2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
P06.053
Association study of microsattelite markers of five candidate
loci in the cleft lip and palate patients of Lithuania
L. Ambrozaitytė 1,2 , A. Matulevičienė 1,2 , V. Kučinskas 1,2 ;
1 Department of Human and Medical Genetics, Faculty of Medicine, Vilnius
University, Vilnius, Lithuania, 2 Centre for Medical Genetics, Vilnius University
Hospital Santariškių Klinikos, Vilnius, Lithuania.
The incidence of cleft lip and/or cleft palate (CL/P) in the population of
Lithuania is 1 in 544 newborns; nonsyndromic CL/P cases are 74 .1%
part of it . Many different genes are considered as candidate loci for
nonsyndromic CL/P responsible for this malformation . And the results
by many study groups are still very inconsistent .
We have investigated five microsattelite markers D2S292 in TGFA
gene, D14S61 in TGFB3 gene, D15S97 in GABRB3 gene, D17S1335
in RARA gene and BCL3 in BCL3 gene in 120 triads (child with nonsyndromic
CL+/-CP and both parents) - 102 triads with a child with
nonsyndromic cleft lip with or without cleft palate (NS-CL+/-P) and 18
triads with a child with nonsyndromic cleft palate only (NS-CPO) . Association
analysis was performed by using transmission disequilibrium
test (TDT) .
Allele-wise and genotype-wise analysis gave no statistically significant
results (p>0 .05) . Nevertheless transmission disequilibrium analysis
of every marker allele separately showed significant association between
three out of investigated five microsattelite markers and NS-
CL+/-CP: allele 6 (182 bp) of D2S292 marker (p=0 .024), allele 11 (206
bp) of D14S61 marker (p=0 .025) and allele 3 (128 bp) of BCL3 marker
(p=0 .015) .
These results suggest the contribution of TGFA, TGFB3 and BCL3
genes to nonsyndromic CL/P as well as indicate that these genes are
probably not the causal genetic risk factors .
P06.054
intron region importance of BCL gene in the nonsyndromic
cleft lip and/or cleft palate
I. Prane 1,2 , B. Lace 1 , L. Piekuse 1 , J. Klovins 2 , B. Barkane 3 , I. Akota 3 , A. Krumina
1 ;
1 Department of Molecular Biology and Genetics, Riga Stradins University, Riga,
Latvia, 2 Latvian Biomedical Research and Study Center, Riga, Latvia, 3 Department
of Oral and Maxillofacial Surgery, Institute of Stomatology, Riga Stradins
University, Riga, Latvia.
Background: Orofacial clefts form as a result of interaction of environmental
and genetic factors . Still up to now the exact mechanism
of how the clefts form are not known . This is why it is so important to
explore and investigate genes constituting to this process . It has been
reported that BCL3 (B-cell leukemia/lymphoma-3) on chromosome
19q13 .1-q13 .2, or a nearby gene may play a role in the etiology of
nonsyndromic cleft lip and/or cleft palate (CLP/CP) . There is possibility
BCL3 gene mutations increase affinity to transcriptional factors thus
inhibited expression of genes, which are important in mesenchymal
development process .
The aim of the study was to evaluate relevance of BCL3 gene intron
region in development of nonsyndromic orofacial clefts .
Materials and methods: Eight SNPs (rs7257231, rs1040117, rs8103315,
rs2927457, rs11671085, rs1979377, rs2927456 and rs2306148) in the
BCL3 gene were analyzed with MALDI-TOFF technique for allelic association
with the nonsyndromic CLP/CP in 75 trios (proband with both
parents) from Latvia . Observed data were analyzed with transmission
disequilibrium test (TDT) .
Results: Three of eight SNPs (rs2927457, rs11671085 and rs2306148)
were not polymorphic, five were found to be polymorphic - rs7257231,
rs1040117, rs8103315, rs1979377 and rs2927456 . TDT analysis
revealed SNP rs10401176 (χ 2 =5 .143, P=0 .023, df 1) in the CLP patient
group and three SNPs rs10401176 (χ 2 =5 .444, P=0 .0196, df 1),
rs7257231 (χ 2 =4.455, P=0.034, df 1), rs2927456 (χ 2 =4 .000, P=0 .045,
df 1) in the CP patient group showed statistically significant association
.
Conclusion: Statistical analysis of obtained results showed BCL3 gene
intron 1 as an meaningful region for further studies .
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P06.055
Role of the c1236t (rs1128503) polymorphism of the mDR-1
Gene on clopidogrel Responsiveness
E. Trabetti 1 , M. Zanoni 1 , P. Prandini 1 , D. J. Angiolillo 2 , E. Bernardo 3 , A. Fernandez-Ortiz
3 , C. Macaya 3 , T. A. Bass 2 , P. F. Pignatti 1 ;
1 Department of Mother and Child and of Biology-Genetics, Section of Biology-
Genetics, Verona, Italy, 2 Division of Cardiology, University of Florida College of
Medicine-Shands Jacksonville, Jacksonville, FL, United States, 3 Cardiovascular
Institute, San Carlos University Hospital, Madrid, Spain.
Background: Clopidogrel intestinal absorption and active metabolite
formation are influenced by P-glycoprotein-mediated efflux. The functional
activity of P-glycoprotein is under genetic control by the Multi
Drug Resistance-1 (MDR-1) gene . If genetic variations of MDR-1 contribute
to variability in clopidogrel response in patients with coronary
artery disease remains poorly explored .
Methods: The C1236T (rs1128503) polymorphism of the MDR-1 gene
was assessed in 62 patients . Patients were divided into 2 groups: carriers
and non-carriers of the T allele . Platelet aggregation was performed
before and 24 hours after clopidogrel administration . Standard
(300mg; n=45) and high (600mg: n=17) loading dose regimens were
used . All patients were on treatment with aspirin (100mg/day) . Peak
platelet aggregation was assessed by LTA using 6 μmol/L ADP stimuli.
Post-treatment platelet reactivity and percentage inhibition of platelet
aggregation (IPA) were determined .
Results: 71% and 29% of the study population were T and non-T allele
carriers, respectively . At baseline, there were no differences in platelet
aggregation between the two groups . At 24 hours there were no differences
in post-treatment platelet reactivity between groups following
a 300mg loading dose administration . However, following a 600mg
loading dose administration, post-treatment platelet reactivity was significantly
higher in T allele carriers (35±11% vs 16±3%; p=0.006). Accordingly,
there were no differences in IPA following a 300mg dose and
IPA was significantly lower in T allele carriers following a 600mg dose
(44±18% vs 73±5%, p=0 .001) .
Conclusions: The C1236T polymorphism of the MDR-1 gene modulates
clopidogrel responsiveness in the acute phase of treatment when
using high loading dose regimens .
P06.056
Association of cocaine dependence and neurotrophic factors:
contribution of the Brain-Derived Neurotrofic Factor (BDNF) and
the Neurotrophic Tyrosine Kinase Receptor 2 (NTRK )
N. Fernandez-Castillo 1 , M. Ribasés 2 , B. Gonzalvo 2 , M. Casas 2,3 , C. Roncero 2,3 ,
B. Cormand 1,4 ;
1 Departament de Genètica, Facultat de Biologia. Universitat de Barcelona,
Barcelona, Spain, 2 Servei de Psiquiatria, Hospital Universitari Vall d’Hebron,
Barcelona, Barcelona, Spain, 3 Departament de Psiquiatria i Medicina Legal,
Universitat Autònoma de Barcelona, Barcelona, Spain, 4 CIBER Enfermedades
Raras, Instituto de Salud Carlos III, Barcelona, Spain.
Drug addiction is a complex psychiatric disorder that results from the
interaction of different genetic and environmental factors . Tolerance,
sensitization, craving and abstinence are common features in drug
addiction, and may be related to neuronal processes such as plasticity
and remodeling . Animal and pharmacological studies suggest that
neurotrophins may play an important role in cocaine addiction through
their effect on these processes . To evaluate the contribution of the
Brain-Derived Neurotrophic Factor (BDNF) and its specific receptor
Neurotrophic Tyrosine Kinase Receptor 2 (NTRK2) we genotyped two
SNPs in the BDNF gene and three SNPs in the NTRK2 gene in a
Spanish sample of 91 cocaine dependent patients and 91 sex and agematched
healthy controls . The single-marker analysis showed association
between cocaine dependence and the Val allele of the p .Val66Met
BDNF polymorphism (rs6265; 2p=0,014; OR=2,14 (1,16-3,96)) and the
c .2732T>C polymorphism of the NTRK2 gene (2p=0,0062) . Additionally,
the multiple-marker analysis supported an overrepresentation of
the C/A/C haplotype (rs1187325/rs1047896/c .2732T>C) of the NTRK2
gene in cocaine addicts (2p=0,005; OR=7,19 (1,77-29,2)) . Our results,
although preliminar, point out that the BDNF and NTRK2 genes may
contribute to the predisposition to cocaine addiction and suggest a potential
participation of neurotrophic factors in drug dependence .