Cystic Fibrosis (CF) is the most commonly inherited, life-shortening genetic condition amongst Caucasians, with an incidence of about 1 in 3,800 newborns and currently affecting about 30,000 Americans. It is chronically debilitating and the annual cost of medical care per person makes it a serious public health concern. Airway inflammation contributes to progressive pulmonary disease, the leading cause of morbidity and mortality in patients with Cystic Fibrosis. The mechanism by which the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene affects airway inflammation has not been fully elucidated to date; however, several mechanisms have been proposed. Despite the need for continued study in determining this mechanism, we do know that mutations in the CFTR gene ultimately result in bacterial colonization in the lungs, reduced mucociliary clearance and airway inflammation. Chronic airway inflammation results in continued assault on the lungs and progresses the course of the disease. Airway inflammation can be monitored through the use of bronchoalveolar lavage to evaluate the influx of neutrophils; however, routine bronchoscopy is an invasive procedure and is less than ideal for routine assessment. Exhaled gas as a marker for airway inflammation is useful in that it is minimally invasive and relatively easy to obtain. Some of the data on the clinical utility of exhaled gas measurements has been conflicting with regard to its efficacy in assessing airway inflammation. If exhaled gas measurements can be used to assess airway inflammation, they could provide a non-invasive alternative to monitor inflammation and do so more frequently than invasive methods, with the ultimate goal of being able to detect inflammation earlier with the intent of earlier treatment and possible reduction in progression of lung disease.

The Center for Minority Health at the University of Pittsburgh aims to eliminate racial and ethnic health disparities especially in the areas of diabetes and hypertension. One avenue for eliminating racial and ethnic health disparities is through biomedical and public health research. The CMH strives to increase African American participation in research through community outreach programs including the Healthy Black Family Project. The HBFP is a community based intervention created to promote health and prevent disease through lifestyle behavior change in the African American community in Pittsburgh. The present study recruited individuals from the HBFP for focus groups to assess the perceptions of African Americans in the Pittsburgh area toward genetics and genetics research. Specifically, the study sought to characterize the willingness of African Americans to donate DNA for research examining the roles of genes and environment in disease development. The CMH is interested in this research because it has been suggested that uncovering the genetic and environmental contributions to common diseases such as diabetes and hypertension may help illuminate causes of racial and ethnic health disparities and allow for more effective strategies for prevention and treatment. Transcripts from four focus groups attended by 43 people were read and coded using thematic analysis. Findings suggest participants are acutely aware of potential negative consequences of donating genetic material however, cautious optimism was expressed when discussing benefits of research. Additionally, the results suggest that researchers must actively work to build trust with potential research participants to increase willingness to participate. The findings also suggest a strong association of the term genetics with family history, a limited understanding of the biological aspects of genetics, and a sensationalized view of genetics research. These last three issues may be addressed through a genetics education outreach program. This study is relevant to the field of public health because it provides researchers with direction in their effort to better characterize the willingness of African Americans to donate DNA for genetics research.

Each year 15-20 infants with sickle cell disease and 600 infants with trait are born in western Pennsylvania with no significant decrease in annual incidence. A 2006 study by Childrens Hospital of Pittsburghs Comprehensive Hemoglobinopathy Program surveying African-American women in the prenatal setting found that these women have a high perception of the severity of sickle cell disease and the importance of sickle cell trait screening but a low perceived susceptibility to sickle cell disease. The current research was designed as a qualitative follow-up study to assess African-American community members attitudes and knowledge of sickle cell, prenatal testing, and newborn screening, to characterize barriers to education and awareness of newborn screening and sickle cell, and to determine if a community-based intervention could be developed to improve awareness of these topics. Four focus groups were conducted with 35 participants at the Kingsley Association in a predominantly African-American community of Pittsburgh. Participants were recruited from the Healthy Black Family Project. Transcripts were analyzed using thematic analysis and demographic information was compiled from a pre-discussion survey. Qualitative analysis has demonstrated that participants fall into one of three knowledge categories: the unaware, those with accurate but incomplete information, and those with misinformation. Participants have an understanding of sickle cell disease course. However, inheritance of sickle cell and the personal risk to have children or family members with the condition is not well understood. Participants have knowledge of the methods and indications for prenatal testing and value prenatal testing for the opportunities for choice and awareness. Risks of prenatal testing were identified as miscarriage as well as personal and family stress. Newborn screening was believed to be beneficial for preparation and treatment. Barriers to education and awareness of sickle cell and newborn screening were classified as personal, familial, and societal. The public health significance of this work is the identification of community members who are eager to decrease the prevalence of sickle cell in their community and the potential to design community discussion groups which address genetics topics and provide African-Americans with the tools to communicate with family and physicians about risk for sickle cell.

Systemic lupus erythematosus (SLE) is a major public health problem in the United States. It is estimated that at least 500,000 Americans suffer from (SLE), which is a complex autoimmune disease of primarily unknown etiology. SLE is about three times more common in African Americans (about 1:250 incidence) than in Caucasian Americans (about 1:1000 incidence), and predominantly affects women of child-bearing age (female to male ratio of 9:1). SLE causes a variable amount of morbidity, shortened life expectancy, and substantial total health expenditures, largely due to complications such as thrombosis, atherosclerosis, renal disease, and antiphospholipid syndrome (APS). Genetics plays a significant role in the etiology of SLE; therefore, understanding the underlying genetic influence of this disease is of significant public health importance. This study dealt with the analysis of one of the genes that has been proposed to play a role in the pathogenesis of SLE: apolipoprotein H (APOH gene, apoH protein), also referred to as B2-glycoprotein I (B2-GPI). ApoH is thought to have anti-atherogenic properties and has been shown to be a major target antigen for antiphospholipid antibodies (APA) present in patients with APS. Twelve APOH SNPs (9 TagSNPs and 3 additional functional coding SNPs) were genotyped in 398 women with a clinical diagnosis of SLE and 496 healthy women as controls. The associations of allele and genotype distributions of these 12 SNPs with SLE, race, renal disease in white patients, and APA in black and white patients and controls were analyzed. Significant allelic distribution differences were observed between whites and blacks for 9 of the 12 SNPs, indicating a race-dependent variation. No associations were found between genotype distributions in any of the 12 SNPs and SLE, renal disease, or APA status. However, haplotype analysis revealed six haplotypes that significantly differed in frequency between cases and controls. Of particular interest was one haplotype that was present in 16.2% of cases and 0.6% of controls, suggesting a potential risk factor for SLE. In conclusion, our study suggests that combined effects of APOH SNPs (haplotype) may be implicated in modifying the risk of SLE.

Bipolar disorder (BPD) is a serious mood disorder that affects about 1% of the population of the United States. Twin, family, and adoption studies have shown evidence for a genetic component of BPD, but monozygotic twin concordance is less than one, indicating that BPD is a mulitfactorial disorder. First-degree relatives of an individual with BPD have approximately a 3-15% risk of developing BPD because of shared genes and environment. No strong genetic susceptibility loci for BPD have been located, although some regions of interest are currently being evaluated. With increasing genetic information, it is expected that demand for genetic counseling for BPD and other psychiatric disorders will increase. This project is relevant to public health because BPD is a common disorder with a significant disease burden. Understanding the needs and concerns of the patient population can help tailor care and reduce the burden of the disease. Using anonymous surveys and a semi-structured interview for individuals with BPD and their first-degree relatives, the knowledge, opinions, and acceptance of genetic counseling in this population have been studied. The Health Belief Model was used to assess current health beliefs relating to BPD. Additionally, using a brief educational session, the effect of education on knowledge and health beliefs was assessed. Preliminary data show that the perceived severity of BPD, susceptibility to BPD, and perceived benefit of genetic information were high at 4.33, 4.45, and 4.36 out of 5, respectively, while the cumulative perceived barriers to testing were moderate to high at 3.09 out of 5. Preliminary data also show that the knowledge of BPD in affected individuals is high at 7 (±1.15) out of 8.

Type 1 diabetes mellitus (T1D) is a disease of major public health concern as it is one of the most common diseases of childhood and costs millions of dollars in health care each year in the U.S. T1D is an autoimmune disease and is caused by multiple factors including genetics, autoimmunity, and environment. The genetics of T1D is complex as there are multiple genes thought to play a role in its susceptibility, with the best defined risks associated with the HLA-DQ molecule. This study analyzes the role of the DQ molecule in 265 diabetic children and 1000 unaffected first degree relatives in order to further support the current literature of the presence of specific DQ alleles and haplotypes with a large representative sample from the U.S. In the diabetic probands, the analysis was supported by the previous literatures for the presence of non-Asp 57 alleles but not for the presence of the DQ2 and DQ8 haplotypes. In this study, 94.14% (96.65% including the DR2 group) have at least one non-Asp allele with a breakdown of 30.54% as non-Asp/Asp (33.05% including DR2) and 63.60% with non-Asp/non-Asp, and 6% Asp/Asp. The distribution of the DQ2 and DQ8 haplotypes includes, 78.63% possessing DQ2 and/or DQ8 haplotypes with 6.49% as DQ2 homozygotes (DQ2/DQ2), 4.96% as DQ8 homozygotes (DQ8/DQ8), and 16.79% as DQ2/DQ8 heterozygotes. These figures are only slightly higher when looking at the Caucasians or the individuals with younger ages of onset. These unexpected results may be the result of clinical or ethnic variability in the population, however further investigation is warranted. While there is limited information available of the non-Asp alleles and DQ2 and DQ haplotypes for first degree relatives, the results in the study seem to be supported both by previous studies and on the risks associated with each haplotype. Results show that 33.59% non-Asp/non-Asp, 58.2% Asp/non-Asp (with 14.55% of these individuals non-Asp/0602 specifically), and 8.21% Asp/Asp. In the DQ2 and DQ8 analysis 68.34% had DQ2 and/or DQ8 haplotypes, with 31.94% as DQ2 homozygotes or heterozygotes, 30.11% were either DQ8 homozygous or heterozygous, and 6.31% were DQ2/DQ8 heterozygotes.

Since September 1992, Sickle Cell Trait (SCT) has been a standard on the state of Pennsylvanias newborn screen. Therefore, as of 2006, all middle school aged children will have had newborn screening. Currently, no information about Sickle Cell Disease or trait is included in the curriculum of the Pittsburgh Public Schools (K-12). There are three goals for this project: To educate the teenagers of Pennsylvania about Sickle Cell Disease and Trait, teaching them what their trait or disease status means for their health, and for their future childrens health; To provide the schools with an appropriate curriculum and; To create a module that can be repeated in school systems throughout the country. Approval of funding by the Pittsburgh Public Schools Board of Education allowed for the hiring of three teachers to aid in the writing of an appropriate curriculum. The curriculum includes three lessons that involve watching a video, writing informational materials, learning about genetics, and creating a poster. To assess this program and its effectiveness, health teachers critiqued the curriculum designed by their peers and provided feedback on ways to improve the implementation of new health material to existing lesson plans. After making modifications from this feedback, future projects may include adding a Sickle Cell Disease and Trait curriculum into the high school and eventually elementary schools. We would like to eventually share the curriculum online through a dependable source so schools throughout the nation have access to the lesson plans. The project is relevant to the field of public health because it directly educates individuals about SCT and SCD at an early age. They will be able to reference this information in the future when they are faced with making reproductive decisions.

The American Cancer Society estimates that >500,000 new cases of squamous cell carcinomas of the head and neck (SCCHN) are diagnosed each year. Although the incidence varies widely around the world, it is especially high in developing countries and is positively associated with higher rates of exogenous risk factors including, smoking, alcohol use, and viral infection. But, only a fraction of the people in these high-risk groups will develop the disease. Treatment times tend to be long and costly with survival rates averaging 50%, one of the lowest for the major cancers. Therefore, further work is needed to aid in our understanding of genetic and environmental risk factors, as well as the underlying biology of SCCHN. To further assess the etiology of SCCHN, the study used the approach of examining one candidate gene, the Ataxia Telangiectasia Mutated gene (ATM), located at 11q22.3 and functioning in the DNA damage response/repair pathway. Compared to other cancers, SCCHN tumors exhibit a very high rate of chromosomal instability, often showing amplification of chromosome 11q13 and loss of 11q22-qter. We hypothesized that SCCHN patients (cases) have a higher incidence of germline alterations in ATM than controls. Three hundred cases and 360 controls were genotyped for nine ATM tag-SNPs and supplemented with one splice-site SNP. Logistic regression analysis showed that two SNPs (rs611646 and rs373759) were associated with increased risk of developing SCCHN: P = 0.012 and P = 0.025, respectively. In SNP rs611646, the TT genotype was more common in cases than controls (45 versus 32%) while the AA and AT genotypes were less common in cases than controls (18 versus 21% and 37 versus 46%, respectively). In SNP rs373759, the CC genotype was more common in cases than controls (56 versus 48%) with the CT type being less common in cases than controls (29 versus 40%). Genetic studies such as this could have a public health impact by identifying markers for early detection of SCCHN, for predicting prognosis, for therapy and drug development, and aiding in the development of new, individualized treatment strategies.

Coronary heart disease (CHD) is a major public health concern, affecting almost 16 million people in the U.S. and leading to 452,300 deaths in 2004 alone. Low levels of high density lipoprotein (HDL) cholesterol have been shown to increase the risk for cardiovascular disease (CVD). The role of genetics in affecting total cholesterol, HDL-cholesterol, and triglycerides levels is significant, with heritability estimates exceeding 50%. Recent studies have identified major loci associated with HDL-cholesterol through genome-wide association studies, which investigated influences of common variants on common traits. Relatively few studies have investigated the impact of rare variants (or common variants with a modest affect) on common disease. The aim of our study was to evaluate the genetic variation in APOA2 (a biological candidate gene involved in HDL metabolism) in relation to HDL-cholesterol levels in epidemiological samples of African Blacks and U.S. Non-Hispanic Whites (NHWs). We resequenced APOA2 in individuals with HDL-cholesterol levels in the upper 5th percentile (47 NHWs and 48 Blacks) and lower 5th percentile (48 NHWs and 47 Blacks), allowing us to identify both rare and common variants. Common tagSNPs and all rare variants have been screened in the larger NHW and Black samples for associations with HDL-cholesterol levels. We detected a total of 26 variants (25 single nucleotide substitutions and 1 microsatellite); 12 of which were previously unreported. Of the 12 new variants, 6 were present in NHWs and 6 in Blacks. We observed an increased number of minor alleles of APOA2 variants (either increased heterozygosity for rare variants or increased homozygosity for common variants) in subjects with low HDL levels, more pronounced in NHWs. We performed a preliminary analysis using a total of 9 variants that were screened in NHWs (n=624, 8 variants) and Blacks (n=788, 5 variants) with TaqMan SNP genotyping assays to date. For the 8 variants that were screened in NHWs, we found significant association in only females for variants 2233C>T/rs6413453 (p=0.028) and 3251A>G (p=0.023). Completing genotyping for remaining variants will allow us to determine the extent to which APOA2 variants influence HDL levels.

Research Purposes: Multiple studies have quantified the direct and indirect costs of cancer care; however, there is little attention to how concerns about costs impact the emotional health of family caregivers. The purpose of this study, using the Pittsburgh Mind Body Center Model, was to evaluate how perceptions of economic hardship influence burden, anxiety, and depressive symptoms in caregivers of persons with a primary malignant brain tumor. Methods: Data were from an ongoing, longitudinal study (NCI R01CA118711). Caregiver (CG)/care recipient (CR) dyads (n=33) were recruited within a month of the CRs diagnosis; data were collected at the point of diagnosis and 4 months later. CRs were questioned using the Neurocognitive Status Exam (NCSE) and CGs completed questionnaires to determine perceptions of economic hardship, burden (Caregiver Reaction Assessment), anxiety (POMS), and depressive symptoms (CES-D). Linear regression was used to examine relationships among variables. Results: Perceived economic hardship had a significant effect on two CG burden subscales: feelings that providing care negatively affected ones schedule, and feelings of abandonment. Economic hardship did not predict CG burden due to schedule at baseline, but did significantly (p<.01) predict burden 4 months later. Alternately, economic hardship predicted burden due to feelings of abandonment at the time of diagnosis (p<.01), but not 4 months into the care situation. CG depression was predicted by economic hardship 4 months after diagnosis (p=.05), but not at the initial interview. Economic hardship predicted CG anxiety at both the time of diagnosis and at the second interview (p<.01). Conclusions: Results suggest that caregivers perception of economic hardship may be an important yet variable aspect of the burden, anxiety, and depression caregivers feel at the time of diagnosis and throughout the care situation. Public Health Significance: Caregivers of persons with a chronic disease such as cancer face financial pressure that may have negative emotional consequences. Although it may not be feasible to alleviate economic hardship, interventions may be effective in decreasing associated feelings of burden and anxiety during the care situation, and preventing the escalation of depressive symptoms.