Heart disease continues to be the leading cause of death in the United States, making it one of the foremost public health concerns. Many factors influence the risk to develop heart disease, including abnormal blood lipid levels. High levels of plasma high-density lipoprotein (HDL)-cholesterol have been shown to have a protective effect. Recent genome-wide association studies (GWAS) and candidate gene studies have identified genes thought to contribute to HDL-cholesterol levels. Two genes, APOA1 and APOA4, have been associated with HDL-cholesterol levels in multiple studies with inconsistent results. The majority of these studies focused on the common variant-common disease hypothesis whereas only one study by Cohen et al. (2004) evaluated APOA1 using the rare variant-common disease hypothesis. The aim of this study was to further investigate the role of common and rare variation in these two genes by sequencing individuals having extremely low and high HDL-cholesterol levels in two populations, U.S. Non-Hispanic Whites (NHWs), and African Blacks, and then screening the identified variants in the entire sample. In the initial sequence analysis, 54 variants were identified in APOA1 (25 of which were new), and 43 in APOA4 (21 of which were new). According to preliminary analysis of the sequencing data for APOA1 and APOA4, no striking difference was noticed between the distribution of rare variants between high and low HDL groups in either population. To date, screening data was compiled for the entire NHWs and Black samples for a total of seven common variants: 2 for APOA1 (rs5070 and rs5072), and 5 in APOA4 (rs5092, rs5100, rs5104, rs5106, and rs5109). All 7 variants were present in the Black population; five were present in NHWs (rs5070, rs5072, rs5092, rs5100, and rs5104). Modest or marginal significant p-values were observed; however, none would maintain significance after multiple testing correction in either population. Additional variants identified in sequencing remain to be screened in the entire NHWs and Black samples.

PURPOSE: Brugada syndrome is an autosomal dominant arrhythmia condition caused by genetic mutations affecting the cardiac conduction system. It is characterized by an abnormal electrocardiogram pattern and a predisposition to syncope and sudden cardiac death. Penetrance is incomplete and expressivity varies greatly within families. This condition is endemic in Southeast Asia, but was described in North America and Europe in 1992. Due to its novelty and complexity there is a scarcity of informational resources. The first aim of this project was to gain insight from individuals and families with Brugada syndrome and to use this information to accomplish the second aim: an educational resource well-suited for families coping with Brugada syndrome. The public health relevance of this project reflects its application to genetic counseling: the development of patient educational resources involves a careful assembly of content and design with attention to patient needs. METHODS: Ten participants completed a questionnaire which addressed general understanding of the condition, personal experiences, terms and concepts related to Brugada syndrome, and individual perspectives. The responses to the questionnaire were used to help shape an educational resource. RESULTS: Analysis of the questionnaire responses revealed that some main concepts are well-understood by this study population, while there is considerable lack of understanding of other important concepts associated with Brugada syndrome. Overall participants expressed needs for more information and tools for coping with the condition. CONCLUSION: A two part educational resource was created to address these needs. A short introductory pamphlet was produced for use as an initial introduction to the condition and an in-depth resource called Brugada syndrome: A Guide for Families was created. The resources include patient-friendly explanations of symptoms, diagnosis, treatment, children, inheritance, genetic testing, and support resources.

The inability to measure individual risk for SUD, particularly at a young age, hinders etiologic research and prevention. Previous research has developed an index of transmissible liability (TLI)that covers the entire range of liability phenotypes, does not rely on SUD symptoms, is derived from items drawn from psychological and psychopathological instruments, and can be applied in a young or otherwise asymptomatic population. TLI has high heritability and has been validated as a measure of transmissible risk for SUD in previous studies. This index, however, requires information obtained not only from the individuals but also from their parents and teachers. Developing SUD liability indices that do not involve those additional informants could augment the feasibility and efficiency of measurement. One of the goals of this study was to construct new indices based on a reduced number of questionnaire items used to derive the original TLI and determine their utility in measuring risk for SUD. Another purpose of this study was to investigate composition of phenotypic variance of the newly developed liability indices. Participants were self-selected twin pairs attending the 2006, 2007, and 2009 Twins Day Festivals in Twinsburg, OH, and participants in the CEDAR database from the University of Pittsburgh. Results of this research indicate that the ability of the newly developed liability indices to predict SUD is similar to that of the original TLI. Biometrical genetic analysis showed that the phenotypic variance of the new SUD liability indices is comprised of approximately equal additive genetic and unique environmental components. This study has public health relevance as it developed new measurement techniques to identify individuals at high risk of developing SUD, which will be beneficial for prevention and intervention.

Heart disease (HD) is a primary public health concern, with HD being one of the leading causes of death every year in the United States. Many risk factors influence HD, including lipid levels, and studies have shown that higher levels of plasma high density lipoprotein (HDL) cholesterol have a protective effect against HD. Recent genome-wide linkage scans have associated a locus on chromosome 7, harboring CD36, as being involved in components of the metabolic syndrome, including HDL-C levels. Therefore, identifying variation in this gene affecting HDL-C levels is of great public health importance. The "common variant-common disease" hypothesis has been tested by a limited number of studies through common SNP genotyping with inconsistent results. To date, no studies to our knowledge have evaluated CD36 using the "rare variant-common disease" hypothesis. The aim of this study was to further evaluate the role of common and rare variation in CD36 by sequencing individuals having extremely low and high HDL-cholesterol levels in two populations, U.S. Non-Hispanic Whites (NHWs), and African Blacks. In our initial sequence analysis, 343 variants were identified in CD36, 168 of which were previously unreported in the SeattleSNPs database. According to preliminary analysis of the sequencing data, our findings support the associations of three SNPs with HDL-C levels reported in the literature. No striking difference was noticed between the distribution of rare variants between high and low HDL-C groups. We identified four common variants (MAF ≥ 5%) in our sequencing data from our small sample that displayed statistically significant differences in MAF between the low and high HDL-C groups but have not been confirmed yet by genotyping in the entire NHW and Black populations while thirteen common variants had p-values between 5-10%, which may be statistically significant due to the small sample size. To date, screening data was compiled for the entire NHWs and Black samples for a total of nineteen common variants. None of these variants displayed a significant p-value in our entire NHW and Black samples. Additional variants identified in sequencing remain to be screened in the entire NHW and Black samples.

Late-onset Alzheimers disease (LOAD) is a multifactorial disease with the potential involvement of multiple genes. Complex diseases such as LOAD have a large affect on public health due to the significant financial burden of health care for these individuals. Genetics plays a significant role in the etiology of the disease, therefore it is of public health importance that the genetics of LOAD be investigated. There is a known association between APOE gene variants and LOAD. No additional genes have been consistently demonstrated to be associated with risk of LOAD. Multiple recent genome-wide association studies (GWAS) have found variants showing significant association with LOAD. Twelve SNPs were chosen from four GWAS for a replication study to determine if the associations seen between SNPs and AD risk in the respective studies were present in our population. Ten additional positional candidate SNPs were chosen on chromosome 10 because of observed linkage peaks for AD and predicted imprinted genes in this region. We genotyped these 22 SNPs as well the E2/E3/E4 APOE polymorphism in up to 993 Caucasian Americans with LOAD and up to 976 age-matched healthy Caucasian Americans. Our data showed no statistically significant associations between the 22 SNPs examined and the risk of AD. Stratification by APOE*4 carrier status also failed to reveal statistically significant associations. Additional analyses were performed to examine the potential associations between the 22 SNPs and age-at-onset, disease duration, and baseline MMSE score. The analysis revealed significant associations between two SNPs, rs3746319 (p=0.002) and rs16934131 (p=0.045), and age-at-onset. One SNP, rs16934131 (p=0.0002), was found to be significantly associated with disease duration. Three SNPs, rs16934131 (p=0.002), rs12781609 (p=0.012), and rs5984894 (p=0.009), were found to be associated with baseline MMSE score in controls. Of note, rs16934131, demonstrated statistically significant association with age at onset, disease duration, and MMSE score. Further study may be necessary to definitively rule out associations between these variants and LOAD.

There is a general lack of awareness regarding sickle cell trait in the field of athletics. While sickle cell trait is usually considered a benign condition, there have been reports of serious complications during extreme conditions (i.e. high altitude or hot temperatures) among competitive athletes. In June 2009, the National Collegiate Athletic Association (NCAA) recommended that all of its student athletes determine their sickle cell trait status, if unknown. Testing athletes for sickle cell trait has possible undesirable implications, such as stigmatization and discrimination against athletes with sickle cell trait. This project aimed to prevent these negative implications by developing a novel program to provide sickle cell education, testing, and pre/post-test counseling for students in collegiate athletic programs. The Pediatric Sickle Cell Program at Childrens Hospital of Pittsburgh (CHP) collaborated with the University of Pittsburgh in July of 2009 to facilitate voluntary testing of student athletes for sickle cell trait. Our program provided pre-test counseling, testing within the University of Pittsburghs athletic training facilities for each student athlete, and post-test counseling, regardless of trait status. We met with athletic department staff to provide sickle cell trait education, methods to prevent exercise-related sudden death, and emphasized the importance against stigmatizing student athletes with sickle cell trait. Testing and education were received well by both coaches and athletes. In total, we tested 79 student athletes; two of which were found to have sickle cell trait. Our program in the future plans to work with the University of Pittsburgh Athletic Department again and expand testing protocols to other universities in the area. In addition, future studies will assess the student athletes experience during testing and reasons why some athletes chose not to be tested. The public health significance of this project is two-fold: to create a testing protocol and educational plan that can be individualized for the needs of a university, while maintaining the autonomy and privacy of the student athletes, and ensuring beneficence and non-malfeasance. In addition, the project raised awareness of sickle cell trait in the field of athletics, which will prevent sudden death among otherwise healthy, young athletes.

Objective: Research has shown that a variety of socio-demographic and health-related variables influence physical activity. In this study, we explored the role of risk perception and other variables in the physical activity level of a group of Black women. Methods: The Healthy Black Family Project (HBFP) is an initiative set forth by the University of Pittsburghs Center for Minority Health. The Family Health History intervention (FHH) is an aspect of the HBFP that assesses disease risk by examining family history. As part of the FHH, information is collected about participants perceived risk for chronic disease, self rated health, self rated weight, and body mass index. In this study, we examined the relationship between these variables and the level of physical activity in two subgroups of Black women at baseline before the FHH intervention; one subgroup of women without disease and one subgroup of women who have at least one chronic condition (cardiovascular disease (CVD), diabetes or high blood pressure (HBP)). We then examined the change in physical activity level in both subgroups 4 weeks after the FHH intervention. Results: In the population of women with no health conditions, there was a significant relationship between physical activity level and risk perception for disease. Women with low risk perception for CVD and diabetes tended to be physically active. In the population of women with at least one health condition, there was a significant relationship between physical activity, self-reported general health and age. Women who perceived their health as excellent/very good/good tended to be physically active. Women over age 60 tended to be physically active and women under age 50 tended not to be physically active. There was no significant difference in the change in physical activity 4 weeks after the intervention between the two groups. Conclusions: The data suggests that Black women affected and unaffected with chronic disease may have different health beliefs and attitudes influencing their decisions to be physically active. The public health significance of this study is that increased knowledge of possible modifiers of physical activity can aid in the implementation of appropriate interventions.

Von Hippel-Lindau disease (VHL) type 2A is a rare inherited tumor predisposition syndrome, which is primarily associated with benign tumors of the blood vessels of the central nervous system and eyes and benign tumors of the adrenal gland, though renal cell carcinoma (RCC) can also be part of this tumor spectrum. Two large regional VHL type 2A kindreds have been assessed over decades at the University of Pittsburgh. Both kindreds have markedly high rates of adrenal and extra-adrenal pheochromocytoma, and almost no cases of RCC. By mutational analysis, each kindred has a separate disease-causing missense mutation of the VHL gene: Y112H (334 T to C) in Family 1, and Y98H (292 T to C) in Family 2. Both gene changes arise from a tyrosine to histidine substitution in exon 1 of the VHL gene on chromosome 3p25. Phenotypic expression in the family with Y112H (Family 1) has been described in the past, however the phenotype related to Y98H (Family 2) has not heretofore been described. Although these mutations are similar and occur within the same region of the gene, I hypothesize that there are differences in disease expression between the families, particularly related to pheochromocytoma. The aim of this study is to evaluate the phenotypic expression of VHL in these genotypically different VHL type 2A kindreds. Public Health Significance: Although VHL disease is clinically rare, the treasure trove of information provided by large VHL type 2A kindreds can help to clarify phenotype, penetrance, and survival patterns as well as further define surveillance algorithms.

OBJECTIVES: The objective of this study is to determine factors which may affect Health Black Family Project members participation in the Minority Research Recruitment Database (MRRD), as established through the Center for Minority Health and the Family Health History initiative. METHODS: MRRD enrollment was offered to 799 African American individuals after participation in a Family Health History session. Of the 799 offered enrollment, 599 (75.0%) agreed to enroll in the database and to be contacted regarded clinical research studies for which they may qualify. Factors assessed to determine their influence on willingness to enroll include demographic data, research attitudes, objective and perceived disease risks, weight, physical activity level, student interviewer, and the degree of control which people believe they possess over their personal health as measured by the Multidimensional Health Locus of Control questionnaire. Chi-square analyses and logistic regression were undertaken to compare these factors with willingness to enroll in the database. RESULTS: Analyses indicate that the following factors significantly affect willingness to enroll in the MRRD: being over age 65, health insurance status, research attitudes, previously declining research participation, reaction to incentives of money and free medical care, how much they believe family and friends benefit from research, degree to which they believe diet contributes to disease risk, student interviewer, Multidimensional Health Locus of Control Powerful Others scale, and self-described weight. Logistic regression of selected variables determined that reaction to monetary incentives, student interviewer, and self-described weight are key factors which may influence MRRD enrollment. CONCLUSIONS: The infrastructure of the MRRD has been shown to be an effective method for recruiting African Americans into a research database. Several factors have emerged as important in the determination of willingness to enroll, which represent both replications of the known literature and new findings unique to this research. PUBLIC HEALTH SIGNIFICANCE: African Americans are underrepresented in many areas of medical and public health research. More effective strategies are needed to increase recruitment into research studies by understanding factors presented here which may play a role in an individuals choice to participate in research.

Bipolar disorder is a mood disorder that affects about 1% of the population, representing a significant public health issue. Bipolar disorder can be associated with substance abuse problems, unemployment, increased marital dysfunction, and increased use of health services. Twin studies provide evidence that genetics plays a role in the etiology of bipolar disorder with heritability estimates as high as 93% in some studies. Molecular genetic studies were initially promising, but no genes with large effect sizes have been discovered. There is also evidence that suggests a multifactorial inheritance pattern. Consequently, genetic testing is not yet available. However, as advances are made in the understanding of genetics and psychiatric disorders, it is expected that the demand for genetic counseling for bipolar disorder will increase. Genetic counselors are well-equipped to educate patients and family members about the condition, to discuss their concerns about the risk of bipolar disorder, and to offer genetic testing should it become available. For this qualitative study, interviews were conducted to explore the opinions and perceptions of individuals with bipolar disorder and/or their siblings. The open-ended questions were designed to elicit the thoughts and attitudes about bipolar disorder and genetic counseling. Thematic analysis was performed on the transcripts from 10 interviews and the following themes were identified: excessive disease burden, variable causal attributions, desire for diagnostic test for BPD, and reproductive considerations.