Summaries of Research Using DNA Samples

The projects are grouped by survey time periods.  DNA was collected in the second phase of NHANES III from 1991 to 1994 and from 1999 to 2002 in the continuous NHANES program.  Beginning in 2007, DNA was again collected and stored.  Research has been conducted on samples from 1991-1994.  As research studies are conducted with the later DNA samples, those results will appear on the website. 

HFE genotype and transferrin saturation in the United States.

We investigated the association between hereditary hemachromotosis (HFE) genotypes and transferrin saturation (an indicator of circulating iron) in individuals who participated in the third National Health and Nutrition Examination Survey (NHANES III).  We found that associations between HFE genotype and high transferrin saturation may vary by sex, age, and ethnic group.

Cogswell ME, Gallagher ML, Steinberg KK, Caudill Ph DS, Looker AC, Bowman BA, Gunter EW, Franks AL, Satten GA, Khoury MJ, Grummer-Strawn LM. HFE genotype and transferrin saturation in the United States. Genet Med 2003;5:304-10.

Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey.

A genetic variant in the aminolevulinic acid dehydratase (ALAD) gene may modify the effect of blood lead levels on cognitive function. We investigated this genetic variant in children and adults who participated in the third National Health and Nutrition Examination Survey. We found some evidence that this genetic variant may modify the relationship between blood lead levels and cognitive function in adults between 20 to 59 years old. However, we did not see a similar effect in children and older adults (60 years old and older).

Krieg EF, Jr., Butler MA, Chang MH, Liu T, Yesupriya A, Lindegren ML, Dowling N. Lead and cognitive function in ALAD genotypes in the third National Health and Nutrition Examination Survey. Neurotoxicol Teratol 2009.

Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994.

Knowing allele frequencies and genotype prevalence is important for studying genetics and disease. We calculated the allele frequency and genotype prevalence for 90 variants in 50 genes chosen for their potential public health significance in non-Hispanic whites, non-Hispanic blacks, and Mexican Americans that participated in Phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III). These results provide a valuable resource for future studies in public health in the United States.

Chang MH, Lindegren ML, Butler MA, Chanock SJ, Dowling NF, Gallagher M, Moonesinghe R, Moore CA, Ned RM, Reichler MR, Sanders CL, Welch R, Yesupriya A, Khoury MJ. Prevalence in the United States of selected candidate gene variants: Third National Health and Nutrition Examination Survey, 1991-1994. American journal of epidemiology 2009;169:54-66.

Gene polymorphisms in association with emerging cardiovascular risk markers in adult women.

This study examined the relationships between genetic variants and emerging cardiovascular risk markers among adult US women who participated in Phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES  III). We found a number of gene variants that were associated with serum C-reactive protein and one variant that was associated with homocysteine in this group of adult women.

Fan AZ, Yesupriya A, Chang MH, House M, Fang J, Ned R, Hayes D, Dowling NF, Mokdad AH. Gene polymorphisms in association with emerging cardiovascular risk markers in adult women. BMC Med Genet 2010;11:6.

Genetic variants associated with fasting blood lipids in the U.S. population: Third National Health and Nutrition Examination Survey

The identification of genetic variants related to blood lipid levels may lead to a better understanding of the biological mechanisms underlying serum lipid and cholesterol concentrations in the U.S. population. Using data from the second phase (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III), we found a number of genetic variants that may influence blood lipids.

Chang MH, Yesupriya A, Ned RM, Mueller PW, Dowling NF. Genetic variants associated with fasting blood lipids in the U.S. population: Third National Health and Nutrition Examination Survey. BMC Med Genet 2010;11:62.

Modification by ALAD of the Association between Blood Lead and Blood Pressure in the U.S. Population: Results from the Third National Health and Nutrition Examination Survey

Environmental lead exposure has been found to be associated with an increased risk of hypertension. Individuals vary greatly in susceptibility to lead toxicity, and genetic susceptibility has often been cited as one possible reason for such variation. We examined the role of a genetic variant in the aminolevulinic acid dehydratase (ALAD) gene in the association between lead exposure and blood pressure (BP) and hypertension in individuals that participated in phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III). We found that blood lead level may be an important risk factor for hypertension and increased systolic and diastolic BP and that these associations may be modified by ALAD gene variant.

Scinicariello F, Yesupriya A, Chang MH, Fowler BA. Modification by ALAD of the Association between Blood Lead and Blood Pressure in the U.S. Population: Results from the Third National Health and Nutrition Examination Survey. Environ Health Perspect 2010;118:259-64.

A Hardy-Weinberg Equilibrium Test for Analyzing Population Genetic Surveys with Complex Sample Designs

Testing for deviations from Hardy-Weinberg equilibrium is a widely recommended practice for population-based genetic association studies. However, current methods for this test may not be appropriate for sample surveys with complex survey designs such as NHANES III. We present a test for Hardy-Weinberg equilibrium that accounts for complex survey designs. We recommend the use of this test when analyzing genetic data from sample surveys with complex survey designs.

Moonesinghe R, Yesupriya A, Chang MH, Dowling NF, Khoury MJ, Scott AJ. A Hardy-Weinberg equilibrium test for analyzing population genetic surveys with complex sample equilibrium test for analyzing population genetic surveys with complex sample designs. American journal of epidemiology 2010;171:932-41.

Gene polymorphisms in association with emerging cardiovascular risk markers in adult women with self-reported stroke in US adults

Research studies have suggested that several gene variants may increase the risk of stroke. We examined nine genetic variants for associations with self-reported stroke in individuals that participated in phase 2 (1991-1994) of the Third National Health and Nutrition Examination Survey (NHANES III). We found a number of genetic variants that may be associated with self-reported stroke in this population.

Fan AZ, Fang J, Yesupriya A, Chang M, Kilmer G, House M, Hayes D, Ned RM, Dowling NF, Mokdad AH. Gene polymorphisms in association with self-reported stroke in US adults. The Application of Clinical Genetics 2010;3:23-8.

Lead and cognitive function in VDR genotypes in the third National Health and Nutrition Examination Survey.

A genetic variant in the aminolevulinic acid dehydratase vitamin D receptor (VDR) gene may modify the effect of blood lead levels on cognitive function. We investigated two VDR genetic variants in children and adults who participated in the third National Health and Nutrition Examination Survey. We found some evidence that these genetic variants may modify the relationship between blood lead levels and cognitive function in children and adults between 20 to 59 years old. However, we did not see a similar effect in older adults (60 years old and older).

Krieg EF, Jr., Butler MA, Chang MH, Liu T, Yesupriya A, Dowling N, Lindegren ML. Lead and cognitive function in VDR genotypes in the third National Health and Nutrition Examination Survey. Neurotoxicol Teratol 2009.

Using DNA fingerprints to infer familial relationships within NHANES III households. 

The NHANES genetics data is an unparalleled opportunity to learn about the potential impact of genetic strategies to improve health of the US population.  However, before these studies can be conducted, accurate information on familial relationships within NHANES households is required.  Unfortunately, such information is unavailable from the NHANES questionnaire data.  Therefore we investigated whether standard DNA markers used to identify individuals for forensic purposes could be used to statistically infer familial relationships between NHANES III household members.  We found that these markers and statistical methods can infer close relationships (parent-child or sibling relationships) but not more distant relationships.  These inferred family relationships can be used to improve the validity and efficiency of all future genetic studies using NHANES data.

Katki HA, Sanders CL, Graubard BI, Bergen AW.  Using DNA fingerprints to infer familial relationships within NHANES III households.  J Am Stat Assoc. 2010 Jun 1;105(490):552-563.

The prevalence of C282Y and H63D mutations to the hemochromatosis gene in the United States

In order for public health professionals to make decisions about whether or not to recommend genetic screening for  disorders that are caused by inherited mutations, it is essential for them to know what the occurrence of the mutation is in the United States population, that is, how many people carry the mutation.  One hereditary disease caused by such a mutation is called hereditary hemochromatosis.  This disease causes an accumulation of iron in certain tissues including the heart and liver and, if undiagnosed, can result in cirrhosis, diabetes, heart failure or death.  Although a rare disease, hemocrhomatosis is relatively common for an inherited genetic disorder.   Hemochromotosis can be diagnosed without genetic testing, but it is important to know how common the mutation causing hemochromotosis is in the U.S. population.  Only one study offered a nationally representative sample for the occurrence of the mutation and that was the Third National Health and Nutrition Examination Survey in which you generously participated.  We learned that 5.4% of people in the US population carry a mutation for hemochromatosis called C282Y and 13.5% of the US population carry a mutation for the H63D mutation.  These mutations are more common in non-Hispanic whites than in non-Hispanic blacks or Mexican-Americans.  At the present, genetic testing is not recommended for detecting these mutations.  Tests are available that will effectively detect the presence of the disorder.

Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM et.al. The prevalence of C282Y and H63D mutations to the hemochromatosis gene in the United States. JAMA 2001;285:2216-2222

Trend tests for genetic association using population based cross-sectional complex survey data.

NHANES III has collected genetic data from a total of 7,159 individuals aged 12 years and older. Our research is focused on three specific genes, i.e. ADRB2, TGFB1, and VDR. Some studies have shown that ADRB2 is associated with obesity while a recent study suggests that there is no association (See Jalba and others (2008) for a meta-analysis). TGFB1 is shown to be associated with severe asthma (de Faria and others, 2008). VDR has been found to modify lead toxic-kinetics (Onalaja and Claudio, 2000) and may be associated with blood lead level (BLL). Our research suggests that there are no significant associations between ADRB2 and obesity, which is consistent with Jalba and others (2008)'s finding, and between VDR and high blood lead level. TGFB1 was found to be associated with asthma, which agrees with de Faria and others (2008)'s finding.

She, D., Li, Y., Zhang, H., Graubard, B. I., & Li, Z. (2009) Trend tests for genetic association using population based cross-sectional complex survey data. Biostatistics 11, 4856.

Racial/Ethnic Differences in Association of Fasting Glucose-Associated Genomic Loci with Fasting Glucose, HOMA-B and Impaired Fasting Glucose in U.S. Adult Population.

Recent large-scale genetics studies have identified genetic differences between people, called single nucleotide polymorphisms, or SNPs, in many as 16 new genetic regions associated with blood levels of glucose or insulin.  In this study, researchers tested how common these SNPs are in the U.S. population and whether the SNPs have different associations with glucose and insulin depending on race/ethnicity.  DNA samples from 3,024 adult fasting participants in NHANES III were tested for 16 blood glucose-associated SNPs. All SNP frequencies varied significantly by race/ethnicity. A genetic risk score created by adding up the number of glucose-raising SNPs was associated with a small but significant 0.022 mmol/L increase in glucose levels per glucose-raising SNP among non-Hispanic whites, a 0.036 mmol/L increase in glucose levels in non-Hispanic blacks and a 0.033 mmol/L increase in glucose levels in Mexican Americans. The odds of having prediabetes was increased about 1.8 times for non-Hispanic whites comparing those in the top fifth of the genetic score with those in the bottom fifth; odds were increased about 2.4 times for non-Hispanic blacks and Mexican Americans. These results show that SNP frequencies of 16 new glucose-associated SNPs vary significantly by race/ethnicity, but the influence of these SNPs on glucose levels and odds of prediabetes were generally consistent across all race/ethnicity groups.

Yang Q, Liu T, Shrader P, Yesupriya A, Chang MH, Dowling NF, Ned RM, Dupuis J, Florez JC; the MAGIC Investigators, Khoury MJ, Meigs JB. Racial/Ethnic Differences in Association of Fasting Glucose-Associated Genomic Loci with Fasting Glucose, HOMA-B and Impaired Fasting Glucose in U.S. Adult Population. [Epub ahead of print] Diabetes Care. 2010 Aug 30. PMID: 20805255

Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans.

In this study, researchers tested the effect of the single nucleotide polymorphisms (SNPs) on aspects of human physiology important to the causes of type 2 diabetes.
They characterized these SNPs using detailed measures of insulin processing, secretion and sensitivity to help understand their role in regulation of glucose control, insulin secretion and/or action, key physiological factors that, if they become abnormal, lead to the development of type 2 diabetes. They found that the glucose-raising SNP in a gene called MADD was associated with abnormal insulin processing. Defects in insulin-processing and insulin secretion were seen in glucose-raising SNP carriers in genes called TCF7L2, SCL30A8, GIPR, and FAM148B. Abnormalities in early insulin secretion were suggested in glucose-raising SNP carriers in genes called MTNR1B, GCK, FADS1, DGKB and PROX1. These results show that new genes identified by associations with simple measures like blood glucose have varied and important effects on more sophisticated measures of physiology related to the causes of type 2 diabetes.

Ingelsson E, Langenberg C, Hivert MF, Prokopenko I, Lyssenko V, Dupuis J, Mägi R, Sharp S, Jackson AU, Assimes TL, Shrader P, Knowles JW, Zethelius B, Abbasi FA, Bergman RN, Bergmann A, Berne C, Boehnke M, Bonnycastle LL, Bornstein SR, Buchanan TA, Bumpstead SJ, Böttcher Y, Chines P, Collins FS, Cooper CC, Dennison EM, Erdos MR, Ferrannini E, Fox CS, Graessler J, Hao K, Isomaa B, Jameson KA, Kovacs P, Kuusisto J, Laakso M, Ladenvall C, Mohlke KL, Morken MA, Narisu N, Nathan DM, Pascoe L, Payne F, Petrie JR, Sayer AA, Schwarz PE, Scott LJ, Stringham HM, Stumvoll M, Swift AJ, Syvänen AC, Tuomi T, Tuomilehto J, Tönjes A, Valle TT, Williams GH, Lind L, Barroso I, Quertermous T, Walker M, Wareham NJ, Meigs JB, McCarthy MI, Groop L, Watanabe RM, Florez JC; MAGIC investigators. Detailed physiologic characterization reveals diverse mechanisms for novel genetic Loci regulating glucose and insulin metabolism in humans. Diabetes. 2010;59:1266-75. PMID: 20185807

CRP polymorphisms and progression of chronic kidney disease in African Americans.

Chronic inflammation may play a role in chronic kidney disease (CKD) progression. CRP gene gene variants are associated with serum C-reactive protein (CRP) concentrations. It is unknown if CRP gene variants will be associated  with CKD progression or modify the effectiveness of anti-hypertensive therapy in delaying CKD progression. We measured this gene variants in 642 participants with CKD from the African American Study of Kidney Disease and Hypertension (AASK). We compared the frequency of these variants (MAF) between the AASK participants and  the African Americans from NHANES III without kidney disease.  We found that one of the CRP gene variants was associated with higher risk of CKD progression in the AASK study participants.

CRP polymorphisms and progression of chronic kidney disease in African Americans.
Hung AM, Crawford DC, Griffin MR, Brown-Gentry K, Lipkowitz MS, Siew ED, Cavanaugh K, Lewis JB, Ikizler TA; AASK Study Group. Clin J Am Soc Nephrol. 2010 Jan;5(1):24-33. Epub 2009 Dec 3.PMID: 19965533 [PubMed - indexed for MEDLINE]

Using DNA Fingerprints to Infer Familial Relationships Within NHANES III Households     

This study assessed whether standard DNA markers used to identify individuals for forensic purposes could be used to statistically infer familial relationships between NHANES III household members, which are currently unavailable from the questionnaire data.  They found that these markers and statistical methods can infer close relationships (parent-child or sibling relationships) but not more distant relationships.

Katki HA, Sanders CL, Graubard BI, Bergen AW.  Using DNA fingerprints to infer familial relationships within NHANES III households.  J Am Stat Assoc. 2010 Jun 1;105(490):552-563.