The Epidemiology of Irritable Bowel Syndrome in the US Military: Findings from the Millennium Cohort Study.

OBJECTIVES: Functional gastrointestinal disorders occur more frequently among deployed veterans, although studies evaluating the relative impact of risk factors, including stress and antecedent infectious gastroenteritis (IGE), are limited. We examined risk factors for new-onset irritable bowel syndrome (IBS) among active duty participants in the military's Millennium Cohort Study. METHODS: Medical encounter data from 2001 to 2009, limited to Cohort members on active duty, were used to identify incident IBS cases (any and highly probable). IGE was identified using medical encounter or self-report. Covariate data were obtained from the Millennium Cohort Study surveys and analyzed using Cox proportional hazards methods. RESULTS: Overall, 41,175 Cohort members met the eligibility criteria for inclusion and 314 new-onset cases of IBS were identified among these. Significant risk factors (adjusted hazard ratio, 95% confidence interval) included antecedent IGE (2.05, 1.53-2.75), female gender (1.96, 1.53-2.52), number of life stressors (1: 1.82, 1.37-2.41; 2: 2.86, 2.01-4.06; 3+: 6.69, 4.59-9.77), and anxiety syndrome (1.74, 1.17-2.58). Limited to highly probable IBS, a stronger association with antecedent IGE was observed, particularly when based on medical encounter records (any IGE: 2.20, 1.10-4.43; medical encounter IGE only: 2.84, 1.33-6.09). Precedent anxiety or depression and IGE interacted with increased IBS risk compared with IGE alone. CONCLUSIONS: These results confirm previous studies on the association between sociodemographic or life stressors and IBS. IGE was significantly associated with IBS risk. Whether deployed or not, US service members often encounter repeated exposure to high levels of stress, which, combined with other environmental factors such as IGE, may result in long-term debilitating functional gastrointestinal disorders.

Comprehensive genetic analysis of cytarabine sensitivity in a cell-based model identifies polymorphisms associated with outcome in AML patients.

A whole-genome approach was used to investigate the genetic determinants of cytarabine-induced cytotoxicity. We performed a meta-analysis of genome-wide association studies involving 523 lymphoblastoid cell lines (LCLs) from individuals of European, African, Asian, and African American ancestry. Several of the highest-ranked single-nucleotide polymorphisms (SNPs) were within the mutated in colorectal cancers (MCC) gene. MCC expression was induced by cytarabine treatment from 1.7- to 26.6-fold in LCLs. A total of 33 SNPs ranked at the top of the meta-analysis (P < 10(-5)) were successfully tested in a clinical trial of patients randomized to receive low-dose or high-dose cytarabine plus daunorubicin and etoposide; of these, 18 showed association (P < .05) with either cytarabine 50% inhibitory concentration in leukemia cells or clinical response parameters (minimal residual disease, overall survival (OS), and treatment-related mortality). This count (n = 18) was significantly greater than expected by chance (P = .016). For rs1203633, LCLs with AA genotype were more sensitive to cytarabine-induced cytotoxicity (P = 1.31 × 10(-6)) and AA (vs GA or GG) genotype was associated with poorer OS (P = .015), likely as a result of greater treatment-related mortality (P = .0037) in patients with acute myeloid leukemia (AML). This multicenter AML02 study trial was registered at www.clinicaltrials.gov as #NCT00136084.

Pharmacogenomic discovery using cell-based models.

Quantitative variation in response to drugs in human populations is multifactorial; genetic factors probably contribute to a significant extent. Identification of the genetic contribution to drug response typically comes from clinical observations and use of classic genetic tools. These clinical studies are limited by our inability to control environmental factors in vivo and the difficulty of manipulating the in vivo system to evaluate biological changes. Recent progress in dissecting genetic contribution to natural variation in drug response through the use of cell lines has been made and is the focus of this review. A general overview of current cell-based models used in pharmacogenomic discovery and validation is included. Discussion includes the current approach to translate findings generated from these cell-based models into the clinical arena and the use of cell lines for functional studies. Specific emphasis is given to recent advances emerging from cell line panels, including the International HapMap Project and the NCI60 cell panel. These panels provide a key resource of publicly available genotypic, expression, and phenotypic data while allowing researchers to generate their own data related to drug treatment to identify genetic variation of interest. Interindividual and interpopulation differences can be evaluated because human lymphoblastoid cell lines are available from major world populations of European, African, Chinese, and Japanese ancestry. The primary focus is recent progress in the pharmacogenomic discovery area through ex vivo models.

The role of TP53 and MDM2 polymorphisms in TP53 mutagenesis and risk of non-melanoma skin cancer.

P53 is a key regulatory molecule in the cellular response to ultraviolet radiation, and TP53 mutation is the most common alteration in non-melanoma skin cancer. The MDM2 oncogene negatively regulates p53 protein levels, and both genes have functional polymorphisms that may modify skin cancer risk. Furthermore, prior research suggests that TP53 mutations preferentially occur on the arginine allele to selectively inactivate the p63 pathway. We tested these hypotheses of susceptibility and preferential mutation in non-melanoma skin cancer. The TP53 Arg72Pro and MDM2 309 polymorphisms were genotyped in a population-based case-control study of non-melanoma skin cancer, and TP53 alteration (mutation and immunohistochemistry staining) was evaluated in case tumors. In 902 cases of basal cell carcinoma (BCC), 676 cases of squamous cell carcinoma (SCC) and 812 controls, no association was found between the TP53 polymorphism and risk of non-melanoma skin cancer [odds ratio (OR)(BCC) 0.98, 95% confidence interval (CI) 0.80-1.20; OR(SCC) 0.93, 95% CI 0.75-1.16]. However, carriers of the MDM2 SNP309 G allele did have an elevated risk of non-melanoma skin cancer (OR(BCC) 1.15, 95% CI 0.93-1.42; OR(SCC) 1.29, 95% CI 1.02-1.63). We observed an association between TP53 alterations in the tumors and constitutive TP53 genotype (P < 0.01), with alterations preferentially occurring on the proline allele. Collectively, these data highlight the significant effects of genotype on gene-specific mutation events in carcinogenesis.

Cigarette smoking patterns among U.S. military service members before and after separation from the military.

U.S. military Service members have consistently smoked more than the general population and the prevalence of smoking is even higher among U.S. veterans. Our study examined cigarette smoking patterns among Service members before and after military separation to better understand the disproportionate rate of smoking among veterans. Data from the Millennium Cohort Study were used. All study participants were in the military at baseline and some transitioned from the military to civilian life during the observation period. We investigated any impact of military separation on smoking, as well as other potential risk factors for smoking. Overall, we observed higher smoking prevalence among veterans than Service members. Additionally, we found that Service members smoked more while approaching their separation from the military. Longitudinal analysis revealed military separation was not a risk factor for smoking, as we had hypothesized. Baseline smoking was the most influential predictor of current smoking status. Other significant factors included alcohol consumption, life stressors, and mental health conditions, among others. Military separation was not a risk factor for smoking. However, Service members in the process of transitioning out of the military, as well as high alcohol consumers and Service members with mental health conditions, may be at higher risk of smoking. Including smoking prevention/cessation programs in pre-separation counseling sessions and developing smoking screening and cessation programs targeting specific high-risk subgroups may reduce smoking among Service members and veterans.

Comparing self-reported physical activity and sedentary time to objective fitness measures in a military cohort.

OBJECTIVES: Regular vigorous physical activity (PA) and high levels of physical fitness (PF) confer health benefits. Conversely, sedentary time is a risk factor for chronic illness, independent of PA. We evaluated associations between self-reported PA, sedentary time, and objective PF measures in military Service members. DESIGN: Cross-sectional study including 10,105 Air Force Millennium Cohort participants with a valid physical fitness assessment (PFA). METHODS: Linear regression assessed associations between self-report PA, screen time, and usual activity and abdominal circumference (AC) and VO2 max; logistic regression was used for PFA failure. We stratified by age and sex. RESULTS: Men who self-reported high versus low levels of PA had greater AC (19-29 years: ß=0.23in., 95% CI 0.07, 0.39; 30-39 years: ß=0.45in., 95% CI 0.17, 0.72). High versus low self-reported PA was also associated with greater VO2Max (ß=:0.81-1.41mL/kg/min). Self-reported strength training for ≥2days/week was associated with greater VO2Max in 19-29year old men (ß=0.84mL/kg/min, 95% CI 0.09, 0.60) and 30-39year old women (ß=0.74mL/kg/min, 95% CI 0.02, 1.46). For younger men and women,<2h of screen time/day was associated with greater VO2Max (Males 19-29years: ß=0.23mL/kg/min, 95% CI 0.44, 1.26; Females 19-29years: ß=0.83mL/kg/min, 95% CI 0.25, 1.42). PA was not associated with PFA failure, while screen time was (Males OR: 0.32-0.65, 95% CI 0.17-0.92, p<0.001-0.016). CONCLUSIONS: Self-reported PA and screen time were associated with some objective PF measures, including VO2Max and AC. However, screen time alone was associated with PFA failure.

A role for ultraviolet radiation immunosuppression in non-melanoma skin cancer as evidenced by gene-environment interactions.

The genotoxic effects of ultraviolet (UV) radiation are well-known causes of skin cancers; however, UV radiation also suppresses the immune system, decreasing the body's surveillance for tumor cells. In experimental systems, UV radiation immunosuppression is at least partially mediated through urocanic acid (UCA), an UV radiation-absorbing molecule in the stratum corneum. We tested the hypothesis that genetic variation in the histidase gene (HAL), which catalyzes the formation of UCA in the skin, modifies risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) in a population-based study (914 BCC, 702 SCC and 848 controls). We observed no evidence of a main gene effect for the HAL I439V polymorphism (rs7297245) and BCC or SCC. However, we found a HAL genotype-sunburn interaction in association with BCC (P for interaction = 0.040) and SCC (P for interaction = 0.018). A HAL genotype-SCC association was observed primarily among women (odds ratio = 1.5, 95% confidence interval 1.1-2.2), and among women, we found an interaction between HAL genotype and oral contraceptive use on SCC risk (P = 0.040). The variant HAL allele likewise appeared to modify the SCC risk associated with glucocorticoid steroid usage (P for interaction = 0.0004). In conclusion, our findings are a first step in determining the genetic underpinnings of UV immune suppression and have identified important new genetic interactions contributing to the etiology of skin cancer.

Deployment-related depression screening, 2001-2008: comparing clinical versus research surveys.

BACKGROUND: Potential adverse mental health effects of deployment, including depression, are an ongoing concern. Although a previous study assessed under-reporting of depression on post-deployment health assessments compared to anonymous surveys, those results were not examined at the individual level to identify demographic or military factors that may be associated with unwillingness to report depression symptoms. PURPOSE: To compare self-reported depression symptoms on post-deployment health assessments with responses to the same depression questions on a research survey. METHODS: This cross-sectional study analyzed depression screening responses from 2001 to 2008 from participants of the Millennium Cohort Study, a longitudinal military cohort study, who completed a post-deployment health assessment within 30 days of a research survey. Kappa statistics and percent positive and negative agreement were calculated. Demographic and military characteristics associated with discordant screening results were examined. Initial analyses were performed in 2011, with additional analyses in 2013. RESULTS: Moderate agreement (κ=0.464) was observed between paired survey responses. A higher proportion of active duty members, the unmarried, and new accessions into military service endorsed depression symptoms on the research survey but not the military-linked survey. In stratified analyses, agreement was higher in Reserve/National Guard members than active duty (κ=0.561 vs 0.409). New active duty accessions showed lower agreement (κ=0.388), as did unmarried active duty participants (κ=0.304). CONCLUSIONS: Deployment health surveys are important tools for identifying returning service members experiencing depression symptoms. However, these findings suggest that ongoing stigma and barriers to appropriate follow-up mental health care remain to be addressed in the military setting.

Genetic determinants of UV-susceptibility in non-melanoma skin cancer.

A milieu of cytokines and signaling molecules are involved in the induction of UV-induced immune suppression and thus the etiology of non-melanoma skin cancer (NMSC). Targeting the UV-induced immunosuppression pathway, and using a large population based study of NMSC, we have investigated the risk associated with functional variants in 10 genes (IL10, IL4, IL4R, TNF, TNFR2, HTR2A, HRH2, IL12B, PTGS2, and HAL). The most prominent single genetic effect was observed for IL10. There was increasing risk for both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) with increasing number of variant IL10 haplotypes (BCC: p(trend) = 0.0048; SCC: p(trend) = 0.031). Having two IL10 GC haplotypes was associated with increased odds ratios of BCC and SCC (OR(BCC) = 1.5, 95% CI 1.1-1.9; OR(SCC) = 1.4, 95% CI 1.0-1.9), and these associations were largely confined to women (OR(BCC) = 2.2, 95% CI 1.4-3.4; SCC: OR(SCC) = 1.8, 95% CI 1.1-3.0). To examine how combinations of these variants contribute to risk of BCC and SCC, we used multifactor dimensionality reduction (MDR) and classification and regression trees (CART). Results from both of these methods found that in men, a combination of skin type, burns, IL10, IL4R, and possibly TNFR2 were important in both BCC and SCC. In women, skin type, burns, and IL10 were the most critical risk factors in SCC, with risk of BCC involving these same factors plus genetic variants in HTR2A, IL12B and IL4R. These data suggest differential genetic susceptibility to UV-induced immune suppression and skin cancer risk by gender.

Genome-wide local ancestry approach identifies genes and variants associated with chemotherapeutic susceptibility in African Americans.

Chemotherapeutic agents are used in the treatment of many cancers, yet variable resistance and toxicities among individuals limit successful outcomes. Several studies have indicated outcome differences associated with ancestry among patients with various cancer types. Using both traditional SNP-based and newly developed gene-based genome-wide approaches, we investigated the genetics of chemotherapeutic susceptibility in lymphoblastoid cell lines derived from 83 African Americans, a population for which there is a disparity in the number of genome-wide studies performed. To account for population structure in this admixed population, we incorporated local ancestry information into our association model. We tested over 2 million SNPs and identified 325, 176, 240, and 190 SNPs that were suggestively associated with cytarabine-, 5'-deoxyfluorouridine (5'-DFUR)-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-4)). Importantly, some of these variants are found only in populations of African descent. We also show that cisplatin-susceptibility SNPs are enriched for carboplatin-susceptibility SNPs. Using a gene-based genome-wide association approach, we identified 26, 11, 20, and 41 suggestive candidate genes for association with cytarabine-, 5'-DFUR-, carboplatin-, and cisplatin-induced cytotoxicity, respectively (p≤10(-3)). Fourteen of these genes showed evidence of association with their respective chemotherapeutic phenotypes in the Yoruba from Ibadan, Nigeria (p<0.05), including TP53I11, COPS5 and GAS8, which are known to be involved in tumorigenesis. Although our results require further study, we have identified variants and genes associated with chemotherapeutic susceptibility in African Americans by using an approach that incorporates local ancestry information.

CTLA4 variants, UV-induced tolerance, and risk of non-melanoma skin cancer.

Although skin tumors are highly immunogenic, exposure to UV radiation is known to suppress immune responses via regulatory T cells. Specifically, the activity of cytotoxic lymphocyte-associated antigen-4 (CTLA-4) is integral in regulating the development of UV-induced tolerance and, concomitantly, skin cancers. Due to the inverse relationship between tumor surveillance and autoimmunity, we hypothesize that the same genetic variant in the CTLA4 locus that increases risk for autoimmune diseases is associated with decreased risk of non-melanoma skin cancer (NMSC). We analyzed whether the polymorphism CT60 or haplotypes of CTLA4 influence odds of developing the major types of NMSC, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), in a population-based case-control study of Caucasians in New Hampshire (849 controls, 930 BCC, and 713 SCC). The CTLA4 CT60 GG genotype was associated with decreased odds for BCC and SCC, controlling for age, sex, lifetime number of severe sunburns, and skin type [BCC: odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-0.9; SCC: OR, 0.7; 95% CI, 0.5-1.0]. For BCC, this decrease was apparent largely among those with a higher lifetime number of severe sunburns (P(interaction) = 0.0074). There were significantly decreased odds of disease associated with two haplotypes, which possess the CT60 G allele. Additionally, lifetime number of severe sunburns modestly altered the effects of the CTLA4 haplotypes in BCC, and the association seemed driven by the CT60 single nucleotide polymorphism. In conclusion, genetic variation at the CTLA4 locus may be etiologically important in NMSC, the most prevalent malignancy in the United States.