Mary Lou Lindegren for the NHANES CDC-Wide Working Group

NHANES III DNA Bank The National Health and Nutrition Examination Survey (NHANES) is a nationally representative survey of the United States population, conducted by the National Center for Health Statistics (NCHS).(1) http://www.cdc.gov/nchs/nhanes.htm. Detailed interviews, clinical, laboratory and radiological examinations are conducted as part of the survey. NCHS has collected these data with an assurance of confidentiality. During the second phase of NHANES III (1991-1994), (2) white blood cells were frozen and cell lines were

Collaborative CDC-Wide Project

A CDC-wide working group of epidemiologists and laboratorians, representing most Centers and Institutes at CDC, was convened to develop a collaborative proposal for determining the prevalence of selected genotypes of public health importance using the nationally representative population-based NHANES III DNA Bank.

Selecting Genetic Variants of Public Health Importance

The criteria used to select genes for the proposal included the following:

• known or hypothesized association with diseases of public health importance,
• role in pathways affecting multiple diseases,
• identified functional variants,
• relatively common variants (prevalence >2%),
• previously described gene-environment or gene-gene interactions,
• relevant phenotypic data available in NHANES datasets, and
• no current use for clinical risk assessment or intervention.

Several challenges that made this process difficult were as follows:

• gaps in published information,
• many available studies demonstrated problems with methodology, including selection bias, small sample size, and lack of attention to potential interaction, and
• non-replication of many published gene-disease associations.

The final proposal included 87 variants of 57 genes known to be important in at least six major pathways:

• nutrient metabolism (e.g., folate and homocysteine; lipids; glucose; alcohol; vitamin D),
• immune and inflammatory responses (e.g., cytokines, cytokine receptors),
• activation and detoxification pathways (e.g., drugs, carcinogens, environmental contaminants),
• DNA repair pathways (e.g., ionizing radiation, environmental toxins),
• hemostasis and renin/angiotension pathways, and
• developmental pathways.

Genotyping will be performed in collaboration with the National Cancer Institute (NCI) at the NCI Core Genotyping Facility.

Potential Value for Public Health

Prevalence data from the NHANES database will be the basis for future analysis of gene-disease associations and gene-environment interactions. Gene-environment interactions are considered to be the fundamental biological processes that both maintain health and bring about disease. As our understanding of these interactions grows, establishing the prevalence of gene variants known to interact with specific environmental factors will be a key factor in assessing the potential impact of environmental interventions. Genotypic information will add another dimension to the analysis of clinical, physical, and lifestyle information collected by NHANES. Additional analysis of
genotype - phenotype relations will be proposed once the prevalence data have been evaluated.

Two Other Projects Using NHANES III DNA Samples

• Prevalence of Gene Variants that Code for Enzymes Involved in Nicotine and Carcinogen Metabolism in the United States Population and their Association with Body Burden of Cotinine
  Karen Steinberg, et al.
  This proposal involves correlating over 40 Single Nucleotide Polymorphisms or SNPs (pronounced "snips") in 14 genes involved in drug-nicotine metabolism and smoking behavior with serum cotinine measurements already performed, and with self-reported smoking variables.

• Frequency of Common Genotypes of Folate-Related Genes and their Effect on the Relation between Intake and Blood Levels of Folate and Homocysteine
  Lorenzo Botto, et al.
  This proposal will evaluate the individual and joint effects (interactions) of selected common polymorphisms of three genes in the folate metabolism pathway and the consumption of folic acid on homocysteine and folate levels.

References

1. National Center for Health Statistics. National Health and Nutrition Examination Survey. [online survey]. Available at: http://www.cdc.gov/nchs/nhanes.htm. Accessed Feb 16, 2004.
2. National Center for Health Statistics. Plan and operation of the Third National Health and Nutrition Examination survey, 1988-94. Vital Health Stat 1994;1:1-62.
3. National Center for Health Statistics. NHANES III Stored Biologic Specimens. Web site. Available at: http://www.cdc.gov/nchs/about/major/nhanes/coverpage.htm. Accessed Feb 16, 2004.
4. National Center for Health Statistics. NHANES III DNA Specimens. Guidelines for Proposals. Web site. Available at: http://www.cdc.gov/nchs/about/major/nhanes/dnafnlgm2.htm. Accessed Feb 16, 2004.
5. Centers for Disease Control and Prevention. National Health and Nutrition Examination Survey III (NHANES) DNA Specimens: Guidelines for Proposals to Use Samples and Proposed
   Cost Schedule. 2002:67:51585-51589. Also available at:
   http://www.access.gpo.gov/su_docs/fedreg/frcont02.html
   and http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=2002_register&docid=
   02-20038-filed. Accessed Feb 18, 2004.