Your title here

1
Genetic variation and degenerative skeletal
disorders intervertebral disc disease as a case
study
Prof. Kathryn S. E. Cheah Department of
Biochemistry
2
Impact of low back pain

• Affect 70-80 of the population world-wide.
• Significant morbidity in young and old people.
• In USA 30B medical treatment, 25B workers
  compensation cost.

3
Disc degeneration increases with age
100
normal
90
mild DDD
80
moderate to severe DDD
70
60
Percentage of individuals in each group
50
40
30
20
10
0
18-29
30-39
40-49
50
Age groups (years)
Spine Dec 2005
4
Hints of genetic involvement
5
Evidence of genetic involvement
6
Study design
Patients presenting at the outpatient clinic in
QMH with complaints of low back pain
Volunteers recruited from the general population
2,860
Cohort
Quantitative assessment of disc condition by MRI
18 families
7
Objective assessment
MRI
Clinical data

• DDD scores (0-3/disc level)
• Schneidermans scoring system (5 lumbar regions)
• Additional phenotype changes also scored
• Bulge/herniation (0-2)
• HIZ / annular tears (0/1)
• Schmorls nodes (0/1)

• Back and leg pain scores (VAS)
• Roland Morris disability score

8
Problems with genetic study of DDD

• Age-related disease
• Selection of age group for recruitment
• Appropriate control and age adjustment
• Others?

9
Candidate genes
50 candidates tested
Proper disc functioning
Cells
stimulus
10
Some known genetic risk factors for DDD
Collagen IX, Collagen XI, Aggrecan, Asporin, CILP
Proper disc functioning
Cells
stimulus
VDR, MMP-2, MMP-3
IL-1, TGF-b
11
Three potential interacting genes for DDD
MMP10
Cleavage
IL1-F10
Aggrecan
Cleavage
ADAMTS-5
12
Family linkage analysis
Strong association for a gene in chromosome 10
Non-synonymous coding G?A SNP (R357Q)
13
Selection of Cases and Controls
Genome-wide Association Study
SD from mean
Age at MRI
14
Whole genome analysis result
Before Eigenstrat
15
Allele frequency variations
Associated with intervertebral disc degeneration
16
CILP, phenotypic and population differences

• Population differences
• Japanese and Finnish cohorts painful disc with
  herniation and sciatica
• Phenotypic differences
• Chinese cohort MRI data independent of pain.

17
How can HKU participate?

• Annotation of variants in specific genes or set
  of genes
• Examine the effect of specific variants on DDD or
  other phenotypes

18
Acknowledgment
Ken Cheung Keith DK Luk John CY Leong Pei Yu
Danny Chan Kathy Cheah Jeffrey Jim Daniel
Ho Patrick Kao Sandy Poon BJ Fan Clara
Tang Julian Yeung
You Qiang Song Pak Sham Shea Ping Yip Jurg Ott
Leena Ala-Kokko Jaro Karpinnen Noora
Noponen-Hietala Iita Virtanen Minna Mannikko
Shiro Ikegawa Kazuhiro Chiba