The Genetics of Asthma

1
The Genetics of Asthma

• Jenifer Parsons

2
Outline

• Heredity of Asthma
• Chromosome 7p2
• Locating the Region
• Finding a Gene
• Conclusions of Authors
• Why Does It Matter?

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Heredity of Asthma

• Interest in finding a genetic susceptibility
  locus is based on the heritability that asthma
  shows.
• Children with one asthmatic parent 3-6 times more
  likely to develop asthma than a child with two
  normal parents1.
• Children with two asthmatic parents 10 times more
  likely to develop asthma than normal1.

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Chromosome 7p2

• Previously completed genome-wide scan for asthma
  implicated six tentative genetic loci.
• One of those was Chromosome 7p.
• Scientists selected 7p for candidate gene study.

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Locating the Region

• Process Began by genotyping the region of
  Chromosome 7p that they were interested in and
  analyzing results. If a haplotype occurred more
  often in patients than controls, density of
  markers was increased to guide further
  genotyping.
• Method of Analysis Haplotype Pattern Mining
  (HPM) Algorithm.
• Searched for haplotypes associated with high
  serum IgE
• Suggested strong association of conserved
  haplotype pattern between NM51 and SNP563704 (47
  kb region).

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Locating the Region

• Next tried to determine limits of critical
  region.
• Did additional genotyping and analysis to reveal
  a strong association of a conserved region of
  133-kb.

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Locating the Region

• Then compared patient homozygous for
  susceptibility and control subject homozygous for
  most nonrisk haplotype with the public sequence.
• Control subject only differed from public
  sequence by two SNPs.
• Patient showed 72 previously unknown SNPs and 8
  deletion/insertion polymorphisms.

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Locating the Region

• There was strong linkage disequilibrium shown
  between the markers in the 133-kb region.
• Means that the observed haplotype frequencies
  differed from predicted haplotype frequencies.

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Locating the Region

• Genotyped two additional populations and found
  that most of the SNPs were shared.
• Figure shows linkage disequilibrium in French
  Canadian population.

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Locating the Region

• Phylogenetic analysis confirmed that risk
  haplotypes were closely related and distinct from
  the nonrisk haplotypes.
• H1, H3, and H6 are considered nonrisk haplotypes.
• H2, H4, H5, and H7 are considered the most common
  risk haplotypes in the populations tested.

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Locating the Region

• The next step was to determine whether the
  heredity displayed by asthma could be explained
  by these conserved haplotypes.
• To resolve this, the researchers looked at
  parent-offspring transmission and sibling-pair
  sharing of high IgE.
• One of the risk haplotypes cosegregated in 26 of
  51 transmissions (51) and was shared in 26 of 40
  siblings (65).

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Finding a Gene

• Now that the scientists had located a
  susceptibility locus, they began scanning the
  region for genes.
• Two were found. One was discounted after none of
  its possible isoforms showed homology to any
  previously identified proteins.
• The other had two isoforms (A and B). It was
  named GPRA (gene protein receptor for asthma
  susceptibility).

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Finding a Gene

• Isoform A is expressed mainly in smooth muscle
  isoform B is expressed mostly in epithelial
  cells.
• In comparisons of bronchial biopsies of both
  asthmatics and control samples, no distinct
  differences in expression were scene for isoform
  A.
• However, there were visible differences in
  isoform B expression.

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Finding a Gene
15
Finding a Gene

• As a final test, lung inflammation was induced in
  mice to monitor the response of GPRA ortholog
  mRNA production.
• As shown in the chart, it increased significantly.

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Conclusions of Authors

• The results of these experiments strongly
  implicate GPRA in asthmatic response.
• However, there have also been other genes
  implicated in asthma susceptibility.
• The biochemical mechanisms linking any of these
  genes to asthmatic processes are not understood
  very well.

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Conclusions of Authors

• For example, GPRA may be part of some unknown
  pathway that is critically altered in asthma.
• GPRA is also expressed in gut epithelia and
  keratinocytes in the skin. It could play a role
  in a number of other allergic diseases (e.g.
  lupus, food allergies).

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Why Does It Matter?

• Further study of GPRA and/or other genes that
  have been related to asthma could help us to
  better understand the disease.
• Finding some way to alter the structure and/or
  function of GPRA could lead to new more effective
  asthma treatments.

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Questions?

• gggctcaggg agggctctgt gcctccgttc agcagagctg
  cagctgctgc ccagctctca ggaggcaagc tggactccct
  cactcagctg caggagcaag gacagtgagg ctcaaccccg
  cctgagccat gccagccaac ttcacagagg gcagcttcga
  ttccagtggg accgggcaga cgctggattc ttccccagtg
  gcttgcactg aaacagtgac ttttactgaa gtggtggaag
  gaaaggaatg gggttccttc tactactcct ttaagactga
  gcaattgata actctgtggg tcctctttgt ttttaccatt
  gttggaaact ccgttgtgct tttttccaca tggaggagaa
  agaagaagtc aagaatgacc ttctttgtga ctcagctggc
  catcacagat tctttcacag gactggtcaa catcttgaca
  gatattaatt ggcgattcac tggagacttc acggcacctg
  acctggtttg ccgagtggtc cgctatttgc aggttgtgct
  gctctacgcc tctacctacg tcctggtgtc cctcagcata
  gacagatacc atgccatcgt ctaccccatg aagttccttc
  aaggagaaaa gcaagccagg gtcctcattg tgatcgcctg
  gagcctgtct tttctgttct ccattcccac cctgatcata
  tttgggaaga ggacactgtc caacggtgaa gtgcagtgct
  gggccctgtg gcctgacgac tcctactgga ccccatacat
  gaccatcgtg gccttcctgg tgtacttcat ccctctgaca
  atcatcagca tcatgtatgg cattgtgatc cgaactattt
  ggattaaaag caaaacctac gaaacagtga tttccaactg
  ctcagatggg aaactgtgca gcagctataa ccgaggactc
  atctcaaagg caaaaatcaa ggctatcaag tatagcatca
  tcatcattct tgccttcatc tgctgttgga gtccatactt
  cctgtttgac attttggaca atttcaacct ccttccagac
  acccaggagc gtttctatgc ctctgtgatc attcagaacc
  tgccagcatt gaatagtgcc atcaaccccc tcatctactg
  tgtcttcagc agctccatct ctttcccctg cagggtcatc
  cgtctccgtc agctccagga ggctgcgcta atgctctgcc
  ctcaacgaga gaactggaag ggtacttggc caggtgtacc
  ttcctgggct cttccaaggt gacagctctc accctgtgct
  gcaggtggcc ctgtgcctgg tgccacttct cactgcttac
  cagggcacaa ggacaccagt ggttcccaaa atgggtcaca
  gcaggatggc ctgcatcaga ttcaccaggg agggctataa
  gaaggcagac

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Bibliography

• 1MedicineNet.com. http//www.medterms.com/
  script/main/art.asp?articlekey2373. April 8,
  2004. November 28, 2004
• 2Laitinen, Tarja, Anne Polvi, Pia Rydman, Johanna
  Vendelin, Ville Pulkkinen, Paula Salmikangas,
  Sira Makela, Marko Rehn, Asta Pirskanen, Anna
  Rautanen, Marco Zuccheli, Harriet Gullsten,
  Marina Leino, Harri Alenius, Tuula Petays, Tari
  Haahtela, Annika Laitinen, Catherine Laprise,
  Thomas J. Hudson, Lauri A. Laitinen, Juha Kere.
  Characterization of a Common Susceptibility Locus
  for Asthma-Related Traits. Science Vol 304. April
  4, 2003. March 9, 2004.