2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
common in our population . But may not be major determinants in genetic
susceptibility to type 2 diabetes .
P06.143
Association study of homocysteine metabolic regulatory genes
with ischemic stroke risk in singapore chinese population
H. Low 1 , K. Kasiman 2 , C. Chen 3 , J. Liu 4 ;
1 Department of Community, Occupational &Family Medicine, National University
of Singapore, Singapore, 2 Centre for Molecular Epidemiology, National
University of Singapore, Singapore, 3 Department of Neurology, Singapore General
Hospital, Singapore, 4 Genome Institute of Singapore, A*STAR (Agency for
Science, Technology and Researc, Singapore.
Moderately elevated plasma homocysteine level has been identified
as an independent risk factor for vascular disease, including ischemic
stroke . There are also substantial evidences for homocysteinaemia to
be, at least partially, influenced by genetic factors. The focus of this
study is to investigate the association between the 25 candidate genes
of the homocysteine metabolic pathway and ischemic stroke risk in
Chinese population . We genotyped 306 polymorphic SNPs from the
25 candidate genes in 376 stroke patients and 354 matched healthy
controls from Singapore . Using genotype-based trend test, we identified
3 novel polymorphic loci from 3 genes (MTRR, SHMT1 and
TCN2) which act as potential genetic risk factors for ischemic stroke .
The effects of these loci are independent from each other as well as
other known risk factors including age, gender, smoking, diabetes, hypertension
and hyperlipidemia . We also found that the association of
TCN2 variants with stroke appears to be more predominant in patients
with lacunar infaction (LACI) than in other stroke subtype (non-LACI) .
In summary, the variants of these genes potentially affect individual
susceptibility to ischemic stroke through the homocysteine metabolic
pathway . Here, through genetic association study, our result supports
the importance of B12 and folate cellular availability to prevent ischemic
stroke in Chinese population . The growing evidence of importance
of folate and B12 has significant implications for the inclusion of
folic acid and B12 as supplement to prevent stroke . To our knowledge,
this is the first comprehensive analysis of the homocysteine metabolic
pathway in stroke .
P06.144
Prevalence and phenotypic spectrum of known genes causative
of Joubert syndrome and Related Disorders: the experience of
the international JsRD study Group
E. M. Valente1,2 , F. Brancati1,3 , L. Travaglini1,4 , M. Iannicelli1,4 , E. Bertini5 , F.
Emma6 , E. Boltshauser7 , A. Mazzotta1 , G. R. Stringini6 , B. Dallapiccola1,4 , J. G.
Gleeson8 ;
1 2 CSS-Mendel Institute, Rome, Italy, Dept. of Medical and Surgical Paediatric
Sciences, University of Messina, Messina, Italy, 3CeSI, Aging Research Centre,
and Dept. of Biomedical Sciences, G. d’Annunzio University Foundation, Chieti,
Italy, 4Dept. of Experimental Medicine and Pathology, Sapienza University,
Rome, Italy, 5Dept. of Laboratory Medicine, IRCCS Bambino Gesù Hospital,
Rome, Italy, 6Dept. of Nephrology, IRCCS Bambino Gesù Hospital, Rome, Italy,
7 8 Dept. of Neurology, Children‘s University Hospital, Zurich, Switzerland, Dept.
of Neurosciences, University of California, La Jolla, CA, United States.
Joubert syndrome is an autosomal recessive condition characterized
by hypotonia, ataxia, psychomotor delay, oculomotor apraxia, neonatal
breathing abnormalities, and a complex midbrain-hindbrain malformation
known as the “molar tooth sign” (MTS) . The variable multiorgan
involvement (mainly the retina and kidneys) defines several pleiotropic
conditions (Joubert Syndrome Related Disorders, JSRDs) sharing the
MTS. The nosological definition of JSRDs has long remained problematical,
and a recently proposed classification is now based on the
extent of retinal and renal involvement. Two loci (JBTS1-2) and five
genes (NPHP1, AHI1, CEP290, MKS3, RPGRIP1L) have been identified
so far. All genes encode for ciliary proteins, and JSRDs present
clinical and genetic overlap with other ciliopathies, such as nephronophthisis
and Meckel syndrome .
Over the past 3 years, on behalf of the International JSRD Study
Group, we have performed mutation screening of known genes in
large cohorts of about 100-150 patients representative of all JSRD
phenotypes . These allowed estimating the prevalence of gene mutations
in different subgroups and drawing preliminary gene-phenotype
correlates . Pure JS is mostly caused by AHI1 mutations (~10%
of cases), and occasionally by MKS3 . Cerebello-retinal phenotypes
are also mainly related to AHI1 (~20% of cases) although CEP290
can be rarely responsible . The genes most frequently causative of cerebello-renal
phenotypes are NPHP1 and RPGRIP1L (~10% of cases
each) . Up to 50% of cerebello-oculo-renal cases are due to mutations
in CEP290, while a minority relates to NPHP1 deletions . Overall, mutations
in known genes are responsible of only 25-30% of JSRDs, supporting
further genetic heterogeneity .
P06.145
Kir 4.1-KCNJ10 potassium channel gene polymorphisms in Type
2 diabetes
S. Oguzkan Balcı 1 , E. Akarsu 2 , S. Aktaran 2 , B. Gogebakan 1 , M. Araz 2 ;
1 University of Gaziantep, Faculty of Medicine, Department of Medical Biology,
Gaziantep, Turkey, 2 University of Gaziantep, Faculty of Medicine, Department
of Endocrinology and metabolism, Gaziantep, Turkey.
Potassium channels play an important role in insuline secretion .
KCNJ10 channel protein is a member of Kir 4 .1 potassium channel
family . KCNJ10 gene is expressed in pancreatic beta cells . We therefore
investigated whether polymorphisms in KCNJ10 gene are associated
with type 2 diabetes in Turkish population .
In this study 166 individuals with type 2 diabetes and 100 age-and sexmatched
healthy controls were tested for three single nucleotide polymorphisms
(SNPs) in KCNJ10 gene . These SNPs were G to A transversion
in intron 1 (SNP1) and G to A transversion in exon 2 (SNP2)
and T to C transition in promoter (SNP3) . All SNPs were genotyped by
PCR-RFLP .
KCNJ10 gene SNP1 in intron 1 and SNP2 in exon 2 which were noninformative
for Turkish population . The distribution of TT, TC, and CC
genotypes for SNP3 in promoter was 56 %, 37% and 5 % in type 2
diabetes compared with 45 %, 51 % and 4 % in the controls (χ 2 =4 .352,
p=0 .113) . The allele frequency of T and C was 0 .705, 0 .295 in type
2 diabetes compared with 0.756, 0.244 in the controls (χ 2 =1 .676,
p=0 .195) . According to the “Hardy-Weinberg Equilibrium” TT genotype
was found higher in type 2 diabetes than TC genotype (χ 2 =4 .07,
p=0 .04) .
We conclude that KCNJ10 gene SNPs were not associated with type
2 diabetes in Turkish population . However, further studies with larger
samples are needed to address the exact role of KCNJ10 gene in type
2 diabetes and its complications such as diabetic retinopathy .
P06.146
Association of the CALM core promoter polymorphism with
knee osteoarthritis in patients of Greek origin
M. Kaliakatsos 1 , M. Poulou 1 , A. Tsezou 2 , E. Kanavakis 1 , K. Malizos 2 , M. Tzetis 1 ;
1 Department of Medical Genetics, Athens University, Athens, Greece, 2 University
of Thessaly, Medical School, Laboratory of Cytogenetics and Medical
Genetics, University Hospital of Larissa, Larissa, Greece.
Osteoarthritis (OA) is characterized by focal areas of loss of articular
cartilage in synovial joints, associated with varying degrees of osteophyte
formation, subchondral bone change and synovitis . Calmodulin-
1 gene (CALM1) encodes a ubiquitous eukaryotic Ca 2+ binding protein
and is the principal mediator of the calcium signal thus affecting the
chondrocyte’s response to mechanical load . A functional core promoter
SNP -16C/T (rs12885713) was recently associated with HOA
in the Japanese but not the British patients . In multifactorial genetic
traits, each gene contributes to disease susceptibility to some extent,
but such genes may also interact with each other . The aspartic-acid
D14 repeat allele of the asporin gene (ASPN) is a susceptibility allele
for both HOA and KOH in the Japanese and Caucasians . Our
case-control study (158 KOA and 193 controls) focuses on genotyping
Greek KOA patients for rs12885713, and investigating its role as
a risk factor for the development of KOA . Our previous work on the
same case-control group indicated that both the D14 and D15 alleles
increased risk for KOA therefore we additionally investigate whether a
combined effect of the ASPN D14/D15 alleles and CALM1 TT exists
in Greek KOA patients. No significant differences were found in genotype
frequencies for the -16T/C SNP of CALM1 gene between cases
and controls (p=0 .581) . Our data implied that the -16TT (rs12885713)
CALM1 core promoter genotype is not a risk factor for KOA etiology
in Greek Caucasians on its own but associated with the ASPN D14 or
D15 risk allele it could influence KOA susceptibility.