Disease Phenotypic Characteristics Research Articles

Differential Activation of NRF2 Signaling Pathway in Renal-Cell Carcinoma Caki Cell Lines

Renal-cell carcinoma (RCC) is a heterogeneous disease consisting of several subtypes based on specific genomic profiles and histological and clinical characteristics. The subtype with the highest prevalence is clear-cell RCC (ccRCC), next is papillary RCC (pRCC), and then chromophobe RCC (chRCC). The ccRCC cell lines are further subdivided into prognostic expression-based subtypes ccA or ccB. This heterogeneity necessitates the development, availability, and utilization of cell line models with the correct disease phenotypic characteristics for RCC research. In this study, we focused on characterizing proteomic differences between the Caki-1 and Caki-2 cell lines that are commonly used in ccRCC research. Both cells are primarily defined as human ccRCC cell lines. Caki-1 cell lines are metastatic, harboring wild-type VHL, whereas Caki-2 are considered as the primary ccRCC cell lines expressing wild-type von Hippel-Lindau protein (pVHL). Here, we performed a comprehensive comparative proteomic analysis of Caki-1 and Caki-2 cells using tandem mass-tag reagents together with liquid chromatography mass spectrometry (LC/MS) for the identification and quantitation of proteins in the two cell lines. Differential regulation of a subset of the proteins identified was validated using orthogonal methods including western blot, q-PCR, and immunofluorescence assays. Integrative bioinformatic analysis identifies the activation/inhibition of specific molecular pathways, upstream regulators, and causal networks that are uniquely regulated and associated with the two cell lines and RCC subtypes, and potentially the disease stage. Altogether, we have identified multiple molecular pathways, including NRF2 signaling, which is the most significantly activated pathway in Caki-2 versus Caki-1 cells. Some of the differentially regulated molecules and signaling pathways could serve as potential diagnostic and prognostic biomarkers and therapeutic targets amongst ccRCC subtypes.

A71 SIGNIFICANT RACIAL/ETHNIC DIFFERENCES EXIST IN THE RECEIPT OF IBD-RELATED SURGERY: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Patients with inflammatory bowel disease (IBD) may require surgical intervention for management of their disease. There is a rising incidence of IBD in racial and ethnic minorities but studies regarding healthcare utilization patterns in these populations have yielded variable results. Purpose We aimed to examine the differences in surgical rates of ethnic and racial groups compared to White patients with IBD. Method Electronic databases were searched through December 20, 2021. Studies that compared ulcerative colitis (UC) or Crohn’s disease (CD) surgery rates between different racial/ethnic groups were included. Both pediatric and adult studies were included. Pooled event rates were generated and p-value < 0.05 was considered statistically significant in generating odds ratios (OR) with 95% confidence interval (CI). We also compared differences in disease location, phenotype, and IBD-medication exposure amongst different groups included. Result(s) Forty-one studies stratified rates of IBD-related surgeries by race or ethnicity (n=1,094,693 patients). Black patients were less likely to undergo IBD-related surgeries compared to White patients (pooled OR 0.70, 95% CI, 0.55-0.89, I2=87.0%). Black patients were also less likely compared to White patients to undergo an emergent colectomy with an incidence rate ratio of 0.43 (95% CI, 0.32-0.58). Furthermore, Hispanic patients were less likely to undergo a CD-related surgery (pooled OR 0.57, 95% CI, 0.48-0.68, I2=0%) compared to White patients. Finally, Asian patients had no significant difference in likelihood of CD-related and UC-related surgeries compared to White patients. Black patients were more likely to have perianal disease (pooled OR 1.40, 95% CI, 1.06-1.86), I2=58.2%) but otherwise disease characteristics and phenotypes were similar across all populations compared to Caucasians. Conclusion(s) Black and Hispanic patients with IBD are less likely to have surgery, including emergent surgery, for IBD compared to White patients with IBD, despite similar disease phenotype characteristics. Disparities in access to care may be contributory toward these findings and efforts should be made to provide equitable care to all persons living with IBD, regardless of race and ethnicity. Please acknowledge all funding agencies by checking the applicable boxes below Other Please indicate your source of funding below: Nil Disclosure of Interest None Declared

A70 FECAL-ADHERENT MUCUS IS A NON-INVASIVE SOURCE OF PRIMARY HUMAN MUC2 FOR STRUCTURAL AND FUNCTIONAL CHARACTERIZATION IN HEALTH AND DISEASE

A70 FECAL-ADHERENT MUCUS IS A NON-INVASIVE SOURCE OF PRIMARY HUMAN MUC2 FOR STRUCTURAL AND FUNCTIONAL CHARACTERIZATION IN HEALTH AND DISEASE

Disease phenotypic and geospatial features vary across genetic lineages for Tuberculosis within Arkansas, 2010-2020.

Tuberculosis (TB) elimination in the United States remains elusive, and community-specific, localized intervention strategies may be necessary to meet elimination goals. A better understanding of the genotypic diversity of Mtb, the population subgroups affected by different TB strains, and differences in disease presentation associated with these strains can aid in identifying risk groups and designing tailored interventions. We analyze TB incidence and genotype data from all Arkansas counties over an 11-year time span from 2010 through 2020. We use statistical methods and geographic information systems (GIS) to identify demographic and disease phenotypic characteristics that are associated with different Mtb genetic lineages in the study area. We found the following variables to be significantly associated with genetic lineage (p<0.05): patient county, patient birth country, patient ethnicity, race, IGRA result, disease site, chest X-ray result, whether or not a case was identified as part of a cluster, patient age, occupation risk, and date arrived in the US. Different Mtb lineages affect different subpopulations in Arkansas. Lineage 4 (EuroAmerican) and Lineage 2 (East Asian) are most prevalent, although the spatial distributions differ substantially, and lineage 2 (East Asian) is more frequently associated with case clusters. The Marshallese remain a particularly high-risk group for TB in Arkansas.

Epidemiological characteristics of Asian children with inflammatory bowel disease at diagnosis: Insights from an Asian-Pacific multi-centre registry network.

BACKGROUNDThere remains a dearth of Asian epidemiological literature for paediatric inflammatory bowel disease (PIBD).AIMTo describe the presenting features of PIBD from 7 Asia-Pacific pediatric gastroenterology centers via a central standardised electronic data platform.METHODSClinical, endoscopic and radiologic data at diagnosis from the registry were extracted between 1st January 1995 to 31st December 2019. Disease phenotypic characteristics were classified as per the Paris classification system.RESULTSThere was a distinct rise in new PIBD cases: Nearly half (48.6%) of the cohort was diagnosed in the most recent 5 years (2015-2019). The ratio of Crohn’s disease (CD):Ulcerative colitis (UC):IBD-Unclassified was 55.9%:38.3%:5.8%. The mean age was 9.07 years with a high proportion of very early onset IBD (VEO-IBD) (29.3%) and EO-IBD (52.7%). An over-representation of the Indian/South Asian ethnic group was observed which accounted for 37.0% of the overall Singapore/Malaysia subcohort (6.8%-9.0% Indians in census). Indian/South Asian CD patients were also most likely to present with symptomatic perianal disease (P = 0.003). CD patients presented with significantly more constitutional symptoms (fever, anorexia, malaise/fatigue and muscle-wasting) than UC and higher inflammatory indices (higher C-reactive protein and lower albumin levels).CONCLUSIONWe observed a high incidence of VEO-IBD and an over-representation of the Indian ethnicity. South Asian CD patients were more likely to have symptomatic perianal disease.

Variable Effects of PD-Risk Associated SNPs and Variants in Parkinsonism-Associated Genes on Disease Phenotype in a Community-Based Cohort.

Genetic risk factors for Parkinson's disease (PD) risk and progression have been identified from genome-wide association studies (GWAS), as well as studies of familial forms of PD, implicating common variants at more than 90 loci and pathogenic or likely pathogenic variants at 16 loci. With the goal of understanding whether genetic variants at these PD-risk loci/genes differentially contribute to individual clinical phenotypic characteristics of PD, we used structured clinical documentation tools within the electronic medical record in an effort to provide a standardized and detailed clinical phenotypic characterization at the point of care in a cohort of 856 PD patients. We analyzed common SNPs identified in previous GWAS studies, as well as low-frequency and rare variants at parkinsonism-associated genes in the MDSgene database for their association with individual clinical characteristics and test scores at baseline assessment in our community-based PD patient cohort: age at onset, disease duration, Unified Parkinson's Disease Rating Scale I-VI, cognitive status, initial and baseline motor and non-motor symptoms, complications of levodopa therapy, comorbidities and family history of neurological disease with one or more than one affected family members. We find that in most cases an individual common PD-risk SNP identified in GWAS is associated with only a single clinical feature or test score, while gene-level tests assessing low-frequency and rare variants reveal genes associated in either a unique or partially overlapping manner with the different clinical features and test scores. Protein-protein interaction network analysis of the identified genes reveals that while some of these genes are members of already identified protein networks others are not. These findings indicate that genetic risk factors for PD differentially affect the phenotypic presentation and that genes associated with PD risk are also differentially associated with individual disease phenotypic characteristics at baseline. These findings raise the intriguing possibility that different SNPs/gene effects impact discrete phenotypic characteristics. Furthermore, they support the hypothesis that different gene and protein-protein interaction networks that underlie PD risk, the PD phenotype, and the neurodegenerative process leading to the disease phenotype, and point to the significance of the genetic background on disease phenotype.

Hyposmia correlates with SNCA variant and non-motor symptoms in Chinese patients with Parkinson's disease.

Hyposmia plays an important role in the early and differential diagnosis of Parkinson's disease (PD); however its underlying mechanism is poorly understood. The aim of the present study is to explore the clinical phenotypic and genotypic correlation of hyposmia in Chinese PD patients. Olfactory function evaluated by 16-item odor identification test from Sniffin' Sticks (SS-16) of 218 Chinese Han PD patients and 110 healthy controls was compared. 186 patients also had the genetic information of two positive GWAS-linked SNCA loci (rs11931074, rs894278) previously validated in our center. The associations of hyposmia with SNCA variants and disease phenotypic characteristics including motor symptoms (UPDRS motor score) and other common NMSs (clinical possible RBD-cpRBD, depression and chronic constipation) were analyzed. Nearly 39.9% (n = 87) of PD reported subjective complaints of hyposmia, while 60.1% (n = 131) patients had objective hyposmia (SS-16 < 8.3). Patients with hyposmia had older age (p = 0.001), later onset age (p = 0.020), higher SCOPA-AUT scores (p = 0.011), higher percentage of chronic constipation (p = 0.001) and cpRBD (p = 0.003). Binary logistic regression analysis revealed that ageing (OR = 1.058; 95%CI: 1.012-1.106; p = 0.013), chronic constipation (OR = 2.072; 95% CI: 1.157-3.710; p = 0.014) and cpRBD (OR = 2.234; 95% CI: 1.040-4.797; p = 0.039) were independent influential factors of hyposmia in Chinese PD patients. Subgroup analysis of patients with both clinical and genetic results demonstrated that after adjusting for age, sex, chronic constipation and cpRBD, rs11931074 TT genotype may increase the risk of hyposmia in PD (OR = 3.24 95% CI = 1.23-8.51, p = 0.017) compared to GG genotype via an additive model. Age, cpRBD, chronic constipation and SNCA rs11931074 may correlate with hyposmia in Chinese PD patients.

Systematic Classification of Disease Severity for Evaluation of Expanded Carrier Screening Panels.

Professional guidelines dictate that disease severity is a key criterion for carrier screening. Expanded carrier screening, which tests for hundreds to thousands of mutations simultaneously, requires an objective, systematic means of describing a given disease's severity to build screening panels. We hypothesized that diseases with characteristics deemed to be of highest impact would likewise be rated as most severe, and diseases with characteristics of lower impact would be rated as less severe. We describe a pilot test of this hypothesis in which we surveyed 192 health care professionals to determine the impact of specific disease phenotypic characteristics on perceived severity, and asked the same group to rate the severity of selected inherited diseases. The results support the hypothesis: we identified four “Tiers” of disease characteristics (1–4). Based on these responses, we developed an algorithm that, based on the combination of characteristics normally seen in an affected individual, classifies the disease as Profound, Severe, Moderate, or Mild. This algorithm allows simple classification of disease severity that is replicable and not labor intensive.

Neutralizing antibodies against adeno-associated viruses in inflammatory bowel disease patients: Implications for gene therapy

Inflammatory bowel diseases (IBDs) are comprised of two major disorders: Crohn's disease (CD) and ulcerative colitis (UC). No curative treatment options are available, but gene therapy may offer an alternative therapeutic approach. For this a safe and reliable vector is needed. The adeno-associated viruses (AAV) have attracted considerable interest as gene therapy vectors. However, neutralizing antibodies (nAb's) made in response to wildtype AAV have been associated with a partial to complete block of transduction in case of reexposure. Therefore, and in order to define AAV vector candidates to treat IBD patients, we characterized preexisting humoral responses to AAV in this population. We measured circulating antibodies against AAV serotypes 1, 2, 3, 4, 5, 6, and 8 using a previously established virus neutralization assay. In all, 100 healthy donors and 200 IBD patient's serum samples (101 CD and 99 UC) were analyzed. A significant difference was detected in the prevalence of nAb's for AAV types 1, 5, 6, and 8 between the healthy donors and the patient population. Furthermore, various disease phenotypic characteristics correlated with the prevalence of nAb's to all the serotypes studied. Our study establishes a foundation for the development of an AAV-based gene therapy approach as a novel treatment for IBD. Furthermore, we show a relationship between disease phenotype in IBD patients and the humoral immune response to AAV.

CARD15 in inflammatory bowel disease and Crohn's disease phenotypes: An association study and pooled analysis

Background Three major polymorphisms of the Caspase-Activation Recruitment Domain containing protein 15 gene have been described to be associated with Crohn's disease. Genotype–phenotype studies reported in literature provide conflicting data on disease localisation and behaviour. We investigated the relation of Caspase-Activation Recruitment Domain containing protein 15 with inflammatory bowel disease and Crohn's disease phenotypic characteristics in a large Dutch cohort and performed a pooled analysis on inflammatory bowel disease patients and Crohn's disease phenotypic characteristics reported in association studies. Methods We genotyped 781 cases and 315 controls for the R702W, G908R and 1007fsinsC variants and for six microsatellite markers in and close to Caspase-Activation Recruitment Domain containing protein 15. In the pooled analysis data of 7201 inflammatory bowel disease patients and 3720 controls from 20 studies were included. Results Association was found for Crohn's disease with R702W and 1007fsinsC, including several disease characteristics, and not for ulcerative colitis. In the pooled analysis all three common Caspase-Activation Recruitment Domain containing protein 15 variants showed strong association with Crohn's disease ( p < 0.00001; odds ratio varying from 3.0 for single heterozygotes to 14.7 for compound heterozygotes) and not with ulcerative colitis. Phenotype analysis showed association with small bowel involvement, stricturing and penetrating disease. Conclusion Caspase-Activation Recruitment Domain containing protein 15 is associated with Crohn's disease and not with ulcerative colitis. All three common Crohn's disease-associated variants are associated with small bowel involvement, the G908R and 1007fsinsC alleles also being associated with a complicated disease course.

Crohn??s Disease Patients Carrying Nod2/CARD15 Gene Variants Have an Increased and Early Need for First Surgery due to Stricturing Disease and Higher Rate of Surgical Recurrence

To study the predictive value of Nod2/CARD15 gene variants along with disease phenotypic characteristics for requirement of initial surgery and for surgical recurrence in Crohn's disease (CD). Nod2/CARD15 gene variants play an important role in the susceptibility to CD. Studies of genotype-phenotype relationship suggest that these variants are associated with development of intestinal strictures. Preliminary reports analyzing the association between these variants and need for surgery have produced inconsistent results. A total of 170 CD patients were included prospectively in the study and followed up regularly for a mean of 7.4 +/- 6.1 years. Clinical characteristics of CD, time and indication for surgery, and recurrence were registered. Nod2/CARD15 gene variants were determined by DNA sequencing analysis. Surgery for stricturing disease was significantly more frequent in patients with Nod2/CARD15 variants in the univariate analysis (odds ratio [OR], 3.63; 95% confidence interval [CI], 1.42-9.27), and it was required at an earlier time (P = 0.004). Only Nod2/CARD15 variants (OR, 3.58; 95% CI, 1.21-10.5) and stricturing phenotype at diagnosis of CD (OR, 9.34; 95% CI, 2.56-33.3) were independent predictive factors of initial surgery for stricturing lesions in the multivariate analysis. Among 70 patients that required surgery, postoperative recurrence was also more frequent in patients with Nod2/CARD15 variants in the univariate and multivariate analysis (OR, 3.29; 95% CI, 1.13-9.56), and reoperation was needed at an earlier time (P = 0.03). Nod2/CARD15 variants are associated with early initial surgery due to stenosis and with surgical recurrence in Crohn's disease. Patients with these variants could benefit from preventive and/or early therapeutic strategies.