Cyclooxygenase-2 polymorphisms confer susceptibility to sarcoidosis but are not related to prognosis (original) (raw)
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Association of the 3050G>C Polymorphism in the Cyclooxygenase 2 Gene with Systemic Sarcoidosis
Archives of Medical Research, 2008
Background. We investigated the potential association between cyclooxygenase-2 (COX-2) gene polymorphisms and clinical manifestations of sarcoidosis. Methods. This observational cross-sectional study involved seven hospitals in Spain. We diagnosed patients with sarcoidosis according to the International Criteria. The following variables were recorded: age, gender, initial diagnostic methods, serum angiotensinconverting enzyme (ACE) levels, pulmonary function tests, radiological stage, and clinical findings at diagnosis. Manifestations of sarcoidosis were classified as systemic vs. nonsystemic. Genotyping of four COX-2 polymorphisms (COX2.5909TOG, COX2.8473TOC, COX2.926GOC, and COX2.3050GOC) was undertaken on DNA extracted from peripheral blood lymphocytes using fluorescent hybridization probes and melting curves. Results. A total of 131 sarcoid patients (63 males, mean age: 47 AE 15 years) were studied. One hundred twenty-six of these patients had one or more positive biopsies. The results demonstrated that genotype distribution for the COX2.3050GOC polymorphism was significantly different between patients with systemic sarcoidosis and those with nonsystemic forms ( p 5 0.046). After adjustment for age, gender, and serum ACE levels, a significant association between the carriage of at least one C allele of the COX2.3050GOC polymorphism and systemic sarcoidosis was observed (odds ratio [OR]: 2.3; 95% confidence interval [CI]: 1.03e5.12, p 5 0.031). Other polymorphisms were not associated with either clinical manifestations of the disease or serum ACE levels.
Genes and metabolic pathway of sarcoidosis: identification of key players and risk modifiers
Archives of Medical Science
Introduction: Sarcoidosis is a rare multisystem granulomatous disease with unknown etiology. The interplay of vitamin D deficiency and genetic polymorphisms in genes coding for the proteins relevant for metabolism of vitamin D is an important, but unexplored area. The aim of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in CYP2R1 (rs10741657), CYP27B1 (rs10877012), DBP (rs7041; rs4588), and VDR (rs2228570) genes and sarcoidosis, as well as the association between these SNPs and 25(OH)D levels in sarcoidosis patients. Material and methods: For that purpose we genotyped 86 sarcoidosis patients and 50 healthy controls using the PCR-RFLP method. Results: Subjects carrying the CC genotype of CYP27B1 rs10877012 have 10 times lower odds of suffering from sarcoidosis. Moreover, DBP rs4588 AA genotype was shown to be a susceptibility factor, where carriers of this genotype had eight times higher odds for developing sarcoidosis. In addition, the A allele of the DBP gene (rs4588) was associated with lower levels of 25(OH)D in sarcoidosis patients. Conclusions: These results suggest that patients with vitamin D deficiency should be regularly tested for genetic modifiers that are related to sarcoidosis in order to prevent development of serious forms of sarcoidosis.
Genetic linkage analysis of sarcoidosis phenotypes: the sarcoidosis genetic analysis (SAGA) study
Genes and Immunity, 2007
The sarcoidosis genetic analysis (SAGA) study previously identified eight chromosomal regions with suggestive evidence for linkage to sarcoidosis susceptibility in African-American sib pairs. Since the clinical course of sarcoidosis is variable and likely under genetic control, we used the affected relative pair portion of the SAGA sample (n ¼ 344 pairs) to perform multipoint linkage analyses with covariates based on pulmonary and organ involvement phenotypes. Chest radiographic resolution was the pulmonary phenotype with the highest LOD (logarithm of the backward odds, or likelihood ratio) score of 5.11 at D1S3720 on chromosome 1p36 (P ¼ 4 Â 10 À5 ). In general, higher LOD scores were attained for covariates that modeled clustered organ system involvement rather than individual organ systems, with the cardiac/renal group having the highest LOD score of 6.65 at chromosome 18q22 (P ¼ 2 Â 10 À5 ). The highest LOD scores for the other three organ involvement groups of liver/spleen/bone marrow, neuro/lymph and ocular/skin/joint were 3.72 at 10p11 (P ¼ 0.0004), 5.16 at 7p22 (P ¼ 4 Â 10 À5 ) and 2.93 at 10q26 (P ¼ 0.001), respectively. Most of the phenotype linkages did not overlap with the regions previously found linked to susceptibility. Our results suggest that genes influencing clinical presentation of sarcoidosis in African Americans are likely to be different from those that underlie disease susceptibility.
Iranian journal of public health, 2016
Sarcoidosis is a multisystem inflammatory disease of unknown origin with characterization of small granulomas. Angiotensin-converting enzyme (ACE) is a pathophysiologic marker of sarcoidosis. We present the ACE insertion/deletion (I/D) polymorphism in correlation with serum ACE level in Iranian patients with sarcoidosis. From Jan 2014 to Jan 2015, 102 Iranian patients who histopathologically diagnosed for sarcoidosis and 192 healthy age and sex-matched controls were recruited. PCR was used for detection of I/D polymorphism in ACE gene. Frequency of II/ID/DD genotype in sarcoidosis disease was 17%, 35.5%, and 47.1%, respectively. The frequency of D allele was 0.65. A significant association between I/D genotypes and mean of sACE level was seen (DD=85.2±22.9, P<0.001). More frequent genotype in sarcoidosis patients was DD (47%), ID genotype (45.9%) was found more in controls. Logistic regression analysis adjusting age and sex showed that ID to II (OR=0.35, 95%CI=0.17-0.73, P=0.005)...
Genes & Immunity, 2017
Sarcoidosis is a complex disease of unknown etiology characterized by the presence of granulomatous inflammation. Though various immune system pathways have been implicated in disease, the relationship between the genetic determinants of sarcoidosis and other inflammatory disorders has not been characterized. Herein, we examined the degree of genetic pleiotropy common to sarcoidosis and other inflammatory disorders to identify shared pathways and disease systems pertinent to sarcoidosis onset. To achieve this, we quantify the association of common variant polygenic risk scores from nine complex inflammatory disorders with sarcoidosis risk. Enrichment analyses of genes implicated in pleiotropic associations were further used to elucidate candidate pathways. In European-Americans, we identify significant pleiotropy between risk of sarcoidosis and risk of asthma (R 2 =2.03%; p=8.89×10 −9), celiac disease (R 2 =2.03%; p=8.21×10 −9), primary biliary cirrhosis (R 2 =2.43%; p=2.01×10 −10), and rheumatoid arthritis Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Orphanet journal of rare diseases, 2016
The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. Despite a sig...
Gene Technology, 2015
Sarcoidosis is a multisystemic immune disorder with unknown etiology. The disease is characterized by the spread of noncaseating epithelioid granulomas. Recent data from Genome Wide Association Studies (GWAS) have identified annexin A11 (ANXA11) as a new sarcoidosis susceptibility gene. These studies further indicated a strong association of a single nucleotide polymorphism (rs1049550) with sarcoidosis. Our aim was to determine whether the rs1049550 is associated with sarcoidosis in Turkish patients and to scan a 306 bp region of ANXA11 for other variations associated with sarcoidosis. Genomic DNA was isolated from the leukocytes of 53 sarcoidosis patients and 52 controls. A 306 bp region of ANXA11 encompassing rs1049550 was amplified by PCR, and the amplicons were sequenced using the Sanger method. The sequence data of both patients and controls were analyzed using the BLAST database to identify variations. The allele and genotype frequencies of the groups were analyzed using the chisquare test. The rs1049550 polymorphism was the only genetic variation observed in the 306 bp region. There was no statistically difference (χ 2 =2.689, P=0.273) when the frequencies of the CC, CT and TT genotypes in the sarcoidosis group (58.5%, 30.2% and 11.3%, respectively) were compared with the corresponding genotypes in the control group (65.4%, 17.3% and 17.3%, respectively). Furthermore, the allele frequencies for the rs1049550 polymorphism were not significantly different (χ 2 =0.006, P=0.940) when comparing the sarcoidosis patients (C=73.6%, T=26.4%) with the controls (C=74.0%, T=26.0%). Our results suggest that the ANXA11 rs1049550 polymorphism is not a genetic predisposition marker for Turkish patients with sarcoidosis.
Genome-wide association analysis reveals 12q13.3-q14.1 as new risk locus for sarcoidosis
European Respiratory Journal, 2013
Sarcoidosis is a systemic inflammatory disease of unknown aetiology, influenced by genetic and environmental factors. However, the loci so far identified for sarcoidosis explain only a part of its assumed heritability. To identify further susceptibility loci, we performed a genome-wide association analysis using the Affymetrix 6.0 Human GeneChip followed by validation and replication stages. After quality control, 637 cases, 1233 controls and 677 619 single-nucleotide polymorphisms (SNPs) were available for an initial screening. 99 SNPs were selected for validation in an independent study panel (1664 patients, 2932 controls). SNP rs1050045 was significantly associated with sarcoidosis (corrected p50.0215) in the validation panel and yielded a p-value of 9.22610-8 (OR 1.24) in the meta-analysis of the screening and validation stage. A meta-analysis of three populations from Germany, the Czech Republic and Sweden confirmed this finding (p50.024; OR 1.14). Fine-mapping and mRNA expression studies pointed to osteosarcoma amplified 9 (OS9) as the most likely candidate for the underlying risk factor. The OS9 protein plays an important role in endoplasmic reticulum-associated protein degradation and acts during Toll-like receptor induced activation of myeloid cells. Expression analyses of OS9 mRNA provide evidence for a functional mechanism underlying the detected association signal.
Sarcoidosis extent relates to molecular variability
Clinical and Experimental Immunology, 2017
Summary The molecular basis of sarcoidosis phenotype heterogeneity and its relationship to effective treatment of sarcoidosis have not been elucidated. Peripheral samples from sarcoidosis subjects who participated in a Phase II study of golimumab [anti-tumour necrosis factor (TNF)-α] and ustekinumab [anti-interleukin (IL)−12p40] were used to measure the whole blood transcriptome and levels of serum proteins. Differential gene and protein expression analyses were used to explore the molecular differences between sarcoidosis phenotypes as defined by extent of organ involvement. The same data were also used in conjunction with an enrichment algorithm to identify gene expression changes associated with treatment with study drugs compared to placebo. Our analyses revealed marked heterogeneity among the three sarcoidosis phenotypes included in the study cohort, including striking differences in enrichment of the interferon pathway. Conversely, enrichments of multiple pathways, including T...