Faculty Bibliography

BACKGROUND: In laboratory experiments, omega-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from omega-6 PUFA metabolism via competitive inhibition, and the omega-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary omega-3 PUFA intake benefits survival after breast cancer are limited and inconsistent. METHODS: The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire). Vital status was determined through 2011, yielding a median follow-up of 14.7 years and 485 deaths. Adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression. RESULTS: All-cause mortality was reduced among women with breast cancer reporting the highest quartile of intake (compared with never) for tuna (HR, 0.71; 95% CI, 0.55-0.92), other baked/broiled fish (HR, 0.75; 95% CI, 0.58-0.97), and the dietary long-chain omega-3 PUFAs docosahexaenoic acid (HR, 0.71; 95% CI, 0.55-0.92) and eicosapentaenoic acid (HR, 0.75; 95% CI, 0.58-0.97). CONCLUSIONS: All-cause mortality was reduced by 16% to 34% among women with breast cancer who reported a high intake of fish and long-chain omega-3 PUFAs. Long-chain omega-3 PUFA intake from fish and other dietary sources may provide a potential strategy to improve survival after breast cancer. Cancer 2015. (c) 2015 American Cancer Society.

BACKGROUND: Epidemiologic data on genetic susceptibility to cardiovascular effects of arsenic exposure from drinking water are limited. OBJECTIVE: We investigated whether the association between well-water arsenic and cardiovascular disease (CVD) differed by 170 single nucleotide polymorphisms (SNPs) in 17 genes related to arsenic metabolism, oxidative stress, inflammation, and endothelial dysfunction. METHOD: We conducted a prospective case-cohort study nested in the Health Effects of Arsenic Longitudinal Study, with a random subcohort of 1,375 subjects and 447 incident fatal and nonfatal cases of CVD. Well-water arsenic was measured in 2000 at baseline. The CVD cases, 56 of which occurred in the subcohort, included 238 coronary heart disease cases, 165 stroke cases, and 44 deaths due to other CVD identified during follow-up from 2000 to 2012. RESULTS: Of the 170 SNPs tested, multiplicative interactions between well-water arsenic and two SNPs, rs281432 in ICAM1 (Padj = 0.0002) and rs3176867 in VCAM1 (Padj = 0.035), were significant for CVD after adjustment for multiple testing. Compared with those with GC or CC genotype in rs281432 and lower well-water arsenic, the adjusted hazard ratio (aHR) for CVD was 1.82 (95% CI: 1.31, 2.54) for a 1-SD increase in well-water arsenic combined with the GG genotype, which was greater than expected given aHRs of 1.08 and 0.96 for separate effects of arsenic and the genotype alone, respectively. Similarly, the joint aHR for arsenic and the rs3176867 CC genotype was 1.34 (95% CI: 0.95, 1.87), greater than expected given aHRs for their separate effects of 1.02 and 0.84, respectively. CONCLUSIONS: Associations between CVD and arsenic exposure may be modified by genetic variants related to endothelial dysfunction.

BACKGROUND: Associations between anthropometry and head and neck cancer (HNC) risk are inconsistent. We aimed to evaluate these associations while minimizing biases found in previous studies. METHODS: We pooled data from 1 941 300 participants, including 3760 cases, in 20 cohort studies and used multivariable-adjusted Cox proportional hazard regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association of anthropometric measures with HNC risk overall and stratified by smoking status. RESULTS: Greater waist circumference (per 5 cm: HR = 1.04, 95% CI 1.03-1.05, P-value for trend = <0.0001) and waist-to-hip ratio (per 0.1 unit: HR = 1.07, 95% CI 1.05-1.09, P-value for trend = <0.0001), adjusted for body mass index (BMI), were associated with higher risk and did not vary by smoking status (P-value for heterogeneity = 0.85 and 0.44, respectively). Associations with BMI (P-value for interaction = <0.0001) varied by smoking status. Larger BMI was associated with higher HNC risk in never smokers (per 5 kg/m2: HR = 1.15, 95% CI 1.06-1.24, P-value for trend = 0.0006), but not in former smokers (per 5 kg/m2: HR = 0.99, 95% CI 0.93-1.06, P-value for trend = 0.79) or current smokers (per 5 kg/m2: HR = 0.76, 95% CI 0.71-0.82, P-value for trend = <0.0001). Larger hip circumference was not associated with a higher HNC risk. Greater height (per 5 cm) was associated with higher risk of HNC in never and former smokers, but not in current smokers. CONCLUSIONS: Waist circumference and waist-to-hip ratio were associated positively with HNC risk regardless of smoking status, whereas a positive association with BMI was only found in never smokers.

BACKGROUND:Herpes simplex virus type 1 (HSV-1) commonly causes orolabial ulcers, while HSV-2 commonly causes genital ulcers. However, HSV-1 is an increasing cause of genital infection. Previously, the World Health Organization estimated the global burden of HSV-2 for 2003 and for 2012. The global burden of HSV-1 has not been estimated. METHODS:We fitted a constant-incidence model to pooled HSV-1 prevalence data from literature searches for 6 World Health Organization regions and used 2012 population data to derive global numbers of 0-49-year-olds with prevalent and incident HSV-1 infection. To estimate genital HSV-1, we applied values for the proportion of incident infections that are genital. FINDINGS/RESULTS:We estimated that 3709 million people (range: 3440-3878 million) aged 0-49 years had prevalent HSV-1 infection in 2012 (67%), with highest prevalence in Africa, South-East Asia and Western Pacific. Assuming 50% of incident infections among 15-49-year-olds are genital, an estimated 140 million (range: 67-212 million) people had prevalent genital HSV-1 infection, most of which occurred in the Americas, Europe and Western Pacific. CONCLUSIONS:The global burden of HSV-1 infection is huge. Genital HSV-1 burden can be substantial but varies widely by region. Future control efforts, including development of HSV vaccines, should consider the epidemiology of HSV-1 in addition to HSV-2, and especially the relative contribution of HSV-1 to genital infection.

Genetic polymorphisms in vitamin D metabolism and signaling genes have been inconsistently associated with risk of breast cancer, though few studies have examined SNPs in vitamin D-related genes other than the vitamin D receptor (VDR) gene and particularly have not examined the association with the retinoid X receptor alpha (RXRA) gene which may be a key vitamin D pathway gene. We conducted a nested case-control study of 734 cases and 1435 individually matched controls from a population-based prospective cohort study, the Northern Sweden Mammary Screening Cohort. Tag and functional SNPs were genotyped for the VDR, cytochrome p450 24A1 (CYP24A1), and RXRA genes. We also genotyped specific SNPs in four other genes related to vitamin D metabolism and signaling (GC/VDBP, CYP2R1, DHCR7, and CYP27B1). SNPs in the CYP2R1, DHCR7, and VDBP gene regions that were associated with circulating 25(OH)D concentration in GWAS were also associated with plasma 25(OH)D in our study (p-trend <0.005). After taking into account the false discovery rate, these SNPs were not significantly associated with breast cancer risk, nor were any of the other SNPs or haplotypes in VDR, RXRA, and CYP24A1. We observed no statistically significant associations between polymorphisms or haplotypes in key vitamin D-related genes and risk of breast cancer. These results, combined with the observation in this cohort and most other prospective studies of no association of circulating 25(OH)D with breast cancer risk, do not support an association between vitamin D and breast cancer risk.

BACKGROUND: High sodium intake increases blood pressure, a risk factor for cardiovascular disease, but the effects of sodium intake on global cardiovascular mortality are uncertain. METHODS: We collected data from surveys on sodium intake as determined by urinary excretion and diet in persons from 66 countries (accounting for 74.1% of adults throughout the world), and we used these data to quantify the global consumption of sodium according to age, sex, and country. The effects of sodium on blood pressure, according to age, race, and the presence or absence of hypertension, were calculated from data in a new meta-analysis of 107 randomized interventions, and the effects of blood pressure on cardiovascular mortality, according to age, were calculated from a meta-analysis of cohorts. Cause-specific mortality was derived from the Global Burden of Disease Study 2010. Using comparative risk assessment, we estimated the cardiovascular effects of current sodium intake, as compared with a reference intake of 2.0 g of sodium per day, according to age, sex, and country. RESULTS: In 2010, the estimated mean level of global sodium consumption was 3.95 g per day, and regional mean levels ranged from 2.18 to 5.51 g per day. Globally, 1.65 million annual deaths from cardiovascular causes (95% uncertainty interval [confidence interval], 1.10 million to 2.22 million) were attributed to sodium intake above the reference level; 61.9% of these deaths occurred in men and 38.1% occurred in women. These deaths accounted for nearly 1 of every 10 deaths from cardiovascular causes (9.5%). Four of every 5 deaths (84.3%) occurred in low- and middle-income countries, and 2 of every 5 deaths (40.4%) were premature (before 70 years of age). The rate of death from cardiovascular causes associated with sodium intake above the reference level was highest in the country of Georgia and lowest in Kenya. CONCLUSIONS: In this modeling study, 1.65 million deaths from cardiovascular causes that occurred in 2010 were attributed to sodium consumption above a reference level of 2.0 g per day. (Funded by the Bill and Melinda Gates Foundation.).

BACKGROUND:: Epidemiological studies have observed protective effects of mid-upper arm circumference (MUAC) against all-cause mortality mostly in Western populations. However, evidence on cause-specific mortality is limited. METHODS:: The sample included 19 575 adults from a population-based cohort study in rural Bangladesh, who were followed up for an average of 7.9 years for mortality. Cox proportional hazards regression was used to evaluate the effect of MUAC, as well as the joint effect of body mass index (BMI) and MUAC, on the risk of death from any cause, cancer and cardiovascular disease (CVD). RESULTS:: During 154 664 person-years of follow-up, 744 deaths including 312 deaths due to CVD and 125 deaths due to cancer were observed. There was a linear inverse relationship of MUAC with total and CVD mortality. Each 1-cm increase in MUAC was associated a reduced risk of death from any cause [hazard ratio (HR) = 0.85; 95% confidence interval (C), 0.81-0.89) and CVD (HR = 0.87; 95% CI, 0.80-0.94), after controlling for potential confounders. No apparent relationship between MUAC and the risk of death from cancer was observed. Among individuals with a low BMI (<18.5 kg/m2), a MUAC less than 24 cm was associated with increased risk for all-cause (HR = 1.81; 95% CI, 1.52-2.17) and CVD mortality (HR = 1.45; 95% CI, 1.11-1.91). CONCLUSIONS:: MUAC may play a critical role on all-cause and CVD mortality in lean Asians.

BACKGROUND: Areca nut, more commonly known as betel nut, is the fourth most commonly used addictive substance in the world. Though recent evidence suggests it may play a role in the development of cardiovascular disease, no studies have investigated whether betel nut use is related to subclinical atherosclerosis. METHODS: We evaluated the association between betel nut use and subclinical atherosclerosis in 1206 participants randomly sampled from the Health Effects of Arsenic Longitudinal Study (HEALS). Frequency and duration of betel nut use were assessed at baseline, and carotid IMT was measured on average 6.65 years after baseline. RESULTS: A positive association was observed between duration and cumulative exposure (function of duration and frequency) of betel nut use and IMT, with above-median use for duration (7 or more years) and cumulative exposure (30 or more quid-years) corresponding to a 19.1 mum [95% confidence interval (CI): 5.3-32.8; P