Abstract Background Psoriasis has long been considered as a complex disease, and gene–gene or gene–environment interactions may jointly influence the etiology for psoriasis. Objective We evaluated ...the associations of single nucleotide polymorphisms (SNPs) in MHC region, and determined the epistasis and combined effects of MHC locus and IL12B , LCE on risk for psoriasis. Methods We genotyped SNP rs1265181 (MHC) in 5067 cases and 6404 controls, combining with the prior GWAS data (1139 cases and 1132 controls), we explored the genetic interaction among MHC locus, LCE and IL12B by using logistic regression analysis. We evaluated the combined effects of MHC locus and two non-MHC loci in the combined sample of 6206 cases and 7536 controls. Results Extremely high significance of association was detected between rs1265181 and psoriasis ( p combined <10E−300, OR = 16.52, 95% CI: 15.28–18.44). We observed significant interactions between MHC and LCE ( p = 0.0016) and between MHC and IL12B ( p = 0.0036). The risk increased some 26-fold in individuals with risk alleles in both MHC and LCE as compared with those without risk alleles, and individual carrying risk alleles of MHC and IL12B has around 36-fold higher risk of psoriasis than those with protective alleles. Conclusions This study provides evidence for the epistatic effects between MHC locus and LCE , IL12B genes. Besides, we suggest that MHC might be the main effect gene on the risk for psoriasis. This data may contribute to our understanding of psoriasis genetic interactions and account for the additional risk of certain patients to develop psoriasis.
Psoriasis (PS; MIM#177900) is a chronic inflammatory immune-mediated skin disorder. Although the disease is believed to be caused by a combination of genetic, immunologic and environmental factors, ...its complete etiology has not been fully understood. Here, we focused on the
BSG
(MIM#109480), a member of the immunoglobulin superfamily expressed ubiquitously in circulating immune cell populations. We observed that the expression level of BSG in PBMCs was elevated in psoriasis patients. To understand the underlying mechanism for this change, we genotyped the
rs8259
T>A SNP located in the 3′UTR of the
BSG
gene from 668 psoriasis patients and 1,143 healthy controls. The
rs8259
T allele was associated with significantly decreased psoriasis susceptibility (OR = 0.758, 95% CI 0.638–0.901,
p
= 0.002). Interestingly, the
rs8259
polymorphism was located in a seed region for miR-492 binding. The miR-492 was able to bind to the
BSG
3′UTR sequence bearing the
rs8259
T allele as assayed by luciferase reporter gene assay. The substitution of T with A abolished miR-492 binding. BSG protein expression in PBMCs from patients carrying the
rs8259
AA genotype was significantly higher than in those from patients carrying the
rs8259
TT genotype. Our study suggests that miR-492 may physiologically suppress BSG expression and the
BSG rs8259
polymorphism is associated with decreased psoriasis susceptibility through affecting miR-492 binding.
Atopic diseases, such as atopic dermatitis (AD) and asthma, are closely related to clinical phenotypes with hypersensitivity, and often share some similar genetic and pathogenic bases. Our recent ...GWAS identified three susceptibility gene/loci FLG (rs11204971 and rs3126085), 5q22.1 (rs10067777, rs7701890, rs13360927 and rs13361382) and 20q13.33 (rs6010620) to AD. The effect of these AD associated polymorphisms in asthma is so far unknown. To investigate whether AD relevant genetic variants is identical to asthma and reveal the differences in genetic factors between AD and asthma in Chinese Han population, seven AD associated single nucleotide polymorphisms (SNPs) as well as 3 other SNPs (rs7936562 and rs7124842 at 11q13.5 and rs4982958 at 14q11.2) from our previous AD GWAS were genotyped in 463 asthma patients and 985 controls using Sequenom MassArray system. We found rs4982958 at 14q11.2 was significantly associated with asthma (P = 3.04×10(-4), OR = 0.73). We also detected one significant risk haplotype GGGA from the 4 SNPs (rs10067777, rs7701890, rs13360927 and rs13361382) at 5q22.1 in AD cases (P(correction) = 3.60×10(-10), OR = 1.26), and the haplotype was suggestive of risk in asthma cases in this study (P = 0.014, P(correction) = 0.084, OR = 1.38). These SNPs (rs11204971, rs3126085, rs7936562, rs712484 and rs6010620) at AD susceptibility genes/loci FLG, 11q13.5 and 20q13.33 were not associated with asthma in this study. Our results further comfirmed that 14q11.2 was an important candidate locus for asthma and demonstrated that 5q22.1 might be shared by AD and asthma in Chinese Han population.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to ...SLE susceptibility in this study.
Forty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software.
This replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (P(meta) <5.00 × 10(-08)): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, P(meta) = 1.08 × 10(-08); rs4916219, OR = 0.80, P(meta )= 7.77 × 10(-09)), IRF8 (rs2934498, OR = 1.25, P(meta) = 4.97 × 10(-09)), miR-146a (rs2431697, OR = 0.69, P(meta) = 1.15 × 10(-22)), CD44 (rs2732547, OR = 0.82, P(meta) = 1.55 × 10(-11)), and TMEM39A (rs12494314, OR = 0.84, P(meta) = 1.01 × 10(-09)). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals.
This study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.
Interleukin (IL)-15 is an important proinflammatory cytokine that can protect epidermal keratinocytes (KCs) from ultraviolet-induced apoptosis and plays a role in the pathogenesis of psoriasis. ...However, the impact of IL-15 on KC differentiation remains unknown. In this study, isolated human primary epidermal KCs were treated with various concentrations of IL-15 for different times, and the expression of differentiation markers (keratin 1, involucrin and loricrin) and p53 as well as the activation of ERK, AKT and Notch induced by IL-15 in the absence or presence of Ca(2+) was detected by real-time PCR and Western blot. The results showed that stimulation with Ca(2+) alone increased the expression of KC differentiation markers and p53 and promoted the activation of Notch1. Pretreatment with IL-15 resulted in a decrease in the Ca(2+) -induced expression of KC differentiation markers and p53. Additionally, Ca(2+) continually inhibited the phosphorylation of ERK1/2 and activated AKT, and IL-15 reduced the effect of Ca(2+) on ERK1/2 and AKT. FR180204, a specific inhibitor of ERK1/2 phosphorylation, slightly attenuated the effect of Ca(2+) on the expression of differentiation markers and p53 and the activation of Notch1. In contrast, MK-2206, an inhibitor of pAKT, strongly blocked the expression of the differentiation markers and p53 and the activation of Notch1. An anti-IL-15 antibody neutralized the effect of IL-15 on KC differentiation. These results indicate that IL-15 inhibits the Ca(2+) -induced differentiation of KCs, mainly via the attenuation of Ca(2+) -stimulated PI3K-AKT signalling.
We have performed a large-scale replication study based on our previous genome-wide association study (GWAS) of SLE in the Chinese Han population to further explore additional genetic variants ...affecting susceptibility to SLE.
Thirty-eight single nucleotide polymorphisms from our GWAS were genotyped in two additional Chinese Han cohorts (total 3152 cases and 7050 controls) using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate.
Association evidence for rs16972959 (PRKCB at 16p11.2) and rs12676482 (8p11.21) with SLE was replicated independently in both replication cohorts (P < 0.05), showing high significance for SLE in combined all 4199 cases and 8255 controls of Chinese Han rs16972959: odds ratio (OR) = 0.81; 95% CI 0.76, 0.87; P(combined) = 1.35 × 10(-9); rs12676482: OR = 1.26; 95% CI 1.15, 1.38; P(combined) = 6.68 × 10(-7)). PRKCB is related to the established SLE immune-related pathway (NF-κB) and 8p11.21 contains important candidate genes such as IKBKB and DKK4. IKBKB is a critical component of NF-κB and DKK4 is an inhibitor of canonical Wnt signalling pathway. Interestingly, PRKCB is required for recruiting IKBKB into lipid rafts, up-regulating NF-κB-dependent survival signal.
Our findings provided novel insights into the genetic architecture of SLE and emphasized the contribution of multiple variants of modest effect. Further study focused on PRKCB, 8p11.21, should advance our understanding on the pathogenesis of SLE.
Interleukin (IL)‐15 is an important proinflammatory cytokine that can protect epidermal keratinocytes (KCs) from ultraviolet‐induced apoptosis and plays a role in the pathogenesis of psoriasis. ...However, the impact of IL‐15 on KC differentiation remains unknown. In this study, isolated human primary epidermal KCs were treated with various concentrations of IL‐15 for different times, and the expression of differentiation markers (keratin 1, involucrin and loricrin) and p53 as well as the activation of ERK, AKT and Notch induced by IL‐15 in the absence or presence of Ca2+ was detected by real‐time PCR and Western blot. The results showed that stimulation with Ca2+ alone increased the expression of KC differentiation markers and p53 and promoted the activation of Notch1. Pretreatment with IL‐15 resulted in a decrease in the Ca2+‐induced expression of KC differentiation markers and p53. Additionally, Ca2+ continually inhibited the phosphorylation of ERK1/2 and activated AKT, and IL‐15 reduced the effect of Ca2+ on ERK1/2 and AKT. FR180204, a specific inhibitor of ERK1/2 phosphorylation, slightly attenuated the effect of Ca2+ on the expression of differentiation markers and p53 and the activation of Notch1. In contrast, MK‐2206, an inhibitor of pAKT, strongly blocked the expression of the differentiation markers and p53 and the activation of Notch1. An anti‐IL‐15 antibody neutralized the effect of IL‐15 on KC differentiation. These results indicate that IL‐15 inhibits the Ca2+‐induced differentiation of KCs, mainly via the attenuation of Ca2+‐stimulated PI3K‐AKT signalling.
Expression quantitative trait loci (eQTL) databases represent a valuable resource to link disease-associated SNPs to specific candidate genes whose gene expression is significantly modulated by the ...SNP under investigation. We previously identified signal inhibitory receptor on leukocytes-1 (SIRL-1) as a powerful regulator of human innate immune cell function. While it is constitutively high expressed on neutrophils, on monocytes the SIRL-1 surface expression varies strongly between individuals. The underlying mechanism of regulation, its genetic control as well as potential clinical implications had not been explored yet.
Whole blood eQTL data of a Chinese cohort was used to identify SNPs regulating the expression of VSTM1, the gene encoding SIRL-1. The genotype effect was validated by flow cytometry (cell surface expression), correlated with electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP) and bisulfite sequencing (C-methylation) and its functional impact studied the inhibition of reactive oxygen species (ROS).
We found a significant association of a single CpG-SNP, rs612529T/C, located in the promoter of VSTM1. Through flow cytometry analysis we confirmed that primarily in the monocytes the protein level of SIRL-1 is strongly associated with genotype of this SNP. In monocytes, the T allele of this SNP facilitates binding of the transcription factors YY1 and PU.1, of which the latter has been recently shown to act as docking site for modifiers of DNA methylation. In line with this notion rs612529T associates with a complete demethylation of the VSTM1 promoter correlating with the allele-specific upregulation of SIRL-1 expression. In monocytes, this upregulation strongly impacts the IgA-induced production of ROS by these cells. Through targeted association analysis we found a significant Meta P value of 1.14 × 10
for rs612529 for association to atopic dermatitis (AD).
Low expression of SIRL-1 on monocytes is associated with an increased risk for the manifestation of an inflammatory skin disease. It thus underlines the role of both the cell subset and this inhibitory immune receptor in maintaining immune homeostasis in the skin. Notably, the genetic regulation is achieved by a single CpG-SNP, which controls the overall methylation state of the promoter gene segment.
Our previous genome-wide association studies on SLE have identified several susceptibility genes involved in NF-κB signaling pathway, including
TNFSF4
,
TNFAIP3
,
TNIP1
,
BLK
,
SLC15A4
and
UBE2L3.
...The aim of this study is to investigate the association model (additive, dominant, recessive) of these genes and search for possible gene–gene interactions between them. In this study, we explored the association model of these six genes and search for possible gene–gene interactions based on identified single-nucleotide polymorphisms (SNPs) among them by using logistic regression analysis in the combined sample of 4,199 cases and 8,255 controls. The most significant association evidence was observed under recessive model for all of these SNPs. Besides, significant interactions between these SNPs were observed in this study: the TNFSF4 and TNIP1 SNPs (
P
adjusted
= 1.68E−10), the TNFSF4 and SLC15A4 SNPs (
P
adjusted
= 3.55E−08), the TNFSF4 and UBE2L3 SNPs (
P
adjusted
= 8.74E−13), the TNIP1 and BLK SNPs (
P
adjusted
= 9.45E−10), the TNIP1 and UBE2L3 SNPs (
P
adjusted
= 8.25E−11), the TNFAIP3 and UBE2L3 SNPs (
P
adjusted
= 3.06E−14) and the BLK and SLC15A4 SNPs (
P
adjusted
= 4.51E−12). These results may contribute to our understanding of SLE genetic interactions and account for the additional risk of certain patients to develop SLE.
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