Sarcoidosis is a systemic inflammatory disease characterized by the formation of granulomas in affected organs. Genome-wide association studies (GWASs) of this disease have been conducted only in ...European population. We present the first sarcoidosis GWAS in African Americans (AAs, 818 cases and 1,088 related controls) followed by replication in independent sets of AAs (455 cases and 557 controls) and European Americans (EAs, 442 cases and 2,284 controls). We evaluated >6 million SNPs either genotyped using the Illumina Omni1-Quad array or imputed from the 1000 Genomes Project data. We identified a novel sarcoidosis-associated locus, NOTCH4, that reached genome-wide significance in the combined AA samples (rs715299, P(AA-meta) = 6.51 × 10(-10)) and demonstrated the independence of this locus from others in the MHC region in the same sample. We replicated previous European GWAS associations within HLA-DRA, HLA-DRB5, HLA-DRB1, BTNL2, and ANXA11 in both our AA and EA datasets. We also confirmed significant associations to the previously reported HLA-C and HLA-B regions in the EA but not AA samples. We further identified suggestive associations with several other genes previously reported in lung or inflammatory diseases.
Sarcoidosis Iannuzzi, Michael C; Rybicki, Benjamin A; Teirstein, Alvin S
The New England journal of medicine,
11/2007, Letnik:
357, Številka:
21
Journal Article
Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate ...biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk.
Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping ...provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions-6p24.3-p12.1, 17p13.3-13.1, 2p13.3-q12.1, and 6q23.3-q25.2-in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3-p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10-11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3-13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10-6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.
Sarcoidosis is a multisystem disease of unknown cause. Löfgren's syndrome (LS) is a characteristic subgroup of sarcoidosis that is associated with a good prognosis in sarcoidosis. However, little is ...known about its genetic architecture or its broader phenotype, non-LS sarcoidosis.
To address the genetic architecture of sarcoidosis phenotypes, LS and non-LS.
An association study in a white Swedish cohort of 384 LS, 664 non-LS, and 2,086 control subjects, totaling 3,134 subjects using a fine-mapping genotyping platform was conducted. Replication was performed in four independent cohorts, three of white European descent (Germany, n = 4,975; the Netherlands, n = 613; and Czech Republic, n = 521), and one of black African descent (United States, n = 1,657), totaling 7,766 subjects.
A total of 727 LS-associated variants expanding throughout the extended major histocompatibility complex (MHC) region and 68 non-LS-associated variants located in the MHC class II region were identified and confirmed. A shared overlap between LS and non-LS defined by 17 variants located in the MHC class II region was found. Outside the MHC region, two LS-associated loci, in ADCY3 and between CSMD1 and MCPH1, were observed and replicated.
Comprehensive and integrative analyses of genetics, transcription, and pathway modeling on LS and non-LS indicates that these sarcoidosis phenotypes have different genetic susceptibility, genomic distributions, and cellular activities, suggesting distinct molecular mechanisms in pathways related to immune response with a common region.
Individual matching in case-control studies improves statistical efficiency over random selection of controls but can lead to selection bias if cases are excluded due to the lack of appropriate ...controls or residual confounding with less strict matching criteria. We introduce flex matching, an algorithm using multiple rounds of control selection with successively relaxed matching criteria to select controls for cases.
We simulated exposure-disease relationships in multiple cohort data sets with a range of confounding scenarios and conducted 16,800,000 nested case-control studies, comparing random selection of controls, strict matching, and flex matching. We computed average bias and statistical efficiency in estimates of exposure-disease relationships under each matching strategy.
On average, flex matching produced the least biased estimates of exposure-disease associations with the smallest standard errors. Strict matching algorithms that excluded cases for whom matched controls could not be identified produced biased estimates with larger standard errors. Estimates from studies with random assignment of controls were relatively unbiased, but the standard errors were larger than from studies using flex matching.
Flex matching should be considered for case-control designs, especially for biomarker studies where matching on technical artifacts is necessary and maximizing efficiency is a priority.
The expression of desmogleins (DSGs), which are known to be crucial for establishing and maintaining the cell-cell adhesion required for tissue integrity, has been well characterized in the epidermis ...and hair follicle; however, their expression in other epithelial tissues such as prostate is poorly understood. Although downregulation of classical cadherins, such as E-cadherin, has been described in prostate cancer tissue samples, the expression of desmogleins has only been previously reported in prostate cancer cell lines. In this study we characterized desmoglein expression in normal prostate tissues, and further investigated whether Desmoglein 2 (DSG2) expression specifically can serve as a potential clinical prognostic factor for patients diagnosed with primary prostate cancer.
We utilized immunofluorescence to examine DSG2 expression in normal prostate (n = 50) and in a clinically well-characterized cohort of prostate cancer patients (n = 414). Correlation of DSG2 expression with clinico-pathological characteristics and biochemical recurrence was analyzed to assess its clinical significance.
These studies revealed that DSG2 and DSG4 were specifically expressed in prostatic luminal cells, whereas basal cells lack their expression. In contrast, DSG1 and DSG3 were not expressed in normal prostate epithelium. Further analyses of DSG2 expression in prostate cancer revealed that reduced levels of this biomarker were a significant independent marker of poor clinical outcome.
Here we report for the first time that a low DSG2 expression phenotype is a useful prognostic biomarker of tumor aggressiveness and may serve as an aid in identifying patients with clinically significant prostate cancer.
Granuloma genes in sarcoidosis: what is new? Fischer, Annegret; Rybicki, Benjamin A
Current opinion in pulmonary medicine,
2015-September, Letnik:
21, Številka:
5
Journal Article
Nonnecrotizing granulomas in the affected organ are the hallmark of sarcoidosis. This review summarizes most recent genetic findings in sarcoidosis with a focus on genes that might influence ...granuloma formation or resolution. Specific results in multiple ethnic groups and certain clinical subphenotypes, such as extra-pulmonary organ involvement, are discussed.
Associations of genetic variants in antigen-presenting molecules (HLA-DRB1) were shown to confer risk to sarcoidosis and certain disease phenotypes in populations of different ethnic origins. Specific DRB1 alleles, such as *0301 and *0302, appear to confer protection against chronic disease, but in an ethnic-specific manner illustrating the extensive genetic heterogeneity and complexity at this locus. Mechanistic studies of putative sarcoid antigens lend further credence to a role of HLA-DRB1 in disease pathogenesis. With relevance to granuloma formation, genes involved in apoptotic processes and immune cell activation were further confirmed (ANXA11 and BTNL2) in multiple ethnicities; others were newly identified (XAF1). Linking mechanism to clinical application, a TNF variant was shown to correlate with anti-TNF response in sarcoidosis patients.
The investigation of known and novel risk variants for sarcoidosis and specific clinical phenotypes in various ethnicities highlights the genetic complexity of the disease. Detailed subanalysis of disease phenotypes revealed the potential for prediction of extra-pulmonary organ involvement and therapy response based on the patient's genotype.
Objective There are known disparities in endometrial cancer survival with black women who experience a greater risk of death compared with white women. The purpose of this investigation was to ...evaluate the role of comorbid conditions as modifiers of endometrial cancer survival by race. Study Design Two hundred seventy-one black women and 356 white women who had been diagnosed with endometrial cancer from 1990-2005 were identified from a large urban integrated health center. A retrospective chart review was conducted to gather information on comorbid conditions and other known demographic and clinical predictors of survival. Results Black women experienced a higher hazard of death from any cause (hazard ratio HR 1.51; 95% confidence interval CI, 1.22–1.87) and from endometrial cancer (HR, 2.42; 95% CI, 1.63–3.60). After adjustment for known clinical prognostic factors and comorbid conditions, the hazard of death for black women was elevated but no longer statistically significant for overall survival (HR, 1.22; 95% CI, 0.94–1.57), and the hazard of death from endometrial cancer remained significantly increased (HR, 2.27; 95% CI, 1.39–3.68). Both black and white women with a history of hypertension experienced a lower hazard of death from endometrial cancer (HR, 0.47; 95% CI, 0.23–0.98; and HR, 0.35; 95% CI, 0.19–0.67, respectively). Conclusion The higher prevalence of comorbid conditions among black women does not explain fully the racial disparities that are seen in endometrial cancer survival. The association between hypertension and a lower hazard of death from endometrial cancer is intriguing, and further investigation into the underlying mechanism is needed.
Purpose: Identify genes associated with ocular sarcoidosis (OS).
Methods: We genotyped 1.1 million genetic variants to identify significant OS associations, defined as those that achieved p < 5 × 10
...−8
in a genome-wide comparison of OS cases to healthy controls in our European- or African-American cohorts (EA, AA). Potential functional roles of all associated variants were assessed.
Results: Eight significant non-HLA variants were found in AA OS cases compared to healthy controls and confirmed as at least suggestive when comparing OS to non-OS cases. Seven of these were within MAGI1 and include transcription factor binding sites and expression quantitative trait loci. Our EA cohort, while showing similar effect sizes at variants within MAGI1, had no significant variants. Association analysis of HLA-DRB1 alleles confirmed association to OS in EA to *04:01.
Conclusion: Our results support organ-specific genetic risk in OS in a compelling candidate, MAGI1, known to be associated with barrier function and autoimmunity.
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