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Supplementary Table 1 from Association between Genetic Variants in the 8q24 Cancer Risk Regions and Circulating Levels of Androgens and Sex Hormone–Binding Globulin

Background: Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder.Methods: To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone), and sex hormone–binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels.Results: Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 × 10−3) and bioavailable testosterone (P < 6.3 × 10−4). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05).Conclusions: These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels.Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 19(7); 1848–54. ©2010 AACR.

PURPOSE: In response to the opioid crisis, opioid analgesic guidelines and prescribing limits have proliferated. The purpose of this narrative review is to examine evidence from studies evaluating the patient or public health impact of federal and state opioid analgesic prescribing guidelines and laws, describe gaps and challenges in current research, and highlight opportunities for improving future research. METHODS: We focused on evidence from a literature review covering 2013 through 2019. We identified 30 studies evaluating opioid analgesic thresholds based on federal policies and guidelines, state laws, and Medicaid state plans that attempt to influence the course of patient care at or when the limit is exceeded (e.g., prior authorization). RESULTS: Most studies evaluated changes in prescribing or dispensing patterns of opioid analgesics, largely finding decreases in prescribing after policy enactment. Fewer studies evaluated patient or public health outcomes beyond changes in prescribing and dispensing patterns; results were infrequently stratified by potentially important sociodemographic and clinical factors. No studies assessed the potential for adverse patient outcomes for which we have emerging evidence of harms. CONCLUSIONS: We describe knowledge gaps and propose opportunities for future research to sufficiently assess the potential impact and unintended consequences of opioid analgesic prescribing laws, regulations, guidelines, and policies.

Aim To determine the rate ratio of neuropsychiatric hospitalizations in new users of varenicline compared to new users of nicotine replacement therapy (NRT) patch in the Military Health System (MHS). Design, setting and participants Varenicline (n = 19,933) and NRT patch (n = 15,867) users who initiated therapy from 1 August 2006 to 31 August 2007 within the MHS were included in this retrospective cohort study. After matching according to propensity scores, 10,814 users remained in each cohort. The study population included those with and without a history of neuropsychiatric disease. Measurements Patients were followed for neuropsychiatric hospitalizations defined by primary neuropsychiatric discharge diagnosis using ICD-9 codes from in-patient administrative claims. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated after propensity score matching on exposure for socio-demographic factors, health-care utilization, comorbidities, medication history and neuropsychiatric history. Findings There was no increase in the rate of neuropsychiatric hospitalizations in patients treated with varenicline compared to NRT patch when followed for 30 days (propensity-score matched HR = 1.14, 95% CI: 0.56-2.34). Results were similar after 60 days of follow-up. Conclusions There does not appear to be an increase in neuropsychiatric hospitalizations with varenicline compared with nicotine replacement therapy patch over 30 or 60 days after drug initiation.

PURPOSE: We report the annual trend, distribution, and determinants of acetaminophen overdose using data from the Military Health System. We also assess the proportion of individuals with an acetaminophen overdose who received a prescription for any acetaminophen-containing medication prior to their event. METHODS: Diagnostic International Classification of Diseases, 9th revision (ICD-9) codes from inpatient medical encounters were used to identify patients with acetaminophen overdose. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) for associations between selected socio-demographic characteristics and acetaminophen overdose. Pharmacy records for individuals with an acetaminophen overdose were obtained to evaluate the proportion who received a prescription for any acetaminophen-containing medication prior to their overdose. RESULTS: Annual age-adjusted and sex-adjusted prevalence of acetaminophen overdose increased by 38.5% from 2004 to 2008. Acetaminophen overdose was significantly more common in female subjects than in male subjects (aPR = 3.24, 95%CI = 2.97-3.55). Individuals aged 15-17 and 18-24 also were significantly more likely to have an overdose compared with those aged 45-64 (aPR = 6.06, 95%CI = 5.25-7.00 and aPR = 4.58, 95%CI = 4.01-5.23, respectively). Among active duty service members, acetaminophen overdose was six times more common in junior enlisted service members than in officers (aPR = 6.06, 95%CI = 3.90-9.40). The proportion of individuals with an inpatient overdose who had any prescription for an acetaminophen-containing medication in the 365, 30, and 7 days before the overdose was 53.3%, 23.7%, and 16.3%, respectively. CONCLUSIONS: Identification of at-risk populations will aid the military in ongoing efforts to decrease medication misuse. Findings suggest a potential need for improved labeling of over-the-counter medications and medication safety education efforts for unintentional acetaminophen overdose and continued efforts to identify individuals at risk for intentional overdose. Published 2012. This article is a US Government work and is in the public domain in the USA. Language: en

Background: Serum lipids, diabetes, and obesity, individual components of metabolic syndrome, are associated with biliary tract cancer and stone risk, but the associations of metabolic syndrome or insulin resistance with biliary tract cancers and stones are not well studied. Methods: In this population-based case-control study in Shanghai, China (627 biliary tract cancers, 1037 biliary stones, and 959 controls), metabolic syndrome was defined as the presence of any three of the five components, including high waist circumference, high triglycerides, low high-density lipoprotein cholesterol (HDL), high blood pressure, and diabetes. Insulin resistance and β-cell function were assessed, using homeostasis assessment models. Results: Metabolic syndrome was significantly associated with gallbladder cancer (odds ratio (OR)=2.75, 95% confidence interval (95% CI)=1.82–4.15) and biliary stones (OR=1.64, 95% CI=1.24–2.16), with a significant dose effect with increasing number of metabolic syndrome components (P trend

To evaluate the associations between dietary carbohydrate, glycemic index (GI), glycemic load (GL), and incident prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.Between September 1993 and September 2000, 38,343 men were randomized to the screening arm of the trial at one of 10 PLCO centers. A food frequency questionnaire administered at baseline assessed usual dietary intake over the preceding 12 months. Prostate cancer was ascertained by medical follow-up of suspicious screening results and annual mailed questionnaires and confirmed with medical records. Cox proportional hazards regression was used to model the associations of carbohydrate, GI, and GL with prostate cancer risk.During follow-up (median = 9.2 years), 2,436 incident prostate cancers were identified among 30,482 eligible participants. Overall, there were no associations of baseline carbohydrate, GI, or GL with incident prostate cancer in minimally or fully adjusted models. There were no associations when the 228 advanced and 2,208 non-advanced cancers were analyzed separately.Dietary carbohydrate, GI, and GL were not associated with incident prostate cancer in PLCO. The narrow range of GI in this cohort may have limited our ability to detect associations, an issue that future studies should address.

BACKGROUND—Androgens and inflammation have been implicated in the etiology of several cancers, including prostate cancer. Serum androgens have been shown to correlate with markers of inflammation and expression of inflammation-related genes. METHODS—In this report, we evaluated associations between 9,932 single nucleotide polymorphisms (SNPs) marking common genetic variants in 774 inflammation-related genes and four serum androgen levels (total testosterone [T], bioavailable T [BioT]; 5α-androstane-3α, 17βdiol glucuronide [3αdiol G], and 4-Androstene-3,17-dione [androstenedione]), in 560 healthy men (median age 64 years) drawn from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Baseline serum androgens were measured by radioimmunoassay. Genotypes were determined as part of the Cancer Genetic Markers of Susceptibility Study genome-wide scan. SNP-hormone associations were evaluated using linear regression of hormones adjusted for age. Gene-based p-values were generated using an adaptive rank truncated product method. RESULTS—Suggestive associations were observed for two inflammation-related genes and circulating androgen levels (false discovery rate [FDR] q-value T in MMP2 and rs3822356T>C in CD14 (FDR q-value=0.09 for both SNPs). Other genes implicated in either SNP or gene-based tests were IK with T and BioT, PRG2 with T, and TNFSF9 with androstenedione. CONCLUSIONS—These results suggest possible cross-talk between androgen levels and inflammation pathways, but larger studies are needed to confirm these findings and to further clarify the interrelationship between inflammation and androgens and their effects on cancer risk.

Background: Genome-wide association studies have identified multiple independent regions on chromosome 8q24 that are associated with cancers of the prostate, breast, colon, and bladder. Methods: To investigate their biological basis, we examined the possible association between 164 single nucleotide polymorphisms (SNPs) in the 8q24 risk regions spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, 3αdiol G, and bioavailable testosterone), and sex hormone–binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial). Age-adjusted linear regression models were used to determine the association between the SNPs in an additive genetic model and log-transformed biomarker levels. Results: Three adjacent SNPs centromeric to prostate cancer risk-region 2 (rs12334903, rs1456310, and rs980171) were associated with testosterone (P < 1.1 × 10−3) and bioavailable testosterone (P < 6.3 × 10−4). Suggestive associations were seen for a cluster of nine SNPs in prostate cancer risk region 1 and androstenedione (P < 0.05). Conclusions: These preliminary findings require confirmation in larger studies but raise the intriguing hypothesis that genetic variations in the 8q24 cancer risk regions might correlate with androgen levels. Impact: These results might provide some clues for the strong link between 8q24 and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 19(7); 1848–54. ©2010 AACR.

Background: Epidemiologic data on serum melatonin, a marker of circadian rhythms, and cancer are sparse due largely to the lack of reliable assays with high sensitivity to detect relatively low melatonin levels in serum collected during daylight, as commonly available in most epidemiologic studies. Methods: To help expand epidemiologic research on melatonin, we assessed the reproducibility and refined a currently available melatonin RIA, and evaluated its application to epidemiologic investigations by characterizing melatonin levels in serum, urine, and/or plasma in 135 men from several ethnic groups. Results: Reproducibility was high for the standard 1.0-mL serum [mean coefficient of variation (CV), 6.9%; intraclass correlation coefficient (ICC), 97.4%; n = 2 serum pools in triplicate] and urine-based (mean CV, 3.5%; ICC, 99.9%) assays. Reproducibility for the 0.5-mL refined-serum assay was equally good (mean CV, 6.6%; ICC, 99.0%). There was a positive correlation between morning serum melatonin and 6-sulfatoxymelatonin in 24-hour urine (r = 0.46; P = 0.008; n = 49 subjects). Melatonin levels in serum-plasma pairs had a high correlation (r = 0.97; P < 1×10−4; n = 20 pairs). Morning serum melatonin levels were five times higher than those from the afternoon (before 9 a.m. mean, 11.0 pg/mL, versus after 11 a.m. mean, 2.0 pg/mL). Chinese men had lower melatonin levels (mean, 3.4 pg/mL), whereas Caucasian, African-American, and Ghanaian men had similar levels (mean, 6.7-8.6 pg/mL). Conclusions: These results suggest that melatonin can be detected reliably in serum samples collected in epidemiologic studies in various racial groups. Impact: With improved assays, it may be possible to investigate the role of melatonin and the emerging circadian rhythm hypothesis in cancer etiology in epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 19(4); 932–7. ©2010 AACR.

OBJECTIVE To examine racial/ethnic disparities in mortality and survival in a large nationwide and population-based cohort of women with breast cancer after simultaneously controlling for differences in comorbidity, treatment, and socioeconomic status. METHODS A cohort of 35,029 women with stage I-IIIA breast cancer at age > or = 65 from 1992 to 1999 was identified from the surveillance, epidemiology, and end results-medicare linked databases with up to 11 years of follow-up. Cox proportional hazard regression analysis was performed to determine the risk of all-cause and breast cancer-specific mortality. RESULTS African-American women with breast cancer were more likely to live in the poorest quartiles of socioeconomic status at the census tract level than whites (73.7% versus 20.7%, P < 0.001). Those living in communities with the lowest socioeconomic status were 11% more likely to die than those in the highest (hazard ratio, 1.10; 95% confidence interval, 1.04-1.16). The risk of dying changed slightly after controlling for race/ethnicity (1.11; 1.05-1.18). Compared with white women with breast cancer, crude hazard ratios of all-cause and breast cancer-specific mortality were 1.35 (1.27-1.45) and 1.83 (1.56-2.16) for African-Americans. After adjusting for treatment and socioeconomic status, hazard ratio of all-cause mortality was no longer significant in African-Americans (1.02; 0.84-1.10), whereas the risk of breast cancer-specific mortality was marginally higher in African-Americans (1.21; 1.01-1.46). CONCLUSIONS Racial disparities in overall survival between African-American and white women with breast cancer were not present after controlling for treatment and socioeconomic status. Efforts to eliminate these barriers have important public health implications for reducing disparities in health outcomes.

Among 397 homeless participants studied, the overall West Nile virus (WNV) seroprevalence was 6.8%. Risk factors for WNV infection included being homeless >1 year, spending >6 hours outside daily, regularly taking mosquito precautions, and current marijuana use. Public health interventions need to be directed toward this high-risk population.

Objective To evaluate whether timely adherence rates differ by race among women with abnormal Pap tests participating in a cost-free or reduced-cost program. Methods Eligible subjects included women aged 47-64 years who received a referral for follow-up care after an abnormal Pap test from 1999 to 2002 in South Carolina (n=330). Adherence was measured as days to receipt of follow-up care after an abnormal Pap test. Cox proportional hazards modeling was used to estimate risk factors associated with time to adherence within 60 and 365 days by race. Results African-American and non-Hispanic white women had similar adherence to follow-up. Among white women, those with high-grade lesions were less likely to adhere in a timely manner relative to those with low-grade lesions (hazard ratio 0.6, 95% confidence interval [CI] 0.4-1.0). For African-American women, rural residence (hazard ratio: 0.5, 95% CI 0.2-0.9) and history of abnormal Pap tests (hazard ratio 0.6, 95% CI 0.3-1.0) were associated with decreased adherence, whereas less education (hazard ratio 2.3, 95% CI 1.3-3.9) was associated with increased adherence. Conclusion Adherence rates do not differ by race. However, risk factors for adherence within race are variable. Interventions tailored to the differential needs of racial and ethnic groups may prove effective toward increasing timely adherence rates. Level of evidence II.

Objective: To determine the risk of prostate cancer associated with farming by duration, recency and specific activities among African-Americans and Caucasians. Methods: This population-based case–control study had information on farming-related activities for 405 incident prostate cancer cases and 392 controls matched for age, race and region in South Carolina, USA, from 1999 to 2001. Cases with histologically confirmed, primary invasive prostate cancer who were aged between 65 and 79 years were ascertained through the South Carolina Central Cancer Registry. Appropriately matched controls were identified from the Health Care Financing Administration Medicare Beneficiary File. Data were collected using computer-assisted telephone interviewing, and adjusted odds ratios (aOR) were estimated using unconditional logistic regression. Results: Farming was associated with increased risk of prostate cancer in Caucasians (aOR 1.8; 95% confidence interval (CI) 1.3 to 2.7) but not in African-Americans (aOR 1.0; 95% CI 0.6 to 1.6). Regarding specific farming activities, farmers who mixed or applied pesticides had a higher risk of prostate cancer (aOR 1.6; 95% CI 1.2 to 2.2). Increased risk of prostate cancer was observed only for those farming Conclusions: Increased risk of prostate cancer for farmers in this study may be attributable to pesticide exposure. Racial differences in the association between farming and prostate cancer may be explained by different farming activities or different gene–environment interactions by race.

BACKGROUND. Few studies have addressed racial disparities in survival for colon cancer by adequately incorporating both treatment and socioeconomic factors, and the findings from those studies have been inconsistent. The objectives of the current study were to systematically review the existing literature and provide a more stable estimate of the measures of association between socioeconomic status and racial disparities in survival for colon cancer by undertaking a meta-analysis. METHODS. For this meta-analysis, the authors searched the MEDLINE database to identify articles published in English from 1966 to August 2006 that met the following inclusion criteria: original research articles that addressed the association between race/ethnicity and survival in patients with colon or colorectal cancer after adjusting for socioeconomic status. In total, 66 full articles were reviewed, and 56 of those articles were excluded, which left 10 studies for the final analysis. RESULTS. The pooled hazard ratio (HR) for African Americans compared with Caucasians was 1.14 (95% confidence interval [95% CI], 1.00–1.29) for all-cause mortality and 1.13 (95% CI, 1.01–1.28) for colon cancer-specific mortality. The test for homogeneity of the HR was statistically significant across the studies for all-cause mortality (Q = 31.69; P < .001) but was not significant across the studies for colon cancer-specific mortality (Q = 7.45; P = .114). CONCLUSIONS. Racial disparities in survival for colon cancer between African Americans and Caucasians were only marginally significant after adjusting for socioeconomic factors and treatment. Attempts to modify treatment and socioeconomic factors with the objective of reducing racial disparities in health outcomes may have important clinical and public health implications. Cancer 2007. © 2007 American Cancer Society.

Harris County, Texas, is an endemic area of St. Louis encephalitis (SLE); and an active surveillance program that monitors SLE virus activity in mosquitoes, birds, and humans has been in place there for the past 28 years. In June of 2002, West Nile (WN) virus appeared in Houston and quickly spread throughout the region. This report describes the results of 12 years of SLE surveillance in Harris County and the contrasting pattern of WN virus activity, when it arrived in 2002. Our data indicate that both SLE and WN viruses can coexist, despite their ecologic, antigenic, and genetic similarities, and that both viruses will probably persist in this geographic region.

The Food and Drug Administration and Department of Defense were interested in detecting sub-optimal use of long-acting beta-agonists (LABAs) in asthmatics within the Military Health System (MHS). Visualizing the patterns of asthma medication use surrounding a LABA prescription is a quick way to detect possible sub-optimal use for further evaluation. Analysis of 100 asthma patients was conducted in EventFlow to display and summarize timepoint and interval data. Epidemiologists reported that EventFlow was a powerful tool for rapidly visualizing possible patterns of sub-optimal LABA use that can be targeted for intervention.

Metabolomic profiling has identified, sarcosine, a derivative of the amino acid glycine, as an important metabolite involved in the etiology or natural history of prostate cancer. We examined the association between serum sarcosine levels and risk of prostate cancer in 1122 cases (813 non-aggressive and 309 aggressive) and 1112 controls in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Sarcosine was quantified using high-throughput liquid chromatography-mass spectrometry. A significantly increased risk of prostate cancer was observed with increasing levels of sarcosine (odds ratio [OR] for the highest quartile of exposure [Q4] versus the lowest quartile [Q1] = 1.30, 95% confidence interval [CI]: 1.02, 1.65; P-trend 0.03). When stratified by disease aggressiveness, we observed a stronger association for non-aggressive cases (OR for Q4 versus Q1 = 1.44, 95% CI: 1.11, 1.88; P-trend 0.006) but no association for aggressive prostate cancer (OR for Q4 versus Q1 = 1.03, 95% CI: 0.73, 1.47; P-trend 0.89). Although not statistically significant, temporal analyses showed a stronger association between sarcosine and prostate cancer for serum collected closer to diagnosis, suggesting that sarcosine may be an early biomarker of disease. Interestingly, the association between sarcosine and prostate cancer risk was stronger among men with diabetes (OR = 2.66, 95% CI: 1.04, 6.84) compared with those without reported diabetes (OR = 1.23, 95% CI: 0.95-1.59, P-interaction = 0.01). This study found that elevated levels of serum sarcosine are associated with an increased prostate cancer risk and evidence to suggest that sarcosine may be an early biomarker for this disease.

While sarcosine was recently identified as a potential urine biomarker for prostate cancer, further studies have cast doubt on its utility to diagnose this condition. The inconsistent results may be due to the fact that alanine and sarcosine coelute on an HPLC reversed-phase column and the mass spectrometer cannot differentiate between the two isomers, since the same parent/product ions are generally used to measure them. In this study, we developed a high-throughput liquid chromatography-mass spectrometry (LC-MS) method that resolves sarcosine from alanine isomers, allowing its accurate quantification in human serum and urine. Assay reproducibility was determined using the coefficient of variation (CV) and intraclass correlation coefficient (ICC) in serum aliquots from 10 subjects and urine aliquots from 20 subjects across multiple analytic runs. Paired serum/urine samples from 42 subjects were used to evaluate sarcosine serum/urine correlation. Both urine and serum assays gave high sensitivity (limit of quantitation of 5 ng/mL) and reproducibility (serum assay, intra- and interassay CVs3% and ICCs99%; urine assay, intra-assay CV = 7.7% and ICC = 98.2% and interassay CV = 12.3% and ICC = 94.2%). In conclusion, this high-throughput LC-MS method is able to resolve sarcosine from α- and β-alanine and is useful for quantifying sarcosine in serum and urine samples.

We report the annual trend, distribution, and determinants of acetaminophen overdose using data from the Military Health System. We also assess the proportion of individuals with an acetaminophen overdose who received a prescription for any acetaminophen-containing medication prior to their event.Diagnostic International Classification of Diseases, 9th revision (ICD-9) codes from inpatient medical encounters were used to identify patients with acetaminophen overdose. We used Poisson regression to estimate adjusted prevalence ratios (aPRs) for associations between selected socio-demographic characteristics and acetaminophen overdose. Pharmacy records for individuals with an acetaminophen overdose were obtained to evaluate the proportion who received a prescription for any acetaminophen-containing medication prior to their overdose.Annual age-adjusted and sex-adjusted prevalence of acetaminophen overdose increased by 38.5% from 2004 to 2008. Acetaminophen overdose was significantly more common in female subjects than in male subjects (aPR = 3.24, 95%CI = 2.97-3.55). Individuals aged 15-17 and 18-24 also were significantly more likely to have an overdose compared with those aged 45-64 (aPR = 6.06, 95%CI = 5.25-7.00 and aPR = 4.58, 95%CI = 4.01-5.23, respectively). Among active duty service members, acetaminophen overdose was six times more common in junior enlisted service members than in officers (aPR = 6.06, 95%CI = 3.90-9.40). The proportion of individuals with an inpatient overdose who had any prescription for an acetaminophen-containing medication in the 365, 30, and 7 days before the overdose was 53.3%, 23.7%, and 16.3%, respectively.Identification of at-risk populations will aid the military in ongoing efforts to decrease medication misuse. Findings suggest a potential need for improved labeling of over-the-counter medications and medication safety education efforts for unintentional acetaminophen overdose and continued efforts to identify individuals at risk for intentional overdose. Published 2012. This article is a US Government work and is in the public domain in the USA.

Magnesium, potassium, and sodium, cations commonly measured in serum, are involved in many physiological processes including energy metabolism, nerve and muscle function, signal transduction, and fluid and blood pressure regulation. To evaluate the contribution of common genetic variation to normal physiologic variation in serum concentrations of these cations, we conducted genome-wide association studies of serum magnesium, potassium, and sodium concentrations using ∼2.5 million genotyped and imputed common single nucleotide polymorphisms (SNPs) in 15,366 participants of European descent from the international CHARGE Consortium. Study-specific results were combined using fixed-effects inverse-variance weighted meta-analysis. SNPs demonstrating genome-wide significant (p, Author Summary Magnesium, potassium, and sodium are involved in important physiological processes. To better understand how common genetic variation may contribute to inter-individual differences in serum concentrations of these electrolytes, we evaluated single nucleotide polymorphisms (SNPs) across the genome in association with serum magnesium, potassium, and sodium levels in 15,366 participants of European descent from the CHARGE Consortium. We then verified the associations in an additional 8,463 study participants. Six different genomic regions contain variants that are reproducibly associated with serum magnesium levels, and only one of the regions had been previously known to influence serum magnesium concentrations in humans. The identified SNPs also show association with clinically defined hypomagnesemia, and some of them with traits that have been linked to serum magnesium levels, including kidney function, fasting glucose, and bone mineral density. We further provide evidence for a physiological role of magnesium transporters in humans which have previously only been studied in model systems. None of the SNPs evaluated in our study are significantly associated with serum levels of sodium or potassium. Additional studies are needed to investigate the underlying molecular mechanisms in order to help us understand the contribution of these newly identified regions to magnesium homeostasis.

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. Although estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Because intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)n] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)n >24 had a significant 2-fold risk of gallbladder cancer [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.07-3.73], relative to those with (CAG)n ≤ 22. In contrast, women with (CAG)n >24 had reduced gallbladder cancer risk (OR, 0.69; 95% CI, 0.43-1.09) relative to those with (CAG)n ≤ 22; P interaction sex = 0.01, which was most pronounced for women ages 68 to 74 (OR, 0.48; 95% CI, 0.25-0.93; P interaction age = 0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved. Cancer Epidemiol Biomarkers Prev; 19(3); 787–93

There is a known inverse association between type 2 diabetes (T2D) and prostate cancer (PrCa) that is poorly understood. Genetic studies of the T2D-PrCa association may provide insight into the underlying mechanisms of this association. We evaluated associations in the Atherosclerosis Risk in Communities study between PrCa and nine T2D single nucleotide polymorphisms from genome-wide association studies of T2D (in CDKAL1, CDKN2A/B, FTO, HHEX, IGF2BP2, KCNJ11, PPARG, SLC30A8, and TCF7L2) and four T2D single nucleotide polymorphisms from pre–genome-wide association studies (in ADRB2, CAPN10, SLC2A2, and UCP2). From 1987 to 2000, there were 397 incident PrCa cases among 6,642 men ages 45 to 64 years at baseline. We used race-adjusted Cox proportional hazards models to estimate associations between PrCa and increasing number of T2D risk-raising alleles. PrCa was positively associated with the CAPN10 rs3792267 G allele [hazard ratio (HR) 1.20; 95% confidence interval (CI), 1.00-1.44] and inversely associated with the SLC2A2 rs5400 Thr110 allele (HR, 0.85; 95% CI, 0.72, 1.00), the UCP2 rs660339 Val55 allele (HR, 0.84; 95% CI, 0.73, 0.97) and the IGF2BP2 rs4402960 T allele (HR, 0.79; 95% CI, 0.61-1.02; blacks only). The TCF7L2 rs7903146 T allele was inversely associated with PrCa using a dominant genetic model (HR, 0.79; 95% CI, 0.65-0.97). Further knowledge of T2D gene-PrCa mechanisms may improve understanding of PrCa etiology. Cancer Epidemiol Biomarkers Prev; 19(2); 558–65

BACKGROUND Hypertension is a risk factor for coronary heart disease (CHD), but the causes of hypertension remain largely unknown. Genetic variation is thought to contribute to the etiology of hypertension. We tested a single-nucleotide polymorphism (SNP) (Lys67Arg, rs197922) in the Golgi SNAP Receptor Complex Member 2 (GOSR2) gene for association with hypertension and blood pressure (BP). We chose this SNP because it was nominally associated with CHD in earlier studies. Further, GOSR2 is located in a linkage region for hypertension and BP in human and animal studies. METHODS We used logistic and linear regression to test associations of the GOSR2 SNP with hypertension and BP among 3,528 blacks and 9,861 whites from the Atherosclerosis Risk in Communities (ARIC) study. Race-specific regression models of hypertension were adjusted for age and gender. Regression models of BP were further adjusted for antihypertensive medication use. RESULTS The GOSR2 Lys67 allele was associated with hypertension in whites (odds ratio (OR) = 1.09, P = 0.01) but not blacks (OR = 0.96, P = 0.47). The Lys67 allele was associated with increased systolic BP (SBP) in both races (0.87 mm Hg, P < 0.001 among whites and 1.05 mm Hg, P = 0.05 among blacks). A similar association in whites was observed for the GOSR2 SNP and SBP in the Women's Genome Health Study (WGHS) (OR = 1.03, P = 0.04). The OR remained unchanged after adjustment for antihypertensive medication use (OR = 1.03, P = 0.11), though it was no longer statistically significant. CONCLUSIONS We found evidence that a SNP in GOSR2 is modestly associated with hypertension in whites from the ARIC study and the WGHS.

Among 397 homeless participants studied, the overall West Nile virus (WNV) seroprevalence was 6.8%. Risk factors for WNV infection included being homeless >1 year, spending >6 hours outside daily, regularly taking mosquito precautions, and current marijuana use. Public health interventions need to be directed toward this high-risk population.

Objective To address socio-demographic factors associated with adherence to follow-up recommendations in a high-risk population of women referred for follow-up care after an abnormal Pap test. Methods 486 women aged 46–64 served by BCCEDP in two southeastern states between 1999–2002 and referred for follow-up care after an abnormal Pap test were the sampling frame for this cross-sectional study; 204 women completed a phone-based interview in 2004. Cox proportional hazards modeling was used to determine the association of various risk factors with time to adherence. Results Among those completing the phone interview (interview rate=61.4%) the mean age was 53.3 years, 64.7% were African–American women, 81.9% had low-grade cervical lesions, and all were either uninsured or under insured. Over 95% received follow-up care for an abnormal Pap test within 365 days of referral. When the BCCEDP criteria of follow-up within 60 days were applied, 52.9% were adherent. Rates of self-reported and program documented adherence differed significantly by state. After adjusting for state of residence, women who reported having symptoms of a chronic disease were more likely to be adherent within 365 days (aHR=1.42; 95% CI=1.00, 2.04). Neither age, race, lesion severity, education, number of dependent adults or children, self-perceived physical health, nor smoking status was associated with time to adherence. Conclusions Findings suggest that institutional factors may be more important than individual factors in predicting time to adherence for an abnormal Pap test.

Introduction and Objective: Existing epidemiologic data do not support an association between circulating levels of sex steroid hormones and risk of prostate cancer. Although it has been suggested that the combined action of androgens and estrogens'specifically their balance'may play a key role in prostate carcinogenesis, epidemiologic studies to evaluate this hypothesis are sparse, have assessed a limited number of sex steroid hormones, and have provided inconsistent results. We investigated associations between serum sex hormones'with a particular focus on estrogen metabolites'and risk of aggressive prostate cancer. Study Population, Design and Methods: In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, we measured 15 parent serum estrogens (estrone and estradiol) and estrogen metabolites, including those in the C-2, -4, or 16 hydroxylation pathways, using a liquid chromatography-tandem mass spectrometry (LC/MS/MS) assay. Cases (n=195) were defined as non-Hispanic white men diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7) between and 1994 and 2009 who were 55–70 years at diagnosis. Controls (n=195) were non-Hispanic white men who were free from prostate cancer for the duration of follow-up and frequency-matched to cases by age at study entry (5-yr intervals), time since baseline screen (1-yr time windows) and year of blood draw. Only cases and controls included in a previous study that measured serum androgens and sex-hormone binding globulin (SHBG) were eligible. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Results: Individual parent estrogens and individual estrogen metabolites were unrelated to risk of aggressive prostate cancer; with the exception of a non-linear inverse relationship between cancer and levels of methylated catechols, namely 2- and 4-methoxyestrone. However, there was an increased risk of aggressive prostate cancer associated with an increasing ratio of 2:16 hydroxyestrone (fourth vs. first quartile: OR 2.44, 95% CI 1.34–4.45, p trend=0.001) and a strong trend of decreasing prostate cancer risk with an increasing ratio of estradiol to testosterone (fourth vs. first quartile: OR 0.27, 95% CI 0.12–0.59, p trend=0.003). Conclusion: We observed a strong protective effect of higher serum estradiol to testosterone levels in relation to risk of aggressive prostate cancer. Men with higher concentrations of methylated catechols in the 2- and 4-hydroxylation pathway may have a reduced risk of aggressive prostate cancer, while those with higher ratios of 2:16 hydroxyestrone may be at increased risk. These findings suggest a role for sex steroid hormone metabolism in prostate carcinogenesis. Citation Format: Amanda Black, Paul F. Pinsky, Robert L. Grubb, III, Roni T. Falk, Ann W. Hsing, Lisa W. Chu, Tamra E. Meyer, Tim Veenstra, Xia Xu, Kai Yu, Louise A. Brinton, Robert N. Hoover, Michael B. Cook. Estrogen metabolism in relation to the risk of aggressive prostate cancer. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A53.

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Multiple genome-wide association studies have identified several independent non-coding regions in chromosome 8q24 associated with risk for cancers of the prostate, breast, colon, and bladder. To explore their biological basis, we investigated the possible association between 164 single nucleotide polymorphism (SNPs) in the 8q24 risk regions, spanning 128,101,433-128,828,043 bp, and serum androgen (testosterone, androstenedione, and 3αdiol G) and sex hormone-binding globulin levels in 563 healthy, non-Hispanic, Caucasian men (55-74 years old) from a prospective cohort study, the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Age-adjusted linear regression using SNPs in an additive genetic model showed that three adjacent SNPs centromeric to prostate cancer risk region 2 (rs12334903, rs1456310, and [rs980171][1]) were associated with measured total testosterone (P

Both inflammation and androgens are likely to be involved in the etiology of prostate cancer. There is evidence for cross-talk between androgen and inflammation pathways, yet little is known about the joint contribution of inflammation and androgens to prostate cancer risk. Thus, we evaluated the joint effects of 9,932 tag single nucleotide polymorphisms (SNPs) in 774 inflammation-related genes and four serum androgen measures (total testosterone [T], bioavailable T, 3α-androstanediol glucuronide [3α diol G], and androstenedione) on risk of prostate cancer in 516 incident cancer cases and 560 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. SNPs included in this study were genotyped as part of the National Cancer Institute Cancer Genetic Markers of Susceptibility genome-wide association study. Likelihood ratio tests (LRT) were used to compare logistic models of prostate cancer regressed on age, center, the androgen (in quartiles), the SNP (additive genetic coding) and the SNP x hormone interaction term to logistic models of prostate cancer regressed on age, center, and the androgen. False discovery rate (FDR) control was used to adjust for multiple testing. Statistically significant LRT P-values were noted for T and three intronic SNPs in linkage disequilibrium (r2>0.7) within the HIPK2 gene on 7q34 (rs10256326, rs7788362, and rs12539357; FDR-adjusted P=0.04 for all SNPs). For each SNP, the minor allele was associated with a reduced prostate cancer risk in men with serum T levels in the lower three quartiles, but was associated with an increased risk among men in the highest quartile of serum T. LRT P-values of borderline statistical significance were also seen for joint effects of these three SNPs and bioavailable T on risk of prostate cancer (FDR-adjusted P=0.07 for all SNPs). There were no significant joint effects for any of the SNPs with 3αdiol G or androstenedione after adjustment for multiple tests. Our preliminary results suggest that T levels could interact with HIPK2 gene variants to influence prostate cancer risk. HIPK2 is an attractive candidate gene for further evaluation because it codes for a serine/threonine kinase involved in transcriptional regulation, particularly involved in p53-dependent and independent regulation of cell cycle control and apoptosis. Future studies are needed to confirm our preliminary findings and to further understand the possible interaction between T and genetic variants in HIPK2, which could contribute to prostate cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 924.