Genetic studies of a cluster of acute lymphoblastic leukemia cases in Churchill County, Nevada.

OBJECTIVE: In a study to identify exposures associated with 15 cases of childhood leukemia, we found levels of tungsten, arsenic, and dichlorodiphenyldichloroethylene in participants to be higher than mean values reported in the National Report on Human Exposure to Environmental Chemicals. Because case and comparison families had similar levels of these contaminants, we conducted genetic studies to identify gene polymorphisms that might have made case children more susceptible than comparison children to effects of the exposures. DESIGN: We compared case with comparison children to determine whether differences existed in the frequency of polymorphic genes, including genes that code for enzymes in the folate and purine pathways. We also included discovery of polymorphic forms of genes that code for enzymes that are inhibited by tungsten: xanthine dehydrogenase, sulfite oxidase (SUOXgene), and aldehyde oxidase. PARTICIPANTS: Eleven case children were age- and sex-matched with 42 community comparison children for genetic analyses. Twenty parents of case children also contributed to the analyses. RESULTS: One bilalleleic gene locus in SUOX was significantly associated with either case or comparison status, depending on which alleles the child carried (without adjusting for multiple comparisons). CONCLUSIONS: Although genetic studies did not provide evidence that a common agent or genetic susceptibility factor caused the leukemias, the association between a SUOXgene locus and disease status in the presence of high tungsten and arsenic levels warrants further investigation. RELEVANCE: Although analyses of community clusters of cancer have rarely identified causes, these findings have generated hypotheses to be tested in subsequent studies.

Investigating childhood leukemia in Churchill County, Nevada.

BACKGROUND: Sixteen children diagnosed with acute leukemia between 1997 and 2002 lived in Churchill County, Nevada, at the time of or before their illness. Considering the county population and statewide cancer rate, fewer than two cases would be expected. OBJECTIVES: In March 2001, the Centers for Disease Control and Prevention led federal, state, and local agencies in a cross-sectional, case-comparison study to determine if ongoing environmental exposures posed a health risk to residents and to compare levels of contaminants in environmental and biologic samples collected from participating families. METHODS: Surveys with more than 500 variables were administered to 205 people in 69 families. Blood, urine, and cheek cell samples were collected and analyzed for 139 chemicals, eight viral markers, and several genetic polymorphisms. Air, water, soil, and dust samples were collected from almost 80 homes to measure more than 200 chemicals. RESULTS: The scope of this cancer cluster investigation exceeded any previous study of pediatric leukemia. Nonetheless, no exposure consistent with leukemia risk was identified. Overall, tungsten and arsenic levels in urine and water samples were significantly higher than national comparison values; however, levels were similar among case and comparison groups. CONCLUSIONS: Although the cases in this cancer cluster may in fact have a common etiology, their small number and the length of time between diagnosis and our exposure assessment lessen the ability to find an association between leukemia and environmental exposures. Given the limitations of individual cancer cluster investigations, it may prove more efficient to pool laboratory and questionnaire data from similar leukemia clusters.

The ethics of access to online genetic databases: private or public?

With the sequencing of the human genome comes the promise of advances in medical science. For this promise to be fully realized, researchers must have access to information resulting from this landmark endeavor as well as from subsequent research initiatives. However, because genomic sequences are potential sources of profit for the biotechnology and pharmaceutical industries, many private companies seek to limit access to this information. Some argue that this will impede scientific progress and increase the cost of basic research, while others argue that the privatization of genetic information is needed to assure profits and generate the considerable funding necessary to bring therapeutic products to the market. In analyzing the arguments for both sides, we conclude that both private funding and public access to information are important in genetic research. Precedents for compromise are necessary, as is increased dialog between private and public interests in order to ensure continued advancements in genetic science and medicine.

Homocyst(e)ine and cardiovascular disease: a systematic review of the evidence with special emphasis on case-control studies and nested case-control studies.

BACKGROUND: Elevated concentrations of homocyst(e)ine are thought to increase the risk of vascular diseases including coronary heart disease and cerebrovascular disease. METHODS: We searched MEDLINE (1966-1999), EMBASE (1974-1999), SciSearch (1974- 1999), and Dissertation Abstracts (1999) for articles and theses about homocyst(e)ine concentration and coronary heart disease and cerebrovascular disease. RESULTS: We included 57 publications (3 cohort studies, 12 nested case-control studies, 42 case-control studies) that reported results on 5518 people with coronary heart disease (11,068 control subjects) and 1817 people with cerebrovascular disease (4787 control subjects) in our analysis. For coronary heart disease, the summary odds ratios (OR) for a 5-micromol/l increase in homocyst(e)ine concentration were 1.06 (95% CI : 0.99-1.13) for 2 publications of cohort studies, 1.23 (95% CI : 1.07-1.41) for 10 publications of nested case-control studies, and 1.70 (95% CI : 1.50-1.93) for 26 publications of case-control studies. For cerebrovascular disease, the summary OR for a 5-micromol/l increase in homocyst(e)ine concentration were 1.10 (95% CI : 0.94-1.28) for 2 publications of cohort studies, 1.58 (95% CI : 1.35-1.85) for 5 publications of nested case-control studies, and 2.16 (95% CI : 1.65-2.82) for 17 publications of case-control studies. CONCLUSIONS: Prospective studies offer weaker support than case-control studies for an association between homocyst(e)ine concentration and cardiovascular disease. Although other lines of evidence support a role for homocyst(e)ine in the pathogenesis of cardiovascular disease, more information from prospective epidemiological studies or clinical trials is needed to clarify this role.

Thrombomodulin Ala455Val Polymorphism and the risk of cerebral infarction in a biracial population: the Stroke Prevention in Young Women Study.

BACKGROUND: The genes encoding proteins in the thrombomodulin-protein C pathway are promising candidate genes for stroke susceptibility because of their importance in thrombosis regulation and inflammatory response. Several published studies have shown that the Ala455Val thrombomodulin polymorphism is associated with ischemic heart disease, but none has examined the association with stroke. Using data from the Stroke Prevention in Young Women Study, we sought to determine the association between the Ala455Val thrombomodulin polymorphism and the occurrence of ischemic stroke in young women. METHODS: All 59 hospitals in the greater Baltimore-Washington area participated in a population-based case-control study of stroke in young women. We compared 141 cases of first ischemic stroke (44% black) among women 15 to 44 years of age with 210 control subjects (35% black) who were identified by random digit dialing and frequency matched to the cases by age and geographical region of residence. Data on historical risk factors were collected by standardized interview. Genotyping of the thrombomodulin Ala455Val polymorphism was performed by pyrosequencing. RESULTS: The A allele (frequency = 0.85) was associated with stroke under the recessive model. After adjustment for age, race, cigarette smoking, hypertension, and diabetes, the AA genotype, compared with the AV and VV genotypes combined, was significantly associated with stroke (odds ratio 1.9, 95% CI 1.1-3.3). The AA genotype was more common among black than white control subjects (81% versus 68%) but there was no significant interaction between the risk genotype and race (adjusted odds ratio 2.7 for blacks and 1.6 for whites). A secondary analysis removing all probable (n = 16) and possible (n = 15) cardioembolic strokes demonstrated an increased association (odds ratio 2.2, 95% CI 1.2-4.2). CONCLUSIONS: Among women aged 15 to 44 years, the AA genotype is more prevalent among blacks than whites and is associated with increased risk of early onset ischemic stroke. Removing strokes potentially related to cardioembolic phenomena increased this association. Further studies are needed to determine whether this polymorphism is functionally related to thrombomodulin expression or whether the association is due to population stratification or linkage to a nearby functional polymorphism.

Laboratory science and public health at CDC.

Laboratory technology is as essential to public health practitioners for monitoring threats to public health as it is to clinical practitioners who depend on laboratory technology to diagnose and monitor disease in individuals. Laboratory technology provides essential information for effective public health interventions, whether monitoring emerging infectious diseases, such as avian influenza globally; identifying pathogens, such as Escherichia coli in the U.S. food supply and pinpointing its source; screening newborns for devastating disorders, such as phenylketonuria, that can be prevented by early intervention; or developing the capacity to quickly screen for exposure to chemical and biologic agents.

Introductory remarks.

The cause of osteoporosis, a condition in which bone mass is decreased to a point where structural failure may occur, is unknown; many factors that contribute to the development of osteoporosis are known.Bone mass increases until the late twenties, the time when people attain peak bone mass. For a time after peak bone mass is reached, bone loss and formation are approximately equal. Soon after that, probably in the early thirties, an uncoupling of bone synthesis and bone resorption occurs, and a net loss of bone mass begins, a process that can ultimately result in osteoporosis.Bone loss occurs most rapidly in white females immediately after menopause. The bone most affected is the spongy, trabecular bone of the vertebrae and pelvis and the ends of long bones.Osteoporosis is classified into two syndromes, which are not distinct but have overlapping features and may have the same pathogenetic mechanism. Type I, or postmenopausal osteoporosis, is associated with estrogen deficiency and is characterized by loss of trabecular bone in the vertebrae and the distal radius (the wrist). Vertebral fractures and wrist fractures (also called Colles' fractures) result. Type II, or senile osteoporosis, is age-related, occurs in men as well as women, and is characterized by fractures of the hip and humerus. There is a loss of cortical as well as trabecular bone.Estrogen deficiency, increasing age, smoking, high alcohol intake, large amounts of caffeine and protein, and lean body mass favor decreased bone density, whereas estrogen replacement after menopause, adequate dietary calcium, and moderate amounts of weight-bearing exercise tend to favor increased bone density.Standard X-rays, computed tomography, single and dual photon absorptiometry, and neutron activation analysis are noninvasive techniques used in evaluating osteoporosis.Calcium, estrogen, and calcitonin are approved drug therapies for osteoporosis.

HFE genotype and transferrin saturation in the United States.

PURPOSE: Examine the penetrance (defined by high transferrin saturation [TS]) of C282Y and H63D in the U.S. population. METHODS: 5171 participants from the Third National Health and Nutrition Examination Survey, 1992 to 1994. RESULTS: 77.1% (95% confidence interval [CI], 2.3, 95.1) of men and 51.9% (95% CI, 0, 84.2) of women with C282Y homozygosity had high TS. The associations of H63D homozygosity with high TS were stronger in people aged 50 years or older than in younger persons. Among Mexican-Americans, simple H63D heterozygosity was associated with high TS. CONCLUSIONS: The associations between HFE genotype and high TS may vary by sex, age, and ethnic group.