Faculty Bibliography

Benzene exposure has been causally linked with acute myeloid leukemia (AML), but inconsistently associated with other hematopoietic, lymphoproliferative and related disorders (HLD) or solid tumors in humans. Many neoplasms have been described in experimental animals exposed to benzene. We used Poisson regression to estimate adjusted relative risks (RR) and the likelihood ratio statistic to derive confidence intervals for cause-specific mortality and HLD incidence in 73,789 benzene-exposed compared with 34,504 unexposed workers in a retrospective cohort study in 12 cities in China. Follow-up and outcome assessment was based on factory, medical and other records. Benzene-exposed workers experienced increased risks for all-cause mortality (RR = 1.1, 95% CI = 1.1, 1.2) due to excesses of all neoplasms (RR = 1.3, 95% CI = 1.2, 1.4), respiratory diseases (RR = 1.7, 95% CI = 1.2, 2.3) and diseases of blood forming organs (RR = infinity, 95% CI = 3.4, infinity). Lung cancer mortality was significantly elevated (RR = 1.5, 95% CI = 1.2, 1.9) with similar RRs for males and females, based on three-fold more cases than in our previous follow-up. Significantly elevated incidence of all myeloid disorders reflected excesses of myelodysplastic syndrome/acute myeloid leukemia (RR = 2.7, 95% CI = 1.2, 6.6) and chronic myeloid leukemia (RR = 2.5, 95% CI = 0.8, 11), and increases of all lymphoid disorders included excesses of non-Hodgkin lymphoma (RR = 3.9, 95%CI = 1.5, 13) and all lymphoid leukemia (RR = 5.4, 95%CI = 1.0, 99). The 28-year follow-up of Chinese benzene-exposed workers demonstrated increased risks of a broad range of myeloid and lymphoid neoplasms, lung cancer, and respiratory diseases and suggested possible associations with other malignant and non-malignant disorders.

BACKGROUND: Concordance with the Dietary Approaches to Stop Hypertension (DASH) diet has been shown to reduce blood pressure (BP) in short-term intervention studies, but long-term effects are unclear. We evaluated the association of DASH diet concordance with BP trajectories and incidence of hypertension, in 2187 men and women (mean age 52.5 years at baseline) participating in the Framingham Offspring cohort. METHOD: Diet and BP were assessed from 1991 to 2008, with a median follow-up time of 13.4 years. DASH scores (ranging from 0 for worst to 10 for best concordance with DASH diet) were calculated by summing 10 food components that comprise the DASH diet pattern, including fruits and vegetables, low-fat dairy products, lean meat, and plant-based protein. Mixed-effect and Cox regression models were applied, to assess the association of DASH diet concordance with BP longitudinal change and with incidence of hypertension, respectively. All analyses were adjusted for age, sex, smoking status, history of diabetes, BMI, and physical activity. RESULT: Overall, SBP increased by 0.34 mmHg and DBP by 0.10 mmHg annually, in the Framingham Offspring cohort. Every unit increase in the DASH score resulted in a modest increase in SBP of 0.054 mmHg/year (P = 0.028). No associations were observed between DASH diet concordance and DBP or incidence of hypertension. CONCLUSION: Long-term concordance with the DASH diet was not associated with a decreasing BP trajectory over time, or with decreased incidence of hypertension, in this population of middle-aged adults.

BACKGROUND: Organochlorine (OC) insecticides and polychlorinated biphenyls (PCBs) have been shown to have estrogenic, antiestrogenic, or antiandrogenic properties; as a result, the impact of exposure to these compounds and risk of hormonal cancers, such as prostate cancer, is a concern. OBJECTIVES: We conducted a nested case-control study, using prospectively collected serum, to estimate associations between OC exposures and metastatic prostate cancer in a population-based cohort from Norway. METHODS: Sera from 150 cases and 314 controls matched on date of blood draw, age at blood draw, and region was used to determine concentrations of 11 OC pesticide metabolites and 34 PCB congeners. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for quartiles of lipid-corrected metabolite levels were calculated using conditional logistic regression. RESULTS: Metastatic prostate cancer was two times as likely among men with serum concentrations of oxychlordane in the highest quartile compared with those in the lowest quartile (OR = 2.03; 95% CI: 1.03, 4.03; p-trend 0.05). Elevated but nonsignificant ORs were estimated for the highest versus lowest quartile of heptachlor epoxide, HCB, and mirex, although these exposures were correlated with oxychlordane. Findings for specific PCB congeners showed a significant inverse association between natural log-transformed lipid-adjusted PCB 44 and metastatic prostate cancer (OR = 0.74; 95% CI: 0.56, 0.97; p-trend = 0.02). CONCLUSIONS: Our study highlights the importance of estimating associations with specific OC chemicals and suggests a possible role of OC insecticides and PCBs in the etiology of metastatic prostate cancer. CITATION: Koutros S, Langseth H, Grimsrud TK, Barr DB, Vermeulen R, Portengen L, Wacholder S, Beane Freeman LE, Blair A, Hayes RB, Rothman N, Engel LS. 2015. Prediagnostic serum organochlorine concentrations and metastatic prostate cancer: a nested case-control study in the Norwegian Janus Serum Bank cohort. Environ Health Perspect 123:867-872; http://dx.doi.org/10.1289/ehp.1408245.

Although genome-wide association studies (GWAS) have separately identified many genetic susceptibility loci for ulcerative colitis (UC), Crohn's disease (CD) and colorectal cancer (CRC), there has been no large-scale examination for pleiotropy, or shared genetic susceptibility, for these conditions. We used logistic regression modeling to examine the associations of 181 UC and CD susceptibility variants previously identified by GWAS with risk of CRC using data from the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. We also examined associations of significant variants with clinical and molecular characteristics in a subset of the studies. Among 11794 CRC cases and 14190 controls, rs11676348, the susceptibility single nucleotide polymorphism (SNP) for UC, was significantly associated with reduced risk of CRC (P = 7E-05). The multivariate-adjusted odds ratio of CRC with each copy of the T allele was 0.93 (95% CI 0.89-0.96). The association of the SNP with risk of CRC differed according to mucinous histological features (P heterogeneity = 0.008). In addition, the (T) allele was associated with lower risk of tumors with Crohn's-like reaction but not tumors without such immune infiltrate (P heterogeneity = 0.02) and microsatellite instability-high (MSI-high) but not microsatellite stable or MSI-low tumors (P heterogeneity = 0.03). The minor allele (T) in SNP rs11676348, located downstream from CXCR2 that has been implicated in CRC progression, is associated with a lower risk of CRC, particularly tumors with a mucinous component, Crohn's-like reaction and MSI-high. Our findings offer the promise of risk stratification of inflammatory bowel disease patients for complications such as CRC.

SCOPE: Only a few studies analyzed the role of allium vegetables with reference to head and neck cancers (HNC), with mixed results. We investigated the potential favorable role of garlic and onion within the International Head and Neck Cancer Epidemiology (INHANCE) Consortium. METHODS AND RESULTS: We analyzed pooled individual-level data from eight case-control studies, including 4590 cases and 7082 controls. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for associations between garlic and onion intakes and HNC risk. Compared with no or low garlic use, the ORs of HNC were 0.95 (95% CI 0.71-1.27) for intermediate and 0.74 (95% CI 0.55-0.99) for high garlic use (p for trend = 0.02). The ORs of HNC for increasing categories of onion intake were 0.91 (95% CI 0.68-1.21) for >1 to 3 portions per week (p for trend = 0.02), as compared to <1 portion per week. We found an inverse association between high onion intake and laryngeal cancer risk (OR = 0.69; 95% CI 0.54-0.88), but no significant association for other subsites. CONCLUSION: The results of this pooled-analysis support a possible moderate inverse association between garlic and onion intake and HNC risk.

PURPOSE: The insulin-signaling pathway plays a pivotal role in cancer biology; however, evidence of genetic alterations in human studies is limited. This case-control study nested within the Framingham Heart Study (FHS) examined the association between inherited genetic variation in the insulin receptor (INSR) gene and obesity-related cancer risk. METHODS: The study sample consisted of 1,475 controls and 396 cases from the second familial generation of the FHS. Participants who provided consent were genotyped. Nineteen single-nucleotide polymorphisms (SNPs) in the INSR gene were investigated in relation to risk of obesity-related cancers combined and breast, prostate and colorectal cancers. Generalized estimation equation models controlling for familial correlations and include age, sex, smoking and body mass index as covariates, assuming additive models, were used. RESULTS: Three SNPs, rs2059807, s8109559 and rs919275, were significantly associated with obesity-related cancers (p value < 0.02) with the most significantly associated SNP being rs2059807 (p value = 0.008). Carriers of two copies of SNP rs2059807 risk allele T were significantly less prevalent among subjects with obesity-related cancers [f(TT)cases = 14 vs. f(TT)controls = 18 %; OR 1.23]. In exploratory analyses evaluating site-specific cancers, the INSR rs2059807 association with these cancers was consistent with that observed for the main outcome (ORs colorectal cancer = 1.5, breast cancer = 1.29, prostate = 1.06). There was no statistically significant interaction between the INSR-SNP and blood glucose in relation to obesity-related cancer. CONCLUSIONS: The INSR gene is implicated in obesity-related cancer risk, as 3 of 19 SNPs were nominally associated, after false discovery rate (FDR) correction, with the main outcome. Risk allele homozygotes (rs2059807) were less prevalent among subjects with obesity-related cancer. These results should be replicated in other populations to confirm the findings.

BACKGROUND: Cross-sectional studies have shown associations between arsenic exposure and prevalence of high BP; however, studies examining the relationship of arsenic exposure with longitudinal changes in blood pressure are lacking. METHOD: We evaluated associations of arsenic exposure in relation to longitudinal change in blood pressure in 10,853 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). Arsenic was measured in well water and in urine samples at baseline and in urine samples every two years after baseline. Mixed effect models were used to estimate the association of baseline well and urinary creatinine-adjusted arsenic with blood pressure annual change during follow-up (median, 6.7 years). RESULT: In the HEALS population, the median water arsenic concentration at baseline was 62 microg/L. Individuals in the highest quartile of baseline water arsenic or urinary creatinine-adjusted arsenic had a greater annual increase in SBP compared with those in the reference group (beta=0.48 mmHg/year; 95% CI: 0.35-0.61, and beta=0.43 mmHg/year; 95% CI: 0.29-0.56) for water arsenic and urinary creatinine-adjusted arsenic, respectively) in fully adjusted models. Likewise, individuals in the highest quartile of baseline arsenic exposure had a greater annual increase in DBP (beta=0.39 mmHg/year; 95% CI: 0.30, 0.49, and beta=0.45 mmHg/year; 95% CI: 0.36, 0.55) for water arsenic and urinary creatinine-adjusted arsenic, respectively) compared with those in the lowest quartile. CONCLUSION: Our findings suggest that long-term arsenic exposure may accelerate age-related increases in blood pressure. These findings may help explain associations between arsenic exposure and cardiovascular disease.

Genetic susceptibility to colorectal cancer is caused by rare pathogenic mutations and common genetic variants that contribute to familial risk. Here we report the results of a two-stage association study with 18,299 cases of colorectal cancer and 19,656 controls, with follow-up of the most statistically significant genetic loci in 4,725 cases and 9,969 controls from two Asian consortia. We describe six new susceptibility loci reaching a genome-wide threshold of P<5.0E-08. These findings provide additional insight into the underlying biological mechanisms of colorectal cancer and demonstrate the scientific value of large consortia-based genetic epidemiology studies.

BACKGROUND: High body mass index (BMI) is consistently linked to increased risk of colorectal cancer for men, whereas the association is less clear for women. As risk estimates from observational studies may be biased and/or confounded, we conducted a Mendelian randomization study to estimate the causal association between BMI and colorectal cancer. METHODS: We used data from 10,226 colorectal cancer cases and 10,286 controls of European ancestry. The Mendelian randomization analysis used a weighted genetic risk score, derived from 77 genome-wide association study-identified variants associated with higher BMI, as an instrumental variable (IV). We compared the IV odds ratio (IV-OR) with the OR obtained using a conventional covariate-adjusted analysis. RESULTS: Individuals carrying greater numbers of BMI-increasing alleles had higher colorectal cancer risk [per weighted allele OR, 1.31; 95% confidence interval (CI), 1.10-1.57]. Our IV estimation results support the hypothesis that genetically influenced BMI is directly associated with risk for colorectal cancer (IV-OR per 5 kg/m(2), 1.50; 95% CI, 1.13-2.01). In the sex-specific IV analyses higher BMI was associated with higher risk of colorectal cancer among women (IV-OR per 5 kg/m(2), 1.82; 95% CI, 1.26-2.61). For men, genetically influenced BMI was not associated with colorectal cancer (IV-OR per 5 kg/m(2), 1.18; 95% CI, 0.73-1.92). CONCLUSIONS: High BMI was associated with increased colorectal cancer risk for women. Whether abdominal obesity, rather than overall obesity, is a more important risk factor for men requires further investigation. IMPACT: Overall, conventional epidemiologic and Mendelian randomization studies suggest a strong association between obesity and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1024-31. (c)2015 AACR.

BACKGROUND:: Observational studies and clinical trials have shown associations of diet and high blood pressure (BP). However, prospective studies on the association between dietary patterns and longitudinal BP change are lacking, especially in low-income populations. METHOD:: We evaluated the association of dietary patterns and food groups with longitudinal change of BP in 10 389 participants in the Health Effects of Arsenic Longitudinal Study, with a median of 6.7 years of follow-up. Dietary information was obtained through a previously validated food-frequency questionnaire. BP was measured at baseline and at each biennial follow-up using the same method. RESULT:: Each standard deviation (SD) increase for the 'gourd vegetable' dietary pattern score was related to a slower annual change of 0.08, 0.04, and 0.05 mmHg in SBP, DBP, or pulse pressure, respectively. Each SD increase in the 'balanced' dietary pattern score was related to a decreasing annual change of 0.06 mmHg (P = 0.012) and 0.08 mmHg in SBP and pulse pressure (P < 0.001). On the contrary, one SD increase in 'western' dietary pattern score was related to a greater annual increase of 0.07 (P = 0.005) and 0.05 mmHg in SBP and pulse pressure (P = 0.013). Higher intake of fruits and vegetables was associated with a slower rate of change in annual SBP and pulse pressure, whereas higher meat intake was related to a more rapid increase in annual pulse pressure. CONCLUSION:: The findings suggest that dietary patterns play a significant role in the rate of BP change over time in a low-income population.