<i><scp>IL</scp>10</i> low‐frequency variants in <scp>B</scp>ehçet's disease patients

Matos, Maria Margarida Nunes Gaspar de; Xavier, Joana M.; Abrantes, Patrícia; Sousa, Inês; Rei, Nádia; Davatchi, Fereydoun; Shahram, Farhad; Jesus, Gorete; Barcelos, Filipe; Vedes, Joana; Salgado, Manuel; Abdollahi, Bahar Sadeghi; Nadji, Abdolhadi; Moraes‐Fontes, Maria Francisca; Shafiee, Niloofar Mojarad; Ghaderibarmi, Fahmida; Patto, José Vaz; Oliveira, Sofia

doi:10.1111/1756-185x.12369

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…These unevaluated variants can have possible effect on BD, and may be responsible for the missing heritability in BD. Indeed, targeted sequencing of ERAP1, MEFV, TLR4, and IL10 in BD patients identified novel population specific functional rare variants strongly associated with BD (Kirino et al, 2013b;Matos et al, 2017). We propose that sequencing of genes with population differentiation estimates higher than their BD associated variants can identify novel BD risk variants, and can contribute to understanding of molecular pathogenesis of BD.…”

Section: Discussionmentioning

confidence: 91%

Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility

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Kaplan²

2022

Front. Genet.

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Behçet disease (BD) is a polygenic, multifactorial, multisystem inflammatory condition with unknown etiology. Global distribution of BD is geographically structured, highest prevalence observed among East Asian, Middle Eastern, and Mediterranean populations. Although adaptive selection on a few BD susceptibility loci is speculated, a thorough evolutionary analysis on the genetic architecture of BD is lacking. We aimed to understand whether increased BD risk in the human populations with high prevalence is due to past selection on BD associated genes. We performed population genetics analyses with East Asian (high BD prevalence), European (low/very low BD prevalence), and African (very low/no BD prevalence) populations. Comparison of ancestral and derived alleles’ frequencies versus their reported susceptible or protective effect on BD showed both derived and ancestral alleles are associated with increased BD risk. Variants showing higher risk to and more significant association with BD had smaller allele frequency differences, and showed less population differentiation compared to variants that showed smaller risk and less significant association with BD. Results suggest BD alleles are not unique to East Asians but are also found in other world populations at appreciable frequencies, and argue against selection favoring these variants only in populations with high BD prevalence. BD associated gene analyses showed similar evolutionary histories driven by neutral processes for many genes or balancing selection for HLA (Human Leukocyte Antigen) genes in all three populations studied. However, nucleotide diversity in several HLA region genes was much higher in East Asians suggesting selection for high nucleotide and haplotype diversity in East Asians. Recent selective sweep for genes involved in antigen recognition, peptide processing, immune and cellular differentiation regulation was observed only in East Asians. We conclude that the evolutionary processes shaping the genetic diversity in BD risk genes are diverse, and elucidating the underlying specific selection mechanisms is complex. Several of the genes examined in this study are risk factors (such as ERAP1, IL23R, HLA-G) for other inflammatory diseases. Thus, our conclusions are not only limited to BD but may have broader implications for other inflammatory diseases.

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Section: Discussionmentioning

confidence: 91%

Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility

Sezgın

Kaplan²

2022

Front. Genet.

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“…DNA was extracted as described previously [ 26 ]. Quantification of genomic DNA was performed in triplicate using the Picogreen ® dsDNA Quantitation Kit (Invitrogen, Oregon, USA) in a PerkinElmer top Fluoroscence reader (PerkinElmer, Inc., Waltham, USA).…”

Section: Methodsmentioning

confidence: 99%

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

et al. 2016

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Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22–2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08–2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29–2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.

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“…The strong association of HLA-51 with increased risk of developing BD is well documented (6)(7). In addition, genome wide association studies (GWAS) demonstrated that variants in IL-23R-IL12RB2, and IL-10 are associated with BD susceptibility (8)(9).…”

Section: Introductionmentioning

confidence: 99%

LPS-induced Src family kinases activity mediates IL-10 production through activation of STAT3 in peripheral blood mononuclear cells of patients with Behçet's Disease

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Bozkurt

et al. 2017

Cell Mol Biol (Noisy-le-grand)

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Behçet's disease (BD) is achronic inflammatory disorder characterized by recurrent oral and genital ulcers, uveitis and skin lesions. Although,the pathogenesis of BD remains poorly understood, excessive or dysregulatedcytokine production including IL-10 is associated with BD. Revealing the key molecular mechanism by which IL-10 expression is regulated is crucial to understanding the pathogenesis of BD. The aim of this study was to investigate whether Src family kinases (SFKs) are upstream mediators of STAT3/IL-10 pathway in peripheral blood mono nuclear cells(PBMCs) of active BD patients.Twenty active BD patients and twenty healthy subjects used as control were included in the study. PBMCs were isolated from total blood by density gradient centrifugation.Western blot and ELISA methods were applied to analyzelipopolysaccharide (LPS)-induced SFKs/STAT3/IL10 signaling pathway in BD.Inhibition of SFKs activity suppressed LPS-induced IL-10 production in PBMCs fromboth controls and active BD patients. Similarly, blockage of STAT3 activation abrogated LPS-induced IL-10 production. However, LPS-induced STAT3 activation required for IL-10 production was found to be dependent on SFKs activity as LPS-induced STAT3 phosphorylation was reduced by the inhibition of SFKs activity in PBMCs of active BD patients.SFKs activity is essential for LPS-induced STAT3/IL-10 pathway in PBMCs of active BD patients. Manipulation of the SFKs activity may offer a novel therapeutic approach for BD.

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IL10 low‐frequency variants in Behçet's disease patients

Cited by 4 publications

References 14 publications

Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility

Diverse selection pressures shaping the genetic architecture of behçet disease susceptibility

Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

LPS-induced Src family kinases activity mediates IL-10 production through activation of STAT3 in peripheral blood mononuclear cells of patients with Behçet's Disease

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