Faculty Bibliography

Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci can facilitate detection of functional candidates and additional independent risk variants. We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested single-variant associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function. Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22.2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We did not observe evidence of additional independent association signals in GWAS-identified regions. Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates that warrant more onerous laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

BACKGROUND AND AIMS: Investigation of microbe-metabolite relationships in the gut is needed to understand and potentially reduce colorectal cancer (CRC) risk. METHODS: Microbiota and metabolomics profiling were performed on lyophilized feces from 42 CRC cases and 89 matched controls. Multivariable logistic regression was used to identify statistically independent associations with CRC. First principal coordinate-component pair (PCo1-PC1) and false discovery rate (0.05)-corrected P-values were calculated for 116,000 Pearson correlations between 530 metabolites and 220 microbes in a sex*case/control meta-analysis. RESULTS: Overall microbe-metabolite PCo1-PC1 was more strongly correlated in cases than in controls (Rho 0.606 vs 0.201, P = 0.01). CRC was independently associated with lower levels of Clostridia, Lachnospiraceae, p-aminobenzoate and conjugated linoleate, and with higher levels of Fusobacterium, Porphyromonas, p-hydroxy-benzaldehyde, and palmitoyl-sphingomyelin. Through postulated effects on cell shedding (palmitoyl-sphingomyelin), inflammation (conjugated linoleate), and innate immunity (p-aminobenzoate), metabolites mediated the CRC association with Fusobacterium and Porphyromonas by 29% and 34%, respectively. Overall, palmitoyl-sphingomyelin correlated directly with abundances of Enterobacteriaceae (Gammaproteobacteria), three Actinobacteria and five Firmicutes. Only Parabacteroides correlated inversely with palmitoyl-sphingomyelin. Other lipids correlated inversely with Alcaligenaceae (Betaproteobacteria). Six Bonferroni-significant correlations were found, including low indolepropionate and threnoylvaline with Actinobacteria and high erythronate and an uncharacterized metabolite with Enterobacteriaceae. CONCLUSIONS: Feces from CRC cases had very strong microbe-metabolite correlations that were predominated by Enterobacteriaceae and Actinobacteria. Metabolites mediated a direct CRC association with Fusobacterium and Porphyromonas, but not an inverse association with Clostridia and Lachnospiraceae. This study identifies complex microbe-metabolite networks that may provide insights on neoplasia and targets for intervention.

BACKGROUND: In developing medical research, particularly in regions where medical research is largely unfamiliar, it is important to understand public perceptions and attitudes towards medical research. In preparation for starting the first cohort study in the United Arab Emirates, the Abu Dhabi Cohort Study (ADCS), we sought to understand how we could improve the quality of the research process for participants and increase public trust and awareness of research. METHODS: We conducted six focus groups (FG), consisting of Emirati men and women aged above 18 years to resemble the target population for the ADCS. Sampling was purposive and convenient. Data collection was an iterative process until saturation was reached with no new themes identified. Text from each FG was analyzed separately by identifying emerging issues and organizing related concepts into categories or themes. A coding tree was developed, consisting of the main concepts, themes, subthemes and corresponding quotes. Both themes and main ideas were identified using inductive analysis. RESULTS: Forty-two participants enrolled at 3 academic centers (New York University Abu Dhabi, UAE University, Zayed University) and the Abu Dhabi blood bank. Focus group participants described lack of awareness of research as a challenge to participation in clinical research studies. Altruism, personal relevance of the research, and the use of role models were commonly identified motivators. Participants were generally satisfied with the informed consent process for the ADCS, but would be disappointed if not provided test results or study outcomes. Fear of a breach in confidentiality was a frequently expressed concern. CONCLUSIONS: Participants join research studies for varied, complex reasons, notably altruism and personal relevance. Based on these insights, we propose specific actions to enhance participant recruitment, retention and satisfaction in the ADCS. We identified opportunities to improve the research experience through improved study materials and communication to participants and the broader community.

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.

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.

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.

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.

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.

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.