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Predisposition to Asthma Among the Utah Population - Utah

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									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
                  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
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
    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’
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
        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
               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
                       No. of relatives   Observed   Expected   RR     P-value

1st degree relatives        7,936           52         30.7     1.69   <0.001

2nd degree relatives       19,319           100        74.8     1.34   0.003

3rd degree relatives       28,601           129       112.2     1.15   0.065
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
                         All cases          Ignoring 1st and 2nd
                                              degree relatives
    Case GIF               3.16                    1.95
    Control GIF            2.42                    1.73
     P-Value             <0.0001                   0.026
       Contribution to the GIF statistic

Contribution to the
GIF statistic by




                                               0.5
genetic distance                                                                            asthma cases
                                                                                            matched controls

between pairs of



                                               0.4
                         contribution to GIF
individuals for asthma


                                               0.3
mortality

                                               0.2
1,553 cases and 1000
sets of matched                                0.1
                                               0.0


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

                                                                         genetic distance
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
                  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
               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
       Acknowledgements, 1
People
   Lisa Cannon-Albright
   Matt Hegewald
Institutions
   Resource for Genetic and Epidemiologic
    Research (Utah Population Database)
   Utah Department of Health Asthma Program
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
   > 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
Previous results from genome-wide scans for asthma8




                                                9    10   11   12
                                           8
                                      7
                         5       6
            3      4


 1    2



                                                21   22
                                      19   20
                        17       18
                  16
      14    15
13
                                                          X
• previously published regions
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
                     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
Genome-wide results

                   3
a.line1[, 2]


                   2




                   1




                   0
                            1        2             3         4          5         6        7       8    9

                                                            a.line1[, 1]


               3
a.line2[, 2]




               2




               1




               0
                       10       11       12   13       14   15     16       17   18   19   20   21 22   X
    Genome-wide results, cont.
A significant10 result occurred on chromosome 5
   LOD = 3.75
   ~ 5600:1 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
   ~ 120:1 odds in favor of linkage
   Evidence from dominant model
   Reported in several other genome-wide scans11
Our results in perspective to other published results




                                                9    10   11   12
                                           8
                                      7
                         5       6
            3      4


 1    2



                                                21   22
                                      19   20
                        17       18
                  16
      14    15
13
                                                          X
• previously published regions
              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
           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
                                 References
1.    American Lung Association, Epidemiology and Statistics Unit, Research and Program Services.
      Trends in asthma morbidity and mortality. May 2005.
2.    Braman SS. The global burden of asthma. Chest. 2006 Jul;130(1 Supp):4S-12S.
3.    Wechsler ME, Israel E. The genetics of asthma. Semin Respir Crit Care Med. 2002 Aug;23(4):331-
      338.
4.    Clark JR, Jenkins MA, Hopper JL, et.al. Evidence for genetic associations between asthma, atopy
      and bronchial hyperresponsiveness: a study of 8- to 18-year old twins. Am J Respir Crit Care Med.
      2000;162(6):2188-2193.
5.    Burke W, Fesinmeyer M, Reed K, Hampson L. Family history as a predictor of asthma risk. Am J
      Prev Med 2003;24:160-169.
6.    Hao K, Chen C, Wang B, Yang J, Fang Z, Xu X. Familial aggregation of airway responsiveness: a
      community-based study. Ann Epidemiol 2005;15:737-743.
7.    Teerlink CC, Hegewald M, Cannon-Albright. A genealogical assessment of predisposition to asthma
      mortality. In press.
8.    Ferreira MAR, O'Gorman L, Le Souef P, et al. Robust estimation of experiment-wise P values applied
      to a genome scan on multiple asthma traits identifies a new region of significant linkage on
      chromosome 20q13. Am J Hum Genet 2005;77:1075-1085.
9.    Contopoulos-Ioannidis DG, Kouri IN, Ioannidis JPA. Genetic predisposition to asthma and atopy.
      Respiration 2007;74:8-12.
10.   Lander E, Kruglyak L. Genetic dissection of complex traits: guidelines for interpreting and reporting
      linkage results. Nat Genet 1995;11(3):241-247.
11.   Nicolae D, Cox NJ, Lester LA, et.al. Fine mapping and positional candidate studies identify HLA-G as
      an asthma susceptibility gene on chromosome 6p21. Am J Hum Genet. 2005;76:349-357.

								
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