Mapping Genes for SLE: A Paradigm for Human Disease?

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Mapping Genes for SLEA Paradigm for Human
Disease?

• Stephen S. Rich, Ph.D.
• Department of Public Health Sciences
• Wake Forest University School of Medicine

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Simple vs Complex Traits
Simple Traits -rare -single gene
(Mendelian) -severe mutations -large phenotypic
effect
Complex Traits -common -many genes
(Oligogenic) -mild mutations -small phenotypic
effect
Complex trait mapping is the major challenge in
human genetics
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Difficulties in Complex Disease

• Identifying genes that contribute to
  susceptibility of complex disease difficult due
  to underlying biological mechanisms
• Phenotypic heterogeneity
• Genetic heterogeneity
• Gene-environment interaction
• Limited study power to detect small effect
  susceptibility genes (QTLs)
• Available sample size for genetic studies

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Gene - Environment Interaction
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Gene - Environment InteractionComplex Genetic
Diseases
Presymptomatic Conditions (Risk Factors or
Markers of Disease Susceptibility)
Genetic/Host Susceptibility
Environmental Influences
Symptomatic Disease (Reversible or Irreversible
Changes in Organ Structure and Function)
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Steps Towards Finding a Gene

• Identification of a population
• Clinical assessment
• Linkage analysis - genome screen
• Fine mapping and gene localization
• Gene identification / sequence variants
• Functional genomics Gene expression

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Issues in Clinical Assessment

• Disease phenotype definitions
• medical history, evidence of sub-clinical
  outcome, and a confirmation through a clinical
  examination
• outpatient clinic records with varying data
• positive answer to the questions
• Have you ever been diagnosed with ...? and
• If yes, has this happened more than once?
• Standardized questionnaires
• Standardized protocols
• Study coordination and training of staff
• Quality Control / Quality Assurance

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Choices of a Population

• Representation
• Isolated, admixed or inbred
• Mixed, heterogeneous populations
• Family structure
• Unrelated individuals
• Families
• Parents and children
• Extended families (pedigrees)
• Source
• Single ethnic group
• Multiple ethnic groups

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Example of Linkage Analysis
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Affected Sib Pair Family
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Systemic Lupus Erythematosus

• SLE is a chronic autoimmune inflammatory disease
  characterized by the production of pathogenic
  autoantibodies
• SLE is a clinically heterogeneous disease that
  affects a variety of organs such as joints, skin,
  blood and kidneys
• SLE disproportionately affects women (gt90) of
  child-bearing age
• Prevalence of SLE in the United States is
  estimated to be between 40 - 45 cases per 100,000
  (Hochberg 1997)

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Familiality of SLE

• SLE has a strong genetic component
• Increased concordance rates among MZ twins
• (Deapen et al., 1992, Reichlin et al., 1992)
• Increased risk to siblings (?S10-20 Vyse and
  Todd, 1996)
• SLE does not exhibit simple Mendelian inheritance
  patterns and may involve
• incomplete penetrance
• phenocopies
• genetic heterogeneity
• polygenic inheritance
• modifying environmental effects

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Affected Relative Pair Collections

• Minnesota cohort
• 187 SLE sib pair families
• 6p11-21, 16q13, 14q21-23, 20p12.3
• Oklahoma cohort
• 94 extended multiplex pedigrees
• 1q23, 13q32, 20q13, 1q31
• Ethnic-specific effects

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NPL Regression Analysis of Combined Genome Scan
for SLE

• Chromosomal LOD-1
  Region Nearest Marker
  LOD Interval
• Chr 1 _at_ 263 D1S2785 2.14 253-285
• Chr 4 _at_ 21 D4S403 3.65 11-28
• Chr 4 _at_ 165 D4S2368 2.00 147-178
• Chr 6 _at_ 68 D6S2410 4.90 61-80
• Chr 6 _at_ 85 D6S1031 3.84 57-100
• Chr 7 _at_ 27 D7S507 2.47 6-37
• Chr 16 _at_ 77 D16S3253/D16S503 3.51
  65-85
• Chr 20 _at_ 62 D20S481/D20S119 1.97
  57-67

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Combined Genome Scan for SLESample Similarities
and Differences

• Chromosomal
  LOD Score
• Region Nearest Marker
  Combined MN OK
• Chr 1 _at_ 263 D1S2785 2.14 2.2
  0.3
• Chr 4 _at_ 21 D4S403 3.65 1.8 1.9
• Chr 4 _at_ 165 D4S2368 2.00 1.9 0.3
• Chr 6 _at_ 68 D6S2410 4.90 4.3 1.0
• Chr 6 _at_ 85 D6S1031 3.84 3.6 0.7
• Chr 7 _at_ 27 D7S507 2.47 1.5 1.0
• Chr 16 _at_ 77 D16S3253/D16S503 3.51 4.3
  0.3
• Chr 20 _at_ 62 D20S481/D20S119 1.97 2.0
  0.3

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Combined Genome Scan for SLEEthnic Differences

• LOD Score
• Chromosomal
  African
• Region Nearest Marker
  Combined American Caucasian
• Chr 1 _at_ 263 D1S2785 2.14 0.0
  1.8
• Chr 4 _at_ 21 D4S403 3.65 0.0
  4.5
• Chr 4 _at_ 165 D4S2368 2.00 0.7
  1.9
• Chr 6 _at_ 68 D6S2410 4.90 1.6
  2.6
• Chr 6 _at_ 85 D6S1031 3.84 2.5
  1.4
• Chr 7 _at_ 27 D7S507 2.47 0.0
  2.9
• Chr 16 _at_ 77 D16S3253/D16S503 3.51
  0.1 3.2
• Chr 20 _at_ 62 D20S481/D20S119 1.97
  0.0 2.7

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Summary

• The Lupus SCOR combined genome scan for SLE
  provides evidence of linkage to several
  chromosomal regions 1q, 4p, 4q, 6, 7p, 16, 20
• With the exception of chromosome 6, our linkage
  peaks tend to be dominated by the Caucasian
  pedigrees in our sample
• Several of our linkage signals appear to be
  supported by published genome scans
• Fine mapping efforts related to these linkage
  regions are underway within the SCOR as part of
  its mission to map and clone genes predisposing
  to SLE and related phenotypes

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Positional Cloning in Complex Diseases
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Acknowledgements

• University of Alabama-Birmingham
• Robert P. Kimberly
• Jeffrey C. Edberg
• University of Minnesota
• Timothy W. Behrens
• Patrick M. Gaffney
• Robert R. Graham

• University of Oklahoma
• John B. Harley
• Jennifer H. Kelly
• Courtney Gray-McGuire
• Kathy L. Moser
• Wake Forest University
• Stephen S. Rich
• W. Mark Brown
• Carl D. Langefeld