Transcript Gene Mapping for Complex Human Diseases

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
ACoRN OVERALL GOALS
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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
Cardiovascular Disease in the US
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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.
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)
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*Kaiser Family Foundation (2002)
Complex genetic diseases
(multifactorial inheritance)
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“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)
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Gene Mapping Studies
Basic Premises
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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
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Linkage analysis or Linkage Disequilibrium studies
Genetic location + gene expression data +
human genome sequence = identification of
disease gene
ACoRN Approaches
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Two Overlapping Networks:
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(1) Researchers
(2) Clinicians at hospitals and rural clinics
Recruiting individuals and families
into genetic studies
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Barriers
Some solutions and success stories
Network 1: ACoRN Researchers
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CURRENT
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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
ACoRN Research Team
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CARDIOLOGISTS:
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DATABASE MANAGER:
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James Denvir PhD, Marshall University
GENETIC ANALYSTS:
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William Neal MD WVU HSC (CARDIAC program)
Todd Gress MD MU Internal Medicine
Ganpat Thakker MD CAMC Cardiovascular Services
Yulia Dementieva PhD, Marshall University
Huey-Miin Lee PhD, West Virginia University*
MOLECULAR GENETICISTS:
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Mark Flood PhD, Fairmont State University*
Robert Kreisberg PhD, West Liberty State College*
Liping Wei MS, MU Genomics Core Manager
ACoRN Research Projects
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Obesity Associated Cardiovascular
Disease
Familial Combined Hyperlipidemia
Familial Combined Hyperlipidemia
(FCHL)
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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
FCH Goals and Objectives
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FCH Long-Range Goal
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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
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family-based linkage analysis
family-based association (linkage disequilibrium)
reliance on juvenile probands
Initial Plan for FCH Patient Recruitment
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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.
Network #2
Participant Recruitment (6 Sites)
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Three Largest Cardio Centers in WV
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Charleston Area Medical Center
WVU Health Science Center
Marshall University Internal Medicine
Three Rural Clinics
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Lincoln Primary Care Center
Valley Health Systems
Tug River Clinic
FCH PATIENT RECRUITMENT
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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
FCH juvenile probands
5th-12th grade students,9-18 years of age
(1)
(2)
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(4)
fasting
fasting
fasting
fasting
total cholesterol >230mg/dl
LDL > 150mg/dl
triglycerides > 150 mg/dl
HDL < 35 mg/dl
Patient Recruitment: Some Barriers (I)
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WV is the third most rural state
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long commutes to medical centers
low average income
large elderly population
Mistrust of genetic studies
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Family or community might be labeled
matriarch/patriarch gets the “blame”
risk of loss of insurance coverage
unwanted notoriety
Patient Recruitment: Some Barriers (II)
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Fasting requirement
Exclusion criteria
Missing work to come to clinic
Need the whole family to participate
Limited short-term benefit to genetic
studies
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We provide lipid panel data to physician
and/or patient but none of the genetic
findings
“Rural Cancer Patients’ Perspectives
on Clinical Trials: A Qualitative Study”
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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
Patient Recruitment: Solutions (1)
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Getting Families Interested:
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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
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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
Patient Recruitment: Solutions (2)
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Go The Distance
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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
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Importance of early diagnosis of disease
and treatment must be stressed
Tell prospective participants about data
safeguards
Patient Recruitment: Solutions (3)
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Getting physicians interested
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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
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Health fairs
Community Health Educators
Direct collaborations with providers
FCH Status Report
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Three IRB protocols in place:
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LabCorp performs serum lipid profiles
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MU, WVU and CAMC (+ three rural clinics)
Central statewide IRB panel would reduce admin load
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.
SUMMARY
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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.