Search

By 2030, early-onset colorectal cancer (EOCRC) is expected to become the leading cancer-related cause of death for people age 20 to 49. To improve understanding of this phenomenon, we analyzed the geographic determinants of EOCRC in Utah by examining county-level incidence and mortality. We linked data from the Utah Population Database to the Utah Cancer Registry to identify residents (age 18–49) diagnosed with EOCRC between 2000 and 2020, and we used spatial empirical Bayes smoothing to determine county-level hotspots. We identified 1,867 EOCRC diagnoses (52.7% in male patients, 69.2% in non-Hispanic White patients). Ten counties (34%) were classified as hotspots, with high EOCRC incidence or mortality. Hotspot status was unrelated to incidence rates, but non-Hispanic ethnic-minority men (incidence rate ratio, 1.49; 95% CI, 1.15–1.91), Hispanic White men and women (incidence rate ratio, 2.24; 95% CI, 2.00–2.51), and Hispanic ethnic-minority men and women (incidence rate ratio, 4.59; 95% CI, 3.50–5.91) were more likely to be diagnosed with EOCRC. After adjustment for income and obesity, adults living in hotspots had a 31% higher hazard for death (HR, 1.31; 95% CI, 1.02–1.69). Survival was poorest for adults with a late-stage diagnosis living in hotspots (chi square (1) = 4.0; p = .045). Adults who were married or who had a life partner had a lower hazard for death than single adults (HR, 0.73; 95% CI, 0.58–0.92). The risk for EOCRC is elevated in 34% of Utah counties, warranting future research and interventions aimed at increasing screening and survival in the population age 18 to 49.

Background Large epidemiologic studies have suggested that a history of tobacco use may be associated with an increased risk of developing chronic rhinosinusitis (CRS). The impact of tobacco use on revision rates of endoscopic sinus surgery (ESS), however, remains limited. Objective This study seeks to define the independent risk of tobacco use (active or prior) on revision rates of ESS among a large cohort of patients with CRS. Methods A state population database was queried for patients age ≥18 years with CRS who underwent at least one ESS between 1996 and 2018. Demographic characteristics, history of ESS, and tobacco use status were compared across patients with CRS, using t tests for continuous variables and χ2 tests for categorical variables. Unadjusted and adjusted logistic regression models were used to understand the impact of tobacco status on revision surgery. Results The final analysis included 34 350 patients (29 916 CRS with no revision surgery and 4434 CRS with revision surgery). Unadjusted regression analysis demonstrated an increased odds of undergoing revision ESS (OR 1.12, 95% CI: 1.00–1.25, P = .05) among males with a history of tobacco use and CRS. Adjusted regression analysis demonstrated that the risk of revision ESS among CRS patients with a history of asthma and tobacco use was 1.72-fold, while the risk among CRS patients who were tobacco users without asthma was 1.11-fold. Conclusion History of tobacco use is an independent risk factor for revision ESS among patients with CRS.

Background: Incidence of small-intestine neuroendocrine tumors (SINT) has been increasing in the United States over the past 40 years, with higher incidence in Utah than elsewhere. As information about how these tumors arise is limited, elucidating lifestyle factors associated with SINT in a statewide cohort could potentially identify those at risk to help mitigate their effects. Methods: Cases of SINT with a carcinoid histology (8240 or 8241) diagnosed in Utah from 1996 to 2014 with no prior history of cancer within 5 years (n = 433) were matched to population controls (1:10 ratio). Tobacco and alcohol exposures before case diagnosis were identified from International Classification of Diseases codes in statewide medical records and from self-reported data captured at patient encounters beginning in 1996. Multivariate logistic regression was used to estimate risk of SINT associated with tobacco and alcohol in cases compared with controls. Results: An increased risk of SINT was observed in tobacco-exposed individuals compared with unexposed [OR, 1.44; 95% confidence interval (CI), 1.11–1.86; P = 0.006]. Those who were exposed to alcohol exhibited an increased risk of SINT (OR, 1.62; 95% CI, 1.05–2.49; P = 0.03). Conclusions: This study supports tobacco and alcohol use as risk factors for SINT, independent of family history. However, low rates of smoking and alcohol use in Utah coupled with higher rates of SINT suggest other factors may contribute to development of these tumors. Impact: Although tobacco and alcohol modestly contribute to risk, our study suggests in addition to greater detection of tumors, other as-of-yet undefined exposures may drive rising SINT incidence.

BACKGROUND The effect of diabetes type on the risk of periprosthetic joint infection is not well documented. We hypothesized that patients with diabetes mellitus type 1 would be at greater risk for periprosthetic joint infection than those with diabetes mellitus type 2 and that a history of diabetic complications would be associated with an increased risk of periprosthetic joint infection. METHODS We performed a retrospective cohort study, within a statewide database, on all adult patients who underwent hip or knee arthroplasty, with follow-up of ≥2 years, from 1996 to 2013. Of the 75,478 patients included, 1,668 had type-1 diabetes and 18,186 had type-2 diabetes. Risk factors were calculated using Cox regression, adjusting for siblings and stratified by age. Logistic regression was used to analyze the effect of diabetic complications on the risk of periprosthetic joint infection, controlling for other known risks for periprosthetic joint infection. RESULTS There was no difference in age or sex between groups (p > 0.05). The frequency of periprosthetic joint infection in patients without diabetes was 2.6% compared with 4.3% in all patients with diabetes (relative risk, 1.47; p < 0.001). Patients with type-1 diabetes were at a 1.8 times greater risk for periprosthetic joint infection than patients with type-2 diabetes (7% compared with 4%; p < 0.001). The following diabetic complications increased the risk of periprosthetic joint infection: peripheral circulatory disorders (odds ratio [OR], 2.59 [95% confidence interval (CI), 1.70 to 3.94]), ketoacidosis (OR, 2.52 [95% CI, 1.51 to 4.19]), neurological manifestations (OR, 2.33 [95% CI, 1.96 to 2.78]), renal manifestations (OR, 2.15 [95% CI, 1.66 to 2.79]), and ophthalmic manifestations (OR, 1.76 [95% CI, 1.24 to 2.51]). The odds of periprosthetic joint infection increased with each added complication and patients with ≥4 complications were 9 times more likely to have a periprosthetic joint infection than patients with uncomplicated diabetes (OR, 9.47 [95% CI, 4.97 to 18.03]). Overweight and obese patients with type-2 diabetes and underweight patients with type-1 diabetes were at greater risk for periprosthetic joint infection compared with the general population (all p < 0.05). CONCLUSIONS Our data showed an increased risk of periprosthetic joint infection in patients with type-1 diabetes compared with those with type-2 diabetes, along with an increasing risk associated with additional diabetic complications. These findings emphasize the need to better understand the medical history of patients with diabetes for more appropriate risk management. LEVEL OF EVIDENCE Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Abnormal serum immunoglobulin (Ig) free light chains (FLC) are established biomarkers of early disease in multiple B-cell lymphoid malignancies, including chronic lymphocytic leukemia (CLL). Heavy chains have also been shown to be biomarkers in plasma cell disorders. An unanswered question is whether these Ig biomarkers are heritable, i.e., influenced by germline factors. CLL is heritable but highly heterogeneous. Heritable biomarkers could elucidate steps of disease pathogenesis that are affected by germline factors, and may help partition heterogeneity and identify genetic pleiotropies across malignancies. Relatives in CLL pedigrees present an opportunity to identify heritable biomarkers. We compared FLCs and heavy chains between relatives in 23 high-risk CLL pedigrees and population controls. Elevated IgM (eIgM) and abnormal FLC (aFLC) ratio was significantly increased in relatives, suggesting that these Ig biomarkers are heritable and could offer risk stratification in pedigree relatives. Within high-risk CLL pedigrees, B-cell lymphoid malignancies were five times more prevalent in close relatives of individuals with eIgM, prostate cancer was three times more prevalent in relatives of individuals with aFLC, and monoclonal B-cell lymphocytosis increased surrounding individuals with normal Ig levels. These different clustering patterns suggest Ig biomarkers have the potential to partition genetic heterogeneity in CLL and provide insight into distinct heritable pleiotropies associated with CLL.

Patients with serrated polyposis syndrome (SPS) and their first-degree relatives (FDRs) have increased colorectal cancer (CRC) risk. Patients with sporadic sessile serrated lesion (SSL) have risk for progression to CRC. Yet familial risks of common extracolonic cancers and even CRC in these cohorts are poorly understood. Our aim was to examine cancer risk for patients with SPS and sporadic SSL and their close and more distant relatives using a large population database.Patients with SPS (n = 59) from hereditary patient registries were eligible for study. Sporadic SSL (n = 754) and sex- and age-matched normal colonoscopy controls (n = 1,624) were selected from clinical data linked to the Utah Population Database. Cox models adjusting for the number of relatives, degree of relatedness, and person-years at risk were used to estimate CRC, extracolonic, and any-site adenocarcinoma/carcinoma cancer risk in patients and their relatives.Compared with controls, CRC risk was elevated 10-fold in patients with SPS (P = 0.04) and 5-fold in their FDRs (P = 0.001). Any-site adenoma/carcinoma risk was increased 2.6-fold in FDRs of patients with SPS. No elevated risks of other common extracolonic cancers were observed in SPS and family members. The FDRs, second-degree relatives, and third-degree relatives of patients with both SSL and adenomatous polyps exhibited a 50% increased CRC risk.Patients with SPS and their FDRs have an increased CRC risk, confirming other reports. Interestingly, patients with SSL were noted to have an increased risk of prostate cancer. Relatives of individuals with both sporadic SSL and adenomas, irrespective of size or dysplasia on examination, may have an elevated CRC risk, suggesting closer colonoscopy surveillance in this population.

Chronic lymphocytic lymphoma (CLL) has one of the highest familial risks among cancers. Monoclonal B-cell lymphocytosis (MBL), the precursor to CLL, has a higher prevalence (13%-18%) in families with 2 or more members with CLL compared with the general population (5%-12%). Although, the rate of progression to CLL for high-count MBLs (clonal B-cell count ≥500/µL) is ∼1% to 5%/y, no low-count MBLs have been reported to progress to date. We report the incidence and natural history of MBL in relatives from CLL families. In 310 CLL families, we screened 1045 relatives for MBL using highly sensitive flow cytometry and prospectively followed 449 of them. MBL incidence was directly age- and sex-adjusted to the 2010 US population. CLL cumulative incidence was estimated using Kaplan-Meier survival curves. At baseline, the prevalence of MBL was 22% (235/1045 relatives). After a median follow-up of 8.1 years among 449 relatives, 12 individuals progressed to CLL with a 5-year cumulative incidence of 1.8%. When considering just the 139 relatives with low-count MBL, the 5-year cumulative incidence increased to 5.7%. Finally, 264 had no MBL at baseline, of whom 60 individuals subsequently developed MBL (2 high-count and 58 low-count MBLs) with an age- and sex-adjusted incidence of 3.5% after a median of 6 years of follow-up. In a screening cohort of relatives from CLL families, we reported progression from normal-count to low-count MBL to high-count MBL to CLL, demonstrating that low-count MBL precedes progression to CLL. We estimated a 1.1% annual rate of progression from low-count MBL, which is in excess of that in the general population.

Neuroendocrine tumors (NETs) of the small intestine undergo large chromosomal and methylation changes. The objective of this study was to identify methylation differences in NETs and consider how the differentially methylated genes may impact patient survival. Genome-wide methylation and chromosomal copy number variation (CNV) of NETs from the small intestine and appendix were measured. Tumors were divided into three molecular subtypes according to CNV results: chromosome 18 loss (18LOH), Multiple CNV, and No CNV. Comparison of 18LOH tumors with MultiCNV and NoCNV tumors identified 901 differentially methylated genes. Genes from the G-protein coupled receptor (GPCR) pathways are statistically overrepresented in the differentially methylated genes. One of the highlighted genes from the GPCR pathway is somatostatin (SST), a clinical target for NETs. Patient survival based on low versus high methylation in all samples identified four significant genes (p OR2S2, SMILR, RNU6-653P, and AC010543.1. Within the 18LOH molecular subtype tumors, survival differences were identified in high versus low methylation of 24 genes. The most significant is TRHR (p

Inherited genetic risk factors play a role in multiple myeloma (MM), yet considerable missing heritability exists. Rare risk variants at genome-wide association study (GWAS) loci are a new avenue to explore. Pleiotropy between lymphoid neoplasms (LNs) has been suggested in family history and genetic studies, but no studies have interrogated sequencing for pleiotropic genes or rare risk variants. Sequencing genetically enriched cases can help discover rarer variants. We analyzed exome sequencing in familial or early-onset MM cases to identify rare, functionally relevant variants near GWAS loci for a range of LNs. A total of 149 distinct and significant LN GWAS loci have been published. We identified six recurrent, rare, potentially deleterious variants within 5 kb of significant GWAS single nucleotide polymorphisms in 75 MM cases. Mutations were observed in BTNL2, EOMES, TNFRSF13B, IRF8, ACOXL and TSPAN32. All six genes replicated in an independent set of 255 early-onset MM or familial MM or precursor cases. Expansion of our analyses to the full length of these six genes resulted in a list of 39 rare and deleterious variants, seven of which segregated in MM families. Three genes also had significant rare variant burden in 733 sporadic MM cases compared with 935 control individuals: IRF8 (P = 1.0 × 10−6), EOMES (P = 6.0 × 10−6) and BTNL2 (P = 2.1 × 10−3). Together, our results implicate six genes in MM risk, provide support for genetic pleiotropy between LN subtypes and demonstrate the utility of sequencing genetically enriched cases to identify functionally relevant variants near GWAS loci.

BACKGROUND: Reported revision rates for endoscopic sinus surgery (ESS) for chronic rhinosinusitis (CRS) vary significantly. Several investigations examining revision rates for ESS have been limited by duration of follow up, academic centers, or small surgeon cohorts. The objective of this study was to define the long-term revision rates for ESS and to determine those unique patient factors that increase the risk of revision ESS. METHODS: The Utah Population Database was queried for Current Procedural Terminology codes for ESS from 1996 to 2016. Patient demographics and comorbid diagnoses were collected. Revision rates and risk factors for surgery were determined by Cox Proportional Hazard modeling. RESULTS: A total of 29,934 patients were identified, with a mean length of follow up of 9.7 years. The long-term revision rate was found to be 15.9%. The mean time between surgeries decreased with higher number of revision surgeries. The time between the 1(st) and 2(nd) surgery was 4.39 years and the time between the 4(th) and 5(th) surgery decreased to 2.18 years. Female gender, older age at first surgery, nasal polyps, comorbid asthma, allergy and a family history of CRS all increased the risk of requiring revision surgery (p

A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of “heterozygote advantage” regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06–1.60; OR MZL = 1.45, 95% CI = 1.12–1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24–3.55; OR MZL = 2.10, 95% CI = 0.99–4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086–96. ©2018 AACR.

Colonoscopy is widely recommended for colorectal cancer (CRC) screening, but evidence to guide the optimal frequency of repeat screening examination is limited. We examined the duration and magnitude of the risk of developing CRC, following a negative colonoscopy in those at average risk and those with a first-degree family history of CRC.A cohort of Utah residents aged 50-80 years who had a negative colonoscopy between 1 January 2001 and 31 December 2011 was identified using the Utah Population Database. Patients were followed from the time of the index colonoscopy until diagnosis of CRC, death, migration out of state, repeat colonoscopy, or end of the study period. CRC incidence after the index colonoscopy was compared with that of the state population by standardized incidence ratios (SIRs).A cohort of 131,349 individuals at average risk with a negative colonoscopy was identified. Compared with the state population, a negative colonoscopy was associated with SIRs of 0.15 (95% confidence interval (CI): 0.08-0.23) at 1 year, 0.26 (95% CI: 0.19-0.32) at 2-5 years, 0.33 (95% CI: 0.22-0.43) at 5-6 years, and 0.60 (95% CI: 0.44-0.76) at 7-10 years for CRC following the index colonoscopy. In a secondary analysis involving only patients with a first-degree relative with CRC, patients had a significantly lower incidence of CRC only for the first 5 years of follow-up (SIR 0.39, 95% CI: 013-0.64). There was also a difference in the risk of proximal (SIR 0.72, 95% CI: 0.45-0.98) and distal (SIR 0.51, 95% CI: 0.30-0.72) colon cancers at 7-10 years following a negative colonoscopy.The risk of developing CRC remains decreased for at least 10 years following the performance of a negative colonoscopy. However, the lower incidence of CRC in those with a family history of CRC differed in magnitude and timing being limited primarily to the first 5 years of follow-up and of lesser magnitude than that in the overall cohort.

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

BACKGROUND It is estimated that the cost to treat periprosthetic joint infection in the United States will approach $1.62 billion by 2020. Thus, the need to better understand the pathogenesis of periprosthetic joint infection is evident. We performed a population-based, retrospective cohort study to determine if familial clustering of periprosthetic joint infection was observed. METHODS Analyses were conducted using software developed at the Utah Population Database (UPDB) in conjunction with the software package R. The cohort was obtained by querying the UPDB for all patients undergoing total joint arthroplasty and for those patients who had subsequent periprosthetic joint infection. The magnitude of familial risk was estimated by hazard ratios (HRs) from Cox regression models to assess the relative risk of periprosthetic joint infection in relatives and spouses. Using percentiles for age strata, we adjusted for sex, body mass index (BMI) of ≥30 kg/m, and a history of smoking, diabetes, and/or end-stage renal disease. Additionally, we identified families with excess clustering of periprosthetic joint infection above that expected in the population using the familial standardized incidence ratio. RESULTS A total of 66,985 patients underwent total joint arthroplasty and 1,530 patients (2.3%) had a periprosthetic joint infection. The risk of periprosthetic joint infection following total joint arthroplasty was elevated in first-degree relatives (HR, 2.16 [95% confidence interval (CI), 1.29 to 3.59]) and combined first and second-degree relatives (HR, 1.79 [95% CI, 1.22 to 2.62]). Further, 116 high-risk pedigrees with a familial standardized incidence ratio of >2 and a p value of

International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

PURPOSE: Rural areas of the U.S. experience disproportionate colorectal cancer (CRC) death compared to urban areas. The authors aimed to analyze differences in CRC survival between rural and urban Utah men and investigate potential prognostic factors for survival among these men. METHODS: A cohort of Utah men diagnosed with CRC between 1997 and 2013 was identified from the Utah Cancer Registry. Survival and prognostic factors were analyzed via five-year CRC survival and Cox proportional hazards models, stratified by rural/urban residence. RESULTS: Among 4,660 men diagnosed with CRC, 15.3% were living in rural Utah. Compared with urban men, rural CRC patients were diagnosed at older ages and in different anatomic subsites; more were overweight, and current smokers. Differences in stage and treatment were not apparent between rural and urban CRC patients. Compared with urban counterparts, rural men experienced a lower CRC survival (Hazard Ratio 0.55, 95% CI=0.53, 0.58 vs 0.58, 95% CI=0.56, 0.59). Race and cancer treatment influenced CRC survival among men living in both urban and rural areas. CONCLUSION: Factors of CRC survival varied greatly among urban and rural men in Utah. The influence of social and environmental conditions on health behaviors and outcomes merits further exploration.

Biliary tract cancers (BTC) including, cholangiocarcinoma (CC) and gallbladder cancer (GBC), are rare and highly fatal malignancies. The etiology and inherited susceptibility of both malignancies are poorly understood. We quantified the risk of BTC in first-degree (FDR), second-degree (SDR), and first cousin (FC) relatives of individuals with BTC, stratified by tumor subsite. BTC diagnosed between 1980 and 2011 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and gender-matched BTC-free controls were selected to form the comparison group for determining BTC risk in relatives using Cox regression analysis. Of the 1302 index patients diagnosed with BTC, 550 (42.2 %) were located in the gallbladder and 752 (57.8 %) were cholangiocarcinomas. There was no elevated risk of BTC (all subsites combined) in FDRs (HR 0.94, 95 % CI 0.29–3.0), SDRs (HR 0.25, 95 % CI 0.06–1.03), and FCs (HR 0.96, 95 % CI 0.61–1.51) of BTC cases compared to cancer-free controls. Similarly, no increased familial risk of GBC or CC was found in relatives of BTC patients stratified by tumor subsite compared to relatives of controls. Relatives of BTC patients are not at an increased risk of GBC or CC in a statewide population. This suggests that biliary tract cancer risk is not associated with a familial predisposition and may be mitigated more strongly by environmental modifiers.

Importance Exfoliation syndrome (XFS) is a systemic connective tissue disease, and abnormal connective tissue metabolism is implicated in inguinal hernias (IH). Associating XFS with comorbid conditions may illuminate their underlying pathophysiology and affect clinical screening and treatment. Exfoliation syndrome involves altered systemic extracellular matrix (ECM) homeostasis involving elastin metabolism. Hernias occur owing to abnormal ECM synthesis, metabolism, or repair. Inguinal hernias involve weakening or rupture of the abdominal/groin wall. Objective To determine an association between patients with XFS and patients with IH in Utah, possibly differing between direct or indirect hernia. Design, Setting, and Participants Cross-sectional study in a large health care system of Utah hospitals and clinics. Conditional logistic regression odds ratios were used to estimate risk of XFS in patients with IH overall and by subtype (direct or indirect) compared with control individuals. Codes specific to direct and indirect IH with additional medical records review of 186 procedures were used to classify IH subtypes that were not prespecified. Bootstrap resampling with jackknife estimation used to calculate 95% confidence intervals. The model accounted for matching on sex and age and adjusted for body mass index and tobacco use. Population-based sample using medical records from 1996 to 2015 that identified 2594 patients 40 years or older on January 1, 1996, with surgical IH repair and 12 966 random control patients with no IH history matched 5:1 on sex and birth year. Data were analyzed between September 10, 2017, and October 23, 2017. Main Outcomes and Measures Exfoliation syndrome outcome defined by diagnosis codes for XFS or exfoliation glaucoma from 1996 to 2015. Results Participants were primarily white (2532 of 2594 patients, [96.1%]; 12 454 of 12 966 control individuals [97.6%]) and non-Hispanic (2396 of 2594 patients [92.4%]); 250 participants were women (9.6%). Of study participants, 22 patients with IH and 43 control individuals were diagnosed as having XFS, respectively. Patients with IH had a 2.3-fold risk for an XFS diagnosis compared with control individuals (95% CI, 1.4-3.5;P = .03), and XFS risk with indirect IH appeared especially pronounced. Conclusions and Relevance Inguinal hernia was associated with an increased risk of XFS in this Utah population. Further work is needed to understand the pathophysiology, genetics, and environmental factors contributing to both diseases.

Background & Aims Individuals with inflammatory bowel diseases (IBDs) have an increased risk of developing colorectal cancer (CRC). Although family history of CRC is a well-established risk factor in healthy individuals, its role in patients with IBD is less clear. We aimed to estimate the risk of CRC in a cohort of patients with IBD from Utah and the significance of family history of CRC in a first-degree relative (FDR). Methods We identified Utah residents with IBD, using the Intermountain Healthcare and University of Utah Health Sciences databases, from January 1, 1996, through December 31, 2011. CRCs were identified using the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. CRC incidence was compared with that of the state population by standardized incidence ratios (SIRs). Results A cohort of 9505 individuals with IBD was identified and 101 developed CRC during the study period. The SIR for CRC in patients with Crohn’s disease was 3.4 (95% CI, 2.3–4.4), and in patients with ulcerative colitis was 5.2 (95% CI, 3.9–6.6). Patients with IBD and a concurrent diagnosis of primary sclerosing cholangitis had the greatest risk of CRC (SIR, 14.8; 95% CI, 8.3–21.2). A history of CRC in a FDR was associated with a nearly 8-fold increase in risk of CRC in patients with IBD (SIR, 7.9; 95% CI, 1.6–14.3), compared with the state population. Conclusions Patients with IBD have a 3- to 5-fold increase in risk of CRC, and those with CRC in a FDR have an almost 8-fold increase in risk. Family history may act as a simple measure to identify individuals with IBD at highest risk for CRC and indicates the need for enhanced surveillance in this population.

Exfoliation syndrome (XFS) is associated with genetic variants of lysyl oxidase-like 1 (LOXL1), a key enzyme in the stabilization of extracellular matrix (ECM) and elastin, and in connective tissue repair. Because patients with chronic obstructive pulmonary disease (COPD) have increased and altered elastin degradation, an association between XFS and COPD was hypothesized and analyzed. Impact of XFS on survival in patients with COPD was evaluated.Case-case and case-control comparison with 5:1 age- and sex-matched controls.Total of 2943 patients with XFS, 20 589 patients with COPD, and 162 patients with both disorders seen between 1996 and 2015 were identified from Utah Population Database-linked medical records. Controls were selected and matched by sex and birth year to patients in a 5:1 ratio.Unconditional logistic regression, using International Classification of Diseases, Ninth Revision codes (365.52 and 366.11) to define XFS and an outcome of COPD (496.0), was used to calculate the odds ratio (OR) to estimate risk of COPD in patients with XFS, adjusting for age and sex. Model covariates included race, obesity, and tobacco use.Whether XFS patients have an increased risk of developing COPD; whether COPD patients have an increased risk of XFS; and, in COPD patients, whether survival differs between those with XFS and those without.In XFS patients, risk of a COPD diagnosis was increased compared with that of non-XFS controls (OR = 1.41; 95% confidence interval [CI], 1.17-1.70; P0.0004), particularly in a tobacco users subset (OR = 2.17; 95% CI, 1.15-4.09; P = 0.02). COPD patients and controls with no COPD did not differ in their risk of an XFS diagnosis. COPD patients with XFS had significantly better survival than patients with COPD and no XFS history.XFS patients may have an increased risk of a COPD diagnosis compared with non-XFS individuals. In COPD patients, risk of XFS was not increased compared with those with no COPD history. In COPD patients with XFS, survival is significantly improved compared with COPD patients with no XFS history.

IF 15.132 (2017); International audience; Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson’s disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th revision (ICD-9) diagnosis codes 314.0–314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson’s disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0–3.0; P

The high-risk pedigree (HRP) design is an established strategy to discover rare, highly-penetrant, Mendelian-like causal variants. Its success, however, in complex traits has been modest, largely due to challenges of genetic heterogeneity and complex inheritance models. We describe a HRP strategy that addresses intra-familial heterogeneity, and identifies inherited segments important for mapping regulatory risk. We apply this new Shared Genomic Segment (SGS) method in 11 extended, Utah, multiple myeloma (MM) HRPs, and subsequent exome sequencing in SGS regions of interest in 1063 MM / MGUS (monoclonal gammopathy of undetermined significance–a precursor to MM) cases and 964 controls from a jointly-called collaborative resource, including cases from the initial 11 HRPs. One genome-wide significant 1.8 Mb shared segment was found at 6q16. Exome sequencing in this region revealed predicted deleterious variants in USP45 (p.Gln691* and p.Gln621Glu), a gene known to influence DNA repair through endonuclease regulation. Additionally, a 1.2 Mb segment at 1p36.11 is inherited in two Utah HRPs, with coding variants identified in ARID1A (p.Ser90Gly and p.Met890Val), a key gene in the SWI/SNF chromatin remodeling complex. Our results provide compelling statistical and genetic evidence for segregating risk variants for MM. In addition, we demonstrate a novel strategy to use large HRPs for risk-variant discovery more generally in complex traits., Author summary Although family-based studies demonstrate inherited variants play a role in many common and complex diseases, finding the genes responsible remains a challenge. High-risk pedigrees, or families with more disease than expected by chance, have aided discovery of genes responsible for less complex diseases, but high-risk pedigrees have not reached their potential in complex diseases. Here, we describe a method to utilize high-risk pedigrees to discover risk-genes in complex diseases. Our method is appropriate for complex diseases because it allows for genetic-heterogeneity, or multiple causes of disease, within a pedigree. This method allows us to identify shared segments that likely harbor disease-causing genes in a family. We apply our method in Myeloma, a heritable and complex cancer of plasma cells. We identified two genes USP45 and ARID1A that fall within shared segments with compelling statistical evidence. Exome sequencing of these genes revealed likely-damaging variants inherited in Myeloma high-risk families, suggesting these genes likely play a role in development of Myeloma. Our Myeloma findings demonstrate our high-risk pedigree method can identify genetic regions of interest in large high-risk pedigrees that are also relevant to smaller nuclear families and overall disease risk. In sum, we offer a strategy, applicable across phenotypes, to revitalize high-risk pedigrees in the discovery of the genetic basis of common and complex disease.

The aim of this study was to determine risk for melanoma among individuals who have a first- or second-degree relative with a history of melanoma, based on the unaffected individual’s age and age at diagnosis of the relative. The study employed a case–control design using a statewide database linked with a Surveillance Epidemiology and End Results cancer registry. A population-based sample of individuals who received at least one diagnosis of first primary, malignant melanoma (n = 14,281), as well as their first- and second-degree relatives, was included. Control individuals with no history of melanoma (n = 70,889) were matched to cases on birth year, gender, race/ethnicity, and county at birth. Risk for melanoma among relatives of melanoma patients declined with relative’s age and age at diagnosis. Individuals between ages 40 and 49 who are first-degree relatives of melanoma patients diagnosed between ages 40 and 49 had the greatest risk for melanoma compared with individuals without a first-degree relative with a melanoma history (HR 4.89; 95% CI 3.11–7.68). Increased melanoma risk among second-degree relatives of patients was typically lower than that for first-degree relatives. Risk for melanoma, at earlier ages than expected, is increased among relatives of individuals with a history of melanoma, particularly if the melanoma case was diagnosed at a young age. Further research on the relationship between age at diagnosis and relative’s melanoma risk could inform melanoma screening recommendations for individuals with a family history of the disease.

Given the frequent and largely incurable occurrence of multiple myeloma, identification of germline genetic mutations that predispose cells to multiple myeloma may provide insight into disease etiology and the developmental mechanisms of its cell of origin, the plasma cell (PC). Here, we identified familial and early-onset multiple myeloma kindreds with truncating mutations in lysine-specific demethylase 1 (LSD1/KDM1A), an epigenetic transcriptional repressor that primarily demethylates histone H3 on lysine 4 and regulates hematopoietic stem cell self-renewal. In addition, we found higher rates of germline truncating and predicted deleterious missense KDM1A mutations in patients with multiple myeloma unselected for family history compared with controls. Both monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma cells have significantly lower KDM1A transcript levels compared with normal PCs. Transcriptome analysis of multiple myeloma cells from KDM1A mutation carriers shows enrichment of pathways and MYC target genes previously associated with myeloma pathogenesis. In mice, antigen challenge followed by pharmacologic inhibition of KDM1A promoted PC expansion, enhanced secondary immune response, elicited appearance of serum paraprotein, and mediated upregulation of MYC transcriptional targets. These changes are consistent with the development of MGUS. Collectively, our findings show that KDM1A is the first autosomal-dominant multiple myeloma germline predisposition gene providing new insights into its mechanistic roles as a tumor suppressor during post-germinal center B-cell differentiation.

Background & Aims Post-colonoscopy colorectal cancers (PCCRCs) may arise from missed lesions or due to molecular features of tumors that allow them to grow rapidly. We aimed to compare clinical, pathology, and molecular features of PCCRCs (those detected within 6–60 months of colonoscopy) and detected CRCs (those detected within 6 months of a colonoscopy). Methods Within a population-based cross-sectional study of incident CRC cases in Utah (from 1995 through 2009), we identified PCCRCs (those cancers that developed within 5 years of a colonoscopy) and matched the patients by age, sex, and hospital site to patients with detected CRC. Archived specimens were retrieved and tested for microsatellite instability (MSI), CpG island methylation, and mutations in KRAS and BRAF. There were 2659 cases of CRC diagnosed within the study window; 6% of these (n = 159) were defined as PCCRCs; 84 of these cases had tissue available and were matched to 84 subjects with detected CRC. Results Higher proportions of PCCRCs than detected CRCs formed in the proximal colon (64% vs 44%; P = .016) and were of an early stage (86% vs 69%; P = .040). MSI was observed in 32% of PCCRCs compared with 13% of detected CRCs (P = .005). The other molecular features were found in similar proportions of PCCRCs and detected CRCs. In a multivariable logistic regression, MSI (odds ratio, 4.20; 95% CI, 1.58–11.14) was associated with PCCRC. There was no difference in 5-year survival between patients with PCCRCs vs detected CRCs. Conclusion In this population-based cross-sectional study of incident CRC cases in Utah, we found PCCRCs to be more likely to arise in the proximal colon and demonstrate MSI, so PCCRCs and detected CRC appear to have different features or processes of tumorigenesis. Additional studies are needed to determine if post-colonoscopy cancers arise through a specific genetic pathway.

The serrated pathway accounts for 15–25% of sporadic colorectal cancer (CRC). In our study, we sought to accurately characterize sessile serrated polyps (SSP) in a population by electronically interrogating colonoscopy patients’ endoscopy and pathology reports using a rules-based text search of pre-defined SSP-related terms. To this aim, we compared a sample of putative SSP and hyperplastic polyps (HP) using our algorithm to a determination of SSP or HP by pathologist and molecular examination to determine the feasibility of large-scale identification of SSP in electronic medical records. In 23,990 endoscopy reports from colonoscopies with pathology performed at a University of Utah Healthcare facility in 2000–2012, we identified serrated lesions and categorized each as putative SSP or HP using a text search algorithm. We obtained 93 tissue samples for histologic and molecular analysis. Serrated polyps were categorized as putative SSP (N = 920) and putative HP (N = 7159) by text search algorithm. Histologic examination of 93 samples identified 37 SSP, 11 probable SSP, and 45 HP. Of 26 putative SSP, 25 were SSP/probable SSP (96%) by histology. Of 67 putative HP, 44 were HP (66%) by histology. Reducing size criterion from ≥1 to ≥5 mm in the search algorithm caused improved sensitivity (77.1%) without decline in specificity (97.8%). A simple rules-based search to identify SSP provides “proof of principle” that SSP can be identified in a large electronic record set. Pilot data indicate defining large, right-sided polyps as ≥5 mm provides adequate sensitivity to detect SSP from electronic records while maintaining high specificity.

Placement of tympanostomy tubes for recurrent or chronic otitis media is the most commonly performed ambulatory procedure in the United States. Etiologies have been speculated to be environmentally based, and studies have suggested a genetic component to the disease. However, no large-scale studies have attempted to define a familial component. The objective of this study was to determine the familial risk of otitis media requiring tympanostomy tubes (OMwTT) in a statewide population.Retrospective observational cohort study with population-based matched controls.Using an extensive genealogical database linked to medical records, the familial risk of OMwTT was calculated for relatives of probands (46,249 patients diagnosed with OMwTT from 1996-2013) compared to random population controls matched 5:1 on sex and birth year from logistic regression models.The median age at time of tympanostomy tube placement was 1 year (interquartile range, 0-2 years). First-degree relatives of patients with OMwTT, primarily siblings, had a 5-fold increased risk of OMwTT (P10In the largest population-based study to date, a significant familial risk is confirmed in OMwTT, suggesting otitis media may have a significant genetic component given the increased risk found in close as well as distant relatives. This could be influenced by shared environments given a five-times risk observed in siblings. Further understanding the genetic basis of OMwTT and its interplay with environmental factors may clarify the etiology and lead to better detection of disease and treatments.3b. Laryngoscope, 127:962-966, 2017.

Chronic rhinosinusitis (CRS) is a highly prevalent inflammatory condition, with significant effects on morbidity and quality of life. Given that other chronic inflammatory conditions have been associated with increased mortality risk, we sought to evaluate the relationship between mortality and CRS including the influence of asthma. Our objective was to determine if CRS, with or without asthma, is associated with altered risk of mortality.Using a statewide population database, we retrospectively identified 27,005 patients diagnosed with CRS between 1996 and 2012, and 134,440 unaffected controls matched 5:1 on birth year and sex. Risk of mortality was determined from Cox models and Kaplan-Meier curves were used to compare survival.A significant interaction between CRS and asthma status was observed in which CRS appeared to confer a protective effect in asthma patients. Asthma, when present, increased mortality in CRS-negative controls (p-interaction0.0001). Independent of asthma status, CRS patients exhibited a decreased mortality risk (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.74 to 0.85) compared to controls. However, in patients diagnosed at or before the median age of CRS onset (42 years) independent of asthma status, survival was not improved (HR = 0.98; 95% CI, 0.81 to 1.18). Risk of mortality was greater in CRS with nasal polyps (n = 1643) compared to 25,362 polyp-negative CRS patients (HR = 1.38; 95% CI, 1.09 to 1.77).CRS was associated with lower risk of mortality compared to controls, and appeared to mitigate increased mortality from asthma. We posit that better survival conferred by CRS may be secondary to treatment. However, the etiology of this relationship and the effect of CRS treatment on mortality are unknown.

International audience; Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 x 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 x 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk

Diet and lifestyle factors have been inconsistently associated with rectal tumors. It is possible that evaluation of specific tumor markers with these factors may help clarify these associations. In this study, we examine energy contributing nutrients, dietary fiber, BMI (kg/m2), and long-term physical activity with TP53 mutations, KRAS2 mutations, and CpG Island Methylator Phenotype (CIMP) in 750 population-based cases of rectal cancer compared to healthy controls. We observed that high levels of physical activity reduced the risk of having TP53 and KRAS2 rectal tumor mutations. Dairy products rich in fat were associated with an increased risk of CIMP+ tumors (OR 1.88 95% CI 0.92, 3.84), while low-fat dairy products reduced risk of CIMP+ tumors (OR 0.56 95% CI 0.29, 1.09). Omega-3 fatty acids were associated with a twofold increased risk of a CIMP+ tumor. High levels of vegetable intake reduced risk of both TP53 mutations (OR 0.73 95% CI 0.54, 1.00; p trend 0.02) and KRAS2 mutations (OR 0.60 95% CI 0.40, 0.89; p trend

Genome-wide association studies (GWAS) have identified SMAD7 on 8q21 as being associated with colorectal cancer. We evaluated single nucleotide polymorphisms (SNP) in the SMAD7 gene, including rs4939827, rs12953717, and rs4464148, previously identified from GWAS in a large population-based case-control study of colon cancer. We observed that rs12953717 was associated with a statistically significant increased risk of colon cancer [odds ratio, 1.38; 95% confidence intervals (CI), 1.13–1.68; P linear trend < 0.01] for the TT genotype compared with the CC genotype, whereas the CC genotype of the rs4939827 SNP was inversely associated with colon cancer (0.77; 95% CI, 0.64–0.93) relative to the TT genotype. There were no significant differences in association for either of these polymorphisms when stratified by age, tumor site, sex, or family history. The odds ratios between SMAD7 and colon cancer among individuals reporting recent aspirin/nonsteroidal anti-inflammatory drug use was 0.60 (95% CI, 0.43–0.85) for the CC genotype of the rs4939827 polymorphism and 1.69 (95% CI, 1.20–2.38) for the TT genotype of the rs1295371 polymorphism. This result compares to odds ratios of 0.86 (95% CI, 0.68–1.09) for rs4939827 and 1.22 (95% CI, 0.96–1.56) among individuals who did not use aspirin/nonsteroidal anti-inflammatory drugs. An assessment of SMAD7 genotypes with tumor markers did not reveal any significant differences by KRAS2, TP53, CpG island methylator phenotype, or microsatellite instability status. No significant associations were observed for the rs4464148 SNP or other SNPs evaluated in the SMAD7. These results corroborate the findings of GWAS in colon cancer pointing to SMAD7 and reinforce interest in SNPs in this gene. Cancer Res; 70(4); 1479–85

DNA repair enzymes function in major pathways to reverse DNA damage, including base excision repair (BER). Missense polymorphisms in BER repair genes may contribute to differences in DNA repair capacity, specific mutations, and susceptibility to cancer in the presence of exposure to carcinogens such as cigarette smoking. In a study of 1,604 incident colon cancer cases and 1,969 matched population-based controls genotyped for BER variants OGG1 (S326C) and XRCC1 (R194W, R280H, and R399Q), we found no associations with colon cancer overall. However, a 2-fold increased risk of BRAF V600E tumor mutation was observed in current and former cigarette smokers homozygous for the OGG1 polymorphism (odds ratio, 2.2; 95% confidence interval, 1.02-4.9, recessive model); similar associations were not observed for microsatellite instability, CpG island methylator phenotype, KRAS2 mutations, or TP53 mutations. The XRCC1 R194W polymorphism was associated with a modest increased risk of TP53 tumor mutations in those who regularly smoked cigarettes (odds ratio, 1.4; 95% confidence interval, 1.02-1.9). These findings point to the importance of studying tumor mutations when examining DNA repair polymorphisms and cigarette smoke exposure to identify potentially relevant associations with colorectal cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(12):3384–8)

Polymorphisms in DNA double-strand break repair gene XRCC2 may play an important role in colorectal cancer etiology, specifically in disease subtypes. Associations of XRCC2 variants and colorectal cancer were investigated by tumor site and tumor instability status in a four-center collaboration including three U.K. case-control studies (Sheffield, Leeds, and Dundee) and a U.S. case-control study of cases from high-risk Utah pedigrees (total: 1,252 cases and 1,422 controls). The 14 variants studied were tagging single nucleotide polymorphisms (SNP) selected from National Institute of Environmental Health Sciences/HapMap data supplemented with SNPs identified from sequencing of 125 cases chosen to represent multiple colorectal cancer groups (familial, metastatic disease, and tumor subsite). Monte Carlo significance testing using Genie software provided valid meta-analyses of the total resource that includes family-based data. Similar to reports of colorectal cancer and other cancer sites, the rs3218536 R188H allele was not associated with increased risk. However, we observed a novel, highly significant association of a common SNP, rs3218499G>C, with increased risk of rectal tumors (odds ratio, 2.1; 95% confidence interval, 1.3-3.3; Pχ2 = 0.0006) versus controls, with the largest risk found for female rectal cases (odds ratio, 3.1; 95% confidence interval, 1.6-6.1; Pχ2 = 0.0006). This difference was significantly different to that for proximal and distal colon cancers (Pχ2 = 0.02). Our investigation supports a role for XRCC2 in colorectal cancer tumorigenesis, conferring susceptibility to rectal tumors. (Cancer Epidemiol Biomarkers Prev 2009;18(9):2476–84)

Cigarette smoking has been identified as a risk factor for rectal cancer. Our investigation evaluates associations between active and passive smoking and TP53, KRAS2, and BRAF V600E mutations, microsatellite instability (MSI), and CpG Island Methylator Phenotype (CIMP) in rectal tumors. We examine how genetic variants of GSTM1 and NAT2 alter these associations in a population-based, case-control study of 750 incident rectal cancer cases and 1,201 controls. Detailed tobacco exposure data were collected in an extensive questionnaire. DNA from blood was examined for GSTM1 and NAT2 variants. Tumor DNA was assessed to determine TP53 (exons 5-8), KRAS2 (codons 12-13) and BRAF mutations, MSI (BAT26 and TGFbetaRII analysis), and CIMP (methylation of CpG islands in CDKN2A, MLH1, MINT1, MINT2 and MINT31). Cigarette smoking (>20 pack-years, relative to nonsmokers) was associated with increased risk of TP53 mutations (OR = 1.4, 95% CI 1.02-2.0), BRAF mutations (OR = 4.2, 95% CI 1.3-14.2) and MSI (OR = 5.7, 95% CI 1.1-29.8) in rectal tumors. Long-term environmental tobacco smoke (ETS) exposure of >10 hr/wk was associated with increased risk of KRAS2 mutation (OR = 1.5, 95% CI 1.04-2.2). All smoking indicators were suggestive of increased risk in CIMP+ rectal cancer. GSTM1 and NAT2 were generally not associated with rectal tumor alterations; however, we observed an interaction of ETS and NAT2 in TP53-mutated tumors (p < 0.01). Our investigation shows active smoking is associated with increased risk of TP53, BRAF and MSI+ in rectal tumors and is suggestive of increased risk of CIMP+ tumors. ETS may increase risk of KRAS2 mutations; association with TP53 mutations and ETS may be influenced by NAT2.

The MLH1 −93 G>A promoter polymorphism has been reported to be associated with an increased risk of microsatellite unstable colorectal cancer. Other than microsatellite instability, however, the genetic and most epigenetic changes of tumors associated with this polymorphism have not been studied. We evaluated associations between the −93 G>A polymorphism and CpG island methylator phenotype (CIMP), BRAF V600E mutations, and MLH1 methylation in tumors from a sample of 1,211 individuals with colon cancer and 1,968 controls from Utah, Northern California, and Minnesota. The −93 G>A polymorphism was determined by the five prime nuclease assay. CIMP was determined previously by methylation-specific PCR of CpG islands in MLH1, methylated in tumors (MINT)1, MINT2, MINT31, and CDKN2A (p16). The BRAF V600E mutation was determined by sequencing exon 15. The MLH1 −93 G>A promoter polymorphism was associated with CIMP (odds ratio (OR) 3.44, 95% confidence interval (CI) 1.85, 6.42), MLH1 methylation (OR 4.16, 95%CI 2.20, 7.86), BRAF mutations (OR 4.26, 95%CI 1.83, 9.91), and older age at diagnosis (OR 3.65, 95%CI 2.08, 6.39) in microsatellite unstable tumors. These associations were not observed in stable tumors. Increased age at diagnosis and tumor characteristics of microsatellite unstable tumors associated with MLH1 −93 G>A suggests the polymorphism is acting at a relatively late stage of colorectal carcinogenesis to drive CIMP+ tumors down the microsatellite instability pathway. © 2008 Wiley-Liss, Inc.

Little is known about the contribution of polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and the folate metabolism pathway in rectal cancer alone. Data were from participants in a case-control study conducted in Northern California and Utah (751 cases and 979 controls). We examined independent associations and interactions of folate, B vitamins, methionine, alcohol, and MTHFR polymorphisms (MTHFR C677T and A1298C) with rectal cancer. Dietary folate intake was associated with a reduction in rectal cancer OR 0.66, 95% CI 0.48-0.92 (>475 mcg day compared to < = 322 mcg) as was a combination of nutrient intakes contributing to higher methyl donor status (OR 0.79, 95% CI 0.66-0.95). Risk was reduced among women with the 677 TT genotype (OR 0.54, 95% CI 0.30-0.9), but not men (OR 1.11, 95% CI 0.70-1.76) and with the 1298 CC genotype in combined gender analysis (OR 0.67, 95% CI 0.46-0.98). These data are consistent with a protective effect of increasing dietary folate against rectal cancer and suggest a protective role of the MTHFR 677 TT genotype in women and 1298 CC in men and women. Folate intake, low methyl donor status, and MTHFR polymorphisms may play independent roles in the etiology of rectal cancer.

Small intestinal neuroendocrine tumors (SI-NETs) are rare tumors arising from the enterochromaffin cells of the gut. Having a first-degree relative with a SI-NET has been shown to confer a substantial risk arising from shared environment and genetics. Heritable risk was examined using a computerized genealogy linked to historical statewide cancer data. A population-based analysis of the observed familial clustering of SI-NETs was performed to assess the genetic risk in distant relatives. A test for significant excess relatedness of 384 individuals with genealogy data and histologically confirmed SI-NETs was performed by comparing pairwise relatedness of cases to 1000 sets of matched controls. Overall significant excess pairwise relatedness was found for the 384 cases (PP=0.041). Relative risks (RRs) for SI-NETs were estimated as a ratio of observed to expected number of SI-NET cases among each relationship class. Siblings have a 13.4-fold (PP=0.143) RR, suggesting both genetic and environmental influences. The risk extends out to third-degree relatives with a 2.3-fold RR (P=0.008). Metachronous cancers were also reported in 26% of the SI-NET cases demonstrating an increased RR of colon, bladder, non-Hodgkin lymphoma, melanoma, and prostate cancers. Although SI-NETs are rare, relatives of these cases are at a significantly elevated risk of developing a SI-NET due to heritable genetic factors. Definition of the genetic risk factors will be an important tool for earlier diagnosis and better outcomes for SI-NETs.

To determine the relative risk of having eosinophilic esophagitis (EoE) coexist with chronic rhinosinusitis (CRS) in probands and their families using the Utah Population Database (UPDB).This retrospective observational cohort study with population-based matched controls utilized the UPDB, a genealogical database linked to medical records. It was used to identify CRS and EoE patients diagnosed at any age between 2008 and 2012. The familial risks of an EoE diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 530.13) in CRS probands, and vice versa, and their first- through fifth-degree relatives and spouses were calculated using logistic regression models in comparison to controls randomly selected from the Utah population and individually matched 6:1 on sex and birth year.Probands with CRS demonstrated a 3.4-fold increased risk of having EoE themselves (P10(-15) ). First-degree relatives (parents, siblings, and children) of CRS probands had a 1.5-fold increased risk of having EoE (P10(-4) ), whereas more distant relatives did not show a significant increased risk. Spouses of probands had a 1.4-fold increased risk of having EoE (P = 0.055). Conversely, risk estimates of having CRS in EoE probands were consistent.We observed an increased risk of comorbid EoE in patients with CRS and their families. An association between CRS and EoE as comorbid conditions suggests that a familial component is contributing to the etiology of both diseases. Further analyses regarding the pathophysiology of the development of CRS in these specific patients will lead to a better understanding of both disease processes and may help target therapy.3b. Laryngoscope, 126:1279-1283, 2016.

Background & Aims Colonoscopy is widely recommended for colorectal (CRC) screening in the United States, but evidence of effectiveness is limited. We examined whether exposure to colonoscopy decreases the odds of incident CRC and death from CRC in Utah. Methods We performed a case-control study of Utah residents, 54 to 90 years old, who received a CRC diagnosis from 2000 through 2010 (cases). Age- and sex-matched controls with no history of CRC (controls) were selected for each case. We determined receipt of colonoscopy 6 months to 10 years before the reference date for each case and control through administrative claims data. Colonoscopy exposure was compared by using conditional logistic regression. Results We identified 5128 cases and 20,512 controls; 741 cases (14%) and 5715 controls (28%) received a colonoscopy. Exposure to colonoscopy reduced the odds for a diagnosis of CRC; the odds ratios (ORs) were 0.41 for any CRC (95% confidence interval [CI], 0.38–0.44), 0.58 for proximal colon cancer (95% CI, 0.51–0.65), and 0.29 for distal colon or rectal cancer (95% CI, 0.25–0.33). This finding was consistent among sexes, age groups, and cancer stages. Similarly, in a subgroup analysis, colonoscopy was associated with decreased odds of death from CRC (OR, 0.33; 95% CI, 0.28–0.39) in both the proximal colon (OR, 0.43; 95% CI, 0.34–0.55) and distal colon or rectum (OR, 0.23; 95% CI, 0.18–0.30). Conclusions In the population of Utah, colonoscopy is associated with a large reduction in risk of new-onset CRC and death from CRC. This reduction in risk for CRC was greatest for the distal colon and rectum, with a more modest reduction for proximal colon cancer.

To determine the risk of chronic rhinosinusitis (CRS) in relatives of children with a diagnosis of CRS.Retrospective observational cohort study with population-based matched controls.A unique genealogical database linked to medical records was used to identify subjects ≤12 years old with a diagnosis of CRS from 1996 to 2011. The familial recurrence risks of CRS in first- through fifth-degree relatives of probands were calculated using Cox models and compared to controls randomly selected from the Utah population and matched 10:1 on sex and birth year.We identified 496 pediatric patients with CRS. Siblings of patients with CRS demonstrated a 57.5-fold increased risk (P 10(-8) ) of also having pediatric CRS. First cousins had a 9.0-fold increased risk (P 10(-3) ) and second cousins had a 2.9-fold increased risk (P = .002) of pediatric CRS. First-degree relatives, second-degree relatives, and first cousins of pediatric cases demonstrated a significant increased risk of having adult CRS. Parents of probands demonstrated a 5.6-fold increased risk (P 10(-15) ). Fifty-five probands had one affected parent versus three probands with two affected parents.In the largest population study to date of children with CRS, a significant familial risk is confirmed. Parents of probands were also at increased risk, although it was much more likely for one parent to be affected than both, suggesting a genetic component of the disease. Further understanding of the genetic basis of CRS and its interplay with environmental factors could clarify the etiology and lead to more effective targeted treatments.3b Laryngoscope, 126:739-745, 2016.

It is not clear whether familial risk of colorectal cancer (CRC) varies with age of index CRC patients or their relatives. We quantified the risk of CRC in first-degree relatives (FDRs), second-degree relatives, and first-cousin relatives of individuals with CRC, stratified by ages and sexes of index patients and ages of relatives.CRCs diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age- and sex-matched CRC-free individuals were selected to form the comparison group. CRC risk in relatives was determined by Cox regression analysis.Of 18,208 index patients diagnosed with CRC, the highest familial risk was observed in FDRs of index CRC patients who were diagnosed at an age younger than 40 years (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.7-3.79). However, familial risk was increased in FDRs even when the index case was diagnosed with cancer at an advanced age (80 years; HR, 1.76; 95% CI, 1.59-1.94). Ages of relatives and ages of index cases of CRC each affected familial cancer risk; the highest risk was found in young relatives (50 years) of individuals with early-onset CRC (40 years; HR, 7.0; 95% CI, 2.86-17.09).All relatives of individuals with CRC are at increased risk for this cancer, regardless of the age of diagnosis of the index patient. Although risk is greatest among young relatives of early-onset CRC cases, relatives of patients diagnosed at advanced ages also have an increased risk.

Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from the largest case-control study of RMS and the Utah Population Database (UPDB). RMS cases (n = 322) were obtained from the Children's Oncology Group (COG). Population-based controls (n = 322) were pair-matched to cases on race, sex, and age. Conditional logistic regression was used to evaluate the association between family history of cancer and childhood RMS. The results were validated using the UPDB, from which 130 RMS cases were identified and matched to controls (n = 1300) on sex and year of birth. The results were combined to generate summary odds ratios (OR(s) ) and 95% confidence intervals (CI). Having a first-degree relative with a cancer history was more common in RMS cases than controls (OR(s) = 1.39, 95% CI: 0.97-1.98). Notably, this association was stronger among those with embryonal RMS (OR(s) = 2.44, 95% CI: 1.54-3.86). Moreover, having a first-degree relative who was younger at diagnosis of cancer (30 years) was associated with a greater risk of RMS (OR(s) = 2.37, 95% CI: 1.34-4.18). In the largest analysis of its kind, we found that most children diagnosed with RMS did not have a family history of cancer. However, our results indicate an increased risk of RMS (particularly embryonal RMS) in children who have a first-degree relative with cancer, and among those whose relatives were diagnosed with cancer at30 years of age.

Background & Aims: Variant genotypes of uridine diphosphate glucuronsyltransferase isoenzyme 1A6 ( UGT1A6 ) associated with decreased metabolic activity have been associated with an enhanced protective effect of aspirin on the development of colorectal adenomas. However, interactions between UGT1A6 variants or variants of another enzyme that metabolizes nonsteroidal anti-inflammatory drugs (NSAIDs), cytochrome P4502C9 ( CYP2C9 ), and NSAIDs in the prevention of colorectal cancer have not been studied extensively. Methods: UGT1A6 and CYP2C9 genotypes were determined in 2295 individuals with colorectal cancer and 2903 controls. Interactions between these genotypes, aspirin or ibuprofen use, and colorectal cancer risk were determined. Results: Variant CYP2C9 genotypes enhanced the protective effect of ibuprofen on the prevention of colorectal cancer, and a dose-response relationship with respect to increasing numbers of variant alleles was seen ( P interaction=.02). CYP2C9 variants were more effective in individuals with wild-type rather than variant UGT1A6 ( P interaction CYP2C9 genotypes showed no interaction with aspirin usage, and variant UGT1A6 genotypes showed no interaction with either NSAID with respect to colorectal cancer protection. Conclusions: In this study, the major effect seen was an enhancement by slower-metabolizing CYP2C9 variants of the chemopreventive activity of ibuprofen against colorectal cancer.

Inherited variants of the vitamin D receptor (VDR) gene may influence cancer risk by altering the effect of vitamin D on cell growth and homeostasis. Studies have examined genotypes for common VDR polymorphisms, including a single nucleotide polymorphism (SNP) detected by Bsm1, a polyadenosine [poly(A)] repeat polymorphism, and a SNP detected by Fok1, as candidates for susceptibility to cancer, but most have not evaluated haplotypes for these markers. We investigated haplotypes for these polymorphisms in case-control studies of colon cancer (1,811 cases and 1,451 controls) and rectal cancer (905 cases and 679 controls). We used the expectation-maximization algorithm to estimate haplotypes for White, Hispanic, African-American, and Asian subjects, tested for differences in VDR haplotype distribution, and calculated odds ratios (OR) for association between haplotype and cancer. The distribution of haplotypes differed by race or ethnic group, but four common haplotypes accounted for the majority of alleles in all groups. VDR haplotype distributions differed between colon cancer cases and controls (P = 0.0004). The common haplotype bLF, containing Bsm1 b (Bsm1 restriction site present), poly(A) long (18-22 repeats), and Fok1 F (restriction site absent) was associated with increased risk of colon cancer, OR 1.15 (95% confidence interval, 1.03-1.28), as was the rare haplotype BLF, containing Bsm1 B (restriction site absent), poly(A) long, and Fok1 F (OR, 2.40; 95% confidence interval, 1.43-4.02). No case-control differences were detected for rectal cancer. In this analysis, haplotypes of the VDR influenced risk of colon cancer, but haplotype variables had only slightly better ability to explain case-control differences than genotype variables. (Cancer Epidemiol Biomarkers prev 2006;15(4):744–9)

Background Associations between colon and rectal cancer and intakes of vegetables, other plant foods, and fiber have stimulated much debate. Objective We examined the association between rectal cancer and plant food and fiber intakes. Design Data from 952 incident cases of rectal cancer were compared with data from 1205 population-based controls living in Utah or enrolled in the Kaiser Permanente Medical Care Program in northern California Results Rectal cancer was inversely associated with intakes of vegetables (odds ratio: 0.72; 95% CI: 0.54, 0.98), fruit (0.73; 0.53, 0.99), and whole-grain products (0.69; 0.51, 0.94), whereas a high intake of refined-grain products was directly associated with an increased risk of rectal cancer (1.42; 1.04, 1.92). Similarly, relative to low fiber intakes, high intakes of dietary fiber reduced the risk of rectal cancer (0.54; 0.37, 0.78). The reduced risk of rectal cancer associated with vegetable (0.48; 0.29, 0.80), fruit (0.63; 0.38, 1.06), and fiber (0.40; 0.22, 0.71) intakes was strongest for persons who received the diagnosis after age 65 y. A threshold effect at approximately 5 servings of vegetables/d was needed to see a reduced risk of rectal cancer. Conclusions The results suggest that plant foods may be important in the etiology of rectal cancer in both men and women. Age at diagnosis appears to play an important role in the association.

Numerous properties suggest that antioxidants and carotenoids may be valuable chemopreventive agents. A population-based case-control study of 952 rectal cancer cases and 1,205 controls from Northern California and Utah was conducted between September 1997 and February 2002. Detailed diet history, medical history, and lifestyle factors interviews were conducted. Dietary antioxidants were not associated with rectal cancer risk in men. For women, relative to the highest level of intake, low intake of dietary lycopene (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.0, 2.8) or vitamin E (OR = 2.2, 95% CI: 1.1, 4.3) was associated with an increased risk of rectal cancer. Alpha-, beta-, and gamma-tocopherol were associated with an approximate twofold increased risk of rectal cancer in women. Associations were stronger for women aged > or = 60 years for vitamin E and tocopherols (alpha-tocopherol OR = 3.6, 95% CI: 1.4, 9.4; gamma-tocopherol OR = 5.3, 95% CI: 2.1, 13.2; delta-tocopherol OR = 1.9, 95% CI: 0.9, 4.0), except for beta-tocopherol, for which risk increased twofold for all women. Associations differed by estrogen status for beta-carotene, lycopene, and vitamin E. These results suggest that vitamin E and lycopene may modestly reduce the risk of rectal cancer in women.

The vitamin D receptor (VDR) may importantly modulate risk of colorectal cancer either independently or in conjunction with calcium and vitamin D intake. We evaluate the association between calcium, vitamin D, dairy products, and VDR polymorphisms in 2 case-control studies of colon and rectal cancer (n = 2,306 cases and 2,749 controls). Dietary intake was evaluated using a detailed diet history questionnaire. Two VDR polymorphisms were evaluated: an intron 8 Bsm 1 polymorphism and a 3' untranslated region poly-A length polymorphism (designated S for short and L for long). The SS genotype reduced risk of colorectal cancer for men (odds ratio [OR] = 0.71; 95% confidence interval [CI] = 0.55-0.92). High levels of calcium intake reduced risk of rectal cancer in women (OR = 0.39; 95% CI = 0.24-0.64) but were not associated with rectal cancer in men (OR = 1.02; 95% CI = 0.66-1.56). Similar reduced rectal cancer risk among women was observed at high levels of vitamin D (OR = 0.52; 95% CI = 0.32-0.85) and low-fat dairy products (OR = 0.61; 95% CI = 0.39-0.94). High levels of sunshine exposure reduced risk of rectal cancer among those diagnosed when

Physical activity has been shown to reduce risk of colon cancer. Some studies have shown site-specific associations while others have not. The inverse association between physical activity and colon cancer is consistent although only 7 of 13 studies that have collected both colon and rectal cancer data in the same manner report reduced risk for rectal cancer; four of these studies detected statistically significant inverse associations. The frequency, duration and intensity of activity are important components of a public health message to reduce risk of colon cancer through performance of physical activity. However, difficulties in estimating the exact amount of activity needed and frequency and intensity of activity result in only crude estimates of dose needed for a protective effect. Much of the literature suggest that more intense activity is needed to reduce colon cancer risk and that somewhere between 3.5 and 4 hours of vigorous activity per week may be needed to optimise protection. Several biological mechanisms have been proposed to explain the association between physical activity and colon cancer; many of these mechanisms also support the observation that intense activities are most protective. Biological mechanisms include: physical activity increasing gut motility; enhancing the immune system; decreasing insulin and insulin-like growth factor levels; decreasing obesity; enhancing free radical scavenger systems; and influencing prostaglandin levels. The evidence taken together provides strong support for lack of physical activity being causally related to colon cancer. It has been estimated that 12–14% of colon cancer could be attributed to lack of frequent involvement in vigorous physical activity.

Despite widespread use of methamphetamine and other amphetamine-type stimulants (METH/AMPH), little is known about the long-term medical consequences of METH/AMPH abuse and dependence. Preclinical neurotoxicity findings raise public health concerns that these stimulants may damage dopamine neurons, resulting in dopamine-related disorders such as Parkinson's disease (PD).A retrospective design was used to examine statewide medical records (1996 through 2011) linked to the Utah Population Database. Individuals 30 years or older on December 31, 2011 were assigned to a METH/AMPH cohort (ICD-9-CM 304.4, 305.7, 969.7, E854.2; N=4935), a cocaine cohort (ICD-9-CM 304.2, 305.6, 968.5, E855.2; N=1867) or a population cohort unexposed to drugs or alcohol for control selection. A competing-risks, proportional hazards model was used to determine whether the METH/AMPH or cocaine cohorts were at increased risk of developing PD (ICD-9-CM 332.0) or PD/parkinsonism/essential tremor (PD/PT; ICD-9-CM 332.0, 332.1, 333.0, 333.1) compared to individually sex- and age-matched controls (5:1 control to case ratio; N=34,010).In METH/AMPH users, we observed an increased risk of PD and PD/PT (HRPD=2.8, 95%CI 1.6-4.8, P10(-3); HRPD/PT=3.1, 95%CI 1.9-4.9, P10(-4)) compared to population-based controls. Conversely, cocaine users exhibited no elevated risk of PD compared to controls.We observed a near three-fold increased risk of PD in METH/AMPH users vs. controls which confirms prior observations and supports that PD risk in users may be higher than previous estimates. A suggestion that female and male users may differ in PD susceptibility warrants further study.