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Genetic NHANES is Important for Research

Over the last few decades, the National Health and Nutrition Examination Surveys (NHANES) have collected important health information for both men and women of all ages and race/ethnicities. This information is used to determine how frequent or common certain diseases (such as heart disease) and risk factors and exposures (such as cigarette smoking) are in Americans for any given year. This information is useful because it helps public health scientists monitor trends over time (such as obesity rates) and helps scientists establish associations between risk factors/exposures and diseases. A better understanding of the relationship between risk factors/exposures and human disease will help scientists develop better and more effective prevention, intervention, and treatment strategies.

Most of the health information in these surveys is collected in interviews and a physical exam conducted by CDC personnel on participants who have agreed to be a part of NHANES. Additional laboratory tests are conducted from blood and urine samples donated by each NHANES participant. With recent advances in technology, NHANES can now collect genetic information from the same blood sample obtained for laboratory testing. The new genetic information is useful to public health scientists because it allows them to test for relationships between diseases and genetics. Also, almost unique to NHANES, scientists can describe the relationship between disease and genetics in the context of exposures.

While DNA is an exciting and useful addition to NHANES for scientific studies, it is important to understand how genetic information is collected in NHANES and what it can and cannot tell us about a participant. The genetic information collected in NHANES to date represents specific locations in the human genome and does not represent the entire genome. In humans, there are 23 chromosomes that contain DNA. DNA is double-stranded and consists of four bases known as A, C, G, and T. Collectively, the human genome contains an estimated 3 billion base-pairs. Scientists typically collect information on only a fraction of the 3 billion base-pairs.

The most common way scientists collect genetic information on a DNA sample is to interrogate a specific point in the genome using a technique we call “genotyping.” Scientists target specific locations in the human genome because they are known to have different bases in some participants compared with others. A point along the DNA that has more than one form is called a “polymorphism.” Some polymorphisms are very common in the human population and some are rare (<1%). Rare polymorphisms that cause disease with high probability are typically referred to as “mutations.”

Because many scientists using NHANES for studies are interested in common diseases that impact public health, most of the genotyping is performed for points along the genome where changes are common in the human population. For example, if scientist genotype hypothetical polymorphism #1, at one point in the DNA, 40% of participants’ chromosomes have an “A” and 60% of the participants’ chromosomes have a “G.” This is an example of a common polymorphism.

In NHANES, we are genotyping mostly common polymorphisms in all participants. The polymorphisms can be in genes, near genes, in between genes, or far away from genes. The genotyping techniques we use for NHANES are standard and range from genotyping one polymorphism at-a-time in all DNA samples up to 96 polymorphisms at-a-time in all DNA samples. In comparison, other genotyping techniques allow scientists to genotype ~1 million polymorphisms.

As mentioned previously, genotyping techniques in general allow scientists to examine specific locations in the human genome that are known to vary from person to person. To do this, we use DNA extracted from cell lines (NHANES III) or blood (NHANES 1999-2002), and we amplify (make several copies of) the specific locations we want to genotype. For each DNA sample, we then “probe” the specific location in the amplified DNA to determine which base is present with the expectation that every DNA sample will have a base inherited from mom and a base inherited from dad. The probe is made-up of bases that compliment the known location containing our polymorphism. We actually use two probes in this experiment: one specific for base #1 of the polymorphism and one specific for base #2 of the polymorphism. If the amplified DNA contains only base #1 (one from mom and one from dad), only the probe with base #1 will bind to it. If the amplified DNA contains both bases (one base from mom and the other base from dad), both probes will bind to the amplified DNA. If the amplified DNA contains only base #2, only the probe with base #2 will bind to it. This basic description of genotyping one polymorphism is just one of many strategies we use in NHANES to determine which bases are present at specific locations in the human genome.

In the last five years, scientists have identified hundreds of common polymorphisms that are associated with common human diseases or laboratory measures used to assess disease risk. These findings are exciting because they allow scientists to identify new genes that are potentially important in risk or development of human diseases. However, these findings still leave many questions. For example, most studies have only examined populations of European-descent and do not know how frequent the polymorphisms are in other populations or how they are related to disease in these populations. Also, very few studies have accounted for environmental exposures, which undoubtedly will affect whether certain polymorphisms have an effect on disease risk or not. NHANES is an invaluable resource to scientists who want to answer the remaining questions about common polymorphisms and their relationship to human disease in diverse populations in the context of environmental exposures.

Scientists using Genetic NHANES are just now beginning to fill the gaps in knowledge about the relationship between disease and genetics and how the environment/exposures can modify this relationship. Unlike medical tests, though, the genotyping results for these polymorphisms are generally not useful to individual participants. The genetic information collected in NHANES is typically for common disease, and each polymorphism contributes only a small amount towards overall disease risk. In fact, knowledge of whether a participant smokes or not or body mass index (a measure of obesity) is a better predictor of future heart attacks than knowledge of a specific polymorphism for that participant. Also, polymorphisms are not like mutations. A participant with mutation will probably develop the disease associated with that mutation, but a participant with a polymorphism may or may not develop the associated disease. This uncertainty in the genotype-phenotype (polymorphism-disease) relationship is the reason why genetic markers are not yet used for disease prediction in individual participants.

Despite the limitations of using polymorphisms for disease risk prediction, scientists continue to use them to better understand the biology behind disease processes. Genetic NHANES is one of the best resources available for these studies because it is a large survey of Americans of both sexes and many racial/ethnic groups of all ages. And, as already mentioned, NHANES is one of the few surveys available in the United States with a wealth of exposure information linked to DNA samples. Continued collection of genetic information in the context of NHANES will ensure that public health scientists will have the most comprehensive data available to better understand the important relationships between disease and risk factors for the benefit of all Americans.