Biennial and Annual Report on the Rare Diseases Research Activities at the National Institutes of Health FY 2004

National Institute of Environmental Health Sciences (NIEHS)

Overview of Rare Diseases Research Activities

The National Institute of Environmental Health Sciences (NIEHS) supports basic research into the fundamental mechanisms of how environmental exposures interact with the human body to produce disease and dysfunction. This research on molecular pathways and environmental interaction has also yielded insights into the basic mechanisms involved in the pathogenesis of rare diseases and conditions. This work continues, with several related announcements either ongoing or nearing the award stage. Applications are currently solicited for studies of environmental influences in the development of amyotrophic lateral sclerosis (a focus of the Program Announcement, Gene/Environment Interactions in Neurodegenerative Disease). In addition, the new program of grants on metabolomics in environmental health science (using metabolomics technologies to study metabolic and regulatory pathways that are perturbed by environmental exposures) will be awarded soon and will provide insights on a wide range of cellular mechanisms by which environmental exposures influence disease.

Parental Exposure to Specific Chemicals May Lead to Mutations in Children Leading to Acute Lymphoblastic Leukemia

NIEHS-funded research is investigating the connection of chemical exposures in parents and their children’s risk of developing acute lymphoblastic leukemia (ALL). The epidemiologic study uses data from a large case-control study of childhood ALL conducted by the Children’s Oncology Group in Southern California. The ras proto-oncogene family of genes has three members: H-ras, K-ras, and N-ras. Ras proto-oncogene mutations have been implicated in the development of many malignancies including pancreatic and breast cancers; however little data exists associating ras mutations with parental exposures and risk of childhood leukemia. DNA samples from the children in the study were examined for ras mutations. A total of 127 out of 837 ALL cases exhibited ras mutations in the K- or N-ras genes. A number of chemical exposures were associated with significantly increased risks for development of ALL in children. Parental use of “mind-altering drugs,” such as marijuana, LSD, and cocaine was associated with increased risk for ALL (three-fold higher risk for maternal use and two-fold higher risk for paternal use). Maternal exposure to solvents and plastics during pregnancy raised the risk about three-fold and seven-fold, respectively, and maternal exposure to plastics after pregnancy was associated with eight times higher risk. Other exposures, such as to oil and coal products, were also associated with increased risks of ALL. In previous studies, parental occupational exposure to hydrocarbons such as chlorinated solvents, benzene, and paints has been linked to elevated childhood leukemia risk. The present study has extended these findings to include drugs of abuse and additional chemical exposures and to link them to ras mutations. The study’s authors conclude that parental exposures to “hydrocarbons and mind-altering drugs, chemicals that have been previously suggested to increase the risk of childhood leukemia, [are] related to specific ras mutations in childhood ALL.”

Women Developing Myositis With and Without Silicone Implants Have Different Genetics

Autoimmune diseases as now defined may consist of multiple distinct entities, each of which is characterized by different genetic and environmental exposures. For this reason, NIEHS clinical researchers compared women who developed myositis after silicone implants (MASI) with women developing myositis without implants (IIM) to determine if they differed in clinical, serologic, and/or genetic features. Two studies were undertaken—a case series followed by a larger, independent matched case-control study. In the case series study, 11 MASI patients differed from 76 IIM patients in having a significantly increased frequency of gene called HLA DQA1*0102 and decreased frequencies of the myositis-associated genes called DRB1*0301 and DQA1*0501. A subsequent matched case-control study revealed that while clinical features and autoantibodies did not differ significantly between MASI and IIM subjects, MASI patients again had decreased frequencies of DRB1*0301 and DQA1*0501 compared to IIM patients. Additional comparisons of MASI patients combined from both studies (n = 37) with a larger population of IIM patients (n = 453) suggested that the gene called HLA DQA1*0102 is uniquely associated with MASI. These studies suggest that women who develop inflammatory myopathy after silicone implants constitute a genetically distinct group of myositis patients. These findings support the growing belief that autoimmune diseases as we think of them today are actually heterogeneous collections of disorders defined by different genetic and environmental factors and suggest new avenues of investigation to dissect out the causes of these conditions.

A Workshop Assessing Human Germ-cell Mutagenesis in the Post-genome Era

NIEHS and the Office of Rare Diseases, with others, cosponsored the workshop “Assessing Human Germ Cell Mutagenesis in the Post-genome Era: A Celebration of the Legacy of William L. Russell.” Russell was one of the pioneers in the field of mammalian germ cell mutagenesis. The workshop was held September 28–30, 2004, at The Jackson Laboratory in Bar Harbor, Maine, for the purpose of assessing current capabilities and projecting future strategies to detect human germ cell mutagens, identify genetic alterations, and evaluate long-term effects in human populations. Mutations in the human population can cause severe diseases and disability; while most are currently incurable, some can be treated with at least partial success. Collectively, they cause untold misery to parents and the affected offspring. The public and government have expressed concern about environmental agents that cause mutations, and many independent programs and international efforts have been funded over the years to study this problem. This workshop assessed whether recent progress in genomics could move the understanding of human germ cell mutagenesis forward. Attendees agreed that we must strive for better answers to the problems of human germ cell mutagenesis by using all the tools and resources available to us in this post-genomic era and that the effort needs to be multidisciplinary, including germ cell biology, genetic toxicology, bioinformatics, epidemiology, toxicogenomics, and other disciplines. Attendees reached consensus that an international program on human germ cell mutagenesis should be established before the end of calendar year 2005. The program should develop and evaluate parallel systems in humans and laboratory animals as well as develop efficient laboratory systems to identify agents that can induce transmissible mutations. The program should use the Human Genome Program as a model, drawing on lessons learned in that program to speed implementation and foster efficiency. Another component of the proposed program would be the establishment of a BioBank that would contain DNA and other biological specimens collected from individuals exposed to suspect mutagenic agents and from those individuals’ children, parents, and grandparents. These specimens would be accompanied by all available information on agents of exposure, dosages, personal profiles (protecting anonymity), and possible confounding factors. A proposed title for the overarching program in human germ cell mutagenesis is “The Etiology of Human Genetic Variation.”

A Workshop on Mold-related Health Effects

The NIEHS and the NIH Office of Rare Diseases, with others, sponsored a workshop on “Mold-related Health Effects: Clinical, Remediation Worker Protection, and Biomedical Research Issues,” June 28–29, 2004, at Washington Court Hotel in Washington, DC. The potential health effects related to exposure to mold and mold products in houses and workplaces have become a large public health concern. However, a lack of good clinical and experimental data is hampering evidence-based decision-making on how and when to conduct interventions, how to treat patients potentially harmed by mold exposure, how best to remediate affected buildings, and how to protect remediation workers. The workshop brought together experts in clinical science, worker protection and education, and basic research to further efforts to prevent, diagnose, and treat conditions related to exposure to indoor mold. The workshop consisted of an opening plenary session followed by two concurrent sessions, one dealing with clinical and biomedical research issues and the other with worker education and protection. Experts presented overviews of various areas along with their own data and some recommendations for future research. A closing plenary session presented overviews of the two concurrent sessions, and a final session presented clinical and research recommendations for future research. After the workshop, a list of the recommendations was compiled and emailed to participants, and they were asked to prioritize the recommendations.

This input has been received by workshop coordinators and is being evaluated, and a writer-contractor is preparing a summary of the meeting. This summary plus information on future research recommendations will be used to prepare a final report, which is scheduled for completion in March 2005.


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Last Reviewed: July 22, 2005