Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

Hamilton, Fergus; Mentzer, Alexander J.; Parks, Tom; Baillie, J Kenneth; Smith, George Davey; Ghazal, Peter; Timpson, Nicholas J.

doi:10.1016/j.ajhg.2023.02.008

Cited by 16 publications

(14 citation statements)

References 46 publications

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“…This does not contradict our findings, since the methods used in those scans were designed to detect directional selection over many generations, which is not the scenario that we proposed for ERAP2. As discussed in our original manuscript, and supported by other studies 3,11,12 , we propose that the ERAP2 variant has evolved under long-term balancing selection, with a short pulse of strong directional selection in response to the Black Death. Specifically, we suggest that the rs2549794-C allele was advantageous during the Black Death, but that it is also associated with a fitness cost that maintains a long-term balanced allele frequency.…”

supporting

confidence: 77%

“…Specifically, in our analysis, we combined a temporal sampling strategy of well dated ancestral remains with tight temporal constraints situated around the Black Death (before, during, and after the putative selective event), replication across two different population cohorts, contemporary evidence for balancing selection, and experimental data on the host cellular response to Yersinia pestis infection, to build a case for selection. Our functional data-which is extremely rare in ancient DNA studies-combined with epidemiological evidence from an independent group, strongly support the case for selection in ERAP2 3 during the Black Death.…”

supporting

confidence: 76%

“…These are all crucial sources of evidence to support natural selection. Notably, recent evidence from an independent group shows that the variant we predict to have been protective during the Black Death is indeed protective against infectious diseases of bacterial origin, while also increasing the risk for Crohn's disease and diabetes 3 . Such convergent evidence is indispensable given the constraints of ancient DNA studies, where achieving large sample sizes remains a challenge.…”

Section: Discussionmentioning

confidence: 79%

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Reply to Barton et al: signatures of natural selection during the Black Death

Vilgalys

Klunk

Demeure

et al. 2023

Preprint

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Barton et al. raise several statistical concerns regarding our original analyses that highlight the challenge of inferring natural selection using ancient genomic data. We show here that these concerns have limited impact on our original conclusions. Specifically, we recover the same signature of enrichment for high FST values at the immune loci relative to putatively neutral sites after switching the allele frequency estimation method to a maximum likelihood approach, filtering to only consider known human variants, and down-sampling our data to the same mean coverage across sites. Furthermore, using permutations, we show that the rs2549794 variant near ERAP2 continues to emerge as the strongest candidate for selection (p = 1.2x10-5), falling below the Bonferroni-corrected significance threshold recommended by Barton et al. Importantly, the evidence for selection on ERAP2 is further supported by functional data demonstrating the impact of the ERAP2 genotype on the immune response to Y. pestis and by epidemiological data from an independent group showing that the putatively selected allele during the Black Death protects against severe respiratory infection in contemporary populations.

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supporting

confidence: 77%

supporting

confidence: 76%

Section: Discussionmentioning

confidence: 79%

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Reply to Barton et al: signatures of natural selection during the Black Death

Vilgalys

Klunk

Demeure

et al. 2023

Preprint

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“…While changes in cytoskeletal structural elements are commonly associated with tumorigenesis, the cytoskeleton also plays a role in the regulation of cellular processes such as proliferation, cell growth, and apoptosis ( 52 ), important features of a robust cellular response. The upregulation of ERAP2, an aminopeptidase that heterodimerizes and homodimerizes with ERAP1 to trim peptides prior to HLA class I loading in the endoplasmic reticulum ( 53 ) as well as shaping the cytokine response ( 54 ), highlights the upregulation of genes encoding proteins involved in antigen processing and presentation following influenza vaccination and also following YF17D vaccination ( 35 ).…”

Section: Discussionmentioning

confidence: 99%

Tracking of activated cTfh cells following sequential influenza vaccinations reveals transcriptional profile of clonotypes driving a vaccine-induced immune response

et al. 2023

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IntroductionA vaccine against influenza is available seasonally but is not 100% effective. A predictor of successful seroconversion in adults is an increase in activated circulating T follicular helper (cTfh) cells after vaccination. However, the impact of repeated annual vaccinations on long-term protection and seasonal vaccine efficacy remains unclear.MethodsIn this study, we examined the T cell receptor (TCR) repertoire and transcriptional profile of vaccine-induced expanded cTfh cells in individuals who received sequential seasonal influenza vaccines. We measured the magnitude of cTfh and plasmablast cell activation from day 0 (d0) to d7 post-vaccination as an indicator of a vaccine response. To assess TCR diversity and T cell expansion we sorted activated and resting cTfh cells at d0 and d7 post-vaccination and performed TCR sequencing. We also single cell sorted activated and resting cTfh cells for TCR analysis and transcriptome sequencing.Results and discussionThe percent of activated cTfh cells significantly increased from d0 to d7 in each of the 2016-17 (p < 0.0001) and 2017-18 (p = 0.015) vaccine seasons with the magnitude of cTfh activation increase positively correlated with the frequency of circulating plasmablast cells in the 2016-17 (p = 0.0001) and 2017-18 (p = 0.003) seasons. At d7 post-vaccination, higher magnitudes of cTfh activation were associated with increased clonality of cTfh TCR repertoire. The TCRs from vaccine-expanded clonotypes were identified and tracked longitudinally with several TCRs found to be present in both years. The transcriptomic profile of these expanded cTfh cells at the single cell level demonstrated overrepresentation of transcripts of genes involved in the type-I interferon pathway, pathways involved in gene expression, and antigen presentation and recognition. These results identify the expansion and transcriptomic profile of vaccine-induced cTfh cells important for B cell help.

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“…Due to linkage disequilibrium (LD) between these SNPs, there are two common ERAP2 haplotypes; one haplotype encodes enzymatically active ERAP2 protein while the alternative haplotype encodes transcript with an extended exon 10 that contains premature termination codons, inhibiting mRNA and protein expression (23). The haplotype that produces full-size ERAP2 increases the risk of autoimmune diseases such as CD, JIA, and BCR, but it also protects against severe respiratory infections like pneumonia (24), as well as historically the Black Death , caused by the bacterium Yersinia pestis (11-13,25). There is a SNP rs2248374 (allele frequency ∼50%) located within a donor splicing site directly after exon 10 that tags these common haplotypes (14,23,26).…”

Section: Introductionmentioning

confidence: 99%

Acis-regulatory element regulatesERAP2expression through autoimmune disease risk SNPs

Venema

Hiddingh

Loosdregt

et al. 2023

Preprint

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Single nucleotide polymorphisms (SNP) near theERAP2gene are associated with autoimmune conditions such asCrohn’s disease, andbirdshot chorioretinopathy, as well as protection against lethal infections, including theBlack Death. Due to high linkage disequilibrium (LD), a great number of trait-associated SNPs are correlated withERAP2expression, however their functional mechanisms remain unidentified. We used genome editing and functional genomics to identify causal variants that remain obscured by LD. We demonstrate by reciprocal allelic replacement thatERAP2expression is directly controlled by the genotype of splice region SNP rs2248374. However, we demonstrate that autoimmune disease-risk SNPs located near the downstreamLNPEPgene promoter are independently associated withERAP2expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between theLNPEPpromoter region and theERAP2promoter and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the disease-associated SNPs in theLNPEPpromoter by reference sequences loweredERAP2expression. These findings show that clustered GWAS signals associated with diverse autoimmune conditions and lethal infections act in concert to control ERAP2 expression and that disease-associated variants can convert a gene promoter region into a potent enhancer of a distal gene.

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Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

Cited by 16 publications

References 46 publications

Reply to Barton et al: signatures of natural selection during the Black Death

Reply to Barton et al: signatures of natural selection during the Black Death

Tracking of activated cTfh cells following sequential influenza vaccinations reveals transcriptional profile of clonotypes driving a vaccine-induced immune response

Acis-regulatory element regulatesERAP2expression through autoimmune disease risk SNPs

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