Heavy metals, organic solvents, and multiple sclerosis: An exploratory look at gene-environment interactions.

Exposure to heavy metals and organic solvents are potential etiologic factors for multiple sclerosis (MS), but their interaction with MS-associated genes is under-studied. The authors explored the relationship between environmental exposure to lead, mercury, and solvents and 58 single-nucleotide polymorphisms (SNPs) in MS-associated genes. Data from a population-based case-control study of 217 prevalent MS cases and 496 age-, race-, gender-, and geographically matched controls were used to fit conditional logistic regression models of the association between the chemical, gene, and MS, adjusting for education and ancestry. MS cases were more likely than controls to report lead (odds ratio [OR] = 2.03; 95% confidence interval [CI]: 1.07, 3.86) and mercury exposure (OR = 2.06; 95% CI: 1.08, 3.91). Findings of potential gene-environment interactions between SNPs in TNF-α, TNF-ß, TCA-ß, VDR, MBP, and APOE, and lead, mercury, or solvents should be considered cautiously due to limited sample size.

Interaction of HLA-DRB1*1501 and TNF-Alpha in a Population-based Case-control Study of Multiple Sclerosis.

This study was conducted to determine whether single nucleotide polymorphisms (SNPs) in nine genes (human leukocyte antigen (HLA), T cell receptor beta (TCA receptor ß), tumor necrosis factor α (TNF α), tumor necrosis factor ß (TNF ß), apolipoprotein E (APOE), interleukin 7 receptor alpha chain (IL7RA) interleukin 2 receptor alpha chain (IL2RA) myelin basic protein (MBP) and vitamin D receptor (VDR)) associated with multiple sclerosis (MS) could be replicated in a population-based sample, and to determine if these associations are modified by presence of HLA DRB1*1501. DNA was available from 722 individuals (223 with MS and 499 controls) who participated in a population-based case-control study. Cases and controls were matched on ancestry, age, gender and geographic area. HLA DRB1*1501 risk allele (T) was confirmed in this population using a genotypic test, controlling for multiple comparisons. Examining the effect of each SNP in the presence or absence of the HLA DRB1*1501 risk allele identified significant associations with TNF α -1031 (rs1799964) among those without the HLA risk allele. No additional interactions were significant in a cases-only analysis. Our results indicate that an interaction between SNPs in TNF α and HLA DRB1*1501 may influence the risk of developing MS.

Improving a Case-Control Study of Multiple Sclerosis Using Formative Research.

Formative research (i.e. focus groups and key informant interviews) was conducted to understand risk perceptions and identify barriers to participation in a case-control study of environmental exposures and genetic susceptibility as risk factors for multiple sclerosis (MS). Individuals with MS were recruited to participate in a focus group discussion and individual interviews. Participants were asked to review and comment on study materials and process including participation, interview, genetic testing, confidentiality, and questionnaire. A structured discussion guide was used with all participants to ensure uniformity and coverage of all predetermined topics. Participants reported an increased likelihood of participation if they were informed about the study by their neurologist and not a government agency. All participants expressed willingness to provide a blood sample for genotyping but disagreed about the setting for the blood draw (at home or in a lab). Participants were concerned that they would not receive their individual genotyping results. The study protocol and materials were revised based on comments from the focus group participants. Formative research is an under-utilized resource for researchers conducting epidemiologic studies. Even with limited resources, piloting study materials with individuals similar to the proposed study population can provide opportunities to make modifications to effectively meet the needs of participants and promote participation and retention.

Prevalence of amyotrophic lateral sclerosis in Texas, 1998-2003.

A prevalence study of amyotrophic lateral sclerosis (ALS) was conducted in 3 areas in Texas to enable the state health department to better respond to community concerns regarding the occurrence of ALS and to contribute to national prevalence estimates. The overall ALS point prevalence was lower than previously published US estimates. This study provides ALS prevalence estimates for Texas, including Hispanic populations.

California Very Preterm Birth Study: design and characteristics of the population- and biospecimen bank-based nested case-control study.

Very preterm birth (VPTB) is a leading cause of infant mortality, morbidity and racial disparity in the US. The underlying causes of VPTB are multiple and poorly understood. The California Very Preterm Birth Study was conducted to discover maternal and infant genetic and environmental factors associated with VPTB. This paper describes the study design, population, data and specimen collection, laboratory methods and characteristics of the study population. Using a large, population-based cohort created through record linkage of livebirths delivered from 2000 to 2007 in five counties of southern California, and existing data and banked specimens from statewide prenatal and newborn screening, 1100 VPTB cases and 796 control mother-infant pairs were selected for study (385/200 White, 385/253 Hispanic and 330/343 Black cases/controls, respectively). Medical record abstraction of cases was conducted at over 50 hospitals to identify spontaneous VPTB, improve accuracy of gestational age, obtain relevant clinical data and exclude cases that did not meet eligibility criteria. VPTB was defined as birth at <32 weeks in Whites and Hispanics and <34 weeks in Blacks. Approximately 55% of all VPTBs were spontaneous and 45% had medical indications or other exclusions. Of the spontaneous VPTBs, approximately 41% were reported to have chorioamnionitis. While the current focus of the California Very Preterm Birth Study is to assess the role of candidate genetic markers on spontaneous VPTB, its design enables the pursuit of other research opportunities to identify social, clinical and biological determinants of different types of VPTB with the ultimate aim of reducing infant mortality, morbidity and racial disparities in these health outcomes in the US and elsewhere.

The prevalence of multiple sclerosis in 3 US communities.

INTRODUCTION: We estimated the prevalence of multiple sclerosis (MS) in 3 large geographic areas in the southern, middle, and northern United States. METHODS: The primary data source was medical records from office visits to private neurologists' practices or to neurology departments in tertiary care facilities during a 3-year period. Additional data sources included patient advocacy groups, nursing homes, and general practitioners. RESULTS: Three-year US age-adjusted prevalence estimates for the study areas varied substantially. The prevalence was lowest (47.2 per 100,000 population) in the Texas study area (33 degrees 30' north latitude), intermediate (86.3 per 100,000 population) in the Missouri study area (39 degrees 07' north latitude), and highest (109.5 per 100,000 population) in the Ohio study area (41 degrees 24' north latitude). The geographic differences remained strong after age-adjustment to the world standard population. The inverse association between UV light exposure and MS prevalence estimates was consistent with this observed latitude gradient. In all 3 areas, MS prevalence was highest among women, people aged 40 to 59 years, and non-Hispanics. CONCLUSION: These results provide necessary prevalence estimates for community cluster investigations and establish baseline estimates for future studies to evaluate temporal trends in disease prevalence.

Effect of population stratification on the identification of significant single-nucleotide polymorphisms in genome-wide association studies.

The North American Rheumatoid Arthritis Consortium case-control study collected case participants across the United States and control participants from New York. More than 500,000 single-nucleotide polymorphisms (SNPs) were genotyped in the sample of 2000 cases and controls. Careful adjustment for the confounding effect of population stratification must be conducted when analyzing these data; the variance inflation factor (VIF) without adjustment is 1.44. In the primary analyses of these data, a clustering algorithm in the program PLINK was used to reduce the VIF to 1.14, after which genomic control was used to control residual confounding. Here we use stratification scores to achieve a unified and coherent control for confounding. We used the first 10 principal components, calculated genome-wide using a set of 81,500 loci that had been selected to have low pair-wise linkage disequilibrium, as risk factors in a logistic model to calculate the stratification score. We then divided the data into five strata based on quantiles of the stratification score. The VIF of these stratified data is 1.04, indicating substantial control of stratification. However, after control for stratification, we find that there are no significant loci associated with rheumatoid arthritis outside of the HLA region. In particular, we find no evidence for association of TRAF1-C5 with rheumatoid arthritis.

Updated prevalence estimates of multiple sclerosis in Texas, 1998 to 2003.

The Texas Department of State Health Services extended a prevalence study of multiple sclerosis (MS) in a 19-county area in North Texas to include 3 additional years of data and included a new geographic area with a predominantly Hispanic population (El Paso County). Patients in whom MS was diagnosed by a neurologist, who resided in the study areas, and who had an office visit between 1998 and 2003 were included in the study. The 6-year MS prevalence estimate for the North Texas counties was 71.5 per 100,000, and for El Paso County it was 49.4 per 100,000. In both areas, prevalence estimates were higher for females, age groups 40 to 49 and 50 to 59, and for non-Hispanic whites. These estimates provide valuable information about the epidemiology of MS in Texas and allow for a comparison with national estimates. The results also provide much needed prevalence data for the Hispanic population.

Current research in preterm birth.

Preterm birth is one of the leading causes of infant mortality and the leading cause of infant morbidity in the United States. It accounts for >70% of neonatal deaths and almost half of long-term neurological disabilities. The Centers for Disease Control and Prevention (CDC) is collaborating with state health departments, universities, communities, and healthcare providers to understand why preterm births occur and how to address preterm birth risk factors. These collaborations include identification of genetic and other biological markers for the early detection of women at high risk of preterm birth; improving understanding of the relationships among psychosocial stress, immune and inflammatory responses, and preterm risk; and designing community strategies to improve the health of pregnant women. By conducting public health research activities that explore the genetic, biological, clinical, behavioral, social, and community determinants of preterm birth, CDC will continue to elucidate the complex interactions of these factors and how they influence preterm birth.

Investigation of a cluster of multiple sclerosis in two elementary school cohorts.

The authors investigated a cluster of multiple sclerosis (MS) among people who had attended two elementary schools in El Paso, Texas, from 1948 through 1970. The community was concerned about the possibility of childhood exposure to heavy metals from a large nearby smelter because historical environmental and biological sampling data demonstrated the potential for study cohort members to have been exposed to heavy metals during their pre-adolescent years. One cohort had no reported cases of MS. In the second cohort, 22 members self-reported a diagnosis of MS, and 16 of these cases were confirmed as MS by an independent board-certified neurologist. The crude MS prevalence estimate was 411 per 100,000 (95 percent confidence interval [CI] = 197-603), Prevalence estimates from four different populations were used for calculation of standardized morbidity ratios (SMRs). At the extremes, the study cohort represents a deficit of cases (SMR= 0.9; 95 percent CI = 0.51-1.44) or a four-fold excess (SMR = 4.0; 95 percent Cl = 2.29-6.5).

Prevalence of multiple sclerosis in 19 Texas counties, 1998-2000.

The study reported here determined the prevalence of multiple sclerosis (MS) between January 1, 1998, and December 31, 2000, for a 19-county study area surrounding Lubbock, Texas. The primary data source for case ascertainment was medical records from the offices of neurologists practicing in the study area. The study found that the overall prevalence for the 19-county study area was 42.8 per 100,000 population (95 percent CI = 36.8-49.5). The prevalence estimate for females was 68.6 per 100,000 (95 percent CI = 58.0-80.6), and for males it was 16.6 per 100,000 (95 percent CI = 11.6-23.1). The prevalence estimate for non-Hispanic whites was 56.0 per 100,000 (95 percent CI = 47.1-66.1); the next highest prevalence was among non-Hispanic blacks at 22.1 per 100,000 (95 percent Cl = 8.1-48.1), and Hispanics at 11.2 per 100,000 (95 percent CI = 6.4-18.2). This project generated the first Texas-specific population-based MS prevalence estimates, including prevalence estimates specific to Hispanics and blacks in Texas. The results underscore the need for additional epidemiologic information on the distribution of MS in other areas of Texas and the United States, as well as information on the underlying etiology of the disease.

Studies of multiple sclerosis in communities concerned about environmental exposures.

Multiple sclerosis (MS) is an autoimmune disease that differentially affects women, people 30-60 years old, and Caucasians. Evidence indicates that it is a complex disease determined by both environmental factors and genetic susceptibility. People across the United States have expressed concern about perceived clusters of MS in their communities and the role of environmental exposures in the development of the disease. The Agency for Toxic Substances and Disease Registry (ATSDR) has funded several studies to address this issue, including a cluster investigation, several prevalence studies, and a case-control study. The cluster investigation illustrated that there are few data regarding the number of individuals with MS in the United States. Prevalence studies were conducted in Ohio, Missouri, and Texas to address this deficiency. The results support a regional difference in MS prevalence, although the reason for this difference is unclear. The results also underscore the need for additional epidemiological information about the distribution of MS in other areas of the United States and information on the underlying etiology of the disease. A case-control study is currently being conducted to examine potential risk factors for MS, including the role of environmental exposures and genetic susceptibility. Future research on MS should focus on large-scale studies and include collaboration among researchers with varied fields of expertise, such as epidemiology, neurology, and genetics.

Evaluation of serum immunoglobulins among individuals living near six Superfund sites.

Residents living in communities near Superfund sites have expressed concern that releases from these facilities affect their health, including adverse effects on their immune systems. We used data from six cross-sectional studies to evaluate whether people who live near several Superfund sites are more likely to have individual immunoglobulin test results (IgA, IgG, and IgM) below or above the reference range than those who live in comparison areas with no Superfund site. Study participants consisted of target-area residents who lived close to a Superfund site and comparison-area residents who were not located near any Superfund or hazardous waste sites. A consistent modeling strategy was used across studies to assess the magnitude of the relationship between area of residence and immunoglobulin test results, adjusting for potential confounders and effect modifiers. In all study areas, the results suggest that people who live near a Superfund site may have been more likely to have IgA test results above the reference range than comparison areas residents regardless of modeling strategy employed. The effect measures were larger for residents who lived in communities near military bases with groundwater contamination. For all analyses the wide confidence intervals reflect uncertainty in the magnitude of these effects. To adequately address the question of whether the immune system is affected by low-level exposures to hazardous substances, we recommend that more functional immunotoxicity tests be conducted in human populations where individual exposure information is available or when it can be reasonably estimated from environmental exposure measurements.

Including residents in epidemiologic studies of adverse health effects in communities with hazardous exposures.

For individuals who live within the shadows of hazardous waste sites, there is a constant worry about what impact releases from these sites are having on their health and environment. Public health agencies at the local, state, and federal levels are routinely asked to investigate these concerns and determine what, if any, exposures are occurring or may have occurred in the past, and what the health risk to nearby residents may be. To ensure the credibility of research findings, full participation of affected communities is needed. Including communities in research activities can, however, be a difficult process. This paper discusses the concerns, needs, and expectations of U.S. communities in which environmental exposures are occurring, or in which exposures have occurred in the past. Three case studies are presented in which activities were undertaken to involve a community in the research process where environmental contaminants were of concern. The strengths and limitations of these activities are discussed, and recommendations for community involvement in future research are made.

Improving data quality in community-based seafood consumption studies by use of two measurement tools.

A seafood consumption study w as conducted in Glynn County, Georgia, to address concern about bioaccumulation of mercury from a nearby hazardous waste site in people who ate potentially contaminated seafood from this area. Seafood consumption levels were ascertained with two data collection tools: a questionnaire and a dietary diary. The use of two instruments allowed for more detailed analysis to reveal discrepancies in responses between the two instruments, to improve reliability of study results, and to reduce recall bias. Implementation of the questionnaire was relatively easy and provided a broad characterization of consumption patterns in the area. The dietary diary was more time-consuming, resulting in a reduction in participation rates. It provided, however, more detailed information with which to address community concerns about adverse health effects from mercury exposure. Overall, individuals who participated in this study were able to make broad generalizations about the amount of seafood in their diet but were less accurate in estimating specific seafood consumption levels. In addition, the level of concordance between the questionnaire and the dietary diary was low with respect to seafood consumption levels. For investigators examining consumption patterns in a community, the decision to use a questionnaire, a dietary diary, or both will be influenced by the objectives of the study, the level of community concern, the number of study staff, and available resources.

Challenges in addressing community concerns regarding clusters of multiple sclerosis and potential environmental exposures.

Citizens living around hazardous waste sites in the USA have expressed concern to public health officials at the local, state and federal level about a perceived high prevalence of multiple sclerosis (MS) in their communities. Many believe the occurrence of the disease is directly linked to exposure to chemical agents from the nearby hazardous waste site. Although the public's concern regarding these clusters should be addressed, epidemiologists have long known that evaluating perceived clusters is rarely fruitful for identifying an etiologic agent. In order to adequately address concerns regarding clusters of MS, as well as examining the role of environmental exposures and genetic susceptibility in the causal mechanism of disease, several activities need to be conducted including characterizing the occurrence of disease, developing a standardized case definition and establishing partnerships to develop innovative research techniques. Only with collaboration across disciplines and lessons learned from past research will we be able to effectively guide research efforts directed at determining the etiology of this disease.