TUMOR NECROSIS FACTOR-ΑLPHA HAPLOTYPE

IS STRONGLY ASSOCIATED
WITH BONE MINERAL DENSITY
IN PATIENTS WITH CROHN’S DISEASE

Naomi Lee,* Elizabeth Fowler,† Susan Mason,‡ Douglas Lincoln,§ Dennis R Taaffe* and
Graham Radford-Smith

DIPRESENTASIKAN OLEH
dr. ANANTA
 BACKGROUND

CROHN’S
DESEASE
INFLAMATORY GENETIC MALABSORPTI CORTICOSTERO
PROSSES SUSCEPTIBILIT ON ID TREATMENT
Y

DECREASE
BONE MINERAL
DENSITY
INCREASE
MOBIDITY OF
 BACKGROUND

CROHN’ CLINICAL DECREASE

BONE
S VARIABLES MINERAL
DESEAS DIFFICULT TO DENSITY
E QUANTIFY AND
COMPARE
FROM STUDY
TO STUDY
MOLECULAR
BASIS OF
COMPLEX
DISORDERS
NOD2/CARD15
CL1A1 gene
TNF α haplotype genes
 METHODS
304 patients
CROHN’S Include: radiologic, hitologic,
DESEASE endoscopic assesement
Exclude : medical condition that may
alter bone metabolism (renal or hepatic
desease, thyrotocsicosis,
hyperparathiroidism,etc

BONE GENOTYPING
TNF CC and TNF GT
DENSITOMETRY haplotype

STATISTICS ANALIZED
Pearson’s correlation coefficients
linear regression models (and t-tests)
analysis of variance (anova)
 RESULTS
Individuals with normal BMD both at the hip and spine
were significantly more likely to inherit the high-TNF CC
genotype (P = 0.002) and had a strong negative association
with the low-TNF GT haplotype (P = 0.002)

The figures for spinal BMD alone were very similar, with
significant associations betweennormal spine BMD and the
CC genotype (P = 0.003), and the strong negative association
with a GT haplotype (P = 0.005)
RESULTS
 DISCUSION
 Crohn’s desease is a cronic inflamatory desease.
 A number of other studies, including measurement of
circulating TNF-a in cronic inflamatory , have suggested an
important role for TNF- α as a skeletal catabolic agent.
 The Problem of difficulties in studying circulating and tissue
cytokines (TNF-α) becouse of their very short half-life.
 genetically determined variation in the concentration of
TNF-a may be a more reliable method to determine whether
this cytokine plays a role in bone metabolism in the long
term
 DISCUSION
 Present study determining a genetic association between
the TNF-a gene and bone loss by incorporating both
genotype and haplotype analysis.
 There is strong correlation between these analyses both
for overall BMD
 True association in the present study is between BMD
and gene that is in linkage disequilibrium with the
reported TNF-a genotypes and haplotype at 6p21
 DISCUSION
 Other stdudy demonstrated a significantly reduced
fracture risk in patients who had undergone bowel
surgery.
 Removal of the inflamed segment may allow temporary
relief from pro-inflammatory cytokines such as TNF α
that play a key role in bone resorption
 Crohn’s Desese patient with high TNF-a genotypes and
haplotype at 6p21 has more circulatory cytokines such as
TNF α. .
 DISCUSION
 The temporary reduction in intestinal inflammation and
associated reduction in steroid usage seen with intestinal
resection may temporarily prevent the abnormal bone
metabolism observed in patients without previous
resection and in those with greater duration since
resection
 More radical treatment to remove inflamatory segmen in
patient that has high TNF-a genotypes and haplotype at
6p21 could reduce complication decrease bone mineral
density.