2008 Barcelona - European Society of Human Genetics

Normal variation, population genetics, genetic epidemiology
phenotypical based testing with genotyping using low cost DNA sequencing
. During this period of time, the birth rate declined from 11 .7 /
1,000 to 10 .3 / 1,000 and the immigrant population of Malta increased
ten fold. Two α globin variants Hb St. Luke and Hb Setif have been
found among 0 .2% of Maltese . The proportion of the variants was between
3 .9% and 17 .5%, depending on the effect of the mutation on
the assembly and the co-current α or β thalassaemia; α thalassaemia
is found among 1.3 % of neonates. Several β globin variants were detected
including Hb Marseilles and Hb S . The Hb Valletta was always
found in very tight linkage disequilibrium with the γ globin variant Hb
F Malta I although a presumed “hot spot” of recombination has been
assumed in between them. β Thalassaemia heterozygotes amount to
1.8% the population with 4 β globin gene mutations accounting for
over 95% . The quantitative data suggested a model based on the differential
assembly of molecular subunits into hetero-dimers albeit from
non-syntenic variant genes that accounted for a broad range of variant
allele expression between less than 5% as in Hb S combined with an α
thalassaemia or around 100% as in Hb S homozygotes or the Hb S- β o
Thalassaemia compound heterozygosity . The globin model appears
broadly applicable to a variety of possibly complex conditions associated
with multiple variant genes having quantitative effects .
P07.125
Genetic analysis of a large French canadian tourette syndrome
family
J. Riviere 1 , J. St-Onge 1 , C. Poulin 1 , F. Richer 2 , P. Lespérance 1 , G. Tellier 3 , S.
Chouinard 1 , G. A. Rouleau 1,3 ;
1 CHUM Research Centre, Montreal, QC, Canada, 2 Université du Québec à
Montréal, Montreal, QC, Canada, 3 Sainte Justine Hospital, Montreal, QC,
Canada.
Tourette Syndrome (TS) is a complex neurodevelopmental disorder
principally characterized by chronic motor and vocal tics and often associated
with other behavioral abnormalities . Despite evidence of a
strong genetic component, little is known about the genes predisposing
to TS . We conducted a genomewide linkage analysis in a large
French Canadian (FC) TS family comprising nine affected individuals
and exhibiting an apparent autosomal dominant mode of inheritance
of the disorder . Five-hundred markers with an average marker density
of 8cM were genotyped . Multipoint linkage and haplotype analyses
were performed using GENEHUNTER and SIMWALK2 programs .
Multipoint linkage analysis of the genomewide scan revealed four
chromosomal regions (2q, 6q, 8q and 13q) with LOD scores greater
than 1.5 using an “affected-only” approach. Subsequent fine-mapping
of these regions resulted in a single significant linkage peak (LOD>3.0)
on chromosome 2q . Screening of candidate genes is needed in order
to identify the causative TS gene in this family .
P07.126
The sex specific effects of UCP2 and 3 promoter polymorphisms
in turkish population
M. Poda 1 , G. Can 2 , A. Onat 3 , E. Bayrak 1 , G. Hergenç 4 , S. E. Humphries 5 , N.
Erginel-Ünaltuna 1 ;
1 Istanbul University, DETAE, Genetics Dept., Istanbul, Turkey, 2 Istanbul University,
Cerrahpasa Medical Faculty, Dept. of Public Health, Istanbul, Turkey,
3 Turkish Cardiology Association, Istanbul, Turkey, 4 Department of Biology, Yildiz
Technical University, Istanbul, Turkey, 5 Centre for Cardiovascular Genetics,
BHF Laboratories, Royal Free and University College London Medical School,
London, United Kingdom.
UCP2 and UCP3 genes are highly homologous,yet they are expressed
in different tissues .UCP2 is expressed in white adipose, heart, pancreas
and kidney, whereas UCP3 is expressed in skeletal muscle
and heart preferentially .Promoter region polymorphisms in UCP2 and
UCP3 genes (-866G/A and-55C/T respectively) have been previously
associated with obesity, diabetes and lipid profiles in different cohorts.
To clarify the contribution of these polymorphisms to dislipidemia and
related conditions, we investigated the associations with the lipid, blood
pressure and anthromorphic measurements, with regard to diabetes
and sex status .The study population consisting of a large (n=1975)
representative cohort of Turkey (‘Turkish Adult Risk Factor Study’-
TARF study, mean age=54,6 ±11,5), was genotyped using sequence
specific Taqman probes.The ANOVA t-test was used to compare the
differences in continuous variables among study subjects subdivided
by sex and/or diabetes status .Continuous variables (having P values
≤ 0,05 in NOVA t-test) were tested further by univariate analysis using
Bonferroni correction .
The genotype distributions for both UCP3-5C/T and UCP2-866G/
A were in accordance with Hardy-Weinberg equilibrium . The resulting
frequencies were 0,75 for UCP2 -866G allele, whereas 0 .78 for
UCP3-55C . After Boneferroni correction the statistical results were as
follows: In male subjects, UCP3-55TT genotype was associated with
decreased total cholesterol (p=0,028) and diastolic blood (p=0,024)
pressure levels, while it was associated with higher fasting glucose
(0,0001) and logHOMA-R (p=0,032) .In female subjects, UCP2-866AA
genotype was associated with decreased levels of trigliceride (p=0,021)
and ApoB levels (p=0,027) .
In conclusion, the UCP3-55C/T and UCP2-866G/A promotor polymorphisms
have gender specific phenotypic effects on human metabolism
.
P07.127
UGt1A genetic polymorphisms in são miguel population
(Azores): implications for pharmacogenetic studies
M. J. Brilhante1 , P. R. Pacheco1,2 , F. Sigallat1 , H. Polena1 , R. Cabral1,2 , C. C.
Branco1,2 , L. Mota-Vieira1,2 ;
1 2 Hospital of Divino Espirito Santo of Ponta Delgada, Azores, Portugal, Instituto
Gulbenkian de Ciência, Oeiras, Portugal.
UGT enzymes are responsible for glucuronidation and detoxification
of endogenous and exogenous compounds . Homozygosity for a polymorphism
in the UGT1A1 TATAA box promoter causes Gilbert’s syndrome
. This sequence contains six TA repeats (UGT1A1*1), whereas
seven repeats (UGT1A1*28) imply reduced gene expression . In
UGT1A6, two missense mutations result in three alleles: UGT1A6*1
(T181-R184), UGT1A6*2 (A181-S184) and UGT1A6*3 (T181-S184) .
UGT1A1*28 and UGT1A6*2 are associated with reduced enzymatic
activity .
Here, we determined UGT1A1 and UGT1A6 polymorphisms prevalence
in São Miguel population (n=469 healthy individuals), and investigated
UGT1A1 association with UGT1A6 polymorphisms . In UGT1A1, we
identified five genotypes: 0.4% (TA) /(TA) , 50 .5% (TA) /(TA) , 39 .7%
5 6 6 6
(TA) /(TA) , 9 .2% (TA) /(TA) and 0 .2% (TA) /(TA) . Five and eight TA
6 7 7 7 6 8
repeats are found only in African-ancestry individuals . These alleles
confirm our previous results on Sao Miguel genetic ancestry, an admixed
population composed of European, Jews and Africans . UGT1A*6
genotype frequencies were 47 .5% (*1*1), 36 .2%, (*1*2), 7 .5% (*2*2),
4 .7% (*1*3) and 4 .1% (2*3) . A strong association between UGT1A1*28
and UGT1A6*2 alleles was observed, since 81 .4% homozygous for
UGT1A1*28 were also homozygous for UGT1A6*2 . Overall, 6 .7%
were homozygous for both UGT1 polymorphisms, and 39% had at least
one variant allele for UGT1A1*28 and UGT1A6*2 . These highly
prevalent polymorphisms result in modified expression and activity of
UGTs, may influence susceptibility to cancers and predispose to side
effects of drugs, such as irinotecan . Currently, we are analyzing three
missense mutations in UGT1A7, to evaluate the extension of linkage
disequilibrium between UGT1A1, UGT1A6 and UGT1A7 . Funded
by Azorean Government (M1 .2 .1 ./I/003/2005) . PRP has PhD grant
SFRH/BD/27453/2006 .
P07.128
Identification of the rare UGT1A1*36 allele in a Caucasian family
of the Azores (Portugal)
M. Soares 1,2 , M. R. Santos 1,2 , A. R. Couto 1,2 , J. P. Pinheiro 1,2 , I. Dutra 1,2 , V. Rodrigues
3 , J. Bruges Armas 1,2 ;
1 SEEBMO - Hospital de Santo Espirito, 9700-856 Angra do Heroismo, Portugal,
2 IBMC - Instituto de Biologia Molecular e Celular da Universidade do Porto,
Porto, Portugal, 3 Centro de Saude de Santa Cruz da Graciosa, 9880-320 Santa
Cruz da Graciosa, Portugal.
The role of UDP-glucuronosyl transferase 1A1 (UGT1A1) as a predictor
of toxicity in cancer patients receiving irinotecan lead to the identification
of a rare UGT1A1 genotype in a 69 years old female of Azorean
ancestry .
The genotype UGT1A1*36/UGT1A1*28 (TA 5 /TA 7 ) was identified in the
index case and after informed consent, three siblings (2 females-F and
1 male-M) were investigated . DNA extraction was performed from peripheral
blood cells. Amplification of region of interest was performed
by PCR using specific primers; forward primer was labelled for subsequent
fragment analysis . Genotyping of (TA) repeats in this region