2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
(RAGE -429T/C, HSP70-2 1267A/G and TNFα -308G/A) were also
determined. We identified 53 polymorphisms in the CYP21 gene; ten
SNPs were previously not reported. C4B*Q0 was found to significantly
linked to two intronic SNPs (1106C/A and 1113T/C) of CYP21 . Analysis
of 34 families confirmed that the haplotype block involving the variant
form of the SNPs has no C4B gene . These results indicate that
the SNPs may contribute to the higher morbidity and mortality rate
of C4B*Q0 carriers, presumably by influencing the expression of the
CYP21 protein .
P06.074
Bisphosphonate related Osteonecrosis of the jaw is associated
with polymorphisms of the cytochrome P450 2c8 in multiple
myeloma: a genome wide single nucleotide polymorphism
analysis
M. E. Sarasquete1 , R. Garcia-Sanz1,2 , L. Marin1 , M. Alcoceba1 , M. C. Chillon1 ,
A. Balanzategui1 , C. Santamaria1 , J. Blade2 , J. de la Rubia2 , J. Petit2 , M. T.
Hernandez2 , J. J. Lahuerta2 , M. Gonzalez2,1 , J. F. San Miguel1,2 ;
1 2 Hospital Universitario de Salamanca, Salamanca, Spain, Grupo Español de
Mieloma. Red Española de Mieloma (G03/136), Spain, Spain.
Osteonecrosis of the jaws (ONJ) is an adverse side effect of bisphosphonate
(BP) therapy . Patients with multiple myeloma (MM) usually receive
BPs for the treatment of bone destruction . ONJ could be caused
by a combination of environmental and genetic risk factors . Our aim
was to asses the role of genetics in ONJ development . We performed
a genome wide association study using 500 .568 SNPs in two series
of MM patients included in the same therapeutic protocol receiving the
same BP therapy: 22 cases (MM with ONJ) and 65 matched controls
(MM without ONJ) .
Clinical and biological characteristics, response to treatment and
survival rates were similar in both subsets of patients . Regarding the
polymorphisms, we identified four SNPs (rs17110453, rs1934951,
rs1934980 and rs1341162) mapped within the Cytochrome P450-2C
gene (CYP2C8) with a singular distribution among cases and controls .
Rs1934980, rs1341162 and rs17110453 showed a significant correlation
with ONJ (p=4 .231e-6 , p=6 .22e-6 and p=2 .15e-5 respectively),
although the association was not significant after Bonferroni correction.
The SNP rs1934951 kept its statistical significant association with
ONJ (P-value=1 .07e-06, P corrected value=0 .02) . Genotyping results
displayed an overrepresentation of the T allele in cases vs . controls
(0 .475 vs . 0 .125) . Thus, individuals homozygous for the risk allele had
a likelihood of ONJ increased by 12.75 (95% confidence interval 3.7
to 43 .5) .
Our data suggest that the rs1934951 polymorphism may play a role
as a risk factor for developing ONJ in MM patients receiving BPs therapy
.
P06.075
cYP2D6 polymorphism in patients with Parkinson‘s disease
M. Lisak, M. Stefanović, M. Roje Bedeković, Z. Trkanjec, E. Topić, V. Demarin;
University Hospital Sestre milosrdnice, Zagreb, Croatia.
Aim: CYP2D6 is an enzyme of cytochrome P-450 system that metabolizes
some of endogenous substances in central nervous system,
including metabolism of dopamine and drugs used for Parkinson’s disease
(PD) treatment . Decreased metabolic capability of this enzyme
could be associated with increased risk of morbidity and of higher risk
for side effects of antiparkinsonian medication . The aim of this study
was determination of the incidence and comparison of non-functional
alleles with the intention of detecting increased risk for PD in individuals
with damaged function of enzyme CYP2D6 .
Materials and methods: Multiplex allele-specific polymerase chain reaction
(PCR) the incidence of non-functional alleles CYP2D6*3, *4,
*6, *7, and *8 was determined in healthy volunteers (n=145) and in
patients with PD (n=41) .
Results: In a group of healthy volunteers the incidence of CYP2D6
alleles was: CYP2D6*3=1 .4%, CYP2D6*4=11 .0%, CYP2D6*6=1 .0%,
CYP2D6-wt=86 .6% .
In a group of PD patients the incidence of CYP2D6 alleles was: CY-
P2D6*3=1 .2%, CYP2D6*4=20 .7%, CYP2D6*6=1 .2% and CYP2D6wt=76.8%.
Statistically significant difference was found only for allele
CYP2D6*4 (relative risk=2 .10; 95% CI: 1 .113-3 .994) .
The relation of genotype distribution was *3/wt 2 .8% and 2 .4%; *4/wt
18 .6% and 26 .8%; *4/*4 1 .4% and 7 .3%; *6/wt 1 .4% and 2 .4%; *4/*6
0 .7% and 0 .0%; wt/wt 75 .2% and 61 .0% in healthy volunteers and PD
patients, respectively). There was no statistically significant difference
between these distributions .
Discussion: Results of this study indicate that the allele CYP2D6*4
could be considered as a weak risk factor for PD, but similar study
should be carried out on larger sample group .
P06.076
contribution of gene sequence variant cYP3A4*1B of the
hepatic cytochrome P450 3A4 enzyme to variability in individual
response to clopidogrel
A. N. Stolyarova, O. V. Sirotkina;
Petersburg Nuclear Physics Institute Russian Academy of Science, Saint-Petersburg,
Russian Federation.
Clopidogrel is an inactive pro-drag that requires oxidation by hepatic
cytochrome CYP3A4 to generate active metabolite . Because genetic
variations are the major determinant of heterogeneity in metabolic activity
of enzyme, we hypothesize that polymorphism of CYP3A4 gene
may influence platelet aggregation in patients treated with clopidogrel.
We examined platelet aggregation in 100 patients with acute coronary
syndrome treated by clopidogrel 75mg/day according to variant
CYP3A4*1B . Aggregation was induced by ADP 20mkM and measured
in two points - before and on day 7 after clopidogrel treatment as level
of light transmission (LT,%) determined by optical aggregometry . For
detection of the CYP3A4*1B the PCR and original endonuclease digestion
with PstI was used and results in patients were compared
with 83 healthy persons . Our study showed that the frequencies
of CYP3A4*1B genotypes were 89%, 10% and 1% in patients and
90 .5%, 8 .5% and 1% in controls for wild, heterozygous and homozygous
genotypes, respectively, and these frequencies didn’t differ in two
groups. The LT was significantly lower in patients in second measuring
point compared to first point - 20.59±1.58% and 34.03±1.96%, respectively
(p