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

Genetic analysis, linkage, and association
death. More than 60 mutations in RYR2 have been reported. They
cluster in 3 regions: the amino terminus, a central domain and the
carboxyl terminus.
The diagnosis CPVT was made in a 10year old boy. He presented with
syncope at the age of 9 years. Family history was remarkable: one
sister died at the age of 3 weeks while crying and another sister died
suddenly at the age of 13 years while being angry. Both parents had
not experienced symptoms of ventricular tachycardias.
In the index-patient, a mutation in the RYR2 gene was identified. The
mutation c.12446A>C, resulted in a p.Tyr4149Ser amino acid change.
Tyr4149 is located in the I-domain, a hydrophobic RYR2 region that
is postulated to transduce cytoplasmic events by regulating the Ca2+
pore-forming domain. This domain is a hot-spot for arrhythmia-linked
RYR2 mutations.
DNA sequencing of the RYR2 gene in the parents suggested that they
were both homozygous for the wild-type allele. A de novo mutation was
not expected, because the parents already lost two daughters with
symptoms compatible with CPVT. Further investigation (dHPLC and
digestion with Bse1) indicated that the mother was somatic mosaic for
the mutation.
This finding confirms the occurrence of somatic mosaicism and has
implications for the genetic counselling of apparently de novo cases
of CPVT.
P0948. Association of variants of the IL2 R and ATG1 L1 genes
with susceptibility to pediatric Crohn’s disease
M. Devoto, R. N. Baldassano, J. P. Bradfield, D. S. Monos, C. E. Kim, J. T.
Glessner, T. Casalunovo, E. C. Frackelton, G. Otieno, S. Kanterakis, J. L. Shaner,
R. M. Smith, A. W. Eckert, L. J. Robinson, C. C. Onyah, D. J. Abrams, R.
M. Chiavacci, R. Skraban, S. F. A. Grant, H. Hakonarson;
The Children’s Hospital of Philadelphia, Philadelphia, PA, United States.
Two recent genome wide association studies reported association of
Crohn’s disease (CD) in adults with single nucleotide polymorphisms
(SNPs) in the interleukin-23 receptor (IL23R) and autophagy-related
16-like 1 (ATG16L1) genes. The aim of this study was to examine the
impact of these SNPs on risk of CD in children. Utilizing data from our
ongoing genome-wide association study, we investigated the association
of the previously reported SNPs at the IL23R (rs11209026) and
ATG16L1 (rs2241880) genes in a preliminary cohort of 142 pediatric
CD cases with the childhood form of this disease and 281 matched
controls. The minor allele frequency (MAF) of SNP rs11209026 in the
cases was 1.75% while it was 6.61% in controls, yielding a protective
odds ratio (OR) of 0.25 (95% CI 0.10 - 0.65; one-sided P = 9.2x10 -4 ). A
transmission disequilibrium test with 65 trios derived from our initial patient
cohort confirmed the significant association with rs11209026 (onesided
P = 0.0017). Similarly, the frequency of allele G of rs2241880 in
the cases was 63.73% while it was 51.96% in the controls, yielding
an allelic OR of 1.62 (95% CI 1.21 - 2.18; one-sided P = 6.93x10 -4 ).
The ORs in our pediatric study are comparable with those reported
previously in adult IBD case-control cohorts. As such, these variants
confer a similar magnitude of risk of CD to children as for their adult
counterparts. Our findings provide an independent confirmation of the
effect of variants of these two genes on risk of CD.
P0949. Crohn’s disease and polymorphisms of the NOD2/
CARD15 and TNFA genes
Y. Nasykhova 1 , T. Ivashchenko 1 , N. Semenov 2 , B. Baranov 1 ;
1 Ott’s Institute of Obstetrics & Gynecology, St-Petersburg, Russian Federation,
2 Medical Academy of Postgraduate Study, St-Petersburg, Russian Federation.
Crohn’s disease (CD) is a complex multifactorial disorder, which is
thought to result from the influence of environmental factors on genetically
predisposed host. We studied the mutation frequencies
(Gly908Arg, Arg702Trp,1007insC) in NOD2/CARD15 gene in the
group of patients with Crohn’s disease and in the control group. The
frequencies of these mutations were following: Gly908Arg - 3,2% Arg702Trp-3,8%,
1007insC - 4,4%. 20,5% of the patients had at least
one mutation in the NOD2/CARD15 gene. We analyzed also polymorphic
variants of TNFA gene within a promoter region. Recently it was
reported that this polymorphism is associated with a level of TNFA
proinflammatory cytokine production and therefore is implicated in an
inflammatory process. The frequency of -308G/-308A genotype was
significantly higher in the group of patients (p=0.003, OR=3.89; 95%
CI:1.57-9.65). According to the odds ratio it was found that the carriers
of the A-allele of TNFA gene have 3-fold increase of Crohn’s disease
risk (OR=3.20, 95% CI:1.43-7.15). Interestingly that combined heterozygous
genotype -238A/238G + -308A/-308G of TNFA gene resulted
in considerable increase of CD risk (OR=18.8; 95% CI:1.02-345.97).
TNFA is a key component of inflammatory process development and
a target for anti-TNFA therapies which are used as a second or thirdline
treatment. Therefore further research may help to develop of new
therapeutic strategies for the treatment of chronic inflammatory diseases
by anti-TNFA medicines.
P0950. Variations in C-reactive protein gene and COPD: tagging
SNPs analysis in case-control study
D. G. Yanbaeva1 , M. A. Dentener1 , M. A. Spruit2 , A. Van de Kruijs2 , A. Derks2 ,
E. F. M. Wouters1,2 ;
1 2 Maastricht University, Maastricht, The Netherlands, Centre for Integrated
Rehabilitation of Organ failure, Horn, The Netherlands.
BACKGROUND Chronic low-grade systemic inflammation (i.e. increased
C-reactive protein, CRP) has been recognized to be present in
COPD and, in turn, may have a systemic impact. However, remarkably
little is known about the underlying mechanisms of systemic inflammation
in COPD. Systemic inflammatory response might be modulated
by genetic background. The aim of this study was to examine whether
variations in CRP gene coding for acute phase protein are associated
with susceptibility for COPD.
METHODS A total of 265 clinically stable patients with moderate-to-severe
COPD (mean age 64 years, FEV1 39% pred, FEV1/VC, 44.6%)
entering pulmonary rehabilitation and 90 healthy smokers (mean age
56 years, FEV1 109% pred, FEV1/VC, 77%) were enrolled. All subjects
were Dutch Caucasians.
Six tagging single nucleotide polymorphisms (SNPs) (rs3091244,
rs1800947, rs113084, rs1205, rs2808630, rs3093077) within CRP
gene have been selected for genotyping from Seattle SNPs database
(r2 0.8, MAF 5%).
RESULTS All tested SNPs were in Hardy-Weinberg equilibrium both
in cases and controls. We found that carriers of 5237TT genotype
(rs2808630) had 50% lower risk of having COPD (p=0.006, recessive
model). In addition, two trends have been shown: homosigosity of
1444A (rs1130864), previously associated with elevated CRP plasma
levels, has increased the disease risk by 2.1-fold (p=0.06, recessive
and additive models), and carriage of 1059C allele (rs1800947) also
was found to be associated with increased risk of COPD (p=0.07,
OR=1.93, additive model). Analysis of CRP haplotypes confirmed
these findings.
CONCLUSIONS Results indicate that SNPs in CRP gene might be
associated with susceptibility for COPD.
P0951. Family based association analysis of TGFB1 as modifier
gene in Cystic Fibrosis
M. D. Bettin1 , C. Bombieri1 , G. Malerba1 , L. Xumerle1 , F. Belpinati1 , C. Castellani2
, B. M. Assael2 , P. F. Pignatti1 ;
1 2 Section of Biology and Genetics, University of Verona, Verona, Italy, Cystic
Fibrosis Veneto Regional Center, Hospital of Verona, Verona, Italy.
Cystic fibrosis (CF) is a lethal, multi-system autosomal recessive genetic
disorder primarily affecting Caucasian populations, caused by
mutations in the cystic fibrosis transmembrane conductance regulator
(CFTR) gene. Severity of clinical presentation in CF, particularly
the pulmonary manifestation, are highly variable, even among CF patients
presenting the same genotype. This variability is only partially
explained by allelic heterogeneity at the CFTR gene. Literature data
suggest that the severity in CF may be correlated with other genetic
factors. Two polymorphisms (-509C/T and Leu10Pro) of the TGFB1
gene, which encodes for a cytokine involved in inflammation and tissue
repair and expressed by several cells, have recently been associated
to a more severe CF pulmonary manifestation in the American
population (Drumm et al, NEJM 353:1443; 2005). We here report a
TDT analysis of three TGFB1 functional polymorphisms (-509C/T,
Leu10Pro e Arg25Pro) in Italian CF patients. Eigthy-three family trios
were collected through a CF patient attending the Veneto Regional CF
Centre of Verona. All the 83 patients were severe/severe CFTR mutation
carriers and were clinically evaluated for respiratory parameters,
gastrointestinal and nutritional status parameters, and other clinical
variables related to the common CF complicances (diabetes, DIOS,
etc). We found evidence of association between Arg25 homozygotes
2