Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

Demirci, F. Yesim; Wang, Xingbin; Morris, David L.; Feingold, Eleanor; Bernatsky, Sasha; Pineau, Christian; Clarke, Ann E.; Ramsey‐Goldman, Rosalind; Manzi, Susan; Kamboh, M. Ilyas

doi:10.1136/jmedgenet-2016-104247

Cited by 14 publications

(14 citation statements)

References 50 publications

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“…Several studies have highlighted the 8p23 locus as a major SLE susceptibility region (44). Our study further expands the significance at this locus.…”

Section: Discussionsupporting

confidence: 77%

STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

Zhang

Day²,

Absher

2021

Preprint

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Mapping of allelic imbalance (AI) at heterozygous loci has the potential to establish links between genetic risk for disease and biological function. Leveraging multi-omics data for AI analysis and functional annotation, we discovered a novel functional risk variant rs1047643 at 8p23 in association with SLE. This variant displays dynamic AI of chromatin accessibility and allelic expression on FDFT1 gene in B cells with SLE. We further found a B-cell restricted super-enhancer (SE) that physically contacts with this SNP-residing locus, an interaction that also appears specifically in B cells. Quantitative analysis of open chromatin and DNA methylation profiles further demonstrated that the SE exhibits aberrant activity in B cell development with SLE. Functional studies identified that STAT3, a master factor associated with autoimmune diseases, directly regulates both the AI of risk variant and the activity of SE in cultured B cells. Our study reveals that STAT3-mediated SE activity and cis-regulatory effects of SNP rs1047643 at 8p23 locus are associated with B cell deregulation in SLE.

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“…Several studies have highlighted the 8p23 locus as a major SLE susceptibility region (44). Our study further expands the significance at this locus.…”

Section: Discussionsupporting

confidence: 77%

STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

Zhang

Day²,

Absher

2021

Preprint

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“…ECHDC3, near a distinct locus (r 2 < 0.01) previously implicated in Alzheimer disease 63 . MN1, which previously has been causally related to familial meningiomas 64 , and XKR6, which has been associated with risk of systemic lupus erythematosus 65 .…”

Section: Discussionmentioning

confidence: 99%

Cerebral small vessel disease genomics and its implications across the lifespan

Sargurupremraj¹,

Suzuki²,

Jian³

et al. 2020

Nat Commun

132

125

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White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.

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“…High-density SNP analysis has identified and facilitated to focus on disease-associated loci where patients and healthy controls exhibit different frequencies of trait-associated alleles which are potential disease-causal variants or their proxies [47]. To date, about 100 SLE susceptibility loci have been identified, mostly in European and Asian populations [49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86], explaining the heritability of SLE up to around 30% [74,75].…”

Section: Genetics In Slementioning

confidence: 99%

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

Kwon

Chun

Kim

et al. 2019

Cells

120

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Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of complex etiology that primarily affects women of childbearing age. The development of SLE is attributed to the breach of immunological tolerance and the interaction between SLE-susceptibility genes and various environmental factors, resulting in the production of pathogenic autoantibodies. Working in concert with the innate and adaptive arms of the immune system, lupus-related autoantibodies mediate immune-complex deposition in various tissues and organs, leading to acute and chronic inflammation and consequent end-organ damage. Over the past two decades or so, the impact of genetic susceptibility on the development of SLE has been well demonstrated in a number of large-scale genetic association studies which have uncovered a large fraction of genetic heritability of SLE by recognizing about a hundred SLE-susceptibility loci. Integration of genetic variant data with various omics data such as transcriptomic and epigenomic data potentially provides a unique opportunity to further understand the roles of SLE risk variants in regulating the molecular phenotypes by various disease-relevant cell types and in shaping the immune systems with high inter-individual variances in disease susceptibility. In this review, the catalogue of SLE susceptibility loci will be updated, and biological signatures implicated by the SLE-risk variants will be critically discussed. It is optimistically hoped that identification of SLE risk variants will enable the prognostic and therapeutic biomarker armamentarium of SLE to be strengthened, a major leap towards precision medicine in the management of the condition.

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Multiple signals at the extended 8p23 locus are associated with susceptibility to systemic lupus erythematosus

Cited by 14 publications

References 50 publications

STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

STAT3-mediated allelic imbalance of novel genetic variant rs1047643 and B cell specific super-enhancer in association with systemic lupus erythematosus

Cerebral small vessel disease genomics and its implications across the lifespan

Update on the Genetics of Systemic Lupus Erythematosus: Genome-Wide Association Studies and Beyond

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