Wonsuk Yoo

Effect of Long-Term Exposure to Lower Low-Density Lipoprotein Cholesterol Beginning Early in Life on the Risk of Coronary Heart Disease: A Mendelian Randomization Analysis

OBJECTIVES The purpose of this study was to estimate the effect of long-term exposure to lower plasma low-density lipoprotein cholesterol (LDL-C) on the risk of coronary heart disease (CHD). BACKGROUND LDL-C is causally related to the risk of CHD. However, the association between long-term exposure to lower LDL-C beginning early in life and the risk of CHD has not been reliably quantified. METHODS We conducted a series of meta-analyses to estimate the effect of long-term exposure to lower LDL-C on the risk of CHD mediated by 9 polymorphisms in 6 different genes. We then combined these Mendelian randomization studies in a meta-analysis to obtain a more precise estimate of the effect of long-term exposure to lower LDL-C and compared it with the clinical benefit associated with the same magnitude of LDL-C reduction during treatment with a statin. RESULTS All 9 polymorphisms were associated with a highly consistent reduction in the risk of CHD per unit lower LDL-C, with no evidence of heterogeneity of effect (I(2) = 0.0%). In a meta-analysis combining nonoverlapping data from 312,321 participants, naturally random allocation to long-term exposure to lower LDL-C was associated with a 54.5% (95% confidence interval: 48.8% to 59.5%) reduction in the risk of CHD for each mmol/l (38.7 mg/dl) lower LDL-C. This represents a 3-fold greater reduction in the risk of CHD per unit lower LDL-C than that observed during treatment with a statin started later in life (p = 8.43 × 10(-19)). CONCLUSIONS Prolonged exposure to lower LDL-C beginning early in life is associated with a substantially greater reduction in the risk of CHD than the current practice of lowering LDL-C beginning later in life.

Profound Cardioprotection With Chloramphenicol Succinate in the Swine Model of Myocardial Ischemia-Reperfusion Injury

Background— Emerging evidence suggests that “adaptive” induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction. Methods and Results— Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with “delayed” treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins. Conclusion— Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.

Tobacco and estrogen metabolic polymorphisms and risk of non-small cell lung cancer in women

To explore the potential role for estrogen in lung cancer susceptibility, candidate single-nucleotide polymorphism (SNPs) in tobacco and estrogen metabolism genes were evaluated. Population-based cases (n = 504) included women aged 18-74, diagnosed with NSCLC in metropolitan Detroit between November 2001 and October 2005. Population-based controls (n = 527) were identified through random digit dialing and matched on race and age. Eleven SNPs in 10 different genes were examined in relation to risk: CYP1A1 Msp1, CYP1A1 Ile462Val, CYP1B1 Leu432Val, CYP17, CYP19A1, XRCC1 Gln399Arg, COMT Val158Met, NQO1 Pro187Ser, GSTM1, GSTT1 and GSTP1 Ile105Val. Lung cancer risk associated with individual SNPs was seen for GSTP1 [A allele; odds ratio (OR) = 1.85; 95% confidence interval (CI), 1.04-3.27] and XRCC1 (A/A genotype; OR = 1.68; 95% CI, 1.01-2.79) in white women and CYP1B1 (G allele; OR = 11.1; 95% CI, 1.18-104) in black women smokers. White women smokers carrying two risk genotypes at the following loci were at increased risk of lung cancer compared with individuals not carrying risk alleles at these loci: CYP17 and GSTM1, COMT and GSTM1, CYP17 and GSTT1, XRCC1 and GSTP1, CYP1B1 and XRCC1 and COMT and XRCC1. The most parsimonious model of lung cancer risk in white smoking women included age, family history of lung cancer, history of chronic lung disease, pack-years, body mass index, XRCC1 A/A genotype, GSTM1 null and COMT A/G or G/G genotype. These findings support the need for continued study of estrogen in relation to lung cancer risk. Polymorphisms in the tobacco metabolism, estrogen metabolism and DNA repair pathways will be useful in developing more predictive models of individual risk.

Relationship of vitamin D and parathyroid hormone with obesity and body composition in African Americans

Background  Obesity disproportionately affects African Americans (AA) (especially women), and is linked to depressed 25‐hydroxyvitamin D (25‐OH D) and elevated parathyroid hormone (PTH). The relationship of 25‐OH D and PTH with body composition and size in AA is not well known.

A Common KIF6 Polymorphism Increases Vulnerability to Low-Density Lipoprotein Cholesterol: Two Meta-Analyses and a Meta-Regression Analysis

Background We sought to determine if a common polymorphism can influence vulnerability to LDL cholesterol, and thereby influence the clinical benefit derived from therapies that reduce LDL cholesterol. Methods We conducted a meta-analysis of the association between a common Trp719Arg polymorphism in the kinesin-like protein 6 (KIF6) gene and the risk of cardiovascular disease (CVD), and a meta-regression analysis to measure the effect modification of this polymorphism on the association between LDL cholesterol and the risk of CVD. We used this measure of genetic effect modification to predict the expected difference in clinical benefit among KIF6 719Arg allele carriers and non-carriers in response to therapies that reduce LDL cholesterol. We then conducted a meta-analysis of statin trials to compare the expected difference in clinical benefit with the observed difference during treatment with a statin. Results In a meta-analysis involving 144,931 participants, the KIF6 719Arg allele was not associated with the relative risk (RR) of CVD (RR: 1.02, 95%CI: 0.98–1.07, p = 0.288). Meta-regression analysis involving 88,535 participants, however, showed that the 719Arg allele appears to influence the effect of LDL cholesterol on the risk of CVD. KIF6 carriers experienced a 13% greater reduction in the risk of CVD per mmol/L decrease in LDL cholesterol than non-carriers. We interpreted this difference as the expected difference in clinical benefit among KIF6 carriers and non-carriers in response to therapies that lower LDL cholesterol. The difference in clinical benefit predicted by the increased vulnerability to LDL cholesterol among KIF6 carriers (ratio of RR: 0.87, 95%CI: 0.80–0.94, p = 0.001) agreed very closely with the observed difference among 50,060 KIF6 carriers and non-carriers enrolled in 8 randomized trials of statin therapy (ratio of RR: 0.87, 95%CI: 0.77–0.99, p = 0.038). Conclusion The KIF6 719Arg allele increases vulnerability to LDL cholesterol and thereby influences the expected clinical benefit of therapies that reduce LDL cholesterol.

Patient web portals, disease management, and primary prevention

Background Efforts aimed at health care reform and continued advances in information technologies have prompted interest among providers and researchers in patient web portals. Patient web portals are password-protected online websites that offer the patients 24-hour access to personal health information from anywhere with an Internet connection. Methods This article, which is based upon bibliographic searches in PubMed, reviews important developments in web portals for primary and secondary disease prevention, including patient web portals tethered to electronic medical records, disease-specific portals, health disparities, and health-related community web portals. Results Although findings have not been uniformly positive, several studies of the effectiveness of health care system patient portals in chronic disease management have shown promising results with regard to patient outcomes. Patient web portals have also shown promising results in increasing adherence with screening recommendations. Racial and ethnic minorities, younger persons, and patients who are less educated or have lower health literacy have been found to be less likely to use patient portals. Conclusion Additional studies are needed of the utility and effectiveness of different elements of web portals for different patient populations. This should include additional diseases and health topics such as smoking cessation and weight management.

Recent trends in racial and regional disparities in cervical cancer incidence and mortality in United States.

Background Although black women experienced greater cervical cancer incidence and mortality rate reduction in recent years, they continue to have higher incidence rates than whites. Great variations also exist among geographic regions of the US, with the South having both the highest incidence and mortality rates compared to other regions. The present study explores the question of whether living in the South is associated with greater racial disparity in cervical cancer incidence and mortality by examining race- and region-specific rates and the trend between 2000 and 2012. Methods The Surveillance, Epidemiology, and End Results (SEER) 18 Program data was used. Cervical cancer incidence and mortality rates, annual percent changes, and disparity ratios were calculated using SEER*Stat software and Joinpoint regression for four groups: US14-Non-Hispanic White (NHW), US14-Non-Hispanic Black (NHB), South-NHW, and South-NHB, where South included 4 registries from Georgia and Louisiana and US14 were 14 US registries except the four South registries. Results The average age-adjusted cervical cancer incidence rate was the highest among South-NHBs (11.1) and mortality rate was the highest among US14-NHBs (5.4). In 2012, the degree of racial disparities between South-NHBs and South-NHWs was greater in terms of mortality rates (NHB:NHW = 1.80:1.35) than incidence rates (NHB:NHW = 1.45:1.15). While mortality disparity ratios decreased from 2000–2012 for US14-NHB (APC: -1.9(-2.3,-1.4), mortality disparity ratios for South-NHWs (although lower than NHBs) increased compared to US14-NHW. Incidence rates for NHBs continued to increase with increasing age, whereas rates for NHWs decreased after age 40. Mortality rates for NHBs dramatically increased at age 65 compared to a relatively stable trend for NHWs. The increasing racial disparity with increasing age in terms of cervical cancer incidence rates became more pronounced when corrected for hysterectomy prevalence. Conclusions Black race and South region were associated with higher cervical cancer incidence and mortality. Cervical cancer rates uncorrected for hysterectomy may underestimate regional and racial disparities. Increasing incidence rates for older NHBs compared to NHWs warrant further research to determine whether screening should continue for NHBs over age 65.

Beliefs and Behaviors about Breast Cancer Recurrence Risk Reduction among African American Breast Cancer Survivors

A growing body of evidence suggests that breast cancer recurrence risk is linked to lifestyle behaviors. This study examined correlations between breast cancer recurrence, risk reduction beliefs, and related behaviors among African American breast cancer survivors (AA BCSs). Study participants included 191 AA BCSs, mean age = 56.3 years, who completed a lifestyle assessment tool. Most respondents believed that being overweight (52.7%), lack of physical activity (48.7%), and a high fat diet (63.2%) are associated with breast cancer recurrence. Over 65% considered themselves overweight; one third (33.5%) agreed that losing weight could prevent recurrence, 33.0% disagreed, while the remaining 33.5% did not know; and nearly half (47.9%) believed that recurrence could be prevented by increasing physical activity. Almost 90% survivors with BMI < 25 Kg/M2 reported no recurrence compared to 75.7% with BMI ≥ 25 Kg/M2 (p = 0.06); nearly all of the women (99.2%) answered “yes” to seeking professional help to lose weight, 79.7% of which were recurrence-free (p = 0.05). These results provide information about AA BCSs’ beliefs and behaviors protective against breast cancer recurrence. Additional research is warranted to determine the effectiveness of educational interventions for AA BCSs that promote consumption of a healthy diet and engaging in regular physical activity.

Systemic levels of estrogens and PGE2 synthesis in relation to postmenopausal breast cancer risk

Background: Prostaglandin E2 (PGE2) induces aromatase expression in adipose tissue, leading to increased estrogen production that may promote the development and progression of breast cancer. However, few studies have simultaneously investigated systemic levels of PGE2 and estrogen in relation to postmenopausal breast cancer risk. Methods: Here, we determined urinary estrogen metabolites (EM) using mass spectrometry in a case–cohort study (295 incident breast cancer cases and 294 subcohort members), and using linear regression estimated the effect of urinary levels of a major PGE2 metabolite (PGE-M) on EMs. HRs for the risk of developing breast cancer in relation to PGE-M and EMs were compared between Cox regression models with and without mutual adjustment. Results: PGE-M was a significant predictor of estrone (E1), but not estradiol (E2) levels in multivariable analysis. Elevated E2 levels were associated with an increased risk of developing breast cancer [HRQ5vs.Q1, 1.54; 95% confidence interval (CI), 1.01–2.35], and this association remained unchanged after adjustment for PGE-M (HRQ5vs.Q1, 1.52; 95% CI, 0.99–2.33). Similarly, elevated levels of PGE-M were associated with increased risk of developing breast cancer (HRQ4vs.Q1, 2.01; 95% CI, 1.01–4.29), and this association was only nominally changed after consideration of E1 or E2 levels. Conclusions: Urinary levels of PGE-M and estrogens were independently associated with future risk of developing breast cancer among these postmenopausal women. Impact: Increased breast cancer risk associated with PGE-M might not be fully explained by the estrogens–breast cancer association alone but also by additional effects related to inflammation. Cancer Epidemiol Biomarkers Prev; 26(3); 383–8. ©2016 AACR.

A Community-Engaged Approach to Developing a Mobile Cancer Prevention App: The mCPA Study Protocol

Background Rapid growth of mobile technologies has resulted in a proliferation of lifestyle-oriented mobile phone apps. However, most do not have a theoretical framework and few have been developed using a community-based participatory research approach. A community academic team will develop a theory-based, culturally tailored, mobile-enabled, Web-based app—the Mobile Cancer Prevention App (mCPA)—to promote adherence to dietary and physical activity guidelines. Objective The aim of this study is to develop mCPA content with input from breast cancer survivors. Methods Members of SISTAAH (Survivors Involving Supporters to Take Action in Advancing Health) Talk (N=12), treated for Stages I-IIIc breast cancer for less than 1 year, 75 years of age or younger, and English-speaking and writing, will be recruited to participate in the study. To develop the app content, breast cancer survivors will engage with researchers in videotaped and audiotaped sessions, including (1) didactic instructions with goals for, benefits of, and strategies to enhance dietary intake and physical activity, (2) guided discussions for setting individualized goals, monitoring progress, and providing or receiving feedback, (3) experiential nutrition education through cooking demonstrations, and (4) interactive physical activity focused on walking, yoga, and strength training. Qualitative (focus group discussions and key informant interviews) and quantitative (sensory evaluation) methods will be used to evaluate the participatory process and outcomes. Results Investigators and participants anticipate development of an acceptable (frequency and duration of usage) feasible (structure, ease of use, features), and accessible mobile app available for intervention testing in early 2017. Conclusions Depending on the availability of research funding, mCPA testing, which will be initiated in Miami, will be extended to Chicago, Houston, Philadelphia, and Los Angeles.