2008 Barcelona - European Society of Human Genetics

Molecular and biochemical basis of disease
tral nervous system-specific manner.
Further studies are now needed to refine the critical interval and to
check putative involvement of PCDH8 in developmental delay .
P06.256
A functional heme oxigenase-1 promoter polymorphism confers
susceptibility to rheumatoid arthritis
B. Rueda 1 , J. Oliver 1 , G. Robledo 1 , M. Lopez-Nevot 2 , A. Balsa 3 , D. Pascual-Salcedo
4 , M. Gonzalez-Gay 5 , M. Gonzalez-Escribano 6 , J. Martin 1 ;
1 Consejo superior de investigaciones científicas (CSIC), Armilla - Granada,
Spain, 2 Division of Immunology, Hospital Virgen de las Nieves, Granada, Spain,
3 Division of Rheumatology, Hospital La Paz, Madrid, Spain, 4 Division of Immunology,
Hospital La Paz, Madrid, Spain, 5 Division of Rheumatology, Hospital
Xeral-Calde, Lugo, Spain, 6 Division of Immunology, Hospital Virgen del Rocio,
Sevilla, Spain.
Objective: To investigate the role of heme oxygenase-1 (HO-1) gene
as a novel functional candidate gene for rheumatoid arthritis (RA) .
Methods: We carried out a case-control study including 736 RA patients
and 846 healthy controls of Spanish Caucasian origin . Two putative
functional HO-1 promoter polymorphisms, a (GT)n microsatellite
and a -413 T/A single nucleotide polymorphism (SNP), were selected
as genetic markers and genotyped using PCR-based methods . In addition,
the intracellular expression of HO-1 was determined in healthy
individuals with different (GT)n genotypes .
Results: The distribution of HO-1 (GT)n alleles (Short [S] ≤ 25 GT repeats
and long [L]> 25 GT repeats) revealed a significant protective
effect of S (GT)n alleles (P = 0 .019; OR 0 .8, [95 % CI 0 .7-0 .9]) and
SS (GT)n genotype (P =0 .002; OR 0 .4, [95 % CI 0 .6-0 .9]) . In contrast,
the -413 HO-1 promoter SNP did not yield any statistically significant
deviation between RA patients and controls considering either allelic or
genotypic frequencies . The haplotype analysis showed a strong protective
effect of the S-A haplotype (P = 7E-07, Pc = 0 .000003; OR 0 .4
[95 % CI: 0 .3-0 .6]), whereas the L-A haplotype showed the opposite
tendency (P = 0 .008, Pc = 0 .03 OR 1 .2 [95 % CI 1 .1-1 .4]) . In addition,
we demonstrate that individuals carrying the SS (GT)n genotype show
a significantly higher percentage of HO-1 expression than LL homozygous
individuals (P=0 .0003) .
Conclusion: In this study we identified the HO-1 (GT)n microsatellite as
a new genetic marker involved in RA genetics in our population .
P06.257
stAt4 gene and the risk of Rheumatoid Arthritis in the tunisian
population
M. Ben Hamad 1 , H. Mbarek 2 , S. Marzouk 3 , Z. Bahloul 3 , F. Fakhfakh 1 , F. Cornelis
2 , H. Ayadi 1 , E. Petit-Teixeira 2 , A. Maalej 1 ;
1 Laboratoire de Génétique Moléculaire Humaine, Sfax, Tunisia, 2 Genotel-
EA3886 Laboratoire de Recherche Européen pour la polyarthrite Rhumatoïde,
Evry, France, 3 Service de Médecine Interne CHU Hédi Chaker, Sfax, Tunisia.
The STAT4 (Signal transducer and activator of transcription 4) gene
encodes a protein that plays an important role in the regulation and
activation of certain cells of the immune system . In order to search an
association of STAT4 rs7574865 T allele in the genetic predisposition
to RA, we have studied 140 Tunisian patients affected with RA and
200 healthy controls . DNAs genotyping was carried out with a Taq-
Man 5’ allelic discrimination assay on an ABI 7500 real time PCR machine
(assay: C__29882391_10) and data were analyzed by χ2-test,
Genotype relative risk and Odds Ratio with 95% confidence interval.
Our results showed that the T allele and the T/T genotype were more
frequent in RA patients compared to controls (p= 0 .008; p= 0 .003, respectively)
(OR = 0 .6; CI = [0 .41-0 .88]) . We next examined patients RA
subgroups according to clinical and immunological data for association
with STAT4. A significant association of both T allele and T/T genotype
were found in patients presented erosion (p=0 .003 and p=0 .006) .
A genotypic association was observed according to the presence of
nodules (p=0 .007) . Morover, an allelic association were found when
patients were stratified according to the presence of rheumatoid factor
antibody (RF) (p=0 .015) as well as the presence of another autoimmune
disease (p=0.021). However, no significant differences in allele
and genotype frequencies of rs7574865 were detected with anti-cyclic
peptides antibodies (ACPA) positive RA patients (p=0 .1 and p=0 .13
respectively) . These results support the involvement of STAT4 gene in
the genetic susceptibility to RA in the Tunisian population .
P06.258
Specific neuromuscular diseases in the Roma population living
in Hungary
V. Karcagi 1 , A. Herczegfalvi 2 , J. S. Müller 3 , A. Abicht 3 , M. C. Walter 3 , R. Horvath
3 , H. Lochmüller 3 , L. Kalaydjieva 4 ;
1 National Institute of Environmental Health, Dept. of Molecular Genetics and
Diagnostics, Budapest, Hungary, 2 Bethesda Children’s Hospital, Dept. of Neurology,
Budapest, Hungary, 3 Ludwig-Maximilians-University Munich, Friedrich-
Bauer-Institute and Dept. of Neurology, Munich, Germany, 4 Western Australian
Institute for Medical Research and Centre for Medical Research, the University
of Western Australia, Perth, Australia.
Interest in the unique genetic background of the Gypsy population
led to the discovery of novel disorders in Bulgaria such as Hereditary
Motor and Sensory Neuropathy type Loom (HMSNL) and type Russe
(HMSNR) and the Congenital Cataracts Facial Dimorphism (CCFDN)
syndrome . Studies across Europe characterized unique founder mutations
in disorders such as Limb-Girdle Muscular Dystrophy 2C (LGM-
D2C), Congenital Myasthenia Syndrome (CMS) and Spinal Muscular
Atrophy (SMA) .
Our group has recently investigated affected Hungarian Gypsy families
. Large experience was obtained with CMS, as 43 Gypsy families
with 65 affected and 90 unaffected family members were analyzed . In
63 patients the 1267delG founder mutation has been detected in homozygous
form in the CHRNE gene, whilst two independent patients
showed compound heterozygosis of the frame shifting founder mutation
and a missense mutation. Out of the other specific neuromuscular
diseases three families showed HSMNL with homozygous R148X mutation
in the NDGR1 gene and another family was linked to 10q22, the
candidate region of HSMNR . Two patients were genetically diagnosed
as having CCFDN with homozygous mutation IVS6+389C→T in the
CTPD1 gene . Four patients were found to be affected by LGMD2C
where the gamma-sarcoglycan gene carried the C283Y founder mutation
in homozygous form .
In Hungary, 8% of the population is represented by Romas . Therefore,
the exact knowledge of the frequent disorders, with the nature and
prevalence of the founder mutations and the carrier frequency is required
. Precise genetic diagnosis, carrier testing and genetic counseling
programs should be offered for this population at risk .
P06.259
integration of omic data in identification of sarcoidosis
candidate genes
A. Maver 1 , I. Medica 1 , B. Salobir 2 , M. Tercelj 2 , M. Sabovic 2 , B. Peterlin 1 ;
1 Clinical Institue of Medical Genetics, Department of Gynecology and Obstetrics,
UMC Ljubljana, Ljubljana, Slovenia, 2 Department of Pulmonary Diseases
and Allergy, UMC Ljubljana, Ljubljana, Slovenia.
Integration of genomic and transcriptomic information together with
linkage analysis data allows for the identification of the genetic background
of complex multifactorial diseases . This approach was performed
in our search for possible candidate genes for sarcoidosis,
combined with literature-based discovery knowledge .
A comprehensive search of Pubmed database for available transcriptomic,
proteomic and genomic scan data for sarcoidosis has been
performed . Additional information on possible candidate genes has
been obtained by using BITOLA software, itself enabling advanced
literature-based discovery searches of the Pubmed database . After
careful inspection of discovered candidate genes, the most plausible
candidates were selected for further analyses . Additionally, after identification
of informative polymorphisms, the association of the candidate
genes with the disease was investigated . In our previous studies we
found a statistically significant association of PPARG and PPARGC1A
polymorphisms with sarcoidosis .
By using omic approach we have identified new genes as potential
gene candidates for sarcoidosis: Glutathione S-transferasePi
(GSTP1), Endothelin-1 (EDN1), 25-(OH)-Vitamin D 3 -1α-hydroxylase
(CYP27B1), Osteopontin (SPP1) .
In our study on 105 sarcoidosis patients and 100 controls, the preliminary
results did not show evidence of significant association of allelic
variants of single polymorphism in GSTP1, EDN1, SPP1, CYP27B1
gene with susceptibility to sarcoidosis . Further studies on larger sample
of patients and multiple polymorphism/gene molecular analyses
are currently in progress .