ABSTRACT
Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease.
Subject(s)
Calbindin 2/genetics , Genetic Predisposition to Disease , Inflammatory Bowel Diseases/genetics , Receptors, Prostaglandin E, EP4 Subtype/genetics , Black or African American/genetics , Aged , Aged, 80 and over , Colitis, Ulcerative/genetics , Colitis, Ulcerative/pathology , Crohn Disease/genetics , Crohn Disease/pathology , Female , Gene Frequency , Genome-Wide Association Study , Humans , Inflammatory Bowel Diseases/pathology , Male , Multifactorial Inheritance/genetics , Polymorphism, Single Nucleotide/genetics , White People/genetics , Whole Genome SequencingABSTRACT
ABSTRACT: Fecal impaction is a common digestive disorder and is considered an acute complication of chronic and untreated constipation. Generally, the factors responsible for fecal impaction are similar to those associated with constipation. Early identification and treatment minimize complications and patient discomfort. Common treatment options to address fecal impaction of the rectum include manual disimpaction or fragmentation, the use of distal and/or proximal softening or washout procedures such as enemas and suppositories, and oral or nasogastric tube placement for the administration of polyethylene glycol solutions containing electrolytes. In severe cases, surgical intervention is necessary. Post-treatment evaluation should include a colonic evaluation by flexible sigmoidoscopy, a colonoscopy, or a barium enema after the fecal impaction resolves. Following treatment, conduct an evaluation of causes and create a preventive therapy plan.
Subject(s)
Fecal Impaction , Humans , Adult , Fecal Impaction/complications , Fecal Impaction/diagnostic imaging , Fecal Impaction/therapy , Constipation/etiology , Constipation/drug therapy , Polyethylene Glycols , Enema , Risk AssessmentABSTRACT
BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci. METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed. RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles. CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.
Subject(s)
Black or African American/genetics , Inflammatory Bowel Diseases/genetics , Polymorphism, Single Nucleotide , White People/genetics , Adult , Aged , Colitis, Ulcerative/genetics , Crohn Disease/genetics , Female , Genetic Loci , Genetic Predisposition to Disease , Humans , Male , Middle Aged , Risk Factors , United States/ethnology , Young AdultSubject(s)
Abdominal Pain/chemically induced , Enteritis/chemically induced , Eosinophilia/chemically induced , Gastritis/chemically induced , Nausea/chemically induced , Proton Pump Inhibitors/adverse effects , Biopsy , Endoscopy, Digestive System , Enteritis/diagnosis , Eosinophilia/diagnosis , Gastritis/diagnosis , Humans , Male , Middle AgedABSTRACT
PURPOSE OF REVIEW: Inflammatory bowel disease (IBD) has long been known to have genetic risk factors because of increased prevalence in the relatives of affected individuals. However, genome-wide association studies have only explained limited heritability in IBD. The observed globally rising incidence of IBD has implicated the role of environmental factors. The hidden unexplained heritability remains to be explored. RECENT FINDINGS: Recent aggregate evidence has highlighted the extent and nature of host genome-microbiome associations, a key next step in understanding the mechanisms of pathogenesis in IBD. An individual's gut microbiota is shaped not only by genetic but also by environmental factors like diet. Minimizing exposure of the intestinal lumen to selected food items has shown to prolong the remission state of IBD. Among a genetically susceptible host, the shift of gut microbiota (or 'dysbiosis') can lead to increasing the susceptibility to IBD. With the advances in high-throughput large-scale 'omics' technologies in combination with creative data mining and system biology-based network analyses, the complexity of biological functional networks behind the cause of IBD has become more approachable. Therefore, the hidden heritability in IBD has become more explainable, and can be attributable to the changing environmental factors, epigenetic modifications, and gene-host microbial ('in-vironmental') or gene-extrinsic environmental interactions. SUMMARY: This review discusses the perspectives of relevance to clinical translation with emphasis on gene-environment interactions. No doubt, the use of system-based approaches will lead to the development of alternative, and hopefully better, diagnostic, prognostic, and monitoring tools in the management of IBD.
Subject(s)
Gene-Environment Interaction , Inflammatory Bowel Diseases/genetics , Gastrointestinal Tract/microbiology , Genetic Predisposition to Disease , Host-Pathogen Interactions , Humans , Inflammatory Bowel Diseases/microbiology , Microbiota/physiology , Research Design , Smoking/adverse effectsABSTRACT
Genome-wide association studies (GWAS) have identified at least 133 ulcerative colitis (UC) associated loci. The role of genetic factors in clinical practice is not clearly defined. The relevance of genetic variants to disease pathogenesis is still uncertain because of not characterized gene-gene and gene-environment interactions. We examined the predictive value of combining the 133 UC risk loci with genetic interactions in an ongoing inflammatory bowel disease (IBD) GWAS. The Wellcome Trust Case-Control Consortium (WTCCC) IBD GWAS was used as a replication cohort. We applied logic regression (LR), a novel adaptive regression methodology, to search for high-order interactions. Exploratory genotype correlations with UC sub-phenotypes [extent of disease, need of surgery, age of onset, extra-intestinal manifestations and primary sclerosing cholangitis (PSC)] were conducted. The combination of 133 UC loci yielded good UC risk predictability [area under the curve (AUC) of 0.86]. A higher cumulative allele score predicted higher UC risk. Through LR, several lines of evidence for genetic interactions were identified and successfully replicated in the WTCCC cohort. The genetic interactions combined with the gene-smoking interaction significantly improved predictability in the model (AUC, from 0.86 to 0.89, P = 3.26E-05). Explained UC variance increased from 37 to 42 % after adding the interaction terms. A within case analysis found suggested genetic association with PSC. Our study demonstrates that the LR methodology allows the identification and replication of high-order genetic interactions in UC GWAS datasets. UC risk can be predicted by a 133 loci and improved by adding gene-gene and gene-environment interactions.
Subject(s)
Colitis, Ulcerative/genetics , Epistasis, Genetic , Gene-Environment Interaction , Alleles , Genome-Wide Association Study , Genotype , Humans , Phenotype , Polymorphism, Single NucleotideSubject(s)
Abdominal Pain/chemically induced , Angioedema/chemically induced , Angiotensin II Type 1 Receptor Blockers/adverse effects , Antihypertensive Agents/adverse effects , Chronic Pain/chemically induced , Intestinal Diseases/chemically induced , Losartan/adverse effects , Abdominal Pain/diagnosis , Angioedema/diagnostic imaging , Chronic Pain/diagnosis , Humans , Intestinal Diseases/diagnosis , Male , Middle Aged , Tomography, X-Ray ComputedABSTRACT
BACKGROUND: Forty distinct primary sclerosing cholangitis (PSC) genomic loci have been identified through multiancestry meta-analyses. The polygenic risk score (PRS) could serve as a promising tool to discover unique disease behaviour, like PSC, underlying inflammatory bowel disease (IBD). AIM: To test whether PRS indicates PSC risk in patients with IBD. MATERIALS AND METHODS: Mayo Clinic and Washington University at St Louis IBD cohorts were used to test our hypothesis. PRS was modelled through the published PSC loci and weighted with their corresponding effect size. Logistic regression was applied to predict the PSC risk. RESULTS: In total, 63 (5.6%) among 1130 patients with IBD of European ancestry had PSC. Among 381 ulcerative colitis (UC), 12% had PSC; in contrast to 1.4% in 761 Crohn disease (CD). Compared with IBD alone, IBD-PSC had significantly higher PRS (PSC risk: 3.0% at the lowest PRS quartile vs 7.2% at the highest PRS quartile, Ptrend =.03). In IBD subphenotypes subgroup analysis, multivariate analysis shows that UC-PSC is associated with more extensive UC disease (OR, 5.60; p=0.002) and younger age at diagnosis (p=0.02). In CD, multivariate analysis suggests that CD-PSC is associated with colorectal cancer (OR, 50; p=0.005). CONCLUSIONS: We found evidence that patients with IBD with PSC presented with a clinical course difference from that of patients with IBD alone. PRS can influence PSC risk in patients with IBD. Once validated in an independent cohort, this may help identify patients with the highest likelihood of developing PSC.
Subject(s)
Cholangitis, Sclerosing , Colitis, Ulcerative , Crohn Disease , Inflammatory Bowel Diseases , Humans , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/genetics , Cholangitis, Sclerosing/diagnosis , Inflammatory Bowel Diseases/complications , Inflammatory Bowel Diseases/genetics , Colitis, Ulcerative/complications , Colitis, Ulcerative/genetics , Colitis, Ulcerative/diagnosis , Crohn Disease/complications , Crohn Disease/epidemiology , Crohn Disease/genetics , Risk FactorsABSTRACT
INTRODUCTION: Patients with ulcerative colitis (UC) who are likely to have primary sclerosing cholangitis (PSC) should be identified because PSC can influence UC clinical behavior and outcomes.The aim of this study was to establish a model incorporating clinical and genetic risk predictors that identifies patients with UC at risk of developing PSC. METHODS: We conducted a retrospective case-control study. Inflammatory bowel disease cohorts from multiple institutions were used as discovery and replicate datasets. Quality control criteria, including minor allele frequency, call rates, Hardy-Weinberg equilibrium, cryptic relatedness, and population stratification (through principal components), were used. Discriminative accuracy was evaluated with area under the receiver operating characteristic curve. RESULTS: Fifty-seven of 581 patients (9.8%) with UC had PSC. Multivariate analysis showed that patients with UC-PSC had more extensive disease (odds ratio [OR], 5.42; P = 1.57E-04), younger diagnosis age (younger than 20 years; OR, 2.22; P = 0.02), and less smoking (OR, 0.42; P = 0.02) than those with UC. After linkage disequilibrium pruning and multivariate analyses, 3 SNPs (rs3131621 at 6p21.33; rs9275596 and rs11244 at 6p21.32) at the HLA region were found associated with a 2- to 3-fold increased risk of PSC. Our model demonstrated good discriminatory power (area under the receiver operating characteristic curve, 88%). DISCUSSION: Three variants in HLA (6p21.3) region significantly distinguished patients with UC-PSC from patients with UC alone. Once further validated in an independent large cohort, our model could be used to identify patients with UC at risk of PSC, and it could also help guide disease management.
Subject(s)
Cholangitis, Sclerosing , Colitis, Ulcerative , Humans , Young Adult , Adult , Colitis, Ulcerative/complications , Colitis, Ulcerative/diagnosis , Colitis, Ulcerative/genetics , Retrospective Studies , Case-Control Studies , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/diagnosis , Cholangitis, Sclerosing/genetics , Risk FactorsABSTRACT
Nasopharyngeal carcinoma (NPC) is a multifactorial malignancy closely associated with genetic factors and Epstein-Barr virus infection. To identify the common genetic variants linked to NPC susceptibility, we conducted a genome-wide association study (GWAS) in 277 NPC patients and 285 healthy controls within the Taiwanese population, analyzing 480,365 single-nucleotide polymorphisms (SNPs). Twelve statistically significant SNPs were identified and mapped to chromosome 6p21.3. Associations were replicated in two independent sets of case-control samples. Two of the most significant SNPs (rs2517713 and rs2975042; p(combined) = 3.9 x 10(-20) and 1.6 x 10(-19), respectively) were located in the HLA-A gene. Moreover, we detected significant associations between NPC and two genes: specifically, gamma aminobutyric acid b receptor 1 (GABBR1) (rs29232; p(combined) = 8.97 x 10(-17)) and HLA-F (rs3129055 and rs9258122; p(combined) = 7.36 x 10(-11) and 3.33 x 10(-10), respectively). Notably, the association of rs29232 remained significant (residual p < 5 x 10(-4)) after adjustment for age, gender, and HLA-related SNPs. Furthermore, higher GABA(B) receptor 1 expression levels can be found in the tumor cells in comparison to the adjacent epithelial cells (p < 0.001) in NPC biopsies, implying a biological role of GABBR1 in NPC carcinogenesis. To our knowledge, it is the first GWAS report of NPC showing that multiple loci (HLA-A, HLA-F, and GABBR1) within chromosome 6p21.3 are associated with NPC. Although some of these relationships may be attributed to linkage disequilibrium between the loci, the findings clearly provide a fresh direction for the study of NPC development.
Subject(s)
Carcinoma/genetics , Chromosomes, Human, Pair 6 , Genome-Wide Association Study , HLA Antigens/genetics , Nasopharyngeal Neoplasms/genetics , Alleles , Asian People/genetics , Asian People/statistics & numerical data , Carcinoma/immunology , Case-Control Studies , Cohort Studies , Female , Gene Frequency , Haplotypes , Histocompatibility Antigens Class I/genetics , Humans , Immunohistochemistry , Linkage Disequilibrium , Male , Nasopharyngeal Neoplasms/immunology , Polymorphism, Single Nucleotide , Receptors, GABA-B/genetics , Receptors, GABA-B/metabolism , TaiwanSubject(s)
Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Clonixin/analogs & derivatives , Crohn Disease/diagnosis , Dipyrone/adverse effects , Lysine/analogs & derivatives , Protein-Losing Enteropathies/chemically induced , Protein-Losing Enteropathies/diagnosis , Adult , Clonixin/adverse effects , Diagnosis, Differential , Double-Balloon Enteroscopy , Female , Humans , Lysine/adverse effects , Protein-Losing Enteropathies/pathologyABSTRACT
Serum antibodies to Epstein-Barr virus (EBV) antigens can be used to predict the risk of nasopharyngeal carcinoma (NPC). To investigate whether EBV seropositivity rates were higher among healthy family members from multiplex and sporadic families with NPC (i.e., families with multiple or single cases) compared to the general population, a study was conducted on 2,665 unaffected individuals from 140 multiplex and 413 sporadic families. The titers of the IgA antibody to the EBV capsid antigen (VCA-IgA) were compared to those of 904 controls from the general population. The VCA-IgA titer was correlated among sibling pairs to a high significance in both family types (P < 0.0001 and P = 0.0005 for the multiplex and the sporadic families, respectively); parent-offspring pairs also showed significant correlation (P < 0.0001 and P = 0.0002, respectively); and spouse pairs were correlated, but at lower significance levels (P = 0.0790 and P = 0.0040, respectively). When compared to the controls, among first-degree relatives in the multiplex families, the age- and gender-adjusted odds ratio (OR) was 2.06 (95% confidence interval 1.56-2.71), 3.55 (2.24-5.64), and 2.25 (1.57-3.23) for siblings, parents, and children, respectively. In the sporadic families, the adjusted OR was 1.55 (1.21-2.00) and 2.08 (1.51-2.86) for siblings and parents, respectively. The adjusted P-value of spouses lost significance in the multiplex families, but remained significant in the sporadic families (P = 0.0146). In conclusion, EBV seropositivity rates were elevated among unaffected family members in both multiplex and sporadic families with NPC.
Subject(s)
Antibodies, Viral/blood , Antigens, Viral/immunology , Capsid Proteins/immunology , Epstein-Barr Virus Infections/epidemiology , Herpesvirus 4, Human/immunology , Nasopharyngeal Neoplasms/epidemiology , Adult , Aged , Biomarkers/blood , Carcinoma , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Family , Female , Humans , Immunoglobulin A/blood , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/virologyABSTRACT
BACKGROUND: We aimed to identify a model of clinical and genetic risk factors through hypothesis-free search across genome that can predict the surgical recurrence risk after the first abdominal surgery in CD patients. MATERIALS AND METHODS: Two independent inflammatory bowel disease (IBD) cohort studies were used to derive and validate the genetic risk profile. The study subjects were genotyped using Illumina Immunochip custom genotyping array. Surgical recurrence was defined as having the second or more abdominal bowel resections after the first abdominal surgery at the time of study enrollment; nonsurgical recurrence was defined as having no further abdominal resection after the first abdominal surgery. RESULTS: Among 372 CD patients who had at least 1 abdominal surgery at the study enrollment, 132 (35.5%) had subsequent surgical recurrence after their first abdominal surgery, and 240 (64.5%) required no subsequent abdominal surgery at the end of follow up. Among clinical factors, multivariable analysis showed that history of immunomodulatory use (odds ratio [OR], 3.96; P = 0.002) and early era of CD first surgery (OR, 1.12; P = 1.01E-04) remained significant. Genotypic association tests identified a genome-wide significant locus rs2060886 in TCF4 at chr18q21.2 associated with surgical recurrence risk (OR, dom, 4.10 [2.37-7.11]; P = 4.58E-08). CONCLUSIONS: Novel genetic locus rs2060886 in TCF4 was associated with surgical recurrence risk at genome-wide significance level among CD patients after their first abdominal surgery. Early era of CD first intestinal surgery predicts higher surgical recurrence risk. These results suggest that genetic variants may help guide the CD management strategy in patients at the highest risk of repeated abdominal surgeries.
Subject(s)
Crohn Disease , Digestive System Surgical Procedures , Cohort Studies , Crohn Disease/genetics , Crohn Disease/surgery , Humans , Recurrence , Reoperation , Risk FactorsABSTRACT
OBJECTIVES: Optimization of medical therapy and specialist care for inflammatory bowel disease (IBD) may reduce morbidity. We sought to characterize racial disparities in utilization of healthcare and medical therapy for IBD. METHODS: We performed a cross-sectional study of black (n=137) and white (n=149) IBD patients recruited from an outpatient IBD clinic and through medical record review and telephone interview, compared utilization of IBD specialist services, emergency department (ED) services, and medications. We adjusted racial comparisons for demographic, socioeconomic, and clinical factors. RESULTS: After adjustment for confounders, blacks were less likely than whites to be under the regular care (defined as at least annual visit) of a gastroenterologist (adjusted odds ratio (aOR) 0.43; 95% confidence interval (CI): 0.25-0.75) or IBD specialist (aOR 0.37; 95% CI: 0.22-0.61). Follow-up with a primary care provider was, however, similar between blacks and whites. Over the preceding 12 months, blacks were more likely than whites to have at least one visit to the ED (aOR 2.02; 95% CI: 1.22-3.35), but there was no difference in hospitalization. Among CD patients with prolonged steroid use, blacks were less likely than whites to have been on infliximab (aOR 0.41; 95% CI: 0.21-0.77), but there were no racial differences in the use of immunomodulators (aOR 0.87; 95% CI: 0.48-1.60). CONCLUSIONS: There are racial differences in utilization of IBD-related specialist services, ED visits, and infliximab that are independent of income and education. Modifiable barriers to health-care access may have a role in these disparities.
Subject(s)
Health Services Needs and Demand/statistics & numerical data , Health Services/statistics & numerical data , Inflammatory Bowel Diseases/ethnology , Adult , Black or African American , Chi-Square Distribution , Cross-Sectional Studies , Female , Health Services Accessibility , Hospitalization , Humans , Inflammatory Bowel Diseases/therapy , Interviews as Topic , Male , Middle Aged , Odds Ratio , Severity of Illness Index , Specialization , Surveys and Questionnaires , White PeopleABSTRACT
INTRODUCTION: Ulcerative colitis (UC) associated with primary sclerosing cholangitis (PSC) is a rare phenotype. We aimed to assess patients with UC-PSC or UC alone and describe differences in clinical and phenotypic characteristics, antitumor necrosis factor (TNF) therapy, and long-term clinical outcomes. METHODS: This retrospective multicenter cohort study included patients who received a diagnosis of UC from 1962 through 2015. We evaluated clinical factors associated with UC-PSC vs UC alone and assessed associations by using multivariable logistic regression models. RESULTS: Among 522 patients with UC, 56 (10.7%) had PSC. Compared with UC alone, patients with UC-PSC were younger (younger than 20 years) at diagnosis (odds ratios [OR], 2.35; adjusted P = 0.02) and had milder UC severity (adjusted P = 0.05), despite having pancolonic involvement (OR, 7.01; adjusted P < 0.001). In the biologics era (calendar year 2005 to 2015), patients with UC-PSC less commonly received anti-TNF therapy compared with patients with UC (OR, 0.38; adjusted P = 0.009), but their response rates were similar. Fewer patients with UC-PSC received corticosteroids (OR, 0.24; adjusted P = 0.005) or rectal 5-aminosalicyte acid (OR, 0.26; adjusted P < 0.001). Other differences were identified that were not statistically significant in a multivariable model: patients with UC-PSC more commonly were male, had lower rates of smoking, and had higher rates of colorectal cancer and colectomy. DISCUSSION: This study identified a unique phenotype of UC with concurrent PSC, which had different clinical behavior compared with UC only. These phenotypic characteristics can help identify high-risk patients with UC before PSC is diagnosed and guide different management and monitoring strategies.
Subject(s)
Cholangitis, Sclerosing/pathology , Colitis, Ulcerative/pathology , Tumor Necrosis Factor Inhibitors/therapeutic use , Adolescent , Adult , Cholangitis, Sclerosing/complications , Cholangitis, Sclerosing/drug therapy , Colitis, Ulcerative/complications , Colitis, Ulcerative/drug therapy , Disease Management , Female , Humans , Logistic Models , Male , Middle Aged , Odds Ratio , Phenotype , Retrospective Studies , Severity of Illness Index , Sex Factors , Treatment Outcome , United States , Young AdultABSTRACT
BACKGROUND: Chronic intra-prostatic inflammation and obesity are thought to influence prostate carcinogenesis. Thus, variants in genes in these pathways could be associated with prostate cancer risk. METHODS: We genotyped 17 common single nucleotide polymorphisms (SNPs) in RNASEL, TLR4, IL1B, IL6, IL8, IL10, TNF, CRP, ADIPOQ, LEP, PPARG, and TCF7L2 in 258 white prostate cancer cases and 258 matched controls nested in CLUE II. Single-locus analyses were conducted using conditional logistic regression. TagSNPs were selected in IL10, CRP, and TLR4 and haplotype analyses were done. RESULTS: The A allele of IL10 -1082G>A (rs1800896), known to result in lower levels of this anti-inflammatory cytokine, was positively associated with risk (AG vs. GG, OR = 1.69, 95% CI: 1.10-2.60; AA vs. GG, OR = 1.81, 95% CI: 1.11-2.96; P (trend) = 0.02). Associations of IL10 haplotypes with prostate cancer were explained by high linkage disequilibrium between two tagSNPs (rs1800890 and rs3024496) and -1082G>A. A TLR4 candidate SNP (rs4986790; AG/GG vs. AA, OR = 0.60, 95% CI: 0.33-1.08; P(trend) = 0.09), known to have decreased expression and be associated with lower circulating levels of inflammatory mediators, and tagSNP (rs10116253; CC vs. TT, OR = 3.05, 95% CI: 1.11-8.41), but not haplotypes, were associated with risk. None of the other candidate SNPs or haplotypes was statistically significantly associated with risk. CONCLUSION: Our prospective study suggests that genetic variation in IL10 and possibly TLR4 is associated with prostate cancer risk. Although none of the SNPs in the obesity genes tested was associated, this does not rule out a complex role of obesity and its metabolic consequences in prostate cancer etiology.
Subject(s)
Genetic Variation , Interleukin-10/genetics , Obesity/genetics , Polymorphism, Single Nucleotide , Prostatic Neoplasms/genetics , Toll-Like Receptor 4/genetics , Adult , C-Reactive Protein/genetics , Case-Control Studies , Cohort Studies , Endoribonucleases/genetics , Exons , Female , Humans , Interleukins/genetics , Introns , Leptin/genetics , Male , Middle Aged , PPAR gamma/genetics , Promoter Regions, Genetic , Prospective StudiesABSTRACT
BACKGROUND: Incidence density sampling is typically the least biased efficient method for control sampling in nested case-control studies. However, in studies of genetic variants and prostate cancer progression, some argue that controls should be sampled from men who did not progress by end of follow-up. Thus, we examined the validity of relative risk (RR) estimates of prostate cancer progression using three methods for control sampling from cohorts of men with prostate cancer generated by Monte Carlo simulation. METHODS: Data were simulated for nine scenarios for combinations of genotype frequency (10%, 30%, and 50%) and association (RR, 1.0, 1.5, and 2.0) using prostate progression rates from Johns Hopkins Hospital. RRs estimated from conditional logistic regression for the genetic association from case-control studies nested in the nine cohort scenarios using three control sampling methods, (a) incidence density sampling, (b) incidence density sampling without replacement of selected controls, and (c) "pure" control sampling (i.e., men who did not progress by end of long-term follow-up), were compared with the true RRs. RESULTS: Use of controls selected by incidence density sampling produced unbiased RR estimates of progression. In our setting, only a slight bias was produced by use of incidence density sampling without replacement. In contrast, use of controls selected by pure control sampling produced biased RR estimates, except when there was no association; extent of bias increased with increasing size of the association and duration of follow-up. CONCLUSIONS: Nested case-control studies designed to estimate the association of genetic variants with risk of prostate cancer progression should use incidence density sampling to provide a valid RR estimate.
Subject(s)
Case-Control Studies , Prostatic Neoplasms/genetics , Research Design , Bias , Biomarkers, Tumor/genetics , Disease Progression , Epidemiologic Methods , Genetic Variation , Genotype , Humans , Incidence , Logistic Models , Male , Monte Carlo Method , Prostatic Neoplasms/epidemiology , Risk Assessment/methods , Sampling StudiesABSTRACT
BACKGROUND AND AIMS: Ulcerative colitis (UC) is a form of inflammatory bowel disease, and antibodies against tumor necrosis factor (anti-TNF) are used for treatment. Many patients are refractory or lose response to anti-TNF, and predicting response would be an extremely valuable clinical tool. Unlike most biomarkers, cytokines directly mediate inflammation, and their measurement may predict the likelihood of response or no response. METHODS: Serum samples were obtained from 49 UC patients before infliximab infusions, and levels of 17 cytokines were measured using a multiplex assay. The Fisher linear discriminant analysis (FLDA) was applied to the cytokine values to predict which patients would respond to infliximab. "Response" was defined as clinical remission after the third infusion, and "no response" was defined as lack of remission after the third infusion. RESULTS: The Fisher linear discriminant analysis model identified a subset of seven predictor cytokines: TNF-α, IL-12, IL-8, IL-2, IL-5, IL1-ß, and IFN-γ. The obtained canonical coefficients enabled to calculate discriminant scores as linear combinations of the cytokines; model classified thepatients as responders and nonresponders with a sensitivity of 84.2% and a specificity of 93.3%. Overall, the yield of the FLDA model was 89.8% of the total 49 patients. CONCLUSIONS: An unbiased, statistically derived, predictive model based on measurement of serum cytokines before therapy may predict a positive or negative outcome from the administration of anti-TNF to UC patients. Because accurately measuring cytokines is simple and inexpensive, the model may be a valuable new tool to complement other laboratory parameters used in the management of IBD patients.