A ppalachian C ardi o vascular R esearch N etwork ( ACoRN )

1. Appalachian Cardiovascular Research Network (ACoRN) Donald A. Primerano, Director Investigators at graduate and undergraduate institutions Funded through NCRR WV-INBRE grant Part 1: ACoRN Part 2: Problems and Solutions to patient Recruitment

2. ACoRN OVERALL GOALS • Scientific Goal: Discover genes that cause or predispose to cardiovascular disease • Programmatic Goals: (1) use multidisciplinary approaches to dissect complex cardiovascular diseases (2) provide training in genetic analysis (3) provide access to human data and samples to network investigators

3. Cardiovascular Disease in the US • Coronary artery disease (CAD) accounts for 27% of all deaths • Although declining, still the leading cause of death in the United States • US average rate: 240.8/100,000* • *Kaiser Family Foundation (2002) Causes of death attributable to heart disease mortality include ICD-10 Codes I00-I09; I11; I13; I20-I51.

4. Cardiovascular Disease in WV • Among the 50 states: • 5th in deaths due to heart disease (288 deaths/100,000) • 2nd in obesity (25% BMI >30) • 1st in overweight (61% BMI>25) • *Kaiser Family Foundation (2002)

5. Complex genetic diseases (multifactorial inheritance) • “run in families” but clearly nonMendelian • Phenotype: one or more genes plus environmental factors • Complex diseases are present at higher population frequency AND therefore a greater public health concern • Complex disease success stories: • Alzheimer’s disease (linkage analysis) • Age Related Macular Degeneration (GWAS)

6. Gene Mapping StudiesBasic Premises • An allele of a given gene causes or confers susceptibility to a particular disease state • The presence of the disease state in a patient means that the disease allele is present. • Co-segregation of the disease allele with a genetic marker gives the genetic position of the disease gene • Linkage analysis or Linkage Disequilibrium studies • Genetic location + gene expression data + human genome sequence = identification of disease gene

7. ACoRN Approaches • Two Overlapping Networks: • (1) Researchers • (2) Clinicians at hospitals and rural clinics • Recruiting individuals and families into genetic studies • Barriers • Some solutions and success stories

8. Network 1: ACoRN Researchers • CURRENT • GENETICISTS: PLAN, ASCERTAINMENT • PHYSICIANS: IDENTIFY CV AFFECTEDS • DATABASE MANAGERS: DATA COLLECTION AND SHARING • STATISTICIANS (GENETIC ANALYSTS): MAP LOCATION OF DISEASE GENES • MOLECULAR BIOLOGISTS: USE MAP INFO TO IDENTIFY DISEASE GENE AND DETERMINE ITS ROLE IN PATHOGENESIS

9. ACoRN Research Team • CARDIOLOGISTS: • William Neal MD WVU HSC (CARDIAC program) • Todd Gress MD MU Internal Medicine • Ganpat Thakker MD CAMC Cardiovascular Services • DATABASE MANAGER: • James Denvir PhD, Marshall University • GENETIC ANALYSTS: • Yulia Dementieva PhD, Marshall University • Huey-Miin Lee PhD, West Virginia University* • MOLECULAR GENETICISTS: • Mark Flood PhD, Fairmont State University* • Robert Kreisberg PhD, West Liberty State College* • Liping Wei MS, MU Genomics Core Manager

10. ACoRN Research Projects • Obesity Associated Cardiovascular Disease • Familial Combined Hyperlipidemia

11. Familial Combined Hyperlipidemia (FCHL) • FCH affecteds have elevated levels of both cholesterol and triglycerides. • FCH affects 1-2% of the population of Westernized societies • One of the most common genetic lipid disorders in patients with coronary artery disease. • Oligogenic disease • Genome-wide linkage analyses point to at least three different genetic loci

12. FCH Goals and Objectives • FCH Long-Range Goal • Understand the molecular and cellular events that lead to disregulation of cholesterol and triglyceride levels • how these events predispose to atherosclerosis. • Objective of this project • Identify gene(s) that predispose to FCH using • family-based linkage analysis • family-based association (linkage disequilibrium) • reliance on juvenile probands

13. Initial Plan for FCH Patient Recruitment • Define affected phenotype for adult and juvenile probands. • Obtain IRB approval for chart reviews and recruitment at multiple sites. • Conduct clinic chart reviews and review statewide CARDIAC database. • Contact potential probands by phone or letter or both. • Interested participants and their relatives come to the clinic sign consent, give blood sample and family history.

14. Network #2Participant Recruitment (6 Sites) • Three Largest Cardio Centers in WV • Charleston Area Medical Center • WVU Health Science Center • Marshall University Internal Medicine • Three Rural Clinics • Lincoln Primary Care Center • Valley Health Systems • Tug River Clinic

15. FCH PATIENT RECRUITMENT • Statewide CARDIAC Project: a population-based screening program designed to raise awareness of CAD risk factors and identify individuals at high risk for premature CAD. • Director: William Neal, MD • > 10,000 5th grade students/yr are screened for BMI, BP and blood cholesterol levels. • 1% (100/yr) may be affected • juvenile probands  FCHL families

16. FCH juvenile probands 5th-12th grade students,9-18 years of age (1) fasting total cholesterol >230mg/dl (2) fasting LDL > 150mg/dl (3) fasting triglycerides > 150 mg/dl (4) fasting HDL < 35 mg/dl

17. Patient Recruitment: Some Barriers (I) • WV is the third most rural state • long commutes to medical centers • low average income • large elderly population • Mistrust of genetic studies • Family or community might be labeled • matriarch/patriarch gets the “blame” • risk of loss of insurance coverage • unwanted notoriety

18. Patient Recruitment: Some Barriers (II) • Fasting requirement • Exclusion criteria • Missing work to come to clinic • Need the whole family to participate • Limited short-term benefit to genetic studies • We provide lipid panel data to physician and/or patient but none of the genetic findings

19. “Rural Cancer Patients’ Perspectives on Clinical Trials: A Qualitative Study” • Interviews with 17 cancer patients in rural WV • Few patients had knowledge of clinical trials. • Findings: Treatment location, MD’s input, disease status and perceived effectiveness influenced decision making process. • Patients should be better informed about the nature of clinical trials. • Physician trust may enhance participation • Coyne et al, J. Cancer Education 19:165-169 2004

20. Patient Recruitment: Solutions (1) • Getting Families Interested: • Critical input and assurances from the specialist, family doctor and the nurse at a regular clinic appointment • Doctor-patient relationship is critical • Finding Interested Families • CARDIAC program involves children and parents, so whole families are identified • Alliances with other Appalachia states (e.g. Kentucky INBRE program) • Access to electronic databases • Need special permission for some clinical networks

21. Patient Recruitment: Solutions (2) • Go The Distance • Doctor, nurse-phlebotomist, and geneticist all go to a central location on a mutually agreed upon Saturday. • Gift cards for enrollees are helpful • Explain Significance of the Study • Importance of early diagnosis of disease and treatment must be stressed • Tell prospective participants about data safeguards

22. Patient Recruitment: Solutions (3) • Getting physicians interested • Physicians are overwhelmed with patient load in some settings. • Visiting speakers can provide updates on the basic/clinical science and improve the understanding of the need for the study. • Getting the community involved • Health fairs • Community Health Educators • Direct collaborations with providers

23. FCH Status Report • Three IRB protocols in place: • MU, WVU and CAMC (+ three rural clinics) • Central statewide IRB panel would reduce admin load • LabCorp performs serum lipid profiles • Accept samples by FEDEX • Send data back by email • Three large families have been enrolled through the CARDIAC program. • Four smaller families through CAMC and MU. • Total enrollment = ~70 participants.

24. SUMMARY • Significant barriers exist in carrying out genetic studies on Appalachian populations. • Motivated physicians and nurses are critical to many aspects. • Geographic isolation can be partly resolved by “traveling teams”. • Basic scientist updates major and rural sites on medical advances. • Several studies suggest that community meetings may be helpful.