Genetic Epidemiology of Cardiovascular Disease

Kari E. NorthAssistant Professor

Department of EpidemiologyUniversity of North Carolina

Chapel Hill, NC

Cardiovascular Disease is a Common Complex Disease

Cardiovascular Disease

Adverse LipidProfile

Elevated BloodPressure

Diabetes

Obesity

Smoking Nutrition

Sedentary Lifestyle

Family History

"At least hundreds of genes are involved in cardiovascular disease"

-Lusis AJ, 2000

Studies

• Strong Heart Family Study

• HyperGEN Study

• Family Heart Study

• Atherosclerotic Risk in Communities

• Add Health Study

• Women's Health Initiative

•Project Name: Strong Heart Family StudyUNC PI: Kari NorthStudy Design: Family based linkage studyStudy Goal: Identify genes that influence CVD risk factors

Strong Heart Family Study: Study Design

• Examines 13 American Indian communities from three geographic regions in Arizona, Oklahoma, and North and South Dakota

• Consists of four phases involving a clinical examination and surveillance of resident tribal members (Phase V submitted for funding)

• A pilot family study of 900 participants (30 extended families) was added in Phase III

• Phase IV recruited 90 additional families (2700 participants)

Strong Heart Family Study Recruitment Criteria

Sibships with at least 3 SHS participants At least 5 total siblingsAt least 12 offspring of the SHS participants

• Blood collected from each participant

• Over 3,600 participants have been genotyped for ~400 highly informative microsatellite polymorphisms

• Budgeted to type 500 SNPs in multiple candidate genes of interest

Strong Heart Family Study: Study Design

Strong Heart Family Study: Study Design

Phenotypes Covariates

Blood Pressure DemographyClotting Factors LifestyleDiabetes Medical HistoryLipids Reproductive HistoryObesityCarotid Ultrasound

Strong Heart Family Study: Data

• All data stored in Pedsys

• 3,600 participants

• Phenotypic data stored in one of many tables with each trait as a field.– Quantitative measures ~500 – 1,000

– Categorical measures~100 - 500

– Text fields ~100

– Calculated phenotypes based on expert opinion ~50 ~2/3 quantitative / ~1/3 dichotomous

• One simple LARGE table describes the relationship between participants (Pedigree file)

• Microsatellite Genotypes 3,600x ~400 (multiple simple tables)

•Project Name: Hypertension Genetic Epidemiology NetworkUNC PI: Kari NorthStudy Design: Family based linkage studyStudy Goal: Identify genes that influence blood pressure regulation and related CVD risk factors

HyperGEN: Study Design

• Examined participants from 5 Field Centers in Massachusetts, Minnesota, North Carolina, Alabama, and Utah

• All participants were given a clinical exam and blood was collected for genotyping

• Over 3,000 participants have been genotyped for ~400 highly informative STR polymorphisms

• Approximately 50 SNPs in multiple candidate genes have been typed

• Budgeted to type additional SNPs in multiple candidate genes of interest

HyperGEN Pedigree Structures

Primary Sample – Two or more hypertensive Siblings

Secondary Sample- Offspring and/or Parents

HyperGEN: Data

• All data stored in SAS

• ~ 4,800 participants

• Phenotypic data stored in one of many tables with each trait as a field.– Quantitative measures ~500 – 1,000

– Categorical measures~100 - 500

– Text fields ~100

– Calculated phenotypes based on expert opinion ~50 ~2/3 quantitative / ~1/3 dichotomous

• One simple LARGE table describes the relationship between participants (Pedigree file)

• Microsatellite Genotypes 3,000 x ~400 (multiple simple tables)

•Project Name: NHLBI Family Heart Study (FHS)UNC PI: Gerardo Heiss Study Design: Family based linkage study, Family based association studyStudy Goal: Identify genes that influence coronary heart disease (calcified coronary plaque); Identify genes that influence body mass regulation on chromosome 13

FHS: Study Design

• Includes a random sample of 2,000 individuals and a second sample of 2,000 individuals with a family history of CHD

• Recruited from Framingham, MA; Salt Lake City, UT; Minneapolis, MN; and Forsyth County, NC

• A total of 5,975 individuals from 588 randomly recruited families and 656 families with an elevated risk of CHD

FHS: Data

• All data stored in SAS

• ~ 6,000 participants

• Phenotypic data stored in one of many tables with each trait as a field.– Quantitative measures ~500 – 1,000

– Categorical measures~100 - 500

– Text fields ~100

– Calculated phenotypes based on expert opinion ~50 ~2/3 quantitative / ~1/3 dichotomous

• One simple LARGE table describes the relationship between participants (Pedigree file)

• Microsatellite Genotypes ~400 (multiple simple tables)

•Project Name: Gene-By-Smoking Interaction and Risk of AtherosclerosisUNC PI: Kari NorthStudy Design: Population based association studyStudy Goal: Identify genes that interact with smoking exposure to influence subclinical atherosclerosis and validated clinical atherosclerotic events

Atherosclerotic Risk in Communities (ARIC)

Case – Cohort Study: NC, MN, MD, MS

Ongoing, bi-racial, population-based longitudinal study of cardiovascular and pulmonary diseases in 15,792 men and women randomly selected from the residents of four U.S. communities

Four Endpoints Quantifying Subclinical Atherosclerosis and Clinical Atherosclerotic Events

• Incident coronary heart disease (CHD) N = 1353 (1062)• Increased carotid artery intima-media thickness (IMT) N = 526 (868)• Peripheral arterial disease (PAD) N = 212 (1062)• Incident stroke N = 462 (1062)

•Project Name: Add HealthUNC PI: Kathie HarrisStudy Design: Population based association studyStudy Goal: Identify genes that interact with environmental factors to influence body mass

•Wave I Adolescent In-Home Interview with AHPVT, Parent In-Home Questionnaire, and Adolescent In-School Questionnaire data attached

•Adolescent In-School Questionnaire

•Wave I, II School Administrator Questionnaire

•Wave II In-Home Interview

•School Information Data

•Wave III In-Home Interview, with field interviewer characteristics and STD assay results

Add Health: Data (N = 17,000)

•In-School Network Data •Wave I Adolescent Pair Data •Wave I, II Respondent Grouping File •In-School Friendship Nominations •Wave I, II In-Home Friendship Nominations •Wave I, II Contextual Data •Wave I Spatial Analysis Data •Wave III Friend ID Numbers •Wave III Sibling ID Numbers •Wave III Full Sib/Twin DNA Results •Wave III Urinalysis Data •Wave III ASHA Data •Wave III HPV MGEN Results

Add Health: Data

•Project Name: Women's Health InitiativeUNC PI: Gerardo HeissStudy Design: Population based association studyStudy Goal: Identify genes that influence chronic kidney disease

Women's Health Initiative

•Long-term national health study that focuses on strategies for preventing heart disease, breast and colorectal cancer and osteoporosis in postmenopausal women.

•15-year project, involves over 161,000 women aged 50-79, and is one of the most definitive, far reaching clinical trials of women's health ever undertaken in the U.S.

•The WHI Clinical Trial and Observational Study is attempting to address many of the inequities in women's health research and provide practical information to women and their physicians about hormone replacement therapy, dietary patterns and calcium/vitamin D supplements, and their effects on the prevention of heart disease, cancer and osteoporosis.

•The WHI study has three components: a randomized clinical trial, an observational study and a community prevention study.

Women's Health Initiative