorylation, decreases at 12-months, pointing to autophosphorylation and substrate phosphorylation as uncoupled events. Taken together, our study provides novel evidence that LRRK2 phosphorylation in mouse brain is differentially impacted by mutations, brain area, and age, with important implications as diagnostic markers of disease progression and stratification.

show abstract

Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen

Cited by 21 publications

References 44 publications

Lessons from precision medicine in rheumatology

Lessons from precision medicine in rheumatology

Population‐Specific Patterns of Epigenetic Defects in the B Cell Lineage in Patients With Systemic Lupus Erythematosus

Divergent Effects of G2019S and R1441C LRRK2 Mutations on LRRK2 and Rab10 Phosphorylations in Mouse Tissues

Contact Info

Product

Resources

About