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// Xiang Shu 1, * , Mark P. Purdue 2, * , Yuanqing Ye 1 , Christopher G. Wood 3 , Meng Chen 1 , Zhaoming Wang 4 , Demetrius Albanes 2 , Xia Pu 1 , Maosheng Huang 1 , Victoria L. Stevens 5 , W. Ryan Diver 5 , Susan M. Gapstur 5 , Jarmo Virtamo 6 , Wong-Ho Chow 1 , Nizar M. Tannir 7 , Colin P. Dinney 3 , Nathaniel Rothman 2 , Stephen J. Chanock 2, * , Xifeng Wu 1, * 1 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA 3 Urology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Cancer Genomics Research Laboratory, SAIC-Frederick Inc., National Cancer Institute-Frederick, Frederick, Maryland, USA 5 Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA 6 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland 7 Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA * These authors have contributed equally to this work Correspondence to: Xifeng Wu, e-mail: xwu@mdanderson.org Keywords: RCC, GWAS, GSEA, eQTL Received: November 07, 2014 Accepted: December 21, 2014 Published: February 25, 2015 ABSTRACT We conducted multilevel analyses to identify potential susceptibility loci for renal cell carcinoma (RCC), which may be overlooked in traditional genome-wide association studies (GWAS). A gene set enrichment analysis was performed utilizing a GWAS dataset comprised of 894 RCC cases and 1,516 controls using GenGen, SNP ratio test, and ALIGATOR. The antigen processing and presentation pathway was consistently significant ( P = 0.001, = 0.004, and < 0.001, respectively). Versatile gene-based association study approach was applied to the top-ranked pathway and identified the driven genes. By comparing the expression of the genes in RCC tumor and adjacent normal tissues, we observed significant overexpression of HLA genes in tumor tissues, which was also supported by public databases. We sought to validate genetic variants in antigen processing and presentation pathway in an independent GWAS dataset comprised of 1,311 RCC cases and 3,424 control subjects from the National Cancer Institute; one SNP, rs1063355, was significant in both populations (P meta-analysis = 9.15 × 10 −4 , P heterogeneity = 0.427). Strong correlation indicated that rs1063355 was a cis -expression quantitative trait loci which associated with HLA-DQB1 expression (Spearman’s rank r = −0.59, p = 5.61 × 10 −6 ). The correlation was further validated using a public dataset. Our results highlighted the role of immune-related pathway and genes in the etiology of RCC.

Prospective studies evaluating risk factors for abdominal aortic aneurysm are few. We studied the association of life-style factors with risk for abdominal aortic aneurysm among 29,133 male smokers 50-69 years of age, participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. During a mean follow-up of 5.8 years, 181 were diagnosed with ruptured abdominal aortic aneurysm or nonruptured abdominal aortic aneurysm plus aneurysmectomy. Risk for abdominal aortic aneurysm was positively associated with age [relative risk (RR) = 4.56, 95% confidence interval (CI) = 2.42-8.61 for65 vsor = 55 years], smoking years (RR = 2.25, 95% CI = 1.33-3.81 for40 vsor = 32 years), systolic blood pressure (RR = 1.92, 95% CI = 1.13-3.25 for160 vsor = 130 mmHg), diastolic blood pressure (RR = 1.80, 95% CI = 1.05-3.08 for100 vsor = 85 mmHg), and serum total cholesterol (RR = 1.85, 95% CI = 1.09-3.12 for6.5 vsor = 5.0 mmol/liter). High-density lipoprotein cholesterol showed a strong inverse association with risk for aortic aneurysm (RR = 0.16, 95% CI = 0.08-0.32 for1.5 vsor = 0.9 mmol/liter). High energy intake was associated with lower risk for aortic aneurysm (RR = 0.59, 95% CI = 0.38-0.94 for the highest quartile vs the lowest), whereas no associations with nutrients were evident. We conclude that classical risk factors for atherosclerotic diseases seem to be important in pathogenesis of large abdominal aortic aneurysms.

Background Interleukin-18 is a pro-inflammatory cytokine suspected to be associated with atherosclerosis and its complications. We had previously shown that one single nucleotide polymorphism (SNP) of the IL18 gene was associated with cardiovascular disease (CVD) through an interaction with smoking. As a further step for elucidating the contribution of the IL-18 pathway to the etiology of CVD, we here investigated the association between the genetic variability of two IL-18 receptor genes, IL18R1 and IL18RAP, with the risk of developing CVD. Methods Eleven tagging SNPs, 5 in IL18R1 and 6 in IL18RAP, characterizing the haplotypic variability of the corresponding genes; were genotyped in 5 European prospective CVD cohorts including 1416 cases and 1772 non-cases, as part of the MORGAM project. Both single-locus and haplotypes analyses were carried out to investigate the association of these SNPs with CVD. Results We did not find any significant differences in allele, genotype and haplotype frequencies between cases and non-cases for either of the two genes. Moreover, the search for interactions between SNPs located in different genes, including 5 IL18 SNPs previously studied in the MORGAM project, and between SNPs and environmental factors remained unfruitful. Conclusion Our analysis suggests that the variability of IL18R1 and IL18RAP genes are unlikely to contribute to modulate the risk of CVD.

Steroid hormones are believed to play an important role in prostate carcinogenesis, but epidemiological evidence linking prostate cancer and steroid hormone genes has been inconclusive, in part due to small sample sizes or incomplete characterization of genetic variation at the locus of interest. Here we report on the results of a comprehensive study of the association between HSD17B1 and prostate cancer by the Breast and Prostate Cancer Cohort Consortium, a large collaborative study. HSD17B1 encodes 17β-hydroxysteroid dehydrogenase 1, an enzyme that converts dihydroepiandrosterone to the testosterone precursor Δ5-androsterone-3β,17β-diol and converts estrone to estradiol. The Breast and Prostate Cancer Cohort Consortium researchers systematically characterized variation in HSD17B1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNPs) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,290 prostate cancer cases and 9,367 study-, age-, and ethnicity-matched controls. We found no evidence that HSD17B1 htSNPs (including the nonsynonymous coding SNP S312G) or htSNP haplotypes were associated with risk of prostate cancer or tumor stage in the pooled multiethnic sample or in U.S. and European whites. Analyses stratified by age, body mass index, and family history of disease found no subgroup-specific associations between these HSD17B1 htSNPs and prostate cancer. We found significant evidence of heterogeneity in associations between HSD17B1 haplotypes and prostate cancer across ethnicity: one haplotype had a significant (p < 0.002) inverse association with risk of prostate cancer in Latinos and Japanese Americans but showed no evidence of association in African Americans, Native Hawaiians, or whites. However, the smaller numbers of Latinos and Japanese Americans in this study makes these subgroup analyses less reliable. These results suggest that the germline variants in HSD17B1 characterized by these htSNPs do not substantially influence the risk of prostate cancer in U.S. and European whites., Synopsis Steroid hormones such as estrogen and testosterone are hypothesized to play a role in the development of cancer. This is the first substantive paper from the Breast and Prostate Cancer Cohort Consortium, a large, international study designed to assess the effect of variation in genes that influence hormone production and activity on the risk of breast and prostate cancer. The investigators first constructed a detailed map of genetic variation spanning HSD17B1, a gene involved in the production of estrogen and testosterone. This enabled them to efficiently measure common variation across the whole gene, capturing information about both known variants with a plausible function and unknown variants with an unknown function. Because of the results with a large number of study participants, the investigators could rule out strong associations between common HSD17B1 variants and risk of prostate cancer among U.S. and European whites. While this sheds some light on the carcinogenic effects of one enzyme involved in the complex process of steroid hormone production, it remains to be determined whether variants in other genes play a more important role or if the combined effects of several genes within these pathways have a larger impact.

Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and 90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (‘Aromatic amine metabolism’ [PGSEA = 0.0100, PARTP = 0.0020], ‘NAD biosynthesis’ [PGSEA = 0.0018, PARTP = 0.0086], ‘NAD salvage’ [PARTP = 0.0068], ‘Clathrin derived vesicle budding’ [PARTP = 0.0018], ‘Lysosome vesicle biogenesis’ [PGSEA = 0.0023, PARTP

Purpose: To study if long-term supplementation with alpha-tocopherol or betacarotene is associated with cataract prevalence and severity. Methods: An end-of-trial random sample of 1828 participants from the randomized, double-blind, placebo-controlled clinical trial the alpha-tocopherol, beta-carotene cancer prevention study. The alpha-tocopherol, beta-carotene cancer prevention study was originally designed to examine whether supplementation with alpha-tocopherol or beta-carotene would reduce the incidence of lung cancer in male smokers. The participants for this study lived in Helsinki City or Uusimaa province and were at entry to the alpha-tocopherol, beta-carotene cancer prevention study 50 to 69 years old and smoked at least 5 cigarettes per day. They received alpha-tocopherol 50 mg/day, beta-carotene 20 mg/day, a combination of the two, or placebo supplements for 5 to 8 years (median 6.6 years). Outcome measures were: cortical, nuclear, and posterior subcapsular cataract, differentiated and quantified with lens opacity classification system (LOCS 11). Lens opacity meter provided a continuous measure of cataract density. Results: Supplementation with alpha-tocopherol or beta-carotene was not associated with the end-of-trial prevalence of nuclear (odds ratio 1.1 and 1.2, respectively), cortical (odds ratio 1.0 and 1.3, respectively), or posterior subcapsular cataract (odds ratio 1.1 and 1.0, respectively) when adjusted for possible confounders in logistic model. Neither did the median lens opacity meter values differ between the supplementation groups, indicating no effect of alpha-tocopherol or beta-carotene on cataract severity. Conclusion- Supplementation with alpha-tocopherol or beta-carotene for 5 to 8 years does not influence the cataract prevalence among middle-aged, smoking men.

Background and objective: Survival of patients with pancreatic adenocarcinoma is limited and few prognostic factors are known. We conducted a two-stage genome-wide association study (GWAS) to identify germline variants associated with survival in patients with pancreatic adenocarcinoma. Methods: We analysed overall survival in relation to single nucleotide polymorphisms (SNPs) among 1005 patients from two large GWAS datasets, PanScan I and ChinaPC. Cox proportional hazards regression was used in an additive genetic model with adjustment for age, sex, clinical stage and the top four principal components of population stratification. The first stage included 642 cases of European ancestry (PanScan), from which the top SNPs (p10(-5)) were advanced to a joint analysis with 363 additional patients from China (ChinaPC). Results: In the first stage of cases of European descent, the top-ranked loci were at chromosomes 11p15.4, 18p11.21 and 1p36.13, tagged by rs12362504 (p=1.63x10(-7)), rs981621 (p=1.65x10(-7)) and rs16861827 (p=3.75x10(-7)), respectively. 131 SNPs with p10(-5) were advanced to a joint analysis with cases from the ChinaPC study. In the joint analysis, the top-ranked SNP was rs10500715 (minor allele frequency, 0.37; p=1.72x10(-7)) on chromosome 11p15.4, which is intronic to the SET binding factor 2 (SBF2) gene. The HR (95% CI) for death was 0.74 (0.66 to 0.84) in PanScan I, 0.79 (0.65 to 0.97) in ChinaPC and 0.76 (0.68 to 0.84) in the joint analysis. Conclusions: Germline genetic variation in the SBF2 locus was associated with overall survival in patients with pancreatic adenocarcinoma of European and Asian ancestry. This association should be investigated in additional large patient cohorts.

BackgroundIt has been suggested that low serum total cholesterol is associated with an increased risk of suicide.AimsTo study the association between serum total cholesterol, depression and suicide using versatile, prospective data.MethodA total of 29 133 men aged 50–69 years were followed up for 5–8 years. Baseline blood samples were analysed for serum total and high-density lipoprotein cholesterol concentrations. Self-reported depression was recorded, data on hospital treatments due to depressive disorders were derived from the National Hospital Discharge Register and deaths from suicide were identified from death certificates.ResultsLow serum total cholesterol was associated with low mood and subsequently a heightened risk of hospital treatment due to major depressive disorder and of death from suicide.ConclusionsOur results suggest that low serum total cholesterol appears to be associated with low mood and thus to predict its serious consequences.

The association between dietary and lifestyle factors and intermittent claudication was investigated in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. The cohort comprised 26,872 male smokers aged 50-69 years who were free of claudication at study entry. At baseline (1985-1988), subjects completed a diet history questionnaire. During a median follow-up period of 4 years (ending in spring 1993), 2,578 men reported symptoms of claudication on the Rose questionnaire, which was administered annually. Smoking status was assessed every 4 months. Smoking, systolic blood pressure, serum total cholesterol, and diabetes mellitus were positively associated with risk for claudication, whereas serum high density lipoprotein cholesterol, education, and leisure time exercise were inversely associated with risk. Dietary carbohydrates, fiber, and n-6 polyunsaturated fatty acids were inversely associated with risk for claudication, as were some dietary and serum antioxidants: dietary vitamin C (highest quartile vs. lowest: relative risk (RR) = 0.86; 95% confidence interval (CI): 0.77, 0.97), dietary gamma-tocopherol (RR = 0.89; 95% CI: 0.79, 1.00), dietary carotenoids (RR = 0.82; 95% CI: 0.73, 0.92), serum alpha-tocopherol (RR = 0.88; 95% CI: 0.77, 1.00), and serum beta-carotene (RR = 0.77; 95% CI: 0.68, 0.86). Smoking cessation reduced subsequent risk for claudication (RR = 0.86; 95% CI: 0.75, 0.99). The authors conclude that classical risk factors for atherosclerosis are associated with claudication. High intakes of antioxidant vitamins may be protective. Further research is needed before antioxidants can be recommended for the prevention of intermittent claudication.

Background To assess the extent of lung cancer mortality differentials by education while adjusting for exposure to tobacco smoke and asbestos based on survey questions. Methods Alpha-Tocopherol, Beta Carotene Cancer Prevention (ATBC) Study of 50-69-year-old Finnish male smokers enrolled 1985-1988. These analyses are based on the placebo group and the alpha-tocopherol supplementation group, altogether 14 011 men, with full information on tobacco smoking. Mortality follow-up was to the end of April 1993 and it was based on the complete death certificate register of the Statistics Finland. Results Lung cancer mortality of basic-educated men was 32% (rate ratio [RR] = 1.32; 95% CI : 0.93-1.87) higher than that of better-educated men in the ATBC Study. The excess is practically unchanged when additional adjustment was made for age at initiation, duration of smoking, current smoking at baseline and at first follow-up, smoke inhalation, occupational exposure to asbestos and interactions between asbestos exposure and all smoking variables. This excess mortality was about 40% of the similar excess observed in the general population of men of similar age. Conclusions Educational differences in lung cancer mortality in the total Finnish population are likely to be mainly caused by differences in exposure, particularly to active smoking. Further understanding of the determinants and consequences of socio-economic differences in smoking behaviour are of major scientific and public health importance.

Abstract We examined the primary preventive effect of vitamin E (α-tocopherol) and β-carotene supplementation on intermittent claudication. The subjects—participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study—were male smokers aged 50 to 69 years who were randomly assigned to receive 50 mg of α-tocopherol daily, 20 mg of β-carotene daily, both, or placebo. At baseline, there were 26 289 men with no history or symptoms of intermittent claudication. The Rose questionnaire on intermittent claudication was administered annually to discover incident cases. We observed 2704 cases of first occurrence of typical intermittent claudication during a median follow-up time of 4.0 years. Compared with placebo, the adjusted relative risk for typical intermittent claudication among those who received α-tocopherol only was 1.11 (95% confidence interval, 1.00-1.24); among those who received α-tocopherol and β-carotene, 1.02 (0.91-1.13); and among those who received β-carotene only, 1.02 (0.92-1.14). When we compared the α-tocopherol–supplemented subjects with those who received no α-tocopherol, the adjusted relative risk for typical intermittent claudication was 1.05 (0.98-1.14), and for β-carotene–supplemented subjects compared with those who did not receive β-carotene, the relative risk was 0.96 (0.89-1.04). In conclusion, no primary preventive effect on intermittent claudication was observed among middle-aged male smokers who were supplemented with α-tocopherol, β-carotene, or both.

Mosaic loss of chromosome Y (mLOY) leading to gonosomal XY/XO commonly occurs during aging, particularly in smokers. We investigated whether mLOY was associated with non-hematological cancer in three prospective cohorts (8,679 cancer cases and 5,110 cancer-free controls) and genetic susceptibility to mLOY. Overall, mLOY was observed in 7% of men, and its prevalence increased with age (per-year odds ratio (OR) = 1.13, 95% confidence interval (CI) = 1.12-1.15; P < 2 × 10(-16)), reaching 18.7% among men over 80 years old. mLOY was associated with current smoking (OR = 2.35, 95% CI = 1.82-3.03; P = 5.55 × 10(-11)), but the association weakened with years after cessation. mLOY was not consistently associated with overall or specific cancer risk (for example, bladder, lung or prostate cancer) nor with cancer survival after diagnosis (multivariate-adjusted hazard ratio = 0.87, 95% CI = 0.73-1.04; P = 0.12). In a genome-wide association study, we observed the first example of a common susceptibility locus for genetic mosaicism, specifically mLOY, which maps to TCL1A at 14q32.13, marked by rs2887399 (OR = 1.55, 95% CI = 1.36-1.78; P = 1.37 × 10(-10)). This project has been funded in whole or in part with federal funds from the National Cancer Institute, US National Institutes of Health, under contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the US Department of Health and Human Services nor does mention of trade names, commercial products or organizations imply endorsement by the US government.

We evaluated the effect of long-term supplementation with vitamin E (alpha-tocopherol) and beta-carotene on occurrence of claudication symptoms and risk for peripheral vascular surgery among men with intermittent claudication. Subjects, 50-69-year old male smokers, were participants in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, who reported intermittent claudication through a structured questionnaire (Rose) at study entry (n=1484). They were randomly assigned to receive either 50 mg/day of alpha-tocopherol, or 20 mg/day of beta-carotene, or both, or placebo, in a 2 x 2 design. During follow-up, claudication was evaluated by repeating use of the questionnaire once a year. Information on peripheral vascular surgery came from the National Hospital Discharge Register. We observed no effect of alpha-tocopherol and beta-carotene supplementation on claudication during a mean follow-up of 3.7 years. A slightly increased risk (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.05-2.44) for vascular surgery was observed among beta-carotene supplemented men compared to those who did not receive beta-carotene. Alpha-tocopherol supplementation had no effect. In conclusion, long-term supplementation with alpha-tocopherol and beta-carotene showed no beneficial effect on symptoms and progression of intermittent claudication.

Omega-3 fatty acids are essential long-chain polyunsaturated fatty acids that are concentrated in the CNS, retina, and testes in humans. Alpha-linolenic acid is present in plants and is needed for the synthesis of eicosapentaenoic and docosahexaenoic acids that are received directly from marine sources. There is some evidence that omega-3 fatty acids are linked to depression (1). Studies have reported reduced levels of omega-3 fatty acids in plasma and cell membranes from depressed patients (2–4). One double-blind, placebo-controlled trial (5) has shown that omega-3 supplements improve the short-term clinical course of patients with bipolar disorder. Our aim was to study the association between the dietary intake of omega-3 fatty acids and low mood, depression, and suicide. Consumption of fish rich in long-chain omega-3 fatty acids, specifically, was assessed.

(et al.)