Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease

Garcia-Etxebarria, Koldo; Jauregi-Miguel, Amaia; Romero-Garmendia, Irati; Plaza-Izurieta, Leticia; Legarda, María; Irastorza, Iñaki; Bilbao, José Ramón

doi:10.1038/ejhg.2016.120

Cited by 18 publications

(18 citation statements)

References 20 publications

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“…In order to ascertain whether methylation changes overlap sequence variants potentially explaining the phenotypic effect of some of the previously associated SNPs, methylation results were analyzed together with the Immunochip SNP genotypes 39 . We identified 1,423 and 1,457 mQTLs in epithelial and immune cells, respectively (FDR < 0.05), using previously defined criteria 40 (Table S6).…”

Section: Resultsmentioning

confidence: 99%

“…mQTL-SNPs that correlated with individual DMPs are shown in pink (none of the DMP-correlated SNPs reached genome-wide significance in the putative cis -mQTLs in which they participated). In turn, SNPs associated to CD according to the Immunochip project 1,39 are highlighted in yellow, and consequently, mark those mQTLs that overlap CD-associated variants, many of which are genome-wide significant.…”

Section: Resultsmentioning

confidence: 99%

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The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

Fernández-Jiménez

García-Etxebarria

Plaza-Izurieta

et al. 2019

Sci Rep

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The Human Leucocyte Antigen (HLA) locus and other DNA sequence variants identified in Genome-Wide Association (GWA) studies explain around 50% of the heritability of celiac disease (CD). However, the pathogenesis of CD could be driven by other layers of genomic information independent from sequence variation, such as DNA methylation, and it is possible that allele-specific methylation explains part of the SNP associations. Since the DNA methylation landscape is expected to be different among cell types, we analyzed the methylome of the epithelial and immune cell populations of duodenal biopsies in CD patients and controls separately. We found a cell type-specific methylation signature that includes genes mapping to the HLA region, namely TAP1 and HLA-B. We also performed Immunochip SNP genotyping of the same samples and interrogated the expression of some of the affected genes. Our analysis revealed that the epithelial methylome is characterized by the loss of CpG island (CGI) boundaries, often associated to altered gene expression, and by the increased variability of the methylation across the samples. The overlap between differentially methylated positions (DMPs) and CD-associated SNPs or variants contributing to methylation quantitative trait loci (mQTLs) is minimal. In contrast, there is a notable enrichment of mQTLs among the most significant CD-associated SNPs. Our results support the notion that DNA methylation alterations constitute a genotype-independent event and confirm its role in the HLA region (apart from the well-known, DQ allele-specific effect). Finally, we find that a fraction of the CD-associated variants could exert its phenotypic effect through DNA methylation.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

Fernández-Jiménez

García-Etxebarria

Plaza-Izurieta

et al. 2019

Sci Rep

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“…KIF21B is expressed in brain, eyes and spleen (Marszalek et al, 1999). Several studies have linked the KIF21B gene to neurodevelopmental and immune-related disorders, including multiple sclerosis and inflammatory conditions such as Crohn's disease and ankylosing spondylitis (Anderson et al, 2009;Asselin et al, 2020;Barrett et al, 2008;Garcia-Etxebarria et al, 2016;Goris et al, 2010;International Multiple Sclerosis Genetics, 2010;Kannan et al, 2017;Kreft et al, 2014;Li et al, 2017;Liu et al, 2013b;Robinson et al, 2015;Yang et al, 2015). Kif21b knock out mice are viable but show behavioral deficits and defects in synaptic transmission (Ghiretti et al, 2016;Gromova et al, 2018;Morikawa et al, 2018;Muhia et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

Hooikaas

Damstra

Gros

et al. 2020

Preprint

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When a T cell and an antigen-presenting cell form an immunological synapse, rapid dynein-driven translocation of the centrosome towards the contact site leads to reorganization of microtubules and associated organelles. Currently, little is known about how the regulation of microtubule dynamics contributes to this process. Here, we show that the knockout of KIF21B, a kinesin-4 linked to autoimmune disorders, causes microtubule overgrowth and perturbs centrosome translocation. KIF21B restricts microtubule length by inducing microtubule pausing typically followed by catastrophe. Catastrophe induction with vinblastine prevented microtubule overgrowth and was sufficient to rescue centrosome polarization in KIF21B-knockout cells. Biophysical simulations showed that a relatively small number of KIF21B molecules can restrict microtubule length and promote an imbalance of dynein-mediated pulling forces that allows the centrosome to translocate past the nucleus. We conclude that proper control of microtubule length is important for allowing rapid remodeling of the cytoskeleton and efficient T cell polarization.

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“…Therefore, rs16868943 may simply be a proxy for other causative, genetically linked polymorphisms. The A allele of rs16868943 has also been associated with Celiac disease in a GWAS study 32 at a genome-wide significant level ( P = 2.06 × 10 −11 ). The clinical significance of such an association is unclear.…”

Section: Discussionmentioning

confidence: 98%

Single nucleotide polymorphism in the COL11A2 gene associated with lowered heat pain sensitivity in knee osteoarthritis

Wallace

Sibille

et al. 2017

Mol Pain

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Pain is one of the most prominent symptoms of osteoarthritis. However, there is often discordance between the pain experienced by individuals with osteoarthritis and the degree of articular pathology. This suggests that individual differences, including genetic variability in the central processing of nociceptive stimuli, may impact the presentation of osteoarthritis. Here, we show that the single nucleotide polymorphism rs16868943 in the collagen gene COL11A2 is significantly associated with lowered heat pain tolerance on the arm in participants with knee osteoarthritis (P = 1.21 × 10−6, P = 0.0053 after Bonferroni correction, beta = −3.42). A total of 161 knee osteoarthritis participants were included and evaluated for heat, punctate and pressure pain sensitivity of the affected knee and the ipsilateral arm. Each participant was genotyped for 4392 single nucleotide polymorphisms in genes implicated in pain perception, inflammation and mood and tested for association with pain sensitivity. The minor A allele of single nucleotide polymorphism rs16868943 was significantly associated with lower arm heat pain tolerance after correction for age, gender, race, and study site. This single nucleotide polymorphism was also nominally associated with other measures of heat pain sensitivity, including lowered knee heat pain tolerance (P = 1.14 × 10−5, P = 0.05 after Bonferroni correction), lowered arm heat pain threshold (P = 0.0039, uncorrected) and lowered knee heat pain threshold (P = 0.003, uncorrected). Addition of genotypes from 91 participants without knee pain produced a significant interaction between knee osteoarthritis status and the rs16868943 single nucleotide polymorphism in heat pain tolerance (P = 1.71 × 10−5), such that rs16868943 was not associated with heat pain tolerance in participants without knee pain (P = 0.12, beta = 1.3). This is the first study to show genetic association with heat pain tolerance in individuals with osteoarthritis. The association is specific to participants who have already developed knee osteoarthritis, suggesting that the COL11A2 gene, which has previously been associated with familial osteoarthritis, may play a role in pain sensitization after the development of osteoarthritis.

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Ancestry-based stratified analysis of Immunochip data identifies novel associations with celiac disease

Cited by 18 publications

References 20 publications

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

The methylome of the celiac intestinal epithelium harbours genotype-independent alterations in the HLA region

Kinesin-4 KIF21B limits microtubule growth to allow rapid centrosome polarization in T cells

Single nucleotide polymorphism in the COL11A2 gene associated with lowered heat pain sensitivity in knee osteoarthritis

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