Predisposition to asthma among the Predisposition to asthma among the Utah populationUtah population

Craig TeerlinkCraig TeerlinkUniversity of UtahUniversity of Utah

Department of Biomedical InformaticsDepartment of Biomedical Informatics

Asthma Genomics ConferenceAsthma Genomics ConferenceUtah Department of Health Asthma ProgramUtah Department of Health Asthma Program

June 7, 2007June 7, 2007

IntroductionIntroductionAsthma is a common disorderAsthma is a common disorder Effects 7% of US populationEffects 7% of US population11

Increased global incidence observed in the last few Increased global incidence observed in the last few decadesdecades22

Complicated etiologyComplicated etiology Both environmental and genetic factors are Both environmental and genetic factors are

recognizedrecognized33

Heritable nature of asthmaHeritable nature of asthmaDiscordance observed between MZ and DZ twinsDiscordance observed between MZ and DZ twins44

Familial aggregation studies and risk factor analyses provide Familial aggregation studies and risk factor analyses provide evidence that asthma clusters in familiesevidence that asthma clusters in families5,65,6

A better understanding of predisposing factors A better understanding of predisposing factors may help improve treatment outcomesmay help improve treatment outcomes

Introduction to familial analysis studyIntroduction to familial analysis study

Such studies have been restricted to first degree Such studies have been restricted to first degree relatives relatives It is difficult to distinguish between evidence for It is difficult to distinguish between evidence for common genetic factors and common common genetic factors and common environmental factors among close relatives environmental factors among close relatives since close relatives often share their immediate since close relatives often share their immediate environmentenvironmentIn contrast, using a unique Utah resource, we In contrast, using a unique Utah resource, we were able to observe increased risk to distant were able to observe increased risk to distant relatives for a severe asthma phenotype relatives for a severe asthma phenotype definitiondefinition77

The Utah Population DatabaseThe Utah Population Database

Computerized genealogy recordsComputerized genealogy records

2.2 million Utah pioneers and their descendents2.2 million Utah pioneers and their descendents

Some genealogies have up to 10 generationsSome genealogies have up to 10 generations

Has been linked to 440,000+ death certificates from UtahHas been linked to 440,000+ death certificates from Utah

The combined resource allows us to identify individuals The combined resource allows us to identify individuals who died from asthma (cases) and investigate their who died from asthma (cases) and investigate their ‘relatedness’‘relatedness’

Benefits of genealogical approach to Benefits of genealogical approach to familialityfamiliality

Well-established methodsWell-established methods The resource has previously been used to The resource has previously been used to

provide evidence for a heritable component in provide evidence for a heritable component in other disease settingsother disease settings

Can extend analyses to distant relatives Can extend analyses to distant relatives (i.e., 2(i.e., 2ndnd or 3 or 3rdrd degree relatives), providing degree relatives), providing potentially more meaningful resultspotentially more meaningful results

Two types of analysisTwo types of analysis

Relative riskRelative risk If asthma mortality is familial, a higher risk of If asthma mortality is familial, a higher risk of

asthma mortality will be found among relatives asthma mortality will be found among relatives of individuals who died from asthma than of individuals who died from asthma than would be found for random controlswould be found for random controls

Average relatednessAverage relatedness If asthma mortality is familial, more If asthma mortality is familial, more

relationships between cases will be found relationships between cases will be found than would be found for random controlsthan would be found for random controls

Relative risk analysisRelative risk analysis

MethodMethod Compare the rate of asthma death in relatives of Compare the rate of asthma death in relatives of

asthma death cases with the rate of asthma death asthma death cases with the rate of asthma death in the population (UPDB)in the population (UPDB)

Results for 1,553 asthma deathsResults for 1,553 asthma deaths

No. of relativesNo. of relatives ObservedObserved ExpectedExpected RRRR P-valueP-value

11stst degree relatives degree relatives 7,9367,936 5252 30.730.7 1.691.69 <0.001<0.001

22ndnd degree relatives degree relatives 19,31919,319 100100 74.874.8 1.341.34 0.0030.003

33rdrd degree relatives degree relatives 28,60128,601 129129 112.2112.2 1.151.15 0.0650.065

Average relatedness analysisAverage relatedness analysisMethodMethod

Calculate the genetic distance between every pair of cases (i.e., Calculate the genetic distance between every pair of cases (i.e., degree of ‘relatedness’)degree of ‘relatedness’)

Calculate the average relatedness of all cases (GIF statistic)Calculate the average relatedness of all cases (GIF statistic) Repeat for 1000 sets of matched controlsRepeat for 1000 sets of matched controls

Results for 1,553 asthma deathsResults for 1,553 asthma deathsAll casesAll cases Ignoring 1Ignoring 1stst and 2 and 2ndnd

degree relativesdegree relatives

Case GIFCase GIF 3.163.16 1.951.95

Control GIFControl GIF 2.422.42 1.731.73

P-ValueP-Value <0.0001<0.0001 0.0260.026

Contribution to the GIF statisticContribution to the GIF statistic

Contribution to the Contribution to the GIF statistic by GIF statistic by genetic distance genetic distance between pairs of between pairs of individuals for asthma individuals for asthma mortalitymortality1,553 cases and 1000 1,553 cases and 1000 sets of matched sets of matched controls controls

genetic distance

cont

ribut

ion

to G

IF

1 2 3 4 5 6 7 8 9 10 12 14

0.0

0.1

0.2

0.3

0.4

0.5

asthma casesmatched controls

Summary of familial investigationSummary of familial investigation

Used a population based genealogy linked Used a population based genealogy linked to death certificatesto death certificatesObserved significantly increased risk to Observed significantly increased risk to relatives of individuals who died from relatives of individuals who died from asthma asthma Cases are significantly more related than Cases are significantly more related than expected by chance expected by chance Both analyses were significant in close Both analyses were significant in close and distant relativesand distant relatives

ImplicationsImplicationsImplications vary according to interest…Implications vary according to interest…Genetic epidemiologist:Genetic epidemiologist: Highly specific phenotype definition and significant Highly specific phenotype definition and significant

results among distant relatives suggests heritable results among distant relatives suggests heritable factorfactor

Department of health:Department of health: Risk estimates are on a population basis, so apply Risk estimates are on a population basis, so apply

well to an entire populationwell to an entire populationAn individual:An individual: Asthma mortality is rare Asthma mortality is rare Increased risk is low and not likely to apply at the Increased risk is low and not likely to apply at the

individual levelindividual level

Next stepNext step

Use of clinical data (instead of mortality) to Use of clinical data (instead of mortality) to distinguish asthma cases within the distinguish asthma cases within the genealogy database may produce more genealogy database may produce more meaningful risk estimates to clinicians, meaningful risk estimates to clinicians, public health practitioners, and individuals.public health practitioners, and individuals.

Utah Asthma Program community mini-Utah Asthma Program community mini-grant may help to perform the next stepgrant may help to perform the next step

Acknowledgements, 1Acknowledgements, 1

PeoplePeople Lisa Cannon-AlbrightLisa Cannon-Albright Matt HegewaldMatt Hegewald

InstitutionsInstitutions Resource for Genetic and Epidemiologic Resource for Genetic and Epidemiologic

Research (Utah Population Database)Research (Utah Population Database) Utah Department of Health Asthma ProgramUtah Department of Health Asthma Program

Introduction to linkage analysis studyIntroduction to linkage analysis study

Linkage analysis Linkage analysis Attempts to identify disease predisposition loci in the genomeAttempts to identify disease predisposition loci in the genome Based on the phenomenon of chromosome recombination that Based on the phenomenon of chromosome recombination that

occur during meiosesoccur during meioses Utilizes inheritance information gathered in disease pedigreesUtilizes inheritance information gathered in disease pedigrees

Previous genome-wide scans for asthma have implicated Previous genome-wide scans for asthma have implicated almost every chromosomealmost every chromosome

22 study populations thus far22 study populations thus far88

> 30 suggestive or significant regions in the genome> 30 suggestive or significant regions in the genome88

Several genes have been identified/hypothesized in Several genes have been identified/hypothesized in association studiesassociation studies99

Replication is needed for these genesReplication is needed for these genes Results are likely to be population-specificResults are likely to be population-specific

1 2

3 45 6

78

9 10 11 12

13 14 1516 17 18

19 2021 22

X

Previous results from genome-wide scans for asthma8

• previously published regions

A unique data resource for asthma linkageA unique data resource for asthma linkage

81 extended pedigrees ascertained for asthma between 81 extended pedigrees ascertained for asthma between 1996 and 20001996 and 2000

3 to 6 generations per pedigree3 to 6 generations per pedigree 6 to 97 individuals per pedigree6 to 97 individuals per pedigree 2 to 40 affected individuals per pedigree 2 to 40 affected individuals per pedigree

1880 individuals included in analysis1880 individuals included in analysis 744 affected (93% genotyped)744 affected (93% genotyped) 628 unaffected628 unaffected 508 undetermined phenotype status508 undetermined phenotype status

GenotypingGenotyping Subjects were genotyped on 540 florescent dye-labeled Subjects were genotyped on 540 florescent dye-labeled

microsatellite markers across the genomemicrosatellite markers across the genome Genotyping was performed by Myriad geneticsGenotyping was performed by Myriad genetics Average spacing of 6 cM between markersAverage spacing of 6 cM between markers

MethodsMethods

Phenotype definitionPhenotype definition Physician confirmed presence or absence of asthmaPhysician confirmed presence or absence of asthma Based on spirometry measures, medical records and Based on spirometry measures, medical records and

questionnairequestionnaire

Parametric analysesParametric analyses Mode of inheritance is not well-characterizedMode of inheritance is not well-characterized general dominant and recessive modelgeneral dominant and recessive model

Disease allele frequency of 0.005 (dom) and 0.05 (rec)Disease allele frequency of 0.005 (dom) and 0.05 (rec)Both models assumed penetrance of 50% for disease allele Both models assumed penetrance of 50% for disease allele carriers and 0.5% for non-disease carrierscarriers and 0.5% for non-disease carriers

Genome-wide resultsGenome-wide results

a.line1[, 1]

a.lin

e1[,

2]

1 2 3 4 5 6 7 8 90

1

2

3a.

line2

[, 2]

10 11 12 13 14 15 16 17 18 19 20 21 22 X0

1

2

3

Genome-wide results, cont.Genome-wide results, cont.A significantA significant1010 result occurred on chromosome 5 result occurred on chromosome 5 LOD = 3.75 LOD = 3.75 ~ 5600:1 odds in favor of linkage~ 5600:1 odds in favor of linkage Evidence from recessive modelEvidence from recessive model Not reported in other genome-wide scans for asthmaNot reported in other genome-wide scans for asthmaA nearly suggestive result occurred on A nearly suggestive result occurred on chromosome 6chromosome 6 LOD = 2.08LOD = 2.08 ~ 120:1 odds in favor of linkage~ 120:1 odds in favor of linkage Evidence from dominant modelEvidence from dominant model Reported in several other genome-wide scansReported in several other genome-wide scans1111

1 2

3 45 6

78

9 10 11 12

13 14 1516 17 18

19 2021 22

X

Our results in perspective to other published results

• previously published regions

ConclusionsConclusionsOur analysis of extended pedigrees identified a Our analysis of extended pedigrees identified a novel asthma susceptibility locus at chromosome novel asthma susceptibility locus at chromosome 5q215q21Our analysis confirmed another region of interest Our analysis confirmed another region of interest (with nearly suggestive evidence) for an asthma (with nearly suggestive evidence) for an asthma susceptibility locus at 6p21.susceptibility locus at 6p21.Inclusion of fine mapping markers in regions of Inclusion of fine mapping markers in regions of interest will improve localizationinterest will improve localizationFuture linkage analysis in this resource should Future linkage analysis in this resource should address phenotypic heterogeneity of asthmaaddress phenotypic heterogeneity of asthmaA better understanding of genetic factors for A better understanding of genetic factors for asthma may improve disease outcomesasthma may improve disease outcomes

Acknowledgements, 2Acknowledgements, 2People:People:

Alun ThomasAlun ThomasLisa Cannon-AlbrightLisa Cannon-AlbrightNicola CampNicola CampMatt HegewaldMatt HegewaldMarlene EggerMarlene EggerJim FarnhamJim FarnhamSteven BackusSteven Backus

Institutions:Institutions:The National Library of MedicineThe National Library of MedicineIntermountain HealthcareIntermountain HealthcareMyriad GeneticsMyriad GeneticsBayer PharmaceuticalsBayer Pharmaceuticals

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