PHARMACOGENOMICS AND GENETIC STUDIES

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PHARMACOGENOMICS AND GENETIC STUDIES

• John D. Reveille, M.D.
• The University of Texas Health Science Center at
  Houston

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International Histocompatibility Working Group
There are gt 200 genes, gt100 functional ( 40
with immune function) in the HLA complex. For
example, for AS, less than half of the genetic
risk can be attributed to MHC genes However it
is difficult to identify other MHC genes because
of strong linkage disequilibrium with HLA-B27
Chromosome 6p21.3, 4 Mb
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SUMMARY OF DATA FROM XIII IHWGSPONDYLOARTHROPATHY
COMPONENTVictoria, Canada, May 2002

• European Component (A. Toubert, Chairman)
• 115 families with 507 individuals including 159
  patients fulfilling the European
  Spondyloarthropathy Study Group (ESSG) criteria
  for SpA, 315 unaffected and 33 individuals with
  unknown disease status fulfilling the European
  Spondyloarthropathy Study Group (ESSG) criteria
  for SpA.
• North American Component (J.D. Reveille)
• 129 families, 187 sib pairs plus 42 trio
  families.
• Mexican Component (Clara Gorodezky)
• 59 Mexican Mestizo AS patients meeting and 50
  healthy controls modified New York criteria for
  AS, all of them HLA-B27 positive.
• Indian Component (Narinder Mehra)
• 104 HLA-B27 positive individuals from North
  India, including 80 patients meeting the ESSG
  criteria (39 with a clinical diagnosis of AS,
  35 with unclassifiable SpA and 6 were affected by
  reactive arthritis, and 24 HLA-B27 positive
  controls).
• None of the microsatellites on HLA-B27 haplotypes
  showed any significant different transmission to
  affected versus non-affected individuals, nor did
  any other HLA-B , DRB1, DQA1, DQB1allele, when
  correcting for B27.

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XIV International Histocompatibility Testing
Workshop-Melbourne, Australia, 2005

• Hypothesis-The contribution of the Major
  Histocompatibility Complex to predisposition to
  AS is only partially explained by HLA-B27
• Aim-to collect families with a proband with AS
  with both parents available from different ethnic
  groups for analysis of transmitted vs.
  nontransmitted haplotypes
• This study is being supported by a grant from
  NIAID

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THE ANKYLOSING SPONDYLITIS GENETICS CONSORTIUM

• Organized at First International Conference on
  the Genetics of Ankylosing Spondylitis, Oxford,
  April 11-12, 2003
• Purpose
• To pool data from the various international
  genetic consortia in AS currently existing for
  meta-analysis
• Members
• Steering committee-M. Brown (Oxford), J. Reveille
  (Houston), M.Breban (Paris), R. Inman (Toronto),
  L. Rubin (Toronto), W. Maksymowych (Edmonton),
  Lyle Palmer (Boston), M Rudwaleit (Germany)
• Groups with large family collections and genome
  screen data
• Oxford, French, North American and possibly Euro
  AS
• North American Uveitis collection (T. Martin, J.
  Rosenbaum)
• Meta-analysis of genomewide scan data between
  Oxford, NASC and Paris planned for 2004

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IS DISEASE SEVERITY IN AS GENETICALLY DETERMINED?

• The traits of disease activity (BASDAI), function
  (BASFI) and age at symptom onset were found to be
  highly heritable
• No linkage was observed between the major
  histocompatibility complex (MHC) and any of the
  traits studied (LOD score lt1.0).
• "Significant" linkage (LOD score 4.0) was
  observed between a region on chromosome 18p and
  disease activity.
• Age at symptom onset showed "suggestive" linkage
  to chromosome 11p (LOD score 3.3).
• Maximum linkage with the function was seen at
  chromosome 2q (LOD score 2.9).
• M Brown et al, AR 2003482234-9).

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Prognosis Study On Ankylosing Spondylitis (PSOAS)

• A multicenter study between Cedars-Sinai (M.
  Weisman), NIAMS (M. Ward), University of
  Texas-Houston (J. Reveille) and the University of
  California-San Francisco (J. Davis)
• Enrollment begun in the fall of 2001.
• Two cohorts of patients
• Cross-sectional-disease duration gt20 years (400
  patients-205 enrolled)
• Longitudinal-disease duration lt20 years (200
  patients-75 enrolled
• Study measures Disease Activity (BASDAI),
  Function (BASFI, HAQ), Damage (Radiographic-BASRI/
  SASS), acute phase reactants (CRP, ESR)
• Genetic markers (MHC HLA-A,-B, DRB1, DQA1, DQB1,
  DPB1-typing, other genetic factors)

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PHARMACOGENOMICS AND RESPONSE TO ANTI-TNF THERAPY

• Although infliximab treatment induces remission
  in a sizable proportion of patients with Crohns
  disease, up to 40 do not respond.
• Exploratory (n90) and confirmatory (n444)
  cohorts of patients were examined for TNF and TNF
  receptor polymorphisms to look for predictors of
  treatment response.
• Despite promising finding in the exploratory
  cohort, no alleles were found that were
  associated with either refractory Crohns disease
  or treatment response.
• Mascheretti et al, Pharmacogenomics 2002 2
  127-36.

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CYTOCHROME P450 2D6 GENE (chromosome 22q)

• involved in the metabolism of xenobiotics, which
  include certain drugs, metals, industrial and
  naturally occurring chemicals.
• xenobiotics have been shown to be promoters of
  inflammation via T-cells
• The pm (poor metabolizer) genotype has been
  found in German and British AS patients
• Beyeler et al Ann Rheum Dis 1996 5566-68
• Brown et al Hum Mol Genet 2000 191563-6

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CYTOCHROME P450 1A1 AND MANGANESE SUPEROXIDE
DISMUTASE GENE POLYMORPGISMS IN AS

• 70 Taiwanese AS patients and 93 healthy controls
  were examined for CYP1A1 and MnSOD genes
• CYP1A1 4887 C/A was significantly lower in AS
  patients than in controls.
• No MnSOD alleles differed in frequency in the AS
  patients compares to controls.
• Yen JH et al. Immunol Lett 2003 88 113-6.

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PROTEOGENETICS AND IBD

• The Multidrug Resistance 1 (MDR1) gene encodes a
  membrane transport protein that alters
  pharmacokinetic profiles for a variety of drugs.
• The MDR1 gene has been mapped to chromosome 7q
• Human polymorphisms have been reported in
  Ala893Ser/Thr and at C335T.
• The Ala893 allele has been associated with IBD
  (especially Crohns disease).
• Although it has not been examined in SpA, its
  role in mediating intestinal epithelial
  homeostasis (as demonstrated by the tendency for
  spontaneous colitis to develop in mdr1-knockout
  mice), makes it an attractive candidate in many
  of the SpA, where intestinal inflammation is
  thought to play a role and needs further study.
• Brant SR et al. - Am J Hum Genet 2003 73
  1282-1292.

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ALLELIC VARIANTS OF DRUG METABOLIZING ENZYMES AS
RISK FACTORS FOR PSORIASIS

• Another recent study of drug metabolizing
  enzymes, including CYP1A1, CYP1B1, CYP2C19,
  CYP2E1, GSTM1, and NQOR found CYP1A1 variant
  alleles 2A and 2C to be negatively associated
  with psoriasis.
• Rihter-Hintz D, et al. J Invest Dermatol 2003
  120 765-770.

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THE FUTURE

• Analyzing genes and chromosomal regions involved
  in susceptibility to AS in different ethnic
  groups
• Analyzing genes and chromosomal regions involved
  in severity and outcome in AS in different ethnic
  groups
• Attempting to predict drug responsiveness by
  genetic profiling