MOLECULAR GENETIC OF

HEAD INJURY OUTCOME

IRAWAN YUSUF
Department of Physiology
Faculty of Medicine and
Division of Biotechnology
Research Center, Hasanuddin University
INTRODUCTION

Virtually all diseases have a genetic component

Cystic fibrosis Adult onset diabetes AIDS

; Genetic component
; Environment component
INTRODUCTION
Head Injury
The most common cause of trauma-related death
Mortality and morbidity affected by many factors
Understanding the pathobiological responses to head injury
offers new therapeutic modalities
Genetic Variation
Human share around 30.000 genes which is varies between
individuals (genetic variation or polymorphism)
Human phenotypes are determined by the interaction of genes
and environmental factors
Genetic variation can influence the risk and outcome of head
injury
WHAT IS GENETIC VARIATION?

Genetic variations or polymorphisms means that a

certain gene locus can have numerous variants or
'alleles
Genetic variations occurring in more than 1% of a
population would be considered useful polymorphism
for genetic linkage analysis.
Genetic variation among individuals means that each of
us has a unique genetic make-up that influences our
susceptibility to disease.
WHAT IS GENETIC VARIATION?

- 15.000 genes play a role in he development, plasticity

and maintenance of the CNS
6 million genetic variations contribute to genetic
variability between individuals
Approximately 5 variations per gene are functional
resulting in change and behavior of proteins
Alleles variants of genes resulting from genetic
variations
A C T C A G T T G A General population

97%

A C T C A G T T T A Polymorphism

3%

A C T C A G T T G A General population

99.8%

A C T C A G T T T A Mutation

0.2%
 U C A G
UUU UCU UAU UGU U
Phe Tyr Cys
UUC UCC UAC UGC C
U UUA UCA
Ser
UAA Stop UGA Stop
Leu A
UUG UCG UAG Stop UGG Trp G
CUU CCU CAU CGU U
CUC CCC CAC His CGC C
C CUA
Leu
CCA
Pro
CAA CGA
Arg
Gin A
CUG CCG CAG CGG G
AUU ACU AAU AGU U
Asn Ser
AUC Ile ACC AAC AGC C
A AUA ACA
Thr
AAA AGA
Lys Arg A
AUG Met ACG AAG AGG G
GUU GCU GAU GGU U
GCC GAC Asp GGC C
GUC
G GUA
Val
GCA
Ala
GAA GGA
Gly
Glu A
GUG GCG GAG GGG G
THE EFFECTS OF POLYMORPHISM

Neutral alteration, a base substitution with no effect on

the amino acid residue encoded
Conservative change, a base substitution that results in
an altered amino acid, but has minimal effect on protein
structure and function
Nonconservative alteration, leading to a change in the
encoded amino acid residue that has dramatic effects on
protein structure and function
 Positions of mutant sites and their functional consequences

Wild type
5 3

Neutral alteration

Conservative change

Nonconservative change

Nonconservative change

Promotor region Components of protein active site

Exons Intron
Mutant site
Functional Consequences of Genetic Variations
Loss of function

+ + m

+ m m

Leak of function

+ + m

+ m m

Gain of function

+ + M

+ M M
ASSOCIATION BETWEEN GENETIC VARIATION
AND BRAIN INJURY

The association or link between genetic variation and brain

injury is based on 3 main sets of evidence:
Epidemiological Evidence

Genotype - Phenotype Relationship

Biological Plausibility

Clinical evidence
 Epidemiological Evidence

The link between genetic polymorphism and brain

injury is not a new concept
Finding between several studies are not consistent
Large-scale studies needed to solve the inconsistent
result
 Genotype - Phenotype Relationship

Transcription Translation Cellular Altered structure

processing and function

DNA RNA Protein Protein modification Phenotype

Genome state Message Gene product Characteristics

variable variable cellular, organ, or
species
 Biological Plausibility

a Gene bAllele c Phenomenon d Diseases

APOE Gene 4 Allele APOE Expression Worsen outcome

of TBI

Larger intracerebral haematomas

Cerebral vasculature integrity
Cerebral amyloid angiopathy
BBB integrity
Coagulopathy
 Apolipoprotein E

Major lipid transport lipoprotein in CSF synthesized

by astrocytes
Cell membrane repair and growth
Promote nerve regeneration
Maintaining the integrity of cerebral vasculature
Clearance of lipid debris after injury
 Apolipoprotein E Gene

Located at chromosome 19. Consist of four exons

There are three allelic variants (2,3, and 4) that
encode three isoforms (APOE2, APOE3, and APOE4
Allele frequencies are 7%, 78%, and 15% in Caucasians
Genetic variations in the promoter region (G-219T and
A-491T) modify APOE expression
 WHAT SHOULD WE LEARN FROM GENETIC
STUDIES IN TBI?

Most studies in TBI have been association studies. Association does not
necessarily causation
Genetic variation affect not all risk factors for TBI outcome (e.g. 4
variant does not affect GOS, but affect verbal memory, motor flexibility
and speed)
There is inconsistent gene-dose effect from different genotype on risk of
disease
Pathological and genetic studies have shown the complexity of the
cause-effect relationship between gene and TBI outcome
 GENERAL IMPLICATION

Understanding Biological Processes

Genetic Genetic Variation Diseases Prevention Diseases Therapies

Susceptibility that Cause Disease Health Promotion

Predisposition Diagnostic Targeting population Gene therapy

screening testing at risk Gene product therapy
Carrier Regulation of gene
testing expression
Presymptomatic Pharmacogenomic
testing
 WHAT SHOULD WE LEARN FROM
ASSOCIATION STUDIES IN TBI?

Population admixture
Methodology (study design, size of the study population, strength
of association, precise phenotypic characterization)
Effects of confounders (gene-gene and gene-environmental
interaction)
 SUMMARY

It seem that any common variations in the population

will have effect on the level of the specific risk factors
We need large-scale studies to identify the genetic
determinants of clinical outcome
Completion of Human Genome Projects, however, will
help us to discriminate between genetic and
environment risk for worse outcome