A plausibly causal functional lupus-associated risk variant in the STAT1–STAT4 locus

Abstract

Systemic Lupus Erythematosus (SLE or lupus) (OMIM: 152700) is a chronic autoimmune disease with debilitating inflammation that affects multiple organ systems. The STAT1-STAT4 locus is one of the first and most highly-replicated genetic loci associated with lupus risk. We performed a fine-mapping study to identify plausible causal variants within the STAT1-STAT4 locus associated with increased lupus disease risk. Using complementary frequentist and Bayesian approaches in trans-ancestral Discovery and Replication cohorts, we found one variant whose association with lupus risk is supported across ancestries in both the Discovery and Replication cohorts: rs11889341. In B cell lines from patients with lupus and healthy controls, the lupus risk allele of rs11889341 was associated with increased STAT1 expression. We demonstrated that the transcription factor HMGA1, a member of the HMG transcription factor family with an AT-hook DNA-binding domain, has enriched binding to the risk allele compared to the non-risk allele of rs11889341. We identified a genotype-dependent repressive element in the DNA within the intron of STAT4 surrounding rs11889341. Consistent with expression quantitative trait locus (eQTL) analysis, the lupus risk allele of rs11889341 decreased the activity of this putative repressor. Altogether, we present a plausible molecular mechanism for increased lupus risk at the STAT1-STAT4 locus in which the risk allele of rs11889341, the most probable causal variant, leads to elevated STAT1 expression in B cells due to decreased repressor activity mediated by increased binding of HMGA1.

Immunogenetics in systemic lupus erythematosus: Transitioning from genetic associations to cellular effects

“…The gene encoding STAT1 is located adjacent to STAT4 , and studies of lymphoblastoid cell lines (LCLs) generated from B cells of SLE patients found increased mRNA levels of STAT1 in STAT4 risk allele carriers. This effect was possibly mediated by allele‐dependent binding of the transcription factor HMGA1 to rs11889341 located in the third intron of STAT4 54 . In contrast to these data, no association between STAT4 genotype and STAT1 protein levels was found in peripheral blood B cells from SLE patients, 51 or healthy donors (unpublished data from 96 healthy individuals, P = .35).…”

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

“…The STAT4 variant has previously been associated with a more severe disease phenotype including ischaemic stroke and increased SDI scores 17–21. Patients with SLE carrying this risk variant display an augmented IFN-γ production in T cells and elevated STAT1 expression in B cells 39 40. Because of the entailed potential therapeutic opportunity, we believe our confirmation of the association of this variant with organ damage is valuable.…”

Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies

“…Furthermore, neither variant was shown with long range chromatin interactions in the in the currently available HI-C data via the 3D genome browser. Despite the lack of functional information from these publicly available databases, functional information is available via a 2018 study, where transancestral mapping identified rs11889341 with strong association with SLE ( 65 ). This study focused on the STAT1-STAT4 region and found rs11889341 was associated with STAT1 expression in B-cells through increased binding of the transcription factor, HMGA1 ( 65 ).…”

“…Despite the lack of functional information from these publicly available databases, functional information is available via a 2018 study, where transancestral mapping identified rs11889341 with strong association with SLE ( 65 ). This study focused on the STAT1-STAT4 region and found rs11889341 was associated with STAT1 expression in B-cells through increased binding of the transcription factor, HMGA1 ( 65 ). Given the relationship between transcription factor binding and DNA topology ( 20 , 31 , 32 , 66 , 67 ), we hypothesize that the identified functional activity of rs11889341 (via HMGA1 binding) may be mediated by the large MGW change imposed by the SNP’s alleles.…”

“…While a SNP’s functional relevance can be supported by publicly-available resources, a lack of information does not necessarily indicate a variant's lack of function. This was illustrated by rs11889341 in STAT4 , which lacked functional information from public resources (GTEx, ENCODE, 3D-genome browser) ( 57 , 58 , 60 ), but in a targeted functional study, rs11889341 was correlated with gene expression and binding of the transcription factor HMGA1 ( 65 ). We identified rs11889341 using ΔMGW as the prioritizing variable.…”