Transcript Gene-Environment Interactions in Development of Asthma

Mapping Genes for SLE:
A Paradigm for Human Disease?
Stephen S. Rich, Ph.D.
Department of Public Health Sciences
Wake Forest University School of Medicine
Simple vs Complex Traits
Simple Traits
Complex Traits
-rare
-common
-single gene (Mendelian)
-many genes (Oligogenic)
-severe mutations
-mild mutations
-large phenotypic effect
-small phenotypic effect
Complex trait mapping is the major challenge in human genetics
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
Gene - Environment Interaction
Gene - Environment Interaction:
Complex Genetic Diseases
Genetic/Host
Susceptibility
Presymptomatic
Conditions
(Risk Factors or
Markers of Disease
Susceptibility)
Symptomatic Disease (Reversible or
Irreversible Changes in Organ
Structure and Function)
Environmental
Influences
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
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
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
Example of Linkage Analysis
D1S218
D1S158
D1S444
D1S218
D1S158
D1S444
D1S218
D1S158
D1S444
Affected Sib Pair Family
a//b
a//c
c//d
25% a//c
50% a//d or b//c
25% b//d
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 (>90%) of childbearing age
• Prevalence of SLE in the United States is estimated to be
between 40 - 45 cases per 100,000 (Hochberg 1997)
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 (S=10-20; 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
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
NPL Regression Analysis of Combined
Genome Scan for SLE
Chromosomal
Region
Chr 1 @ 263
Chr 4 @ 21
Chr 4 @ 165
Chr 6 @ 68
Chr 6 @ 85
Chr 7 @ 27
Chr 16 @ 77
Chr 20 @ 62
Nearest Marker
D1S2785
D4S403
D4S2368
D6S2410
D6S1031
D7S507
D16S3253/D16S503
D20S481/D20S119
LOD
2.14
3.65
2.00
4.90
3.84
2.47
3.51
1.97
LOD-1
Interval
253-285
11-28
147-178
61-80
57-100
6-37
65-85
57-67
Combined Genome Scan for SLE
Sample Similarities and Differences
Chromosomal
Region
Chr 1 @ 263
Chr 4 @ 21
Chr 4 @ 165
Chr 6 @ 68
Chr 6 @ 85
Chr 7 @ 27
Chr 16 @ 77
Chr 20 @ 62
LOD Score
Nearest Marker
Combined MN
D1S2785
2.14
2.2
D4S403
3.65
1.8
D4S2368
2.00
1.9
D6S2410
4.90
4.3
D6S1031
3.84
3.6
D7S507
2.47
1.5
D16S3253/D16S503 3.51
4.3
D20S481/D20S119
1.97
2.0
OK
0.3
1.9
0.3
1.0
0.7
1.0
0.3
0.3
Combined Genome Scan for SLE
Ethnic Differences
Chromosomal
Region
Chr 1 @ 263
Chr 4 @ 21
Chr 4 @ 165
Chr 6 @ 68
Chr 6 @ 85
Chr 7 @ 27
Chr 16 @ 77
Chr 20 @ 62
LOD Score
African
Nearest Marker
Combined American Caucasian
D1S2785
2.14
0.0
1.8
D4S403
3.65
0.0
4.5
D4S2368
2.00
0.7
1.9
D6S2410
4.90
1.6
2.6
D6S1031
3.84
2.5
1.4
D7S507
2.47
0.0
2.9
D16S3253/D16S503 3.51
0.1
3.2
D20S481/D20S119
1.97
0.0
2.7
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
Positional Cloning in Complex Diseases
Genetic
DNA
Phenotypes
Mapping
Genome Screening
and Linkage Analyses
Mapping
Diagnostic
Tests
Susceptibility
Gene(s)
Fine
ACGCCACC
ACGTCACC
New Mechanisms
New Drugs
Gene-Environment
Interactions
Acknowledgements
University of Alabama-Birmingham
Robert P. Kimberly
Jeffrey C. Edberg
University of Oklahoma
John B. Harley
Jennifer H. Kelly
Courtney Gray-McGuire
Kathy L. Moser*
University of Minnesota
Timothy W. Behrens
Patrick M. Gaffney
Robert R. Graham
Wake Forest University
Stephen S. Rich
W. Mark Brown
Carl D. Langefeld