Biology subjects

Kuiper, J. J.

Publications and source records attributed to Kuiper, J. J..

6 recordsLinked to original sources

bioRxiv2023

A cis-regulatory element regulates ERAP2 expression through autoimmune disease risk SNPs

Single nucleotide polymorphisms (SNP) near the ERAP2 gene are associated with autoimmune conditions such as Crohns disease, and birdshot chorioretinopathy, as well as protection against lethal infections, including the Black Death. Due to high linkage disequilibrium (LD), a great number of trait-associated SNPs are correlated with ERAP2 expression, 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 that ERAP2 expression is directly controlled by the genotype of splice region SNP rs2248374. However, we demonstrate that autoimmune disease-risk SNPs located near the downstream LNPEP gene promoter are independently associated with ERAP2 expression. Allele-specific conformation capture assays revealed long-range chromatin contacts between the LNPEP promoter region and the ERAP2 promoter and showed that interactions were stronger in patients carrying the alleles that increase susceptibility to autoimmune diseases. Replacing the disease-associated SNPs in the LNPEP promoter by reference sequences lowered ERAP2 expression. 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.

genomics↗

bioRxiv2020

ERAP2 facilitates a subpeptidome of Birdshot Uveitis-associated HLA-A29

Birdshot Uveitis (BU) is a blinding inflammatory eye condition that only affects HLA-A29-positive individuals. Genetic association studies linked ERAP2 with BU, an aminopeptidase which trims peptides before their presentation by HLA class I at the cell surface, which suggests that ERAP2-dependent peptide presentation by HLA-A29 drives the pathogenesis of BU. However, it remains poorly understood whether the effects of ERAP2 on the HLA-A29 peptidome are distinct from its effect on other HLA allotypes. To address this, we focused on the effects of ERAP2 on the immunopeptidome in patient-derived antigen presenting cells. Using complementary HLA-A29-based and pan-class I immunopurifications, isotope-labelled naturally processed and presented HLA-bound peptides were sequenced by mass spectrometry. We show that the effects of ERAP2 on the N-terminus of ligands of HLA-A29 are shared across endogenous HLA allotypes, but discover and replicate that one peptide motif generated in the presence of ERAP2 is specifically bound by HLA-A29. This motif can be found in the amino acid sequence of putative autoantigens. We further show evidence for internal sequence specificity for ERAP2 imprinted in the immunopeptidome. These results reveal that ERAP2 can generate an HLA-A29-specific antigen repertoire, which supports that antigen presentation is a key disease pathway in BU.

immunology↗

bioRxiv2019

Bridging theories for ecosystem stability through structural sensitivity analysis of ecological models in equilibrium

Ecologists are challenged by the need to bridge and synthesize different approaches and theories to obtain a coherent understanding of ecosystems in a changing world. Both food web theory and regime shift theory shine light on mechanisms that confer stability to ecosystems, but from a different angle. Empirical food web models are developed to analyze how equilibria in real multi-trophic ecosystems are shaped by species interactions, and often include linear functional response terms for simple estimation of interaction strengths from observations. Models of regime shifts focus on qualitative changes of equilibrium points in a slowly changing environment, and typically include non-linear functional response terms. Currently, it is unclear how the stability of an empirical food web model, expressed as the rate of system recovery after a small perturbation, relates to the vulnerability of the ecosystem to collapse. Here, we conduct structural sensitive analyses of classical consumer-resource models in equilibrium along an environmental gradient. Specifically, we change non-proportional interaction terms into linear ones, while maintaining the equilibrium biomass densities and flux of matter, to analyze how alternative model formulations shape the stability properties of the equilibria. The results reveal no consistent relationship between the stability of the original models and the linearized versions, even though they describe the same biomass values and material flows. We use these findings to discuss whether stability analysis of observed equilibria by empirical food web models can provide insight into regime shift dynamics, and highlight the challenge of bridging alternative modelling approaches in ecology and beyond.

ecology↗

bioRxiv2018

Functionally distinct ERAP1 and ERAP2 are a hallmark of HLA-A29-(Birdshot) Uveitis.

Birdshot Uveitis (Birdshot) is a rare eye condition that affects HLA-A29-positive individuals and could be considered a prototypic member of the recently proposed \"MHC-I-opathy\" family. Genetic studies have pinpointed the ERAP1 and ERAP2 genes as shared associations across MHC-I-opathies, which suggests ERAP dysfunction may be a root cause for MHC-I-opathies. We mapped the ERAP1 and ERAP2 haplotypes in 84 Dutch cases and 890 controls. We identified association at variant rs10044354, which mediated a marked increase in ERAP2 expression. We also identified and cloned an independently associated ERAP1 haplotype (tagged by rs2287987) present in more than half of the cases; this ERAP1 haplotype is also the primary risk and protective haplotype for other MHC-I-opathies. We show that the risk ERAP1 haplotype conferred significantly altered expression of ERAP1 isoforms in transcriptomic data (n=360), resulting in lowered protein expression and distinct enzymatic activity. Both the association for rs10044354 (meta-analysis: OR[95% CI]=2.07[1.58-2.71], p=1.24 x 10(-7)) and rs2287987 (OR[95% CI]: =2.01 [1.51-2.67], p=1.41 x 10(-6)) replicated and showed consistent direction of effect in an independent Spanish cohort of 46 cases and 2,103 controls. In both cohorts, the combined rs2287987-rs10044354 haplotype associated with Birdshot more strongly than either SNP alone (meta-analysis: p=3.9 x 10(-9)). Finally, we observed that ERAP2 protein expression is dependent on the ERAP1 background across three European populations (n=3,353). In conclusion, a functionally distinct combination of ERAP1 and ERAP2 are a hallmark of Birdshot and provide rationale for strategies designed to correct ERAP function for treatment of Birdshot and MHC-I-opathies more broadly.

genetics↗

bioRxiv2018

Quantification of double stranded DNA breaks and telomere length as proxies for corneal damage and replicative stress in 64 human keratoconus corneasThe role of DNA damage in the development of keratoconus

PurposeThe pathogenesis of keratoconus (KC) is multifactorial and associated with oxidative stress and subsequent DNA damage. The aim of this study was to investigate differences in DNA damage and replicative stress in patients with KC, and in both healthy and diseased controls.\n\nMethodsSixty-four corneal buttons were obtained from 27 patients with KC after corneal transplant surgery, 21 patients with a decompensated graft (DG), and 16 healthy controls (HC). The amount of intact Alu elements per genome copy as measured by qPCR was used to quantify intact DNA. Telomere length was measured as a proxy for replicative stress. In addition, telomerase reverse transcriptase (hTERT) gene expression level was assessed.\n\nResultsMean ({+/-}SD) DNA damage was similar between the KC (5.56 {+/-}14.08), DG (3.16 {+/-}8.22), and HC (3.51 {+/-}6.66) groups (P=0.807). No associations were found between DNA damage and patient age (P=0.523), atopic constitution (P=0.240), or contact lens wear (P=0.393). Telomere length differed (P=0.034), most notably in the KC group, and hTERT was not detected in any corneal sample. Three cross-linked (CXL) KC corneas did not contain significant more DNA damage (2.6x, P = 0.750).\n\nConclusionsBased on these findings, differences in actual corneal DNA damage in KC could not be identified, and the longer telomere length in KC did not support replicative stress as a major etiological factor in the pathogenesis of KC. Future longitudinal investigations on KC etiology should assess progressive early cases to better comprehend the cellular and molecular processes preceding the archetypical morphological changes.\n\nPrecisOxidative stress is allegedly linked with the development of keratoconus. Whether these stressors actually lead to persisting DNA damage and replicative stress is debated. DNA damage was comparable with control samples, and a shortened telomere length was not identified.

molecular biology↗

bioRxiv2018

mTOR complex 1 pathway activation in severe keratoconus; the functional implications of GWAS identified loci.

PurposeKeratoconus (KC) is an eye condition that can lead to a severe vision loss and may warrant a corneal grafting procedure. Meta-analyses of genome wide association studies have identified several genes that confer risks for differences in corneal curvature, corneal thickness, and developing keratoconus. Currently, there is limited evidence of a functional role for the identified loci in the affected corneal tissues.\n\nMethodsWe investigated the gene expression profiles of 4 GWAS confirmed risk loci and several related pathways that function in cellular ageing and cell cycle control in corneal tissue of a discovery and replication cohort comprising in total 27 keratoconus patients, 16 healthy controls, and 21 diseased controls (failed corneal grafts).\n\nResultsWe confirmed the MTOR gene locus as differentially expressed in KC corneas in a discovery cohort Next, we replicated these results in a second cohort and found evidence of increased expression of various mTORC1 pathway signature genes, namely MTOR itself (P=0.040), AKT1 (P=0.028), IGF1R (P=0.022) and RAPTOR (P=0.007).\n\nConclusionsGene expression profiling in cornea tissues revealed robust up-regulation of the mTORC1 pathway in KC and substantiates a potential role for this pathway in its pathogenesis. Functional implications should be further studied since biomarkers for disease activity are needed and selective targeting of the mTOR pathway is a promising treatment concept.

molecular biology↗