Seed Funding for Public Health Genomics Research

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Fiscal Year 2006

In March 2006, the Centers for Disease Control and Prevention’s (CDC’s) Office of Public Health Genomics (OPHG) announced the availability of seed funding for innovative CDC projects that integrate genomics into public health research and programs. Thirty-two proposals were received and 11 were selected, with priority given to those with potential to demonstrate health impact within two years. The following list provides information about 2006 seed funding recipients.

 

Genetic Predictors of Developing Hemolytic-Uremic Syndrome among persons infected with Shiga toxin-producing Escherichia coli (STEC)

Principal Investigators: Frederick J. Angulo and Linda J. Demma* (NCZVED)
* Has been replaced by L. Hannah Gould (NCZVED)

Escherichia coli O157:H7 and other Shiga toxin-producing enterohemorrhagic E. coli (STEC) are estimated to cause over 110,000 illnesses, 3000 hospitalizations, and 90 deaths each year in the U.S. Approximately 8% of persons infected with E. coli O157 develop hemolytic-uremic syndrome (HUS). HUS is associated with substantial morbidity and mortality, with case fatality rates as high as 5%; HUS is the leading cause of renal failure in children. This project will apply genomic methods to determine host factors associated with HUS within a large, population-based cohort study persons infected with STEC.

Activities/Achievements

  • Enrolled 375 persons (as of April 2009). Data collection expected to be completed in December 2010.
  • Presented poster at CDC’s 10 Years of Public Health Genomics Meeting, January 2008.

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Microarray Analyses of MHC Genetic Variations in Diisocyanate-induced Occupational Asthma (OA)

Principal Investigators: Michael I. Luster (NIOSH), Berran Yucesoy (NIOSH), Victor J. Johnson (NIOSH), and Eugene Demchuk (ATSDR)

Diisocyanates are the most common cause of occupational asthma from low-molecular weight chemicals, still causing disease in 5-15 % of chronically exposed workers despite improved industrial hygiene efforts. With the recent development of genotype microarrays we are now capable of rapidly examining a large number of variants in the highly relevant MHC region in a case-control study of exposed workers. The results could be used to assess the genetic contribution in the risk of OA, identify the most susceptible (genetic) populations and apply relevant information to the risk assessment process by determining safe exposure levels for the most susceptible groups of workers.

Activities/Achievements

  • Genotyped all 350 subjects as proposed with high-density microarray of the MHC locus (as of May 2009). Efforts to expand the patient population are underway.
  • Clinical characterization is complete and data analyses are in progress.
  • Project successfully integrated a microarray platform for high-throughput genetic profiling into occupational disease research.
  • Investigators developed a high throughput genotyping strategy that can be applied to existing and new projects in their branch.
  • Presented at 2nd CDC Public Health Genomics Collaboration Meeting, March 2007.

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Maternal Smoking, Polymorphisms of Genes Involved with Metabolism of Tobacco Smoke, and Risk for Gastroschisis and Anorectal Atresia/Stenosis in the National Birth Defects Prevention Study

Principal Investigators: Margaret A. Honein (NCBDDD), Mary Jenkins (NCBDDD), Margaret (Peg) Gallagher (NCEH), Sonja A. Rasmussen (NCBDDD), Patricia Richter (NCCDPHP), Robert Merritt (NCCDPHP)

Gastroschisis and anorectal atresia/stenosis are two common, major birth defects. Gastroschisis, a herniation of the intestines through a defect in the abdominal wall, affects approximately 3.7 infants per 10,000 US births; anorectal atresia/stenosis, the congenital absence or narrowing of the anal or rectal canal, affects approximately 4.8 infants per 10,000 US births. Both of these birth defects are believed to have a multifactorial etiology including both environmental and genetic risk factors. Because some studies have reported maternal smoking as a risk factor for both defects, this case-control study will focus on potential interaction of maternal smoking with genes involved in metabolizing tobacco smoke (CYP2A6, CYP2B6, CYP2D6, CYP1A1, CYP1A2, CYP2E1, GSTT1, NAT1, and NAT2).

Activities/Achievements

  • Expansion of the initial project and the addition of two cardiac birth defects to the study resulted in collaborations with other National Birth Defects Prevention Study (NBDPS) investigators and provision of approximately 4,000 additional samples and more than 400 additional polymorphisms for testing.
  • Project strengthened the role of genomics in the NBDPS and allowed CDC to play a leadership role in the genomics efforts across the Centers for Birth Defects Research and Prevention that collaborate on the NBDPS.
  • Presentations/Posters:
    • NCBDDD Birth Defects Branch Research in Progress meeting, March 2007.
    • 2nd CDC Public Health Genomics Collaboration Meeting, March 2007.
    • American Society of Human Genetics meeting, October 2007.
    • Centers for Birth Defects Research and Prevention annual meetings, November 2007 and January 2009.
    • CDC’s 10 Years of Public Health Genomics Meeting, January 2008 (abstract).

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Identifying Genetic Determinants of Susceptibility to M. Tuberculosis

Principal Investigator: Mary Reichler (NCHHSTP)

Tuberculosis continues to be a major global health problem. Each year 54 million people worldwide are infected with Mycobacterium tuberculosis, 8.8 million develop clinical disease, and 1.75 million die of tuberculosis. In 1999, CDC’s Division of Tuberculosis Elimination launched a prospective multi-site study of epidemiologic, immunologic, and immunogenetic correlates of susceptibility to TB among contacts of infectious TB patients in a U.S. and Canadian-born study population. A total of 1,947 contacts have been enrolled in the study to date, with a total planned enrollment of 2,500. Specimens are being tested for three cytokine surrogate markers, HLA, and a dozen candidate gene single nucleotide polymorphisms (SNPs). This proposal seeks to: 1) strengthen laboratory capacity, expanding testing from 18 candidate gene SNPs to all 33 SNPs with demonstrated associations with tuberculosis or strong biologic plausibility; and 2) to build specialized capacity to perform complex analyses, including haplotype analysis, while carefully evaluating multiple potential gene-gene and gene-environment interactions.

Activities/Achievements

  • Enrollment completed (December 2006).
  • Presentations:
    • 2nd CDC Public Health Genomics Collaboration Meeting, March 2007.
    • Laboratory of Clinical Infectious Diseases, NIAID, NIH, January 2008.
    • American Thoracic Society Conference, Toronto, Canada, May 2008.
  • Increased visibility and SNP testing capacity which resulted from this funded project also facilitated development of a new DTBE genomics project (launched in 2007). The DTBE project seeks to identify genetic determinants of response to treatment among active pulmonary TB patients (enrolled at 28 sites in the United States and three international sites) as part of the TB Trials Consortium.

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Investigation of Immunoglobulin (Ig) GM and KM Gene Polymorphisms in Susceptibility to and Pathogenesis of Malaria and HIV in Children and Pregnant Women in Kenya

Investigator: Ya Ping Shi (NCID)

Malaria is a major global public health problem, currently estimated to cause 300-500 million clinical cases and 1.1-2.7 million deaths annually throughout the world. Sub-Saharan Africa accounts for 90% of all these cases and the disease exerts an adverse impact on the health of young children, pregnant women and their unborn infants. Previous studies conducted in Kenya, a malaria holoendemic and HIV epidemic area, have shown that gene polymorphisms of the Fc receptor IIa for Ig (FcgRIIa), which determines differential affinity for human IgG subclasses, are associated with: 1) high density malaria infection in children; 2) malaria infection in HIV positive women; and 3) perinatal HIV infection. The specific objectives of the proposed study are: 1) to determine the association between Ig GM/KM gene polymorphisms and malaria morbidity, including severe anemia, and mortality in children; 2) to determine the association of gene polymorphisms of Ig GM/KM with outcomes of malaria infection in pregnant women, including maternal anemia, birth defects, and vertical transmission of HIV; 3) to determine the effects of Ig GM/KM gene polymorphisms on the interaction between malaria and HIV-1 infection during pregnancy; and 4) to determine the differential interaction between Ig GM gene haplotype profiles and FcgRIIa genotypes and acquired antibody responses in relation to the above epidemiological and clinical parameters.

Activities/Achievements

  • All genotyping is complete for approximately 2,400 samples from two large, longitudinal epidemiological cohorts in western Kenya (the community-based Asembo Bay Cohort Project and the facility-based Vertical Transmission Project).
  • Data analyses are ongoing; 3-4 manuscripts are being planned (as of April 2009).

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Effectiveness and Cost-effectiveness of Using Family History of Diabetes for Population–level Health Promotion

Principal Investigator: Scott Grosse (NCBDDD)

Type 2 diabetes is a growing national health problem because of its rapidly increasing incidence and associated health impacts, including premature mortality, disabling sequelae, and risk of birth defects in offspring. Family history has been shown to be a strong predictor of diabetes risk, which could reflect both genetic risk and shared behaviors or environment. This project will develop a decision analytic and cost-effectiveness model to assess the likely outcomes of health promotion efforts that focus on the use of family history information on type 2 diabetes. The two specific aims are: 1) to develop a decision analytic and cost-effectiveness model to assess the effects on health outcomes and costs of health promotion efforts that focus on the use of family history of diabetes; and 2) to use this decision model to assess the effects of targeting health promotion efforts based on family history of diabetes on the outcomes and costs of: i) individuals with a family history of diabetes, ii) individuals without a family history of diabetes, and iii) the overall population of individuals.

Activities/Achievements

  • Completed the decision analytic model.
  • Findings of the project:
    • Public health programs that teach the importance of diabetes family history (FH) can increase the lifetime incidence of diabetes among a 35-year-old cohort or decrease it, depending on whether it has only the desired behavioral effect on FH+ persons or an undesirable behavioral effect on FH- persons.
    • Programs emphasizing the importance of family history may want to target risk factor education only to those at high risk or to emphasize the continuing risk for those at lower risk.
  • Presented at Society for Medical Decision Making, October 2008.

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Should Genetic Testing Be Used to Guide Warfarin Therapy? An Evidence-based Cost-Utility Analysis

Principal Investigator: Scott Grosse (NCBDDD)

Warfarin is a common, chronically administered oral anticoagulant; 16 million prescriptions were dispensed in 2004. Warfarin reduces the risk of thromboembolic events by 50-79% in atrial fibrillation (AF) patients, yet is prescribed for only about half of the 2 million patients diagnosed with AF in the US each year, due in part to concerns about the risk of major bleeding and the challenges of closely monitoring and adjusting warfarin therapy. Recently, variants in the CYP2C9 and VKORC1 genes have been shown to significantly influence warfarin dose requirements, and in the case of CYP2C9, the risk of major bleeds. The use of CYP2C9 and VKORC1 genetic testing has thus been proposed to help guide warfarin therapy. Although the analytic and clinical validity of these associations has been established, their clinical utility is just beginning to be evaluated. This project will develop a disease-based simulation model and perform a cost-utility analysis from multiple stakeholder perspectives to help inform treatment decisions and guidelines and reimbursement policies.

Activities/Achievements

  • The outcomes analysis (the retrospective study), the cost-utility analysis (economic model), and the survey of anticoagulation clinicians are all completed.
  • Findings of the project:
    • Patients with CYP2C9 variants achieved stable warfarin dose later and had higher odds of over-anticoagulation compared to patients without. Patients homozygous for the VKORC1 low-dose haplotype had higher odds of over-anticoagulation than heterozygotes.
    • CYP2C9 alone, VKORC1 alone, and a combination of genetic and clinical factors explained 12%, 27%, and 50%, respectively, of variation in warfarin maintenance dose.
  • Publications:

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Effect of Folic Acid Intake on Blood Folate and Homocysteine Levels in Persons Classified by Genotype of Folate-related Genes

Principal Investigators: Quanhe Yang (NCBDDD), Margaret Gallagher (NCEH), David Erickson (NCBDDD), and Karen Steinberg (CoCHP)

Abnormalities in the metabolism of folate and homocysteine are associated with cardiovascular disease and other conditions that contribute significantly to morbidity and mortality in the United States. Recently, researchers have identified several common polymorphisms of genes related to folate and homocysteine metabolism, including the C677T and the A1298C alleles of 5,10 methylenetetrahydrofolate reductase (MTHFR), the 844ins68 allele of cystathionine-beta-synthase (CBS), and the A66G allele of methionine synthase reductase (MTRR). These genetic variants may influence folate metabolism and disease risk, and that some of their effects may be mediated by gene-gene and gene-environment interactions. This study will assess whether the effect of folic acid intake on the blood levels of folate and homocysteine varies by genotype of folate-related genes, using data and DNA samples from NHANES III.

Activities/Achievements

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An Early Childhood Mortality Study using a Newborn Blood Spot Screening Test for Severe Combined Immunodeficiency Disorder (SCID)

Principal Investigators: Barbara Adam and Robert Vogt (NCEH), Richard Olney (NCBDDD), Franco Scinicariello (ATSDR), Chin-Yih Ou (NCHSTP)

Severe Combined Immunodeficiency Disorder (SCID) is a group of genetic conditions characterized by profound defects in both cellular and humoral immunity. Caused by the nearly complete failure to develop functional T-cells, SCID leads to severe bacterial and viral infections; without treatment, affected infants usually die within a year of birth. NIH and CDC have developed assays to detect profound T-cell lymphocytopenia by testing dried blood spots. Both assays use realtime PCR to measure T-cell recombination excision circles (TREC), the episomal circular DNA that is excised from T-cells when their V-genes recombine with the constant region genes of the T-cell receptor. The goals of this proposal are: 1) to establish authoritative methods for the standardization of the TREC assay to foster its systematic translation to public health newborn screening; 2) to determine the extent to which SCID contributes to early childhood mortality; and 3) to establish an ongoing partnership with the Newborn Screening Program in the California Department of Health Services to facilitate the investigation of other occult contributors to early childhood mortality.

Activities/Achievements

  • Expanded the number of matched controls to bring total sample size to 4,000.
  • Worked on assay development and standardization; mortality records gathered and linked.
  • Sample analysis is underway and expected to be completed in early 2010.
  • Project is contributing to the increasing momentum among state screening laboratories to incorporate newborn screening for SCID into pilot programs and is laying the groundwork for routine screening.
  • Presentations:
    • Wisconsin Newborn Screening-Severe Combined Immunodeficiency Disorder (NBS-SCID) Advisory meeting, January 2008.
    • Association of Public Health Laboratories (APHL) Newborn Screening Symposium, November 2008.
    • HHS Secretary’s Advisory Committee meetings, January 2009 and May 2009.
    • NBS-SCID workshop cosponsored by the Jeffrey Modell Foundation, November 2009.

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Osteoporosis: A Multi-determinate Approach to Prevention: Implications for the CDC Health Protection Goal of Living Better and Longer

Principal Investigator: Anne Looker (NCHS)

Osteoporosis is a major cause of morbidity in the elderly. Inherited factors are important determinants of peak bone mass, although the influence of genetic factors on bone turnover and changes in bone mass with aging is less clear. Over the past 20 years, several candidate genes have been associated bone mineral density (BMD); however, most studies have been conducted on relatively small convenience samples and few have examined the role of candidate genes on bone loss or fracture occurrence. This study will help fill these gaps by examining the relationship between these endpoints and two candidate genes: low-density lipoprotein -receptor related protein 5 (LRP5) and the 116 T/G (Ser37Ala) polymorphism of the bone morphogenetic protein 2 (BMP2) in a very large, community-based sample. The study takes advantage of an existing relationship with Kaiser Permanente San Diego.

Activities/Achievements

  • Decided to identify de novo more single-nucleotide polymorphisms (SNPs) in candidate genes LRP5 and BMP2 to expand the project.
  • Genotyping is ongoing of approximately 27,000 participants from an existing cohort and approximately 5,000 new recruits for genetic studies on osteoporosis, both from the Kaiser San Diego Health Appraisal Clinic.
  • Gathered and linked health information. Statistical analyses are underway (as of April 2009).
  • DNA and plasma samples from the new cohort of approximately 5,000 subjects recruited under this project are available for studies of other gene-disease associations, another broad goal of the project.

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The Interaction of Community-level Social and Environmental Stress and Inflammatory Pathway Genes with Risk for Very Preterm Birth

Dhelia Williamson (NCCDPHP)*
*formerly Althea Grant (NCCDPHP) and then Karon Abe (NCCDPHP)

Preterm birth, which accounts for 12% of births in the United States, is the leading cause of perinatal mortality in the United States. Preterm birth is also a leading cause of long-term neurological and pulmonary disorders. Furthermore, there are striking disparities in the rate and consequences of preterm birth across racial and ethnic groups in the United States. For instance, blacks have almost twice the rate of preterm birth as whites and have a four-fold higher rate of infant mortality due to preterm birth compared to whites. One of the major obstacles to reducing preterm birth has been our inability to effectively predict which women are at greatest risk of spontaneous preterm delivery (PTD). Genetic differences may be the key to identifying women at greatest risk for PTD and for designing and targeting effective therapies. This study aims to determine the association between neuroendocrine and inflammatory pathway gene polymorphisms, environmental factors, and spontaneous preterm birth among mother-infant pairs from three race/ethnic groups (Mexican Hispanics, Non-Hispanic whites and Non-Hispanic blacks) through a retrospective population-based nested case-control study within a cohort of term (gestational age ≥37 weeks) and preterm (gestational age <37 weeks) births in California.

Activities/Achievements

  • Genotyping being conducted on approximately 4,000 maternal and infant specimens from an existing population-based investigation as part of a collaboration between the CDC and the California Department of Health Services.
  • Changed genotyping platform to expand number of polymorphisms tested to approximately 1,500.
  • Developed medical record abstraction process.
  • Completion of data cleaning, analyses, and manuscript development expected April 2010 or later.
  • Presentations/posters:
    • Maternal and Child Health Branch Conference, California Department of Health Services, Sacramento, CA, March 2006.
    • Neonatal Medicine Grand Rounds, University of Miami School of Medicine, Miami, FL, September 2007.
    • CDC’s 10 Years of Public Health Genomics Meeting, January 2008 (poster [PDF 3.23 MB]).
    • Society for Pediatric and Perinatal Epidemiologic Research annual meeting, June 2009.
  • Future plans: a literature review of Maternal and Infant Genetic Contributions to Spontaneous Very Preterm Birth Using a State-Based Biobank.

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