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Finding genes that influence risk of cardiovascular disease

ND. SD. OK. AZ. Strong Heart Family Study. Finding genes that influence risk of cardiovascular disease. Measuring Heart Disease Risk is Complicated. • Heart disease is not an all-or-none trait - we are all at some risk • Risk increases as we age

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Finding genes that influence risk of cardiovascular disease

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  1. ND SD OK AZ Strong Heart Family Study Finding genes that influence risk of cardiovascular disease

  2. Measuring Heart Disease Risk is Complicated •Heart disease is not an all-or-none trait - we are all at some risk • Risk increases as we age • Heart disease risk is influenced by many factors, e.g. cholesterol levels, obesity, diabetes • Heart disease can cluster in families

  3. Why is it Important to Identify Heart Disease Risk Genes? •To learn more about the disease process • To find out who should modify lifestyle • To develop personalized therapies

  4. Why Look for Heart Disease Risk Genes In American Indians? •Heart disease is a serious and increasing health problem in American Indians • Are the same genes important in every tribe? • What therapies will be most effective in American Indians?

  5. Female Male Married couple Parents and daughter Parents and 3 children Man, 2 wives, 7 children Drawing Family Trees: Conventions

  6. The Strong Heart Family Study We identified extended families using name matching

  7. 1 2 3 Identifying extended families using name matching

  8. 1 2 3 Identifying extended families using name matching

  9. 1 2 3 Identifying extended families using name matching

  10. 1 2 3 Identifying extended families using name matching

  11. 1 2 3 Identifying extended families using name matching

  12. 1 2 3 Identifying extended families using name matching

  13. 1 2 3 Identifying extended families using name matching ≥ 3 sibs who are members of original cohort ≥ 2 additional sibs ≥ 12 offspring > 1,200 family members from each field center

  14. 1 2 3 The Strong Heart Family Study Arizona: 30 families, sizes 35-288 Dakotas: 27 families, sizes 37-476 Oklahoma: 36 families, sizes 42-243

  15. Who Are the Participants? • > 3600 members of American Indian families in Arizona, Oklahoma, and South Dakota • People who - wish to participate - are at least 15 years old - have a relative in the Strong Heart Study cohort - are in large families • Most participants are relatively healthy

  16. At Each Field Center: •> 1200 people recruited from Strong Heart Study families • For each family member: - explained the study and get consent - completed a Family Information Form - administered questionnaires - conducted a physical exam - took a blood sample for DNA and to measure risk factors • Sent Family Information Forms and blood samples (buffy coats) for DNA to San Antonio

  17. Strong Heart Family Study • To what extent do genes influence risk of heart disease beginning when we are young and healthy? • What are the genes? • What traits (risk factors) should we study?

  18. What Traits Are We Studying? • Total cholesterol, LDL-C, HDL-C, triglycerides • LDL size, ApoAI, ApoB, ApoE phenotype • Insulin, glucose, glycated hemoglobin • Urine microalbumin, plasma creatinine • Body fat, BMI, waist circumference • Systolic and diastolic blood pressure • Carotid ultrasound measures • ECG measures • Etc.

  19. Heritability The proportion of variance in a trait that is due to the additive effects of genes

  20. Strong Heart Study:Heritabilities for Selected Risk Factors Total cholesterol 0.39 LDL-C 0.32 HDL-C 0.41 Triglycerides 0.42 Fibrinogen 0.42 Creatinine 0.36 LV mass 0.42 Fasting insulin 0.41 Fasting glucose 0.37 HbA1C 0.59 Height 0.75 Weight 0.56 BMI 0.51 Waist 0.54

  21. If we want to identify the genes that make us susceptible to CVD, we first have to find them.

  22. Human Chromosomes (n = 46)

  23. Karyotype

  24. APOB HMGCS LFABP HMGCR APOA2 ATH-1 CR39-1 LPA IFABP APOD CRBP CRBP-II 5 6 4 2 3 1 LPL APOA1 APOC3 10 12 11 APOA4 8 9 7 CR39-15 CETP LIPC LCAT 16 18 17 13 14 15 LDLR APOC1 APOC2 CR39-3 APOE 22 Y 21 20 19 X Candidate Loci for Atherosclerosis Adapted from Lusis, 1989

  25. F8VWFP 4 D22S57 6 D22S75 11 BCR1 6 Human Chromosome 22 D22S257 2 D22S156 3 TOP1P2 5 D22S41 10 D22S85 2 D22S29 3 MB 5 D22S102 IL2RB 4 2 2 1 G22P1 D22S90 D22S92 5 PDGFB CYP2DP8 7 D22S97 2 D22S94 7 D22S21 10 D22S55

  26. Genetic Marker a polymorphic gene whose exact chromosomal location is known, but whose function usually is not known

  27. Mapping Disease Genes on Chromosomes Create a “road map” of 400 genetic markers whose locations are known

  28. 12 34 12 34 12 34 12 34 23 13 14 24 Genotype genetic constitution; the kinds of genes (= alleles) that a person has received from her/his parents

  29. ABI 377 Image of 9 Genetic Markers (Microsatellite Polymorphisms)

  30. father mother child 1 child 2 child 3 Segregating Genotypes: Electrophoretograms

  31. Strong Heart Family Study High-Throughput Genotyping • >3600 family members have been genotyped for about 400 anonymous markers • Linkage analyses to detect gene locations for risk factor genes are in progress

  32. AB CD BC BB AD AC CC BD DD AA AC AD BE BD BB AD AB AB AD CD BD BC CD AC AC AB “Data Cleaning”: Resolving Genotyping Discrepancies

  33. BB AD BB CC AD BC BC AD BD AC BE Recognizing Genotype Discrepancies • Child doesn’t have either allele of one of the parents •Child has an allele that neither parent has • More than four alleles in sibship

  34. Causes of Genotype Discrepancies •Sample mixup • Genotyping error • Data entry error • Incorrect information concerning family relationships

  35. Resolution of Genotype Discrepancies • Check for data entry errors • Re-examine gel • Re-genotype • (Re-draw blood) • For one or more family members, delete genotype information - for this marker - for all markers • Break link between parent and child

  36. How do genetic markers help us find genes that influence disease phenotypes?

  37. Segregation of a Disease Risk Factor in a Family

  38. 12 34 14 23 11 44 13 13 14 24 33 23 11 14 34 34 13 12 13 12 12 13 34 12 13 34 Segregation of a Disease Risk Factor and a Marker

  39. 12 34 1 2 1 1 2 1 2 14 13 23 13 44 11 14 24 33 23 11 1 - 2 2 1 2 2 - 1 - 14 34 34 13 12 13 12 12 13 12 34 13 34 Segregation of a Disease Risk Factor and a Marker

  40. AB CD B A A B A A B BC BD AD DD AC BB AC CC BC AA AD A A A A B A A AD CD AD BD BD AB AB BD CD CD AC AB AC Cosegregation of a Disease Risk Factor and a Marker

  41. AB CD * B A A B A B B BC AD BD DD AC BB AC CC BC AA BD A A A B B A B AD CD AD BD BD AB AB BD CD AB CD BC BC Cosegregation of a Disease Risk Factor and a Marker

  42. Linkage Analysis Does a phenotype cosegregate with a specific genetic marker?

  43. How do we measure the strength of the evidence for cosegregation (= linkage)? • LOD score - a measure of the odds in favor of linkage to a specific marker • LOD score > 3 corresponds to significant evidence (1000 to 1 odds) in favor of linkage

  44. SOLAR Strong Heart Family Study: Tools for Data Cleaning and Analysis Sequential Oligogenic Linkage Analysis Routines

  45. Ln Fasting Insulin-AZ,DK Chromosome 2 Diego VP, Göring HHH, Cole SA, Almasy L, Dyer TD, Blangero J, Duggirala R, Laston S, Wenger C, Cantu T, Dyke B, North KE, Schurr T, Best LG, Devereux RB, Fabsitz RR, Howard BV, MacCluer JW. Fasting insulin and obesity-related phenotypes are linked to chromosome 2p: The Strong Heart Family Study. Diabetes, in press

  46. Some Preliminary Linkage Results Strong Heart Family Study Trait Chromosome Location (cM) LOD Score LV mass 12 37 5.4 * Weight 4 210 5.2 * BMI 4 210 5.2 * Fasting insulin (DK) 2 51 3.4 * Ejection fraction 18 1363.4 * Lean body mass 2 68 3.3 * Weight 4 219 3.3 * Systolic BP (females) 17 136 3.3 * Fasting glucose 16 91 2.6 LDL-C 17 892.6 Plasma creatinine 5 53 2.5 * Significant evidence

  47. After a Disease Risk Factor Gene Has Been Located: Identify it! •Further refine the location • Identify candidate genes in regions with high LOD scores • Do high-density SNP typing & resequencing • Do extensive statistical analysis • Examine expression profiles to understand gene function

  48. After a Disease Risk Factor Gene Has Been Identified: •Find out what it does • Develop a therapy • Determine who has the gene • Provide therapy and/or counseling

  49. The Eventual Payoff: •Better understanding of the disease process • More accurate identification of people who are at risk • Development of personalized therapies • Better health for future generations

  50. smoking! Heart Disease Courtesy of Wen-Chi Hsueh

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