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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 Glaucoma is the leading cause of irreversible blindness globally. During the COVID-19 pandemic, an enforced reduction in capacity resulted in the deferral of routine outpatient appointments for glaucoma patients. Aim This study analyses patient outcomes following the establishment of a drive-through intra-ocular pressure (IOP) clinic during the COVID-19 pandemic to alleviate increased pressure on the tertiary glaucoma services at Royal Victoria Eye and Ear Hospital (RVEEH) and Mater Misericordiae University Hospital (MMUH) between August 2020 and June 2021. Methods A 1-lane driveway system was established in a marquee on the grounds of City West hotel. IOPs were measured in patients’ cars using a hand held iCare100 tonometer. Results were reviewed by a consultant ophthalmologist. At hospital follow-up clinic visits, IOP was measured using the Goldmann applanation tonometer (GAT). Results Three hundred one patients of a total of 672 who attended the drive-through clinic have subsequently attended a designated hospital follow-up appointment. In this cohort, the mean drive-through iCare IOP of 19.4 mmHg ± 6.0 was significantly higher (

Background: Comorbid chronic rhinosinusitis (CRS) of adulthood is increasing among patients with cystic fibrosis (CF) due to improved median survival. However, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate the revision rate of ESS and associated risk factors among adults with CRS and CF (CRSwCF). Methods: The Utah Population Database was queried for patients age >18 with CRS who underwent at least one ESS between 1996 and 2018. Demographic information and ESS history were collected and compared for CRSwCF versus CRS without CF (CRSsCF) using chi-square and t-tests. Risk factors for revision were analyzed using Cox proportional hazard models and logistic regression analysis. Results: A total of 34 050 patients (33 639 CRSsCF and 411 CRSwCF) were included in the final analysis. The mean duration of follow-up was 9.3 and 9.3 years, respectively ( P = .98). Adult patients with CF were significantly more likely to undergo revision ESS (18.7%) than those without CF (13.4%; P

Background: Mammographic density (MD) is strongly associated with breast cancer risk. We examined whether body mass index (BMI) partially explains racial and ethnic variation in MD. Methods: We used multivariable Poisson regression to estimate associations between BMI and binary MD [Breast Imaging Reporting and Database System (BI-RADS) A&B versus BI-RADS C&D] among 160,804 women in the Utah mammography cohort. We estimated associations overall and within racial and ethnic subgroups and calculated population attributable risk percents (PAR%). Results: We observed the lowest BMI and highest MD among Asian women, the highest BMI among Native Hawaiian and Pacific Islander women, and the lowest MD among American Indian and Alaska Native (AIAN) and Black women. BMI was inversely associated with MD [RRBMI≥30 vs. BMI Conclusions: While we observed substantial differences in the distributions of BMI and MD by race and ethnicity, associations between BMI and MD were generally similar across groups. Impact: Distributions of BMI and MD may be important contributors to breast cancer disparities.

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.

PURPOSE Exfoliation syndrome, a systemic disorder with ocular manifestations, is associated with lysyl oxidase-like gene variants. Along with transforming growth factor beta-1, lysyl oxidase-like 1 is a key enzyme in stabilizing extracellular matrix and remodelling collagen/elastin. Given the role that transforming growth factor beta-1, lysyl oxidase-like gene variants and fibrosis play in atrial fibrillation, an association with exfoliation syndrome was investigated. METHODS An exfoliation syndrome cohort of 2803 patients and an atrial fibrillation cohort of 43 694 patients aged 60-90 years at disease onset were identified using the Utah Population Database (1996-2015). Conditional logistic regression was used to estimate risk of atrial fibrillation in exfoliation syndrome patients and risk of exfoliation syndrome in atrial fibrillation patients compared with respective 5:1 sex- and age-matched control cohorts. Kaplan-Meier curves were examined to assess survival in atrial fibrillation patients by exfoliation syndrome status. RESULTS Exfoliation syndrome patients had a 21% greater risk (95% CI 1.06-1.37; p

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.

BACKGROUND. The link between hypertensive disorders of pregnancy (HDP) and short-term adverse outcomes has long been recognized. However, there is now evidence that survivors of HDP remain at risk of adverse biological events long after giving birth, including ocular complications. We sought to determine whether HDP is associated with development of the choroidal neovascular (CNV) form of age-related macular degeneration (AMD), a leading cause of blindness. METHODS. We identified women who experienced HDP (preeclampsia/eclampsia, HELLP syndrome, and gestational hypertension) as recorded in Utah birth certificates from 1939-2013. Exposed subjects were matched 1:2 to unexposed women on: mother’s age at delivery, and on child’s birth year, sex, and birth order. An AMD outcome from 1992-2015 was determined from electronic medical records. Risk of CNV AMD was estimated using stratified Cox regression with a competing risk of death. FINDINGS. We included 31,454 HDP-exposed and 62,908 unexposed women for study. Of 681 exposed and 1,355 unexposed with subsequent AMD, 158 and 284 developed choroidal neovascularization, respectively. Women with HDP exhibited an 80% higher risk for early-onset CNV AMD before age 70 [adjusted hazard ratio (aHR) 1.8, 95%CI 1.23-2.58; p

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

BACKGROUND Chronic rhinosinusitis with asthma (CRS-A) has a significant impact on patient morbidity and quality of life. Nevertheless, little is known about the natural history of endoscopic sinus surgery (ESS) in this cohort. The objective of this study was to evaluate revision rates of ESS in CRS-A and identify risk factors associated with increased likelihood for revision surgery compared to those with CRS without asthma (CRS-alone). METHODS The Utah Population Database was queried for patients age >18 years with CRS who underwent at least 1 ESS between 1996 and 2018. Demographic information and history of ESS were collected and compared between CRS-A and CRS-alone using chi-square tests for categorical variables and t tests for continuous variables. Risk factors for revision surgery were analyzed using Cox proportional hazard models. RESULTS A total of 33,090 patients (7693 CRS-A and 25,397 CRS-alone) were included in the final analysis. Mean follow up was 9.8 years in CRS-A and 9.1 years in CRS-alone (p < 0.001). The revision rate among patients with CRS-A (21.5%) was twice that of CRS-alone (10.8%) (p < 0.001). Among patients with CRS, a history of allergy (p < 0.001), asthma (p < 0.001), and nasal polyposis (p < 0.001) was independently associated with increased risk of revision ESS. Patients with CRS-A and nasal polyposis were 6 times more likely to require revision surgery than those with CRS-alone (p < 0.010). CONCLUSION The rate of revision ESS in CRS-A was twice that of CRS-alone; patients with CRS-A and nasal polyposis were 6 times more likely to require revision than those with CRS-alone. ©2021 ARSAAOA, LLC.

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.

PURPOSE: Exfoliation syndrome (XFS), the most common recognizable cause of open-angle glaucoma worldwide, is a systemic disorder with genetic predisposition due to variations in lysyl oxidase-like 1 (LOXL1) function, leading to altered elastin matrices in ocular and systemic tissues. Obstructive sleep apnea (OSA) is a highly prevalent disorder also involving elastic tissue dysfunction and has been found to be associated with glaucoma. Due to similarities between the disorders, we sought to uncover any relationship in the prevalence of these diagnoses. DESIGN: Case-control retrospective cohort study. SUBJECTS: A cohort of 81,735 patients diagnosed with OSA at ages 50–90 years were identified from medical records from 1996 to 2017 in the Utah Population Database. Case subjects were matched to random controls on to sex and birth year in a 4:1 ratio. METHODS: International Classification of Diseases, Ninth Revision (ICD-9) codes or their ICD-10 equivalent were used to define a diagnosis of OSA (ICD-9 327.23) and a diagnosis of XFS (ICD-9 365.52 and 366.11). Conditional logistic regression odds ratios accounting for individual matching on sex and birth year was used to estimate the risk of XFS in OSA patients. Models included adjustment for race, obesity, tobacco use, hypertension, atrial fibrillation, and chronic obstructive pulmonary disease. OUTCOME: Whether OSA patients have an increased risk of diagnosis of XFS compared with non-OSA population controls. RESULTS: There was an increased risk of an XFS diagnosis in OSA patients compared with non-OSA controls (OR = 1.27; 95% CI, 1.02–1.59; P = 0.03). In a stratification of patients by hypertension diagnosis history, OSA patients with hypertension exhibited an increased risk of XFS compared to non OSA controls with hypertension (OR = 2.67; 95% CI, 2.06–3.46; P

Women are at risk of colorectal cancer (CRC) during pregnancy but this fact is underappreciated. We performed a population-based study to evaluate the rate, predictors, and familial risk for pregnancy associated CRC in Utah. All newly diagnosed cases of CRC between 1973 and 2014 were obtained from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Of the 12,886 females diagnosed with CRC, 73 were diagnosed with CRC (0.57%) during the period of obstetric delivery/childbirth. Pregnancy associated CRC was diagnosed at a mean age of 31.9 years, and cancers were less frequently located in the proximal colon compared with women with non-pregnancy associated CRC. First-degree relatives of cases with pregnancy associated CRC had a nearly threefold higher risk of CRC (OR, 2.76; 95% CI, 1.26–6.01) compared with relatives of CRC-free individuals. Of women diagnosed with CRC, less than 1% were diagnosed during or soon after obstetric delivery/childbirth. Relatives of these patients have a nearly threefold greater risk of CRC than those without a family history of CRC. These results provide physicians with data to guide the care of patients and their relatives with pregnancy associated CRC.

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.

IntroductionThe last two decades have seen a twofold increase in colorectal cancer (CRC) incidence among individuals under the recommended screening age of 50 years. Although the origin of this early-onset CRC (EOCRC) spike remains unknown, prior studies have reported that EOCRC harbours a distinct molecular and clinical phenotype in younger individuals. The sharp increase in EOCRC incidence rates may be attributable to a complex interplay of factors, including race; lifestyle; and ecological, sociodemographic and geographical factors. However, more research that address psychosocial experiences and accounts for lifestyle-related behaviours before, during and after an EOCRC diagnosis are warranted. This study aims to develop and pilot test a theory-driven, community-based intervention to increase awareness of EOCRC, reduce its associated risk factors and improve early detection among adults aged 18–49 years.Methods and analysisGuided by the Behaviour Change Wheel, we will use a multistage mixed-methods study design. We will pilot a sequential mixed-methods intervention study as follows: (1) First, we will analyse linked quantitative data from the Utah Cancer Registry and National Cancer Institute Surveillance, Epidemiology and End Results registry, linked to state-wide demographic and vital records in the Utah Population Database to identify EOCRC hotspots in Utah by examining the EOCRC incidence and survival variance explained by personal and county-level factors. (2) Next, we will conduct one-on-one interviews with 20 EOCRC survivors residing in EOCRC hotspots to ascertain psychosocial and lifestyle challenges that accompany an EOCRC diagnosis. (3) Finally, we will consider existing evidence-based approaches, our integrated results (quantitative +qualitative) and community action board input to design a community-based intervention to increase EOCRC awareness that can feasibly be delivered by means of outdoor mass media, and via social media. We will pilot the multicomponent media campaign with a quasiexperimental design among 17 EOCRC hotspot residents and 17 EOCRC ‘coldspot’ residents.Ethics and disseminationEthics approval was obtained from the University of Utah Institutional Review Board (IRB_00138357). Signed informed consent will be obtained from all participants prior to any data collection. Study results will be disseminated through CRC community blogs, targeted infographics, conference presentations at national and international professional conferences and publications in peer-reviewed journals. Final intervention-specific data will be available on reasonable request from the corresponding author.Trial registration numberNCT04715074.

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.

The Utah Project on Exfoliation Syndrome (UPEXS) study was created to investigate the association between exfoliation syndrome (XFS) and systemic disorders or pathologies. The study utilizes the resources of the Utah Population Database, which is linked to the Utah genealogy, a compilation of large pedigrees extending back 3 to ≥11 generations, representing most families in the state. These family members medical and health records are linked to vital records and can be used effectively to identify familial clustering of disorders, like XFS, with comorbid diseases or health-related data. There is growing evidence that XFS patients have an increased risk for systemic disorders that may reflect the systemic tissue involvement of this disease. Epidemiologic studies of individuals with XFS have reported an increased risk of various pathologies that have abnormalities in extracellular matrix metabolism and repair. For this reason, the UPEXS has focused on disorders that involve the extracellular matrix in general and elastin specifically, such as pelvic organ prolapse, atrial fibrillation, inguinal hernias, and chronic obstructive pulmonary disease. In this paper we present our results from the analysis of pelvic organ prolapse, as well as, preliminary data for atrial fibrillation.

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

Chronic lymphocytic leukemia (CLL) is a common lymphoid malignancy with strong heritability. To further understand the genetic susceptibility for CLL and identify common loci associated with risk, we conducted a meta-analysis of four genome-wide association studies (GWAS) composed of 3,100 cases and 7,667 controls with follow-up replication in 1,958 cases and 5,530 controls. Here we report three new loci at 3p24.1 (rs9880772, EOMES, P=2.55 × 10−11), 6p25.2 (rs73718779, SERPINB6, P=1.97 × 10−8) and 3q28 (rs9815073, LPP, P=3.62 × 10−8), as well as a new independent SNP at the known 2q13 locus (rs9308731, BCL2L11, P=1.00 × 10−11) in the combined analysis. We find suggestive evidence (P, Chronic lymphocytic leukemia is a highly inheritable cancer. Here the authors conduct a metaanalysis of four genome-wide association studies and identify three novel loci located near EOMES, SERPINB6 and LPP associated with risk of this disease.

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.

Background: Genome-wide association studies of colorectal cancer (CRC) have identified genetic variants that reproducibly associate with CRC. Associations of 12 single nucleotide polymorphisms at 8q24, 9p24, and 18q21 (SMAD7) and CRC were investigated in a three-center collaborative study including two U.K. case-control cohorts (Sheffield and Leeds) and a U.S. case-control study of CRC cases from high-risk Utah pedigrees. Methods: Our combined resource included 1,092 CRC case subjects and 1,060 age- and sex-matched controls. Meta statistics and Monte Carlo significance testing using Genie software provided a valid combined analysis of our mixed independent and related case-control resource. We also evaluated whether these associations differed by sex, age at diagnosis, family history, or tumor site. Results: At 8q24, we observed two independent significant associations at single nucleotide polymorphisms located in two different risk regions of 8q24: rs6983267 in region 3 [Ptrend = 0.01; per allele odds ratio (OR), 1.17; 95% confidence intervals (95% CI), 1.03-1.32] and rs10090154 in region 5 (Ptrend = 0.05; per allele OR, 1.24; 95% CI, 1.01-1.51). At 18q21, associations were observed in distal colon tumors but not in proximal or rectal cancers: rs4939827 (Ptrend = 0.007; per allele OR, 0.77; 95% CI, 0.64-0.93; case-case pdiff = 0.03) and rs12953717 (Ptrend = 0.01; per allele OR, 1.27; 95% CI, 1.06-1.52). We were unable to detect any associations at 9p24 with CRC. Conclusions: Our investigation confirms that variants across multiple risk regions of 8q24 are associated with CRC, and that associations at 18q21 differ by tumor site. (Cancer Epidemiol Biomarkers Prev 2009;18(2):616–21)

The power of genetic association studies to identify disease susceptibility alleles fundamentally relies on the variants studied. The standard approach is to determine a set of tagging-SNPs (tSNPs) that capture the majority of genomic variation in regions of interest by exploiting local correlation structures. Typically, tSNPs are selected from neutral discovery panels - collections of individuals comprehensively genotyped across a region. We investigated the implications of discovery panel design on tSNP performance in association studies using realistically-simulated sequence data. We found that discovery panels of 24 sequenced 'neutral' individuals (similar to NIEHS or HapMap ENCODE data) were sufficient to select well-powered tSNPs to identify common susceptibility alleles. For less common alleles (0.01-0.05 frequency) we found neutral panels of this size inadequate, particularly if low-frequency variants were removed prior to tSNP selection; superior tSNPs were found using panels of diseased individuals. Only large neutral panels (200 individuals) matched diseased panel performance in selecting well-powered tSNPs to detect both common and rarer alleles. The 1000 Genomes Project initiative may provide larger neutral panels necessary to identify rarer susceptibility alleles in association studies. In the interim, our results suggest investigators can boost power to detect such alleles by sequencing diseased individuals for tSNP selection.