2009 Vienna - European Society of Human Genetics

Complex traits and polygenic disorders
to three SNPs in strong linkage disequilibrium with the deletion was
observed. This is the first risk factor predisposing only to skin-type of
psoriasis supporting the concept of partially overlapping, but different
etiological factors underlying skin and joint manifestations.
P09.101
High-resolution association mapping in the mHc region
identifies multiple independent loci for psoriatic arthritis
P. Rahman1 , N. Roslin2 , F. Pellett3 , A. Paterson2 , J. Beyene4 , M. Lemire5 , L.
Peddle1 , A. Pope1 , C. Greenwood3 , D. Gladman3 ;
1 2 Memorial University of Newfoundland, St. John’s, NL, Canada, Program in
Genetics and Genome Biology, The Hospital for Sick Children Research Institute,
Toronto, ON, Canada, 3Toronto Western Hospital, University of Toronto,
Toronto, ON, Canada, 4Child Health and Evaluative Science, The Hospital for
Sick Children Research Institute, Toronto, ON, Canada, 5Informatics and Biocomputing,
Ontario Institute for Cancer Research, Toronto, ON, Canada.
Objectives: To identify SNPs in the MHC region which are associated
with PsA using a high density map.
Methods: 909 individuals (422 cases and 487 controls) were genotyped
for 2299 SNPs in a 5 Mb region on chromosome 6 encompassing the
MHC region, using Illumina’s MHC Panel Set. The patients were from
two well established centers with an expertise in PsA. A stratified case/
control analysis was conducted on each SNP separately to test for allelic
association with PsA. A Breslow-Day test was used to determine if
the odds ratio estimates differed between the two populations.
Results: 17 SNPs from 13 regions were associated with PsA (p-values
< 10-5 ); we report the results for these SNPs, noting their location relative
to genes, and their linkage disequilibrium (LD, based on r2 ) with
each other. SNPs rs2734922 (between HLA-H and HLA-A), rs1150735
(between RNF39 and TRIM31), rs11965214 (KIAA1949), rs3130933
(between TCF19 and POU5F1), rs879882 and rs887468 (both between
POU5F1 and HGC27), rs2523619 and rs2442719 (both between
HLA-C and HLA-B; the latter tags HLA-C*0802), rs6936035 (between
HLA-B and MICA) and rs2516470 (between MICA and HCP5)
were associated with PsA, however, none were in strong pairwise LD.
In a subset of controls who have also been genotyped for HLA-Cw6,
we observed that rs12191877 and rs3906272 are in LD with this allele
(r2 =0.69 and 0.60, respectively).
Conclusions: Multiple regions within the MHC are associated with PsA
and pairwise LD information suggests that the majority of these signals
are independent.
P09.102
TNFα promoter polymorphisms in psoriatic arthritis patients in
Romania
O. M. Popa 1 , C. Ciofu 2 , M. Dutescu 3 , M. Bojinca 2 , R. Sfrent-Cornateanu 1 , V.
Bojinca 4 , M. Milicescu 5 , C. Bara 1 , L. Popa 6 ;
1 Department of Immunology and Physiopathology, University of Medicine and
Pharmacy Carol Davila, Bucharest, Romania, 2 Department of Rheumatology
and Internal Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest,
Romania, 3 National Hematology Institute Prof. C.T. Nicolau, Bucharest,
Romania, 4 Department of Rheumatology, University of Medicine and Pharmacy
Carol Davila, Bucharest, Romania, 5 University of Medicine and Pharmacy Carol
Davila, Bucharest, Romania, 6 Molecular Biology Department, Grigore Antipa
National Museum of Natural History, Bucharest, Romania.
Background Tumour necrosis factor α (TNFα) is a proinflammatory
cytokine of critical importance in psoriatic arthritis (PsA) due to his
high levels in synovial membrane and fluid and by the efficiency of
anti-TNFα treatments in PsA patients [1, 2]. Genetic studies of TNFα
polymorphisms in PsA have produced different results that may reflect
differences in the ethnic background [3].
Objectives The aim of this study was to investigate two TNFα most
studied polymorphisms in PsA patients from Romania.
Methods 45 unrelated well diagnosed patients with PsA (25/20 F/M)
and 109 healthy unrelated organ donors (46/63 F/M) were typed for
TNFα -308G/A (rs 1800629) and -238G/A (rs 361525) polymorphisms
by TaqMan SNP Genotyping Assay C_7514879_10 and C_2215707_
10 respectively (Applied Biosystems, USA).
Results The observed genotypes for the TNFα-308G/A polymorphism
(1AA, 6GA, 38GG in cases, respectively 4AA, 24GA, 79GG in controls)
and for the TNFα-238G/A polymorphism (0AA, 5GA, 40GG in cases,
respectively 0AA, 5GA, 102GG in controls) showed no departure from
Hardy-Weinberg equilibrium (HWE). The same results were obtained
when only B27 negative cases and controls were analyzed.
Conclusion The present study shows no departure from HWE in PsA
patients in Romania, and no potential association of any investigated
allele with the susceptibility to this disease, although a larger number
of patients may be required to verify this conclusion.
References:
1.Goupille P., Joint Bone Spine 2005;72:466-470
2.Seitz M et al., Rheumatology 2007; 46:93-96
3.Rahman P et al., Ann. Rheum. Dis. 2006; 65:919-923
P09.103
Autoimmune-associated LYP-W620 variant reduces t cell
activation by altering a recirpocal feedback mechanism
E. Fiorillo 1,2 , V. Orrù 1,3 , Y. Liu 1 , S. Stanford 1 , M. Salek 4 , N. Rapini 5 , L. Delogu 1 ,
P. Saccucci 5 , F. Angelini 5 , M. Manca Bitti 5 , M. C. Rosatelli 6 , O. Acuto 7 , N. Bottini
1 ;
1 Institute for Genetic Medicine, Los Angeles, CA, United States, 2 Dept. of Biomedical
Science and Biotechnology, University of Cagliari, Cagliari, Italy, 3 Dept.
of Biomedical Science, University of Sassari, Sassari, Italy, 4 Sir William Dunn
School of Pathology, Oxford University, Oxford, United Kingdom, 5 Dept. of Biopathology,
Division of Pediatrics, University of Rome “Tor Vergata”, Rome, Italy,
6 Dipartimento di Scienze Biomediche e Biotecnologie, Università degli Studi
di Cagliari, Cagliari, Italy, 7 Sir William Dunn School of Pathology, Università di
Oxford, Oxford, United Kingdom.
A missense C1858T single nucleotide polymorphism (SNP) in the
PTPN22 gene recently emerged as a major risk factor for human autoimmunity.
PTPN22 encodes the lymphoid tyrosine phosphatase LYP,
which forms a complex with the kinase Csk and is a critical negative
regulator of signaling through the T cell receptor (TCR). The C1858T
SNP results in the LYP-R620W variation within the LYP-Csk interaction
motif. LYP-W620 exhibits a greatly reduced interaction with Csk and
is a gain-of-function inhibitor of signaling. Here we show that LYP constitutively
interacts with its substrate Lck in a Csk-dependent manner.
TCR-induced phosphorylation of LYP by Lck on an inhibitory tyrosine
residue releases tonic inhibition of signaling by LYP. The R620W variation
disrupts the interaction between Lck and LYP, leading to reduced
phosphorylation of LYP and ultimately to gain-of-function inhibition of
T cell signaling.
P09.104
PTPN gene polymorphism in autoimmune endocrine diseases
M. Fichna1 , M. Żurawek1 , J. Nowak1 , P. Fichna2 , D. Januszkiewicz1,2 ;
1 2 Institute of Human Genetics, Poznan, Poland, University of Medical Sciences,
Poznan, Poland.
Autoimmune destruction of glandular cells is the main reason of type
1 diabetes (T1DM) and Addison’s disease (AAD). Both diseases present
complex genetic background, with prominent role of predisposing
polymorphisms in genes involved in immune reaction. Intriguing candidate
is PTPN22 gene, which encodes lymphoid tyrosine phosphatase
LYP. Aim of study was to analyse associations of PTPN22 G(-1123)C
and C1858T polymorphisms with susceptibility to T1DM and AAD in
Polish population. Study comprised 215 T1DM patients (120 females
and 95 males) and 87 with AAD (65 females and 22 males), compared
to 236 control subjects (133 females and 103 males). Mean age of
disease onset was 8.3 (±4.3) years for T1DM and 35.2 (±11.5) years
for AAD. No difference was found in distribution of G(-1123)C polymorphism
between T1DM patients and controls, whereas the same analysis
in AAD subjects revealed slightly higher frequency of C(-1123)
allele (p=0.052). C(-1123) allele was significantly more frequent only
in affected AAD males, than in controls (OR 2.79; 95%CI 1.39-5.56;
p=0.003). C1858T polymorphism in PTPN22 gene presented significant
association with T1DM (OR 1.73; 95%CI 1.19-2.51; p=0.004) and
AAD (OR 1.84; 95%CI 1.15-2.94; p=0.010). Association of T1858 allele
with T1DM remained significant for both genders, while in AAD
patients it seemed restricted to male population (OR 2.89; 95%CI
1.24-6.76; p=0.011). The haplotype consisting of both mutant alleles,
C(-1123)-T1858, was significantly more frequent in T1DM (p=0.003)
and in AAD (p=0.008) than in healthy controls.
Supported in part by Grant N402162533.