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1.  Identification of Immune-Relevant Factors Conferring Sarcoidosis Genetic Risk 
Rationale: Genetic variation plays a significant role in the etiology of sarcoidosis. However, only a small fraction of its heritability has been explained so far.
Objectives: To define further genetic risk loci for sarcoidosis, we used the Immunochip for a candidate gene association study of immune-associated loci.
Methods: Altogether the study population comprised over 19,000 individuals. In a two-stage design, 1,726 German sarcoidosis cases and 5,482 control subjects were genotyped for 128,705 single-nucleotide polymorphisms using the Illumina Immunochip for the screening step. The remaining 3,955 cases, 7,514 control subjects, and 684 parents of affected offspring were used for validation and replication of 44 candidate and two established risk single-nucleotide polymorphisms.
Measurements and Main Results: Four novel susceptibility loci were identified with genome-wide significance in the European case-control populations, located on chromosomes 12q24.12 (rs653178; ATXN2/SH2B3), 5q33.3 (rs4921492; IL12B), 4q24 (rs223498; MANBA/NFKB1), and 2q33.2 (rs6748088; FAM117B). We further defined three independent association signals in the HLA region with genome-wide significance, peaking in the BTNL2 promoter region (rs5007259), at HLA-B (rs4143332/HLA-B*0801) and at HLA-DPB1 (rs9277542), and found another novel independent signal near IL23R (rs12069782) on chromosome 1p31.3.
Conclusions: Functional predictions and protein network analyses suggest a prominent role of the drug-targetable IL23/Th17 signaling pathway in the genetic etiology of sarcoidosis. Our findings reveal a substantial genetic overlap of sarcoidosis with diverse immune-mediated inflammatory disorders, which could be of relevance for the clinical application of modern therapeutics
PMCID: PMC4595678  PMID: 26051272
Immunochip; HLA; IL23; BTNL2; association
2.  Variation in the IL1B, TNF and IL6 genes and individual susceptibility to prosthetic joint infection 
BMC Immunology  2012;13:25.
Prosthetic joint infection (PJI) is an important failure mechanism of total joint arthroplasty (TJA). Here we examine whether the particular genetic variants can lead to increased susceptibility to PJI development.
We conducted a genetic-association study to determine whether PJI could be associated with functional cytokine gene polymorphisms (CGP) influencing on innate immunity response. A case–control design was utilized and previously published criteria for PJI were included to distinguish between cases and control subjects with/without TJA. Six single nucleotide polymorphisms (SNPs) located in the genes for interleukin-1beta (SNP: IL1B-511, +3962), tumour necrosis factor alpha (TNF-308, -238) and interleukin-6 (IL6-174, nt565) were genotyped in 303 Caucasian (Czech) patients with TJA (89 with PJI / 214 without PJI), and 168 unrelated healthy Czech individuals without TJA. The results showed that carriers of the less common IL1B−511*T allele were overrepresented in the group of TJA patients with PJI (69%) in comparison with those that did not develop PJI (51%, p = 0.006, pcorr = 0.037) and with healthy controls (55%, p = 0.04, pcorr = N.S.). There was no significant difference in the distribution of the remaining five investigated CGPs and their haplotypes between groups.
A functional variant of the gene encoding for IL-1beta was preliminarily nominated as a genetic factor contributing to the susceptibility to PJI. Our results should be independently replicated; studies on the functional relevance of IL1B gene variants in PJI are also needed.
PMCID: PMC3475038  PMID: 22568934
3.  Association of C1QB gene polymorphism with schizophrenia in Armenian population 
BMC Medical Genetics  2011;12:126.
Schizophrenia is a complex, multifactorial psychiatric disorder. Our previous findings indicated that altered functional activity of the complement system, a major mediator of the immune response, is implicated in the pathogenesis of schizophrenia. In order to explore whether these alterations are genetically determined or not, in the present study we evaluated the possible association of complement C1Q component gene variants with susceptibility to schizophrenia in Armenian population, focusing on four frequent single nucleotide polymorphisms (SNPs) of C1QA and C1QB genes.
In the present study four SNPs of the complement C1Q component genes (C1QA: rs292001, C1QB rs291982, rs631090, rs913243) were investigated in schizophrenia-affected and healthy subjects. Unrelated Caucasian individuals of Armenian nationality, 225 schizophrenic patients and the same number of age- and sex-matched healthy subjects, were genotyped. Genotyping was performed using polymerase chain reaction with sequence-specific primers (PCR-SSP) and quantitative real-time (qRT) PCR methods.
While there was no association between C1QA rs292001, C1QB rs913243 and rs631090 genetic variants and schizophrenia, the C1QB rs291982*G minor allele was significantly overrepresented in schizophrenic patients (G allele frequency 58%) when compared to healthy subjects (46%, OR = 1.64, pcorr = 0.0008). Importantly, the susceptibility for schizophrenia was particularly associated with C1QB rs291982 GG genotype (OR = 2.5, pcorrected = 9.6E-5).
The results obtained suggest that C1QB gene may be considered as a relevant candidate gene for susceptibility to schizophrenia, and its rs291982*G minor allele might represent a risk factor for schizophrenia at least in Armenian population. Replication in other centers/populations is necessary to verify this conclusion.
PMCID: PMC3192735  PMID: 21951915
4.  Functional characterization of the complement receptor type 1 and its circulating ligands in patients with schizophrenia 
Whereas the complement system alterations contribute to schizophrenia, complement receptors and regulators are little studied. We investigated complement receptor type 1 (CR1) expression on blood cells, the levels of circulating immune complexes (CIC) containing ligands of CR1, C1q complement protein and fragments of C3 complement protein (C1q-CIC, C3d-CIC), and CR1 C5507G functional polymorphism in schizophrenia patients and controls.
We found an increased C1q-CIC level and CR1 expression on blood cells, elevated number of CR1 positive erythrocytes and reduced number of CR1 positive lymphocytes and monocytes in patients compared to controls. No difference in the levels of C3d-CIC between groups was observed. Higher CR1 expression on erythrocytes in CC genotype versus CG+GG for both groups was detected, whereas no difference was observed for other cell populations. Our results indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level.
Our study for the first time indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level. Further studies in other ethnic groups are needed to replicate these findings.
PMCID: PMC3176470  PMID: 21867543
5.  CCL5/RANTES Gene Polymorphisms in Slavonic Patients with Myocardial Infarction 
Mediators of Inflammation  2011;2011:525691.
Coronary artery inflammation is a critical process in the pathogenesis of myocardial infarction (MI). The chemokine CCL5/RANTES (regulated upon activation, normal T cells expressed and secreted) is expressed in advanced atherosclerotic lesions. Functional polymorphisms of the RANTES gene can, therefore, be involved in the pathogenesis of coronary artery disease. We examined the association of polymorphisms in the RANTES gene with myocardial infarction in Slavonic populations of Czech and Russian origin. A total of 467 post-MI patients and 337 control subjects were genotyped for RANTES promoter G-403A (rs2107538) and intron 1.1 T/C (rs2280789) variants by PCR-SSP. Both RANTES genotypes and allele frequencies did not differ between case and control groups. Haplotype-based analysis also failed to reveal an association between MI and investigated markers. Strong linkage disequilibrium was detected between particular RANTES alleles. The data do not support an association between RANTES G-403A polymorphism and MI, as reported previously.
PMCID: PMC3086320  PMID: 21547257
6.  Variation in cytokine genes can contribute to severity of acetabular osteolysis and risk for revision in patients with ABG 1 total hip arthroplasty: a genetic association study 
BMC Medical Genetics  2009;10:109.
The differences in total hip arthroplasty (THA) survivorship may be influenced by individual susceptibility to periprosthetic osteolysis. This may be driven by functional polymorphisms in the genes for cytokines and cytokine receptors involved in the development of osteolysis in THA, thereby having an effect on the individual's phenotype.
We performed a study on 22 single-nucleotide polymorphisms (SNPs) for 11 cytokines and two cytokine receptor candidate genes for association with severity of acetabular osteolysis and risk to failure in THA. Samples from 205 unrelated Caucasian patients with cementless type THA (ABG 1) were investigated. Distribution of investigated SNP variants between the groups of mild and severe acetabular osteolysis was determined by univariate and multivariate analysis. Time-dependent output variables were analyzed by the Cox hazards model.
Univariate analysis showed: 1) TNF-238*A allele was associated with severe osteolysis (odds ratio, OR = 6.59, p = 0.005, population attributable risk, PAR 5.2%); 2) carriers of the IL6-174*G allele were 2.5 times more prone to develop severe osteolysis than non-carriers (OR = 2.51, p = 0.007, PAR = 31.5%); 3) the carriage of IL2-330*G allele was associated with protection from severe osteolysis (OR = 0.55, p = 0.043). Based on logistic regression, the alleles TNF-238*A and IL6-174*G were independent predictors for the development of severe acetabular osteolysis. Carriers of TNF-238*A had increased cumulative hazard of THA failure according to Cox model (p = 0.024). In contrast, IL2-330*G allele predicted lower cumulative hazard of THA failure (p = 0.019).
Genetic variants of proinflammatory cytokines TNF-alpha and IL-6 confer susceptibility to severe OL. In this way, presence of the minor TNF allele could increase the cumulative risk of THA failure. Conversely, SNP in the IL2 gene may protect carriers from the above THA complications.
PMCID: PMC2774318  PMID: 19860911
7.  Association of MCP-1 -2518 A/G Single Nucleotide Polymorphism with the Serum Level of CRP in Slovak Patients with Ischemic Heart Disease, Angina Pectoris, and Hypertension 
Mediators of Inflammation  2009;2009:390951.
The aim of our work was to find if MCP-1 -2518 (A/G) single nucleotide polymorphism (SNP) influences somehow the serum concentrations of high-sensitive CRP (hsCRP) both in patients suffering from ischemic heart disease (IHD), myocardial infarction (MI), angina pectoris (AP), and hypertension (HT) and in control group of healthy subjects. Totally, 263 patients with the diagnosis of IHD, out of them 89 with MI, 145 with AP, 205 with HT, and also 67 healthy subjects were included in the study. First, we estimated the serum levels of hsCRP. We found that patients with AP had significantly higher serum level of hsCRP than both control group of healthy subjects (P = .043) and IHD patients without AP (P = .026). The presence of the mutant G allele statistically significantly correlated with the higher serum levels of hsCRP in patients with IHD (P = .016), AP (P = .004), and HT (P = .013). Higher correlations were found in men (AP: P = .019; HT: P = .047). In all cases the highest levels of hsCRP were found both in patients and healthy controls with homozygous GG genotype.
PMCID: PMC2715824  PMID: 19639050
8.  PSMB2 and RPL32 are suitable denominators to normalize gene expression profiles in bronchoalveolar cells 
For accuracy of quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), normalisation with suitable reference genes is required. To date, no reference genes have been validated for expression studies of bronchoalveolar (BAL) cells. The aims of this study were to identify gene(s) with stable mRNA expression in BAL cells irrespective of gender, smoking, BAL cellular composition, lung pathology, treatment; and to assess the influence of reference genes on target gene expression data.
The mRNA expression of ten housekeeping genes (ACTB, ARF1, CANX, G6PD, GAPDH, GPS1, GNB2L1, PSMB2, PSMD2, RPL32) was investigated by qRT-PCR in BAL cells from 71 subjects across a spectrum of lung diseases. The analyses were validated in an independent BAL cohort from 63 sarcoidosis patients and 17 control subjects. A second derivative method was used to calculate expression values (CTt); an equivalence test, applets BestKeeper, geNorm and NormFinder were applied to investigate gene expression stability. Of the investigated genes, PSMB2 (CTt ± SD, 23.66 ± 0.86) and RPL32 (18.65 ± 0.92) were the most stable; both were constantly expressed in BAL samples from parallel investigated cohorts irrespective of evaluated variables. Finally, to demonstrate effect of traditional (ACTB/GAPDH) and novel (PSMB2/RPL32) reference genes as denominators, expression of two cytokines known associated with sarcoidosis was investigated in sarcoid BAL cells. While normalization with PSMB2/RPL32 resulted in elevated IFNG mRNA expression (p = 0.004); no change was observed using GAPDH/ACTB (p > 0.05). CCL2 mRNA up-regulation was observed only when PSMB2/RPL32 were used as denominators (p < 0.03).
PSMB2 and RPL32 are, therefore, suitable reference genes to normalize qRT-PCR in BAL cells in sarcoidosis, and other interstitial lung disease.
PMCID: PMC2529339  PMID: 18671841
9.  MCP-1 −2518 A/G Single Nucleotide Polymorphism in Slovak Patients with Systemic Sclerosis 
Mediators of Inflammation  2008;2008:204063.
Recent study in a group of German patients with SSc has implicated the SNP in the MCP-1 gene (−2518 A to G) as a factor of susceptibility to SSc. Reflecting the need for replication of genetic association studies, we investigated if this SNP is associated with SSc in another Caucasian population. MCP-1 −2518 A/G genotypes were determined using PCR-SSP in 46 SSc patients and in 449 healthy subjects, all unrelated and of Slovak (Slavonic) origin. The distribution of MCP-1 −2518 A/G genotypes complied with the Hardy-Weinberg equilibrium both in patient and healthy control groups. There was no difference in MCP-1 −2518*G allele frequency between SSc patients and healthy subjects (patients: 0.23; controls: 0.24; P > .05). Furthermore, MCP-1 −2518 GG homozygotes were similarly represented among SSc patients and healthy subjects (P > .05). The association of MCP-1 −2518 A/G SNP with SSc observed originally in German population was not replicated in the Slovak population.
PMCID: PMC2408933  PMID: 18528529
10.  In vitro pharmacoregulation of CC chemokine ligand 5 and its receptor CCR5 in diffuse lung diseases. 
Mediators of Inflammation  2003;12(4):215-220.
BACKGROUND: CC chemokine ligand (CCL)5 and its receptor CCR5 contribute to leukocyte migration into lungs of patients with diffuse lung diseases (DLD). Pharmacological regulation of CCL5 and CCR5 expression was therefore explored in bronchoalveolar cells obtained from patients with DLD. METHODS: Cells from 21 patients were co-cultivated in vitro with tumour necrosis factor-alpha and dexamethasone, cyclosporin A (CyA) or pentoxifylline. Chemokine mRNA expression and protein production was assessed by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Dexamethasone altered CCL5 mRNA expression and suppressed its protein levels. CyA inhibited chemokine mRNA expression but not protein production. Pentoxifylline did not affected chemokine expression. Both dexamethasone and CyA suppressed CCR5 mRNA transcripts. CONCLUSION: In conclusion, while dexamethasone downregulates the CCL5 functional form, CyA and pentoxifylline have no effects on CCL5 protein. These data provide in vitro correlation for clinical applications of immunomodulators in therapy of DLD.
PMCID: PMC1781614  PMID: 14514472

Results 1-10 (10)