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

Genetic analysis, linkage, and association
Domaine de la Merci, Université Joseph Fourrier, Grenoble, France, 3 Inserm,
U758, Lyon, France, 4 Ecole Normale Supérieure de Lyon, Unité de Virologie
Humaine, IFR 128, Lyon, France, 5 Inserm U309, Institut Albert Bonniot, Grenoble,
France, 6 Laboratoire d’analyse médicales, Rabat, Morocco, 7 Centre privé
de Fécondation In vitro, Rabat, Morocco.
An estimated 80 million people face reproductive difficulties worldwide.
An important proportion of these cases is believed to be caused by
genetic defects, yet few genes have formally been associated with
infertility in the human. We performed a genome-wide microsatellite
scan on 14 unrelated infertile men, all originating from North Africa and
born from first degree cousin. All presented very characteristic sperm
parameters with close to 100% abnormal spermatozoa with anomalies
of the head, several flagellae and polyploidy. A common homozygous
region harboring the Aurora Kinase C gene (AURKC) known to be
highly expressed in the testis and involved in cytokinesis and mitosis/
meiosis was detected in 10/14 patients. Sequence analysis of AURKC
coding sequence showed the presence of a homozygous single nucleotide
deletion in all 14 patients. This mutation results in premature
termination of translation thus yielding a truncated protein which lacks
its kinase domain. We conclude that the absence of AURKC leads
to male infertility due to the production of «large-headed multiflagella
spermatozoa».
P1002. The study of Insulin, Igf2 and NAIP mutations in
romanian population
L. Dumitrescu1 , P. Apostol1 , D. Cimponeriu1 , M. Stavarachi1 , M. Toma1 , D.
Cheta2 , L. Gavrila1 ;
1 2 Institute of Genetics, Bucharest, Romania, Institute of Diabetes, Nutrition and
Metabolic Diseases “Nicolae Paulescu”, Bucharest, Romania.
The balance between proliferation and apoptotic processes is involved
in some pathologic phenotype, including type 1 diabetes mellitus
(T1DM), type 2 diabetes mellitus (T2DM) and obesity. The genetic
markers from IDDM2 region were associated with these phenotypes.
Neuronal apoptosis inhibitory protein (NAIP, 5q) was found also to
have anti-apoptotic effects in different cells and to be up-regulated during
adipocytes differentiation.
The aims of our study were to test the contribution of Insulin, IGF2 and
NAIP polymorphisms to diabetes onset and obesity.
Clinical information and blood samples were collected from unrelated
obese T2DM subjects (n=70, BMI between 32,5-39 kg/m2), nonobese
T1DM (n=70, BMI between 20-25kg/m2) and 150 controls (non obese,
non-diabetic subjects). All samples were genotyped for Insulin -23Hph,
Insulin +1127Pst1, IGF2Apa and NAIP exon 5 polymorphisms.
We observed a higher frequency (4%) of NAIP exon 5 homozygous
deletion in control group compared with obese T2DM (2,85%) and
T1DM (1,42%) patients. This value is also higher than in other populations.
Interesting, all subjects with homozygous absence of NAIP exon
5 have low BMI .The IGF2 AA genotype was more frequent in T2DM
comparing with T1DM and control subjects (OR=1,9) and polymorphisms
from insulin region (OR-23Hph AA= 2,7, OR +1127Pst CC =
2,0983) were more frequent in T1DM subjects.
Taken together, we found a high frequency of -23Hph AA and +1127Pst
CC in T1DM patients, of IGF2 AA in T2DM and of NAIP exon 5 homozygous
deletion in control group.
P1003. Analysis of IGF1 gene polymorphism in newborn and
elderly people from North-West region of Russia
S. V. Potulova 1 , O. S. Glotov 2 , V. G. Vakharlovsky 2 , O. N. Bespalova 2 , T. E.
Ivaschenko 2 , V. S. Baranov 2,1 ;
1 Saint-Petersburg State University, St-Petersburg, Russian Federation, 2 Ott’s Institute
of Obstetrics and Gynecology RAMS, St-Petersburg, Russian Federation.
The serum insulin growth factor IGF-1 level differs in various human
ages. The individual variations in the level of this enzyme depend on
the number of CA repeats in the promoter region of IGF-1 gene. In this
study IGF-1 (CA repeats) gene polymorphism was analyzed by PCR
method in 102 newborns and also in 136 elderly people from North-
West Region of Russia. Increasing of the frequency of 20/- genotype
in elderly people when compared to newborn group (26.7%, 44.1%,
respectively, p=0.0034) with concomitant age-related decrease of
19/19 genotype frequency (51%, 27.9%, respectively, p=0.0001) were
found. According our data 19/20 genotype in male newborns was twice
more frequent than in female ones (23.2%, 11.3%). The same ration
remained constant in elderly people as well but the proportion of 19/20
genotype in this group increased almost twice (44.4%, 21.1%, respectively,
p=0.025). The association of 20CA allele with lower body weight
(Z=2.2, p=0.028) and reduced height in female newborns has been
registered. We suggest that increased number of CA repeats (more
than 20 CA) being responsible for low production of IGF-1 enzyme is
associated with longevity in man as well as with reduced body weight
and the height in female newborns. Allele 19 responsible for the high
level of serum IGF-1 might be associated with longevity for women.
Our final finding was the correlation between 20 CA allele of IGF-1 and
cataract (Z=2.4, p=0.018). There was no correlation between IGF-1
gene polymorphism and stroke, essential hypertension, coronary heart
disease and Type 2 diabetes.
P1004. Interleukin-23 receptor (IL23R) gene C2370A
polymorphism in scleroderma patients
E. Sáfrány 1 , B. Faragó 1 , V. Csöngei 1 , L. Magyari 1 , A. Maász 1 , C. Sipeky 1 , L.
Járomi 1 , K. Horvatovich 1 , J. Radics 2 , L. Czirják 2 , B. Melegh 1 ;
1 Department of Medical Genetics and Child Development, University of Pécs,
Pécs, Hungary, 2 Department of Immunology and Rheumatology, University of
Pécs, Pécs, Hungary.
Scleroderma or systemic sclerosis is a chronic connective tissue
disease generally classified as one of the autoimmune rheumatic
diseases. The cause of scleroderma is still unknown but there are
several factors presumed: abnormal immune or inflammatory activity
stimulating the fibroblasts to produce too much collagen, as well
as not yet discovered genetic and enviromental factors. Interleukin-
23 plays an important role in the Th17 mediated immune response.
The IL23R gene located on chromosome 1p31 encodes a subunit of
the IL23-receptor. Recent investigations (Duerr et al, Science, 2006;
314:1461-1463) identified several IL23R gene polymorphisms as risk
factors for inflammatory bowel diseases. Theoretical considerations
also suggested possible association of these SNPs with other autoimmune
diseases. Our aim was to test whether the 3’-UTR C2370A SNP
of the IL23R gene (rs10889677), one of the verified IBD susceptibility
genes also confers risk for scleroderma. We performed genotyping
using DNA samples collected from 244 patients with scleroderma and
135 unrelated, healthy controls. The genotypes were analysed using
PCR/RFLP-methods. We found no significant difference between the
allele frequencies of the two groups (73% and 71% for the C allele
and 27% and 29% for the A allele in patients with scleroderma and in
the control group, respectively). Our results show that eventhough the
C2370A polymorphism of IL23R can associate with selected autoimmune
diseases like the Crohn’s disease, but not with others, including
the scleroderma, thereby it is not an universal autoimmune disease
associated susceptibility factor.
P1005. Interleukin-23 receptor 3‘-UTR C2370A SNP confers risk
for rheumatoid arthritis
B. Faragó 1 , L. Magyari 1 , V. Csöngei 1 , L. Járomi 1 , E. Sáfrány 1 , K. Horvatovich 1 ,
C. Sipeky 1 , A. Maász 1 , J. Radics 2 , L. Czirják 2 , B. Melegh 1 ;
1 Department of Medical Genetics and Child Development, University of Pécs,
Pécs, Hungary, 2 Department of Immunology and Rheumatology, University of
Pécs, Pécs, Hungary.
INTRODUCTION: Interleukin-23 (IL23) is a proinflammatory cytokine
that plays a crucial role in the development of chronic inflammation,
being a master regulator of the IL17/23 molecular pathway. IL23-receptor
gene (IL23R) on chromosome 1p31 encodes one subunit of
the IL23-receptor. Duerr et al. (Science, 2006; 314:1461-1463) using
genome-wide association study found association between Crohn’s
disease and the IL23R gene; amongst the reported SNPs the 3’-UTR
C2370A (rs10889677) conferred risk for Crohn’s disease in a non-Jewish
population. Since the IL17/23 pathway is known to associate with
experimental allergic encephalomyelitis, inflammatory bowel disease,
multiple sclerosis, collagen-induced arthritis, rheumatoid arthritis (RA),
and perhaps other autoimmune diseases, we theoretized that this SNP
described originally for Crohn’s disease might also have significance
in the development of RA. Therefore, the aim of the present study was
to test this hypothesis. METHODS: Genotyping was performed on 226
well-characterized RA-patients and 135 age-and sex-matched controls
using a PCR-RFLP method. All RA-patients were characterized
for RF- and anti-CCP seropositivity. RESULTS: We observed a highly
increased prevalence of the homozygous AA genotype compared to
the controls (15.0% vs. 4.44%; p