European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Genetic analysis, linkage, and association
Setting: The study was conducted at the China Medical University
Hospital, Taichung, Taiwan.
Design: A retrospective observational study.
Patients: A total of 100 GHD children who underwent GH therapy for
one year were recruited.
Interventions: PCR-RFLP (restriction fragment length polymorphism)
and PCR experiments were carried out to detect single nucleotide
polymorphisms (SNPs) in the following genes: growth hormone receptor
(GHR), Janus-activated kinase 2 (JAK2), signal transducers and
activators of transcription-5a (STAT-5a), STAT-5b, suppressor of cytokine
signaling-2 (SOCS-2), Insulin Growth Factor-1 (IGF-1), insulinlike
growth factor binding protein-3 (IGFBP-3), and acid-labile subunit
(ALS). We then evaluated the correlations among these gene polymorphisms
with various parameters (gender, age, bone age, parents’
heights, serum GH concentration, birth weight) on first year growth
velocity.
Main Outcome Measure: Growth velocity was measured every two
months for a total of 12 months.
Results: GHR codon 440 G/T was the only polymorphism of the GHR
gene which correlated with increased growth velocity. The G homozygote
was associated with low growth velocity, the G/T heterozygote
corresponded with moderate growth velocity and the T homozygote
correlated with high growth velocity. The GHR codon 440 T allele
showed higher transcriptional activity and stronger Stat5 Tyr694 phosphorylation.
Conclusion: The GHR codon 440 T allele is associated with the therapeutic
efficacy of GH replacement therapy.
P0985. Exceptional mosaicism in grandpaternal haemophilia
patient in a family with isolated haemophilia A
C. Costa 1,2 , A. Frances 3 , S. Letourneau 1 , P. Comteville 1 , E. Girodon-Boulandet
1,2 , M. Goossens 1,2 ;
1 AP-HP Groupe Henri-Mondor-Chenevier, Laboratoire de Génétique Moléculaire,
Créteil, France, 2 INSERM U841, IMRB Dept Génétique, Créteil, France,
3 Hôpital Font-Pré, Génétique Médicale, Toulon, France.
About one third of cases of haemophilia have no family history of the
disorder and 20% are thought to be due to a new mutation. A proportion
of such mutations occurs in a single germ cell but some, occurring
during early embryogenesis produce a germline or somatic mosaic. In
haemophilia somatic mosaicism is generally observed in women. Only
3 cases have been reported in grandfathers.
We report here a case of somatic mosaicism in the asymptomatic
grandfather of a male patient with a severe haemophilia A. The mutation
identified in the proband was found in the mother and her sister,
suggesting the grandmother was a carrier. This mutation was not
found in her leucocytes, buccal and uroepithelial cells, eliminating somatic
mosaicism. Haplotypes analysis using intragenic and extragenic
markers allowed to identify the origin of the deleterious allele in the
grandfather. Analysis of his leucocytes, buccal and uroepithelial cells
by PCR-sequencing revealed the presence of the allele with a proportion
estimated between 15-20%. Somatic mosaicism, varies from
0.2 to 25%, is not always detected with conventional methods. This
requires mutation-enrichment procedures that are not used during
routine tests analysis. Analysis with denaturing-high-liquid-pressurechromatography,
which is now widely used, increases the proportion
of allele in our patient.
This report suggests that somatic mosaicism is probably underestimated
and points to the need of using methods with higher sensitivity
in such sporadic cases and if necessary, to perform linkage analysis to
identify the origin of the deleterious allele.
P0986. Association study of ALOX5AP gene variants with the
risk of coronary artery disease.
E. Trabetti 1 , U. Cavallari 1 , G. Malerba 1 , M. Biscuola 1 , D. Girelli 2 , N. Martinelli 2 ,
O. Olivieri 2 , F. Busti 2 , S. Friso 2 , F. Pizzolo 2 , R. Corrocher 2 , P. Pignatti 1 ;
1 Section of Biology and Genetics - Dept Mother & Child/Biol & Genet, Univ
Verona, Italy, Verona, Italy, 2 Dept Clinical and Experimental Medicine, Univ
Verona, Italy, Verona, Italy.
Leukotrienes are a group of proinflammatory lipid mediators that are
implicated in the pathogenesis and progression of atherosclerosis. Arachidonate
5-Lipoxygenase-Activating Protein gene (ALOX5AP), which
encodes an essential regulator of the biosynthesis of the leukotriene
A4, has been recently associated to the risk of thrombotic disease.
2 2
The aim of this study was to explore the role of variants of the AL-
OX5AP as possible susceptibility factors for coronary artery disease
(CAD) and myocardial infarction (MI) in patients with or without angiographically
proven CAD. A total of 1,431 patients with or without angiographically
documented CAD were examined simultaneously for seven
ALOX5AP SNPs, allowing reconstruction of the at-risk haplotypes
(HapA and HapB) previously identified in the Icelandic and British populations
(Nat Genet 2004;36:233-239; Am J Hum Genet 2005;76:505-
509). Using a haplotype-based approach, HapA was not associated
with either CAD or MI. On the other hand, HapB and another haplotype
within the same region (that we named HapC) were significantly more
represented in CAD versus CAD-free patients, and these associations
remained significant after adjustment for traditional cardiovascular risk
factors by logistic regression (HapB: OR 1.67, 95% CI 1.04 to 2.67;
P=0.032; HapC: OR 2.41, 95% CI 1.09 to 5.32; P=0.030). No difference
in haplotype distributions was observed between CAD subjects
with or without a previously documented MI. This study points out a
possible role of ALOX5AP in the development of the atheroma rather
than in its late thrombotic complications such as MI.
P0987. The genetic background of β + IVSI-6: a primary step,
in determining the origin and spread of β-globin mutations in
Romania.
L. Cherry 1 , C. Calo 2 , L. Dan 1 , R. Talmaci 1,3 , D. Coriu 4 , D. Cimponeriu 1 , P. Apostol
1 , M. Stavarachi 1 , D. Usurelu 1 , L. Zahed 5 , L. Gavrila 1 ;
1 University of Bucharest,, Bucharest, Romania, 2 University of Cagliari, Monserrato,
Italy, 3 University of Medicine, Bucharest, Romania, 4 Fundeni Clinical Institute,
Bucharest, Romania, 5 American University of Beirut, Beirut, Lebanon.
Romania belongs to a low-prevalence area of beta-thalassemia. In the
last few years we have identified the most frequent causative mutations
of beta-thalassemia in the Romanian population. To elucidate the
origin and the flow of these mutated alleles, we have started our work,
by studying one of the most frequent mutations: the β + IVSI-6 which
has the highest frequency at homozygous state among the other mutations
found in Romania. Seven restriction fragment polymorphisms
(RFLP) haplotype have been determined in a sample including homozygous
IVSI-6 patients and carriers. Our study revealed a strong
linkage of IVSI-6 to haplotype VI (-++---+) 70%, relative to VII (+-----+)
18% and V (+----+-) 12%. This result confirms what was found in the
Mediterranean countries regarding the association of β + -IVSI-6 mutation
to haplotype VI, the presence of haplotype V seems to demonstrate
the gene flow between Romania and Bulgaria.
The diversity of the β + -IVSI-6 genetic backgrounds found in Romania
reinforces the picture of the β-globin gene cluster as highly dynamic.
On the other hand this diversity highlighted the old age characterizing
the β-thalassemia alleles. Furthermore this study should be continued
to examine normal individuals and all the thalassemia alleles to determine
the relationships between Romanian and neighboring populations.
Funding from the European Commission for the „eInfrastructure for
Thalassaemia Research Network“, Coordination Action - Contract no
026539 - for which this study was partially funded is gratefully acknowledged.
P0988. Mapping Genes Influencing Human Stature - Where are
We?
S. Sammalisto 1 , M. Perola 1,2 , L. Peltonen 1,2 ;
1 Department of Molecular Medicine, National Public Health Institute, Helsinki,
Finland, Helsinki, Finland, 2 University of Helsinki, Faculty of Medicine, Department
of Medical Genetics, Helsinki, Finland.
Human stature is a highly heritable complex trait which is oligo- or
polygenic in nature. Despite many genome-wide efforts attempting to
localize genes influencing stature findings have been difficult to replicate
and convincing evidence for quantitative trait loci (QTL) has been
sparse.
In order to facilitate the mapping of stature genes and prioritizing positional
candidate loci we have collected the results of the published
genome-wide linkage studies on a publicly available web site www.genomeutwin.org/stature_gene_map.htm
which is updated accordingly.
From these published results it seems likely there are multiple minor
loci underlying the genetic background of human stature although converging
evidence from multiple independent studies also suggests that
some loci such as 3p, 6q, 7q and 9q probably harbour stature genes of