Faculty Bibliography

BACKGROUND:Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts. METHODS:In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis. FINDINGS/RESULTS:During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence. CONCLUSIONS:Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.

Associations between anthropometric factors and breast cancer (BC) risk have varied inconsistently by estrogen and/or progesterone receptor (ER/PR) status. Associations between prediagnostic anthropometric factors and risk of premenopausal and postmenopausal BC overall and ER/PR status subtypes were investigated in a pooled analysis of 20 prospective cohorts, including 36,297 BC cases among 1,061,915 women, using multivariable Cox regression analyses, controlling for reproductive factors, diet and other risk factors. We estimated dose-response relationships and tested for nonlinear associations using restricted cubic splines. Height showed positive, linear associations for premenopausal and postmenopausal BC risk (6-7% RR increase per 5 cm increment), with stronger associations for receptor-positive subtypes. Body mass index (BMI) at cohort baseline was strongly inversely associated with premenopausal BC risk, and strongly positively-and nonlinearly-associated with postmenopausal BC (especially among women who never used hormone replacement therapy). This was primarily observed for receptor-positive subtypes. Early adult BMI (at 18-20 years) showed inverse, linear associations for premenopausal and postmenopausal BC risk (21% and 11% RR decrease per 5 kg/m², respectively) with stronger associations for receptor-negative subtypes. Adult weight gain since 18-20 years was positively associated with postmenopausal BC risk, stronger for receptor-positive subtypes, and among women who were leaner in early adulthood. Women heavier in early adulthood generally had reduced premenopausal BC risk, independent of later weight gain. Positive associations between height, baseline (adult) BMI, adult weight gain and postmenopausal BC risk were substantially stronger for hormone receptor-positive versus negative subtypes. Premenopausal BC risk was positively associated with height, but inversely with baseline BMI and weight gain (mostly in receptor-positive subtypes). Inverse associations with early adult BMI seemed stronger in receptor-negative subtypes of premenopausal and postmenopausal BC.

BACKGROUND:Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer. METHODS:Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression. RESULTS:Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24). CONCLUSIONS:In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw. IMPACT/CONCLUSIONS:Our finding suggests that p53 seropositivity may not be a useful predictor of long-term colorectal cancer risk; however, it might be considered as a marker to aid in the early diagnosis of colorectal cancer.

This study aimed to evaluate self-reported exposure to the Ringwood Mines/Landfill Superfund Site in relation to chronic health outcomes among members of the Ramapough Lunaape Turtle Clan nation and other local residents of Ringwood, New Jersey. Community surveys on personal exposure to the nearby Superfund site, self-reported health conditions, and demographics were conducted with 187 members of the Ramapough Lunaape Turtle Clan Nation and non-Native Americans residing in Ringwood, New Jersey from December 2015 to October 2016. Multiple logistic regression was performed to assess the association between ethnicity and a Superfund site exposure score developed for this study, as well as between exposure score and several chronic health conditions. Native Americans were 13.84 times (OR 13.84; 95% CI 4.32, 44.37) more likely to face exposure opportunities to Superfund sites as compared to non-Native Americans in the same New Jersey borough. For the entire surveyed cohort, increased Superfund site exposure routes was significantly associated with bronchitis (OR 4.10; 95% CI 1.18, 14.23). When the analyses were restricted to Native Americans, the association between self-reported Superfund site exposure and bronchitis remained significant (OR 17.42; 95% CI 1.99, 152.45). Moreover, the association between greater exposure score and asthma in this same population also reached statistical significance (OR 6.16; 95% CI 1.38, 27.49). This pilot study demonstrated a significant association between being a Ringwood resident of Native American ethnicity and self-declared opportunities for Superfund site exposure. It also showed a strong association between self-reported Superfund site exposure and the prevalence of bronchitis and asthma.

Elevated blood pressure in childhood is an important risk factor for hypertension in adulthood. Environmental exposures have been associated with elevated blood pressure over the life course and exposure to mercury (Hg) has been linked to cardiovascular effects in adults. As subclinical vascular changes begin early in life, Hg may play a role in altered blood pressure in children. However, the evidence linking early life Hg exposure to altered blood pressure in childhood has been largely inconsistent. In the ongoing New Hampshire Birth Cohort Study, we investigated prenatal and childhood Hg exposure at multiple time points and associations with blood pressure measurements in 395 young children (mean age 5.5 years, SD 0.4). Hg exposure was measured in children's toenail clippings at age 3 and in urine at age 5-6 years, as well as in maternal toenail samples collected at ∼28 weeks gestation and 6 weeks postpartum, the latter two samples reflecting early prenatal and mid-gestation exposures, respectively. Five measurements of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean arterial pressure (MAP) were averaged for each child using a standardized technique. In covariate-adjusted linear regression analyses, we observed that a 0.1 μg/g increase in child toenail Hg at age 3 or a 0.1 μg/L urine Hg at age 5-6 were individually associated with greater DBP (toenail β: 0.53 mmHg; 95% CI: -0.02, 1.07; urine β: 0.48 mmHg; 95% CI: 0.10, 0.86) and MAP (toenail β: 0.67 mmHg; 95% CI: 0.002, 1.33; urine β: 0.55 mmHg; 95% CI: 0.10, 1.01). Neither early prenatal nor mid-gestation Hg exposure, as measured by maternal toenails, were related to any changes to child BP. Simultaneous inclusion of both child urine Hg and child toenail Hg in models suggested a potentially stronger relationship of urine Hg at age 5-6 with DBP and MAP, as compared to toenail Hg at age 3. Our findings suggest that Hg exposure during childhood is associated with alterations in BP. Childhood may be an important window of opportunity to reduce the impacts of Hg exposure on children's blood pressure, and in turn, long-term health.

BACKGROUND:Excess body weight is an established cause of postmenopausal breast cancer, but it is unknown if weight loss reduces risk. METHODS:Associations between weight change and risk of breast cancer were examined among women aged ≥50 years in the Pooling Project of Prospective Studies of Diet and Cancer. In 10 cohorts, weight assessed on three surveys was used to examine weight change patterns over approximately 10 years (Interval 1 median= 5.2 years; Interval 2 median = 4.0 years). Sustained weight loss was defined as ≥ 2kg lost in Interval 1 that was not regained in Interval 2. Among 180,885 women, 6,930 invasive breast cancers were identified during follow-up. RESULTS:Compared with women with stable weight (± 2kg), women with sustained weight loss had a lower risk of breast cancer. This risk reduction was linear and specific to women not using postmenopausal hormones (>2-4.5kg lost: Hazard Ratio (HR)= 0.82, 95% confidence interval (CI): 0.70-0.96; >4.5-<9kg lost: HR = 0.75, 95% CI: 0.63-0.90; ≥9kg lost: HR = 0.68, 95% CI: 0.50-0.93). Women who lost ≥9kg and gained some (but not all) of it back were also at a lower risk of breast cancer. Other patterns of weight loss and gain over the two intervals had a similar risk of breast cancer to women with stable weight. CONCLUSIONS:These results suggest that sustained weight loss, even modest amounts, is associated with lower breast cancer risk for women aged ≥50 years. Breast cancer prevention may be a strong weight loss motivator for the two-thirds of American women who are overweight or obese.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors, and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g. HR per 5kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors. This article is protected by copyright. All rights reserved.

BACKGROUND:In almost all countries, incidence rates of liver cancer are 100-200% higher in males than in females. However, this difference is predominantly driven by hepatocellular carcinoma (HCC), which accounts for 75% of liver cancer cases. Intrahepatic cholangiocarcinoma (ICC) accounts for 12% of cases and has rates only 30% higher in males. Hormones are hypothesized to underlie observed sex differences. We investigated whether prediagnostic circulating hormone and sex hormone binding globulin (SHBG) levels were associated with liver cancer risk, overall and by histology, by leveraging resources from five prospective cohorts. METHODS:hormone value (approximate doubling of circulating concentration) and liver cancer were calculated using multivariable-adjusted conditional logistic regression. RESULTS:A doubling in the concentration of 4-androstenedione was associated with a 50% decreased liver cancer risk (OR=0.50,95%CI=0.30-0.82), while SHBG was associated with a 31% increased risk (OR=1.31,95%CI=1.05-1.63). Examining histology, a doubling of estradiol was associated with a 40% increased risk of ICC (OR=1.40,95%CI=1.05-1.89), but not HCC (OR=1.12,95%CI=0.81-1.54). CONCLUSIONS:This study provides the first evidence that higher levels of 4-androstenedione may be associated with lower, and SHBG with higher, liver cancer risk in women. However, this study does not support the hypothesis that higher estrogen levels decrease liver cancer risk. Indeed, estradiol may be associated with an increased ICC risk.

INTRODUCTION/BACKGROUND:Epidemiological studies that investigate alterations in the gut microbial composition associated with smoking are lacking. This study examined the composition of the gut microbiome in smokers compared with non-smokers. METHODS:Stool samples were collected in a cross-sectional study of 249 participants selected from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Microbial DNA was extracted from the fecal samples and sequenced by 16S rRNA gene sequencing. The associations of smoking status and intensity of smoking with the relative abundance or the absence and presence of individual bacterial taxon from phylum to genus levels were examined. RESULTS:The relative abundance of bacterial taxa along the Erysipelotrichi-to-Catenibacterium lineage was significantly higher in current smokers compared to never smokers. The odds ratio comparing the mean relative abundance in current smokers with that in never smokers was 1.91 (95% confidence interval [CI] = 1.36 to 2.69) for the genus Catenibacterium and 1.89 (95% CI = 1.39 to 2.56) for the family Erysipelotrichaceae, the order Erysipelotrichale, and the class Erysipelotrichi ((FDR-adjusted p-values = 0.0008 to 0.01). A dose-response association was observed for each of these bacterial taxa. The presence of Alphaproteobacteria was significantly greater comparing current with never smokers (OR = 4.85, FDR-adjusted p-values = 0.04). CONCLUSIONS:Our data in a Bangladeshi population are consistent with evidence of an association between smoking status and dosage with change in the gut bacterial composition. IMPLICATIONS/CONCLUSIONS:This study for the first time examined the relationship between smoking and the gut microbiome composition. The data suggest that smoking status may play an important role in the composition of the gut microbiome, especially among individuals with higher levels of tobacco exposure.