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End stage renal disease (ESRD) is associated with substantial morbidity and mortality. Strategies to prevent the renal function decline that can ultimately result in ESRD are essential. The impact of environmental exposures has received relatively little attention in this regard, despite the fact that exposures such as cadmium and lead are known renal toxicants that are stored long-term in the body and ubiquitous in humans. Therefore, this study is investigating a broad set of causes of renal function decline, including lead, cadmium, and genetic polymorphisms while controlling for other known renal risk factors such as blood pressure, diabetes, nephrotoxic medication use, and age. We are continuing to study a large cohort of current and former lead workers and participants without occupational lead exposure from an earlier grant. Study subjects have a wide range of lead exposure and dose measures and renal outcome data from three visits each over an average of 2.2 years.
Analysis of existing data to date has revealed evidence of longitudinal decline in renal function associated with lead dose measures; interaction between age and lead dose on renal function and renal function decline; interaction between ALAD and VDR genotypes and lead dose on renal function; and associations of environmental level cadmium dose with elevated NAG in a subset of lead workers.
The current study will include 675 participants from the original cohort and enroll 225 new current or former lead workers over age 45 years, those at greater risk for renal function decline. We will characterize cumulative cadmium dose in all participants, measure additional genotypes (ACE and VDR FokI), and extend the follow-up period. We will also obtain blood and tibia lead, BUN, serum creatinine, measured and calculated creatinine clearances, NAG and RBP during 3 evaluations at yearly intervals. The specific aims are to determine: 1) if lead and cadmium dose are or continue to be associated with renal function at cross-section and longitudinally; 2) if there is effect modification by lead or cadmium dose, respectively, on associations between cadmium or lead dose and renal function decline; 3) if hypertension modifies the relations of lead or cadmium dose with renal function decline; and 4) whether polymorphisms in the genes for ALAD, VDR, ACE, and eNOS modify or continue to modify relations of lead and/or cadmium dose with renal outcomes.
Researchers
Bernard G. Jaar
Byung-Kook Lee
Brian Schwartz
Virginia Weaver
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The Overarching goal of the "Minority Global Health Disparities Research Training Program" is to provide international health disparity research opportunities for undergraduate and graduate/medical students who are from health disparities populations. The program is also directed at increasing the students'' ability to function effectively in a global environment as well as gain insights into different cultures and ethical aspects of research. Inherent in this objective is for the trainees to realize the universality of requirements for critical thinking and quantitative thought in the global human health research arena, as well as the cultural and ethical aspects of conducting research abroad. The ultimate goal of this program is to meet the nation''''s need for increasing the number of highly motivated minority researchers who pursue biomedical, biobehavioral, and clinical research careers. In essence, our plan has four components: 1) planning, assessment and student selection; 2) student preparation for foreign research experience; 3) research experience in a foreign country; and 4) evaluation. Even though the research at foreign sites will be at different institutions, the research and other components are united by their focus on health disparities of underserved populations. A consortium of U.S., (Johns Hopkins University, Winston-Salem State University, North Carolina A&T State University, and The Leadership Alliance at Brown University) and foreign faculty (Goteborgs University, Gothenburg Sweden; University of New Castle, Australia; University of KwaZulu Natal, Durban, South Africa; Medical Research Council, Cape Town, South Africa; and Kung Hee University, Seoul, South Korea) will further develop, implement and evaluate the program. The program will accommodate 27 undergraduate and 5 graduate/medical students over a four year period. Our capabilities to contribute to the pool of highly motivated and competitive baccalaureates from health disparities populations who enter graduate/doctoral degree programs in the biomedical, biobehavioral and clinical sciences will be greatly enhanced. Such participation will have both short-term and long-term positive effects. The program plans include evaluation and strategic recruitment with special emphasis on underrepresented minorities, as well as training in the ethical conduct of research, scientific integrity and cultural competence.
Researchers
Fannie Gaston-Johansson
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Large-scale cohort study of active and passive smoking and risk for cancer and other diseases among the Korean population. The cohort consists of over one million adult Koreans who had a physical examination as part of their care by the national health insurance program. Recent analyses have addressed diabetes, blood sugar, and cancer risk; white blood cells and risk for cancer and cardiovascular disease; and body mass index and mortality and morbidity. Publications have addressed active smoking and cancer risk, risk factors for liver cancer, and diabetes, blood sugar and cancer risk.
2001-ongoing
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Researchers
Jonathan Samet
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Consultation regarding the use of the theoretical framework for care at the end of life and negotiation about participation in an international statement on the ethics of nursing care at the end of life. I will be presenting the Conceptual Framework for End-of-Life Care and my research on decision making at the end of life at The World Health Organization Collaborating Center for Hospice and Palliative Care at the Catholic University of Korea in Seoul. I will also be exploring the possibility of the WHO Collaborating Center involvement in an international statement on the ethics of nursing care at the end of life. I will also be providing consultation on doctoral education.
Researchers
Marie T. Nolan
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Current status of metabolic syndrome and future challenges in Korea.
Researchers
Sun Ha Jee
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Oral clefts, which include cleft lip (CL), cleft lip and palate (CLP) and cleft palate (CP), and collectively represent one of the most common birth defects in humans. Oral clefts have a complex and heterogeneous etiology, with strong evidence for both genetic and environmental causal factors. Candidate gene studies and genome wide linkage studies have yielded compelling but inconsistent evidence that multiple genes control risk to oral clefts, and several studies have shown evidence for interaction between genes and environmental exposures, especially maternal smoking and nutrients. We have assembled a consortium of experienced investigators who have accumulated a very large collection of DNA samples on cases and their families (mostly case-parent trios) that are now available for genome wide studies, which represents the next level of genetic investigation for oral clefts. Specific aims are: 1. To conduct a genome wide analysis on 2000 case-parent trios ascertained through a case with isolated, non-syndromic oral cleft (CL, CLP or CP) and their parents using high throughput genotyping of single nucleotide polymorphic (SNP) markers to test for linkage and LD. The initial analysis will consist of individual tests for gene effects, with appropriately haplotype analysis and novel mapping approaches for larger chromosomal regions that allows for heterogeneity among populations. 2. To test for interaction between genes and common maternal exposures including vitamin supplementation, cigarette smoking and alcohol consumption (collected by interview) which have been implicated as environmental risk factors for oral clefts. Availability of serum biomarker measures of nutritional status from one component populations (Utah) allows important further tests for GxE interactions. 3. To test for interaction between genes that may explain some of the conflicting results in the literature with regard to genes controlling risk to oral clefts. This proposal offers a unique opportunity to expand and extend the search for genes controlling risk to oral clefts, creates the opportunity for quick replication across populations and will direct further molecular studies of genes controlling normal craniofacial development.
Researchers
Terri Beaty
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Prevention strategies for end stage renal disease are essential, however, environmental nephrotoxicants are seldom considered. We are investigating a broad set of causes of renal function decline, including lead and cadmium dose, blood pressure, diabetes, and age, in a longitudinal study of current and former Korean lead workers and controls. This cohort had three annual evaluations from 1997-2001 and is currently undergoing the fourth evaluation (first of three in the current competing continuation grant (NIEHS 2 R01 ES07198)). We are enrolling 610 participants from the original grant and 200 new current or former lead workers over age 40 years to enrich our population with workers at greater risk for renal function decline. Study subjects have a wide range of lead dose measures and renal outcome data. Analysis to date has identified two potential mechanisms for the adverse renal effects of lead: 1) associations between higher lead levels and worse renal function in older lead workers may be mediated by uric acid; and 2) inverse associations (higher lead dose with higher creatinine clearances) suggest hyperfiltration may be a factor in younger lead workers and those with the ALAD variant allele. Recent research indicates that the adverse impact of lead on renal function may be reduced with chelation, even at lead body burdens previously considered normal. Information on mechanisms for lead-related nephrotoxicity would be extremely useful in targeting therapy. Thus, the specific aims of this supplement are to determine if: 1) lead dose is associated with uric acid measures longitudinally in all participants; 2) uric acid, measures are associated with renal function longitudinally, and, if so, whether associations between lead dose and renal function are altered by adjustment for uric acid, and; 3) lead dose is associated with 6 hemodynamic biomarkers (urinary prostaglandin E2, prostaglandin F2 alpha, 6-keto-prostaglandin F1 alpha, thromboxane B2, and total nitrites/nitrates and plasma renin level), and whether these biomarkers are associated with adverse renal outcomes, at cross-section, in a subset of 200 participants. The proposed work will inform research on specific treatments for high-risk populations, such as those with chronic renal insufficiency who also have increased lead body burdens.
Researchers
Virginia Weaver
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