Predisposition to asthma among the Utah population

1
Predisposition to asthma among the Utah population

• Craig Teerlink
• University of Utah
• Department of Biomedical Informatics
• Asthma Genomics Conference
• Utah Department of Health Asthma Program
• June 7, 2007

2
Introduction

• Asthma is a common disorder
• Effects 7 of US population1
• Increased global incidence observed in the last
  few decades2
• Complicated etiology
• Both environmental and genetic factors are
  recognized3
• Heritable nature of asthma
• Discordance observed between MZ and DZ twins4
• Familial aggregation studies and risk factor
  analyses provide evidence that asthma clusters in
  families5,6
• A better understanding of predisposing factors
  may help improve treatment outcomes

3
Introduction to familial analysis study

• Such studies have been restricted to first degree
  relatives
• It is difficult to distinguish between evidence
  for common genetic factors and common
  environmental factors among close relatives since
  close relatives often share their immediate
  environment
• In contrast, using a unique Utah resource, we
  were able to observe increased risk to distant
  relatives for a severe asthma phenotype
  definition7

4
The Utah Population Database

• Computerized genealogy records
• 2.2 million Utah pioneers and their descendents
• Some genealogies have up to 10 generations
• Has been linked to 440,000 death certificates
  from Utah
• The combined resource allows us to identify
  individuals who died from asthma (cases) and
  investigate their relatedness

5
Benefits of genealogical approach to familiality

• Well-established methods
• The resource has previously been used to provide
  evidence for a heritable component in other
  disease settings
• Can extend analyses to distant relatives (i.e.,
  2nd or 3rd degree relatives), providing
  potentially more meaningful results

6
Two types of analysis

• Relative risk
• If asthma mortality is familial, a higher risk of
  asthma mortality will be found among relatives of
  individuals who died from asthma than would be
  found for random controls
• Average relatedness
• If asthma mortality is familial, more
  relationships between cases will be found than
  would be found for random controls

7
Relative risk analysis

• Method
• Compare the rate of asthma death in relatives of
  asthma death cases with the rate of asthma death
  in the population (UPDB)
• Results for 1,553 asthma deaths

8
Average relatedness analysis

• Method
• Calculate the genetic distance between every pair
  of cases (i.e., degree of relatedness)
• Calculate the average relatedness of all cases
  (GIF statistic)
• Repeat for 1000 sets of matched controls
• Results for 1,553 asthma deaths

9
Contribution to the GIF statistic

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

10
Summary of familial investigation

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

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Implications

• Implications vary according to interest
• Genetic epidemiologist
• Highly specific phenotype definition and
  significant results among distant relatives
  suggests heritable factor
• Department of health
• Risk estimates are on a population basis, so
  apply well to an entire population
• An individual
• Asthma mortality is rare
• Increased risk is low and not likely to apply at
  the individual level

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Next step

• Use of clinical data (instead of mortality) to
  distinguish asthma cases within the genealogy
  database may produce more meaningful risk
  estimates to clinicians, public health
  practitioners, and individuals.
• Utah Asthma Program community mini-grant may help
  to perform the next step

13
Acknowledgements, 1

• People
• Lisa Cannon-Albright
• Matt Hegewald
• Institutions
• Resource for Genetic and Epidemiologic Research
  (Utah Population Database)
• Utah Department of Health Asthma Program

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Introduction to linkage analysis study

• Linkage analysis
• Attempts to identify disease predisposition loci
  in the genome
• Based on the phenomenon of chromosome
  recombination that occur during meioses
• Utilizes inheritance information gathered in
  disease pedigrees
• Previous genome-wide scans for asthma have
  implicated almost every chromosome
• 22 study populations thus far8
• gt 30 suggestive or significant regions in the
  genome8
• Several genes have been identified/hypothesized
  in association studies9
• Replication is needed for these genes
• Results are likely to be population-specific

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Previous results from genome-wide scans for
asthma8
9
10
11
12
8
7
6
5
4
3
2
1
21
22
19
20
18
17
16
15
14
13
X
previously published regions
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A unique data resource for asthma linkage

• 81 extended pedigrees ascertained for asthma
  between 1996 and 2000
• 3 to 6 generations per pedigree
• 6 to 97 individuals per pedigree
• 2 to 40 affected individuals per pedigree
• 1880 individuals included in analysis
• 744 affected (93 genotyped)
• 628 unaffected
• 508 undetermined phenotype status
• Genotyping
• Subjects were genotyped on 540 florescent
  dye-labeled microsatellite markers across the
  genome
• Genotyping was performed by Myriad genetics
• Average spacing of 6 cM between markers

17
Methods

• Phenotype definition
• Physician confirmed presence or absence of asthma
• Based on spirometry measures, medical records and
  questionnaire
• Parametric analyses
• Mode of inheritance is not well-characterized
• general dominant and recessive model
• Disease allele frequency of 0.005 (dom) and 0.05
  (rec)
• Both models assumed penetrance of 50 for disease
  allele carriers and 0.5 for non-disease carriers

18
Genome-wide results
19
Genome-wide results, cont.

• A significant10 result occurred on chromosome 5
• LOD 3.75
• 56001 odds in favor of linkage
• Evidence from recessive model
• Not reported in other genome-wide scans for
  asthma
• A nearly suggestive result occurred on chromosome
  6
• LOD 2.08
• 1201 odds in favor of linkage
• Evidence from dominant model
• Reported in several other genome-wide scans11

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Our results in perspective to other published
results
9
10
11
12
8
7
6
5
4
3
2
1
21
22
19
20
18
17
16
15
14
13
X
previously published regions
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Conclusions

• Our analysis of extended pedigrees identified a
  novel asthma susceptibility locus at chromosome
  5q21
• Our analysis confirmed another region of interest
  (with nearly suggestive evidence) for an asthma
  susceptibility locus at 6p21.
• Inclusion of fine mapping markers in regions of
  interest will improve localization
• Future linkage analysis in this resource should
  address phenotypic heterogeneity of asthma
• A better understanding of genetic factors for
  asthma may improve disease outcomes

22
Acknowledgements, 2

• People
• Alun Thomas
• Lisa Cannon-Albright
• Nicola Camp
• Matt Hegewald
• Marlene Egger
• Jim Farnham
• Steven Backus
• Institutions
• The National Library of Medicine
• Intermountain Healthcare
• Myriad Genetics
• Bayer Pharmaceuticals

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