The Ramazzini Institute
for Occupational and Environmental Health Research   

Who Are We?

Genetic Determinants

     The purpose of this feature of our journal  is to connect information on genetic determinants of disease usually seen and researched separately, and thus the domain of three separate communities: disease genes, susceptibility genes and sensitivity genes.

     In The Aspen Report, Contributing Editor Mark Yarborough is developing connecting material from the July 2000 conference at the University of Colorado’s Given Institute. Click on that section and you will find two slides from a presentation at Aspen by Dr. Richard R. Sharp, ethicist for the National Institute of Environmental Health Sciences. “Genetic Influences on Disease” defines what we mean by these three categories of genetic determinants.

Alpha-1 Antitrypsin Deficiency

     Alpha-1-Antitrypsin Deficiency (also known as Alpha-1) is a hereditary condition predisposing affected individuals to lung and liver damage that can be life threatening.  Alpha-1-Antitrypsin is a circulating protein that blocks the activity of inflammatory proteases (protein-degrading enzymes).  Alpha-1 can lead to destructive lung disease (pulmonary emphysema) in young adults and the liver failure caused by Alpha-1 can affect individuals of all ages, and is particularly severe in newborns. Although virtually unknown by the general public and under diagnosed by the medical community, approximately 100,000 individuals in the US have the severe form of the deficiency and an additional 5 million individuals carry at least one abnormal gene.  There are a similar number of affected individuals in Europe.  Demonstrating co-dominant allelic expression, Alpha-1 carriers have approximately 50% of the normal circulating levels of this protein.  There is some evidence of increased risks of liver and lung disease even in carriers.

     The most common abnormal gene appears to have originated in Scandinavia.  The distribution of this gene matches the area of Viking conquests at the start of the last millennium.  Thus it is fitting that the association between familial precocious pulmonary emphysema and the deficiency of Alpha-1-Antrypsin was first described in 1963 by investigators at Malmo General Hospital in Sweden.

     It appears that in the absence of additional risk factors, individuals with the severe deficiency of Alpha-1-Antitrypsin may lead healthy lives.  While some individuals without identified risk factors do develop liver or lung injury, the majority of individuals who develop lung disease have one of four identified environmental risk factors: personal smoking history, parental smoking history, frequent lung infections, significant occupational exposures to dust and/or fumes.  The risk factors that lead to the liver disease of Alpha-1 are currently unknown.

     Neonatal liver disease often leads to liver transplantation with its attendant risks and lifelong morbidity.  The lung disease of Alpha-1 leads to premature death in most individuals.  The only specific therapy currently available to individuals with Alpha-1 lung disease is intravenous augmentation therapy with pooled human plasma-derived Alpha-1-Antitrypsin, an expensive therapy with poorly documented efficacy.

Future Profiles

      In the next issue, the second profile – for Late Onset Tay-Sachs – is being prepared by Shirley Webb, Vice President of the LOTS Foundation. Others will be added in future issues. All will be amplified to create a catalog of “ecological” profiles, i.e., they will include social, economic, demographic, psychological, biomedical and environmental data. The objective is to help make clear the connections between all three categories of genetic determinants.

     Each of the affected populations face special problems, but share common research, legislative, employment, insurance, and health care needs. There may also be unexplored environmental questions that need to be highlighted, not only in terms of causation, but also in terms of protection as a population especially vulnerable to contaminated environments. Some members of each population are likely to have “membership” in other populations, creating an overlap of biomedical and environmental research and protection needs. 

      The section connects with other information in News & Commentary, which in this issue features Nancye Buelow’s article on genetic discrimination, a commentary on the nexus of the gene and its environment: “Professor Lewontin Sums It Up!” and “What Judges and Lawmakers Are Told!”