European Caucasian Population Research Articles

DNMT1 genetic polymorphisms affect breast cancer risk in the central European Caucasian population

IntroductionDNA methylation of CpG islands within the promoter region of genes is an epigenetic modification with an important role in the development of cancer and it is typically mediated by DNA methyltransferases (DNMTs). In cancer cells, global hypomethylation of the genome as a whole and regional hypermethylation of CpG islands have been reported. Four groups of DNMTs have been identified: DNMT1, DNMT2 (TRDMT1), DNMT3A and DNMT3B. DNMT2 uses the catalytic mechanism of DNMTs, but does in fact methylate RNA. Little is known about the significance of these genes in human breast cancer. In the study presented herein, we analyzed five distinct DNMT single SNPs with regard to potential associations with breast cancer risk.Case descriptionIn this study, we genotyped 221 female Caucasian breast cancer patients and 221 female Caucasian healthy controls, and we used five allele-specific real-time polymerase chain reaction (qPCR) assays. We selected one locus within the DNMT1 gene and two loci within the DNMT3A and DNMT3B genes, respectively. Statistics were calculated using the chi-squared and Fisher’s exact tests, and correlated with clinical parameters such as age, diagnosis, histology, TNM stage, hormonal receptor status, human epidermal growth factor receptor 2 (HER2) status, response to treatment and survival. Statistically significant results were obtained for correlations with the DNMT1 gene.Discussion and EvaluationFive genomic loci within the DNMT1, DNMT3A and DNMT3B genes were assessed. Statistical significance (P = 0.030) was identified for DNMT1 SNP (A201G, rs2228612): six women within the control group were GG homozygous (variant), while this mutation was absent in the breast cancer group.ConclusionsWe conclude that women with the DNMT1 SNP (A201G, rs2228612) GG homozygous genotype (variant) have a lower risk of developing breast cancer compared to heterozygous or wildtype genotypes. To date, alterations within the DNMT1 gene have not been reported to be associated with cancer in the Caucasian population.

Association study of CRP gene in systemic sclerosis in European Caucasian population

Opsonization and apoptotic cell elements are critical in systemic lupus erythematosus (SLE) and could act through the activation of the innate immunity. C-reactive protein (CRP) belongs to opsonins, and polymorphisms of CRP gene have been shown to be associated with SLE susceptibility. Accumulating evidences show that SLE and systemic sclerosis (SSc) share some genetic susceptibility factors. To determine whether polymorphisms of CRP confer susceptibility to SSc, four SNPs (rs1130864, rs1205, rs1800947 and rs1341665), chosen using Hapmap linkage disequilibrium data and published data, were genotyped in a cohort of 651 SSc patients (569 with antinuclear antibodies, 258 with anti-centromere and 153 with anti-topoisomerase I) and 442 controls. All individuals were of French Caucasian origin. The four polymorphisms were in Hardy-Weinberg equilibrium in the control population. Allelic and genotypic frequencies for these four polymorphisms were found to be similar in SSc patients and controls. Moreover, subphenotype analyses in particular for subgroups having antinuclear antibodies did not detect any difference between SSc patients and controls. These results obtained through a large cohort of European Caucasian SSc patients do not support the implication of CRP gene in the pathogenesis of SSc.

Population-specific influence of SLC2A9 genotype on the acute hyperuricaemic response to a fructose load

BackgroundSLC2A9 is a strong genetic risk factor for hyperuricaemia and gout. SLC2A9 (GLUT9) is a high capacity urate transporter and reportedly transports glucose and fructose. Intake of fructose-containing beverages is...

Molecular and Clinical Characterization of the Variable Phenotype in Korean Families with Hearing Loss Associated with the Mitochondrial A1555G Mutation

Hearing loss, which is genetically heterogeneous, can be caused by mutations in the mitochondrial DNA (mtDNA). The A1555G mutation of the 12S ribosomal RNA (rRNA) gene in the mtDNA has been associated with both aminoglycoside-induced and non-syndromic hearing loss in many ethnic populations. Here, we report for the first time the clinical and genetic characterization of nine Korean pedigrees with aminoglycoside-induced and non-syndromic hearing loss. These Korean families carry in the A1555G mutation of 12S rRNA gene and exhibit variable penetrance and expressivity of hearing loss. Specifically, the penetrance of hearing loss in these families ranged between 28.6% and 75%, with an average of 60.8%. These results were higher than the 29.8% penetrance that was previously reported in a Chinese population but similar to the 65.4% and 54.1% penetrance observed in a large Arab-Israeli population and nineteen Spanish pedigrees, respectively. The mutational analysis of the complete mtDNA genome in these families showed that the haplogroups of the Korean population, which belongs to the eastern Asian population, were similar to those of the Chinese population but different from the Spanish population, which belongs to the European-Caucasian population. The mtDNA variants that may act as modifier factors were also found to be similar to the Chinese population. Although the mtDNA haplogroups and variants were similar to the eastern Asian population, we did find some differing phenotypes, although some subjects had the same variants. This result suggests that both the ethnic background and environmental factors lead to a variable phenotype of the A1555G mutation.

Drug/xenobiotic metabolizing enzyme polymorphisms in a Turkish population

Genetic polymorphisms of drug/xenobiotic metabolizing enzymes can have great impact on the inter-individual variation in drug response or susceptibility to toxicities of xenobiotics. The frequencies of the polymorphic enzymes not also differ from ethnicity, but also differ from country to country in the same ethnic group. In this study, CYP2E1*5B, GSTM1, GSTT1,GSTP1 exon 5 and GSTP1 exon 6 genetic polymorphisms were determined in 302 unrelated healthy individuals in a Turkish population and the results were compared with previous reports. The frequencies of CYP2E1*5B c1/c1, c1/c2 and c2/c2 genotypes were 94.7, 5.3 and 0%, respectively. The frequencies of the deleted GSTM1 and GSTT1 genotypes were 54.6 and 22.2%, respectively. The GSTP1 exon 5 genotype frequencies were Ile/Ile: 56.0%, Ile/Val: 34.8% and Val/Val: 9.3%; GSTP1 exon 6 genotype frequencies were Ala/Ala: 84.8%, Ala/Val: 14.2% and Val/Val: 1.0%. These results revealed that the frequencies of CYP2E1*5B,GSTM1, GSTT1, GSTP1 exon 5 and GSTP1 exon 6 genetic polymorphisms in a Turkish population are similar to European Caucasian populations. Key words: Drug metabolism, CYP2E1 polymorphism, GST polymorphism, Turkish population.

Management of patients with difficult autoimmune hepatitis

Autoimmune hepatitis (AIH) is characterized by a T-cell rich infiltrate associated with lobular and interface hepatitis, hypergammaglobulinemia and production of autoantibodies. Genetic risk is linked to the HLA particularly DRB1*0301 and DRB1*0401 alleles in North American and European Caucasian populations. It has recently been suggested that functional deficiencies in CD4(+)CD25(+)CD127(low)FOXP3(+) regulatory T cells contribute to the breakdown of immune tolerance that results in AIH. Most patients respond to immunosuppressive therapy with corticosteroids and can be maintained in remission by low-dose corticosteroid treatment and/or azathioprine. For those who progress to end-stage disease liver transplantation is an effective treatment although it is associated with recurrence. In the future it is likely that biological therapies will allow more targeted therapy designed to switch the balance to immune regulation and thereby restore immune homeostasis. Although treatment for many cases is relatively straightforward and successful problems are encountered in those who fail to respond to standard treatment, are unable to tolerate it or relapse. In such cases alternative therapies should be considered. In addition treatment is complicated in some patients by comorbidity and special care is required during and after pregnancy. We will discuss the current and future therapeutic options for patients with difficult to treat AIH.

Common polymorphisms in GSTM1, GSTT1, GSTP1, GSTA1 and susceptibility to colorectal cancer in the Central European population

BackgroundCentral Europe presents with the highest incidence of sporadic colorectal cancer (CRC) worldwide. As sporadic CRC represents a typical multifactorial disease, it is characterized by intense interaction of the genetic background with the environment. Glutathione S-transferases could act as attractive susceptibility genes for CRC, as they are directly involved in conjugation between glutathione and chemotherapeutics, environmental pollutants and a wide spectrum of xenobiotics.MethodsIn this study, we investigated associations of polymorphisms in glutathione S-transferases (GSTs) genes, that is GSTA1, GSTT1, GSTM1 and GSTP1, with CRC in a total of 197 cases and 218 controls originating from the Czech Central European population. Polymorphisms were assessed by polymerase chain reaction/restriction fragment length polymorphism-based methods, allele-specific multiplex and allelic discrimination by real-time polymerase chain reaction.ResultsNone of investigated polymorphisms showed any associations with CRC, with the exception of GSTP1; where the heterozygote genotype Ile105Val was associated with decreased risk of CRC (P = 0.043).ConclusionsThe frequencies observed in our study are in accordance with those from other European Caucasian populations. Based on our studies, examined variability in GST genes is not a major determinant of CRC susceptibility in the Central European population.

Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population

ObjectiveTo evaluate the actual impact of MEFV mutations on clinical manifestations associated with fever attacks in Caucasian children with periodic fever.Methods113 children carrying MEFV mutations (44 with mutations in two...

Interaction Analysis between HLA-DRB1 Shared Epitope Alleles and MHC Class II Transactivator CIITA Gene with Regard to Risk of Rheumatoid Arthritis

HLA-DRB1 shared epitope (SE) alleles are the strongest genetic determinants for autoantibody positive rheumatoid arthritis (RA). One of the key regulators in expression of HLA class II receptors is MHC class II transactivator (CIITA). A variant of the CIITA gene has been found to associate with inflammatory diseases.We wanted to explore whether the risk variant rs3087456 in the CIITA gene interacts with the HLA-DRB1 SE alleles regarding the risk of developing RA. We tested this hypothesis in a case-control study with 11767 individuals from four European Caucasian populations (6649 RA cases and 5118 controls).We found no significant additive interaction for risk alleles among Swedish Caucasians with RA (n = 3869, attributable proportion due to interaction (AP) = 0.2, 95%CI: −0.2–0.5) or when stratifying for anti-citrullinated protein antibodies (ACPA) presence (ACPA positive disease: n = 2945, AP = 0.3, 95%CI: −0.05–0.6, ACPA negative: n = 2268, AP = −0.2, 95%CI: −1.0–0.6). We further found no significant interaction between the main subgroups of SE alleles (DRB1*01, DRB1*04 or DRB1*10) and CIITA. Similar analysis of three independent RA cohorts from British, Dutch and Norwegian populations also indicated an absence of significant interaction between genetic variants in CIITA and SE alleles with regard to RA risk.Our data suggest that risk from the CIITA locus is independent of the major risk for RA from HLA-DRB1 SE alleles, given that no significant interaction between rs3087456 and SE alleles was observed. Since a biological link between products of these genes is evident, the genetic contribution from CIITA and class II antigens in the autoimmune process may involve additional unidentified factors.

Single-nucleotide polymorphism associations for colorectal cancer in southern Chinese population

Genome-wide association studies (GWAS) have identified 11 loci that influence the risk of developing colorectal cancer (CRC). Given that these studies were conducted in European Caucasian populations, it is not clear whether the results are relevant for populations with different ethnicities. The aim of this study was to examine these associations in a southern Chinese population. Eleven single-nucleotide polymorphisms (SNPs), rs12701937, rs16892766, rs7014346, rs6983267, rs719725, rs10795668, rs3802842, rs4444235, rs9929218, rs10411210, and rs961253, were genotyped in 229 CRC patients and 267 controls using the MassArray SNP genotyping system. Evidence of an association with CRC was found for four of the 11 loci. The strongest associations were with rs4444235 and rs961253, with significant odds ratios close to those reported in previous GWAS. Among these four loci, rs719725 and rs4444235 were significantly associated with female gender, rs3802842, rs961253, and rs4444235 with early disease onset, and rs3802842 with later disease onset. However, no associations with CRC risk were detected for six other loci (rs9929218, rs10411210, rs12701937, rs7014346, rs6983267, and rs10795668), and one SNP, rs16892766, was not polymorphic in any of the study participants. The rs4444235 and rs961253 loci are strongly associated with the risk of CRC in southern Chinese.

Association between the Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor Gamma 2 and Inflammatory Bowel Disease: A Meta-Analysis

BackgroundPeroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor, has been implicated playing a role in the development of inflammatory bowel disease (IBD). However, previous studies evaluating the association between the PPARγ2 Pro12Ala polymorphism and IBD are inconsistent. We performed a meta-analysis to determine whether the PPARγ2 Pro12Ala mutation was associated with the presence of IBD.Methods and FindingsElectronic databases were searched for case-control studies evaluating the association between the Pro12Ala mutation and the presence of IBD. Effects were summarized with the methods recommended by the Cochrane Collaboration. A total of 7 studies including 1002 ulcerative colitis (UC) cases, 1090 Crohǹs disease (CD) cases and 1983 controls were involved in this meta-analysis. In the overall analysis, no significant association of this polymorphism with UC or CD was found. In the subgroup analyses in different populations, AlaAla genotype seemed to protect the European Caucasian population against the development of CD (Pro vs Ala: OR = 1.135, 95%CI = 0.951–1.354, P = 0.162, Bon = 1.000; ProPro vs ProAla: OR = 1.042, 95%CI = 0.852–1.273, P = 0.690, Bon = 1.000; ProPro vs AlaAla: OR = 2.379, 95%CI = 1.110–5.100, P = 0.026, Bon = 0.156; ProAla vs AlaAla: OR = 2.315, 95%CI = 1.064–5.037, P = 0.034, Bon = 0.204; Pro homozygotes vs Ala positives: OR = 1.094, 95%CI = 0.899–1.330, P = 0.371, Bon = 1.000; Pro positives vs Ala homozygotes: OR = 2.360, 95%CI = 1.103–5.053, P = 0.027, Bon = 0.162; heterozygotes vs all homozygotes: OR = 0.976, 95%CI = 0.799–1.192, P = 0.809, Bon = 1.000). There was no significant association of this polymorphism with UC or CD in the East Asian population and the Turkish population.ConclusionAlaAla genotype may be a protective factor in the European Caucasian population against the development of CD in a recessive way.

Molecular phylogenetics and historical biogeography of the west-palearctic common toads (Bufo bufo species complex)

In most pan-Eurasiatic species complexes, two phenomena have been traditionally considered key processes of their cladogenesis and biogeography. First, it is hypothesized that the origin and development of the Central Asian Deserts generated a biogeographic barrier that fragmented past continuous distributions in Eastern and Western domains. Second, Pleistocene glaciations have been proposed as the main process driving the regional diversification within each of these domains. The European common toad and its closest relatives provide an interesting opportunity to examine the relative contributions of these paleogeographic and paleoclimatic events to the phylogeny and biogeography of a widespread Eurasiatic group. We investigate this issue by applying a multiproxy approach combining information from molecular phylogenies, a multiple correspondence analysis of allozyme data and species distribution models. Our study includes 304 specimens from 164 populations, covering most of the distributional range of the Bufo bufo species complex in the Western Palearctic. The phylogenies (ML and Bayesian analyses) were based on a total of 1988bp of mitochondrial DNA encompassing three genes (tRNAval, 16S and ND1). A dataset with 173 species of the family Bufonidae was assembled to estimate the separation of the two pan-Eurasiatic species complexes of Bufo and to date the main biogeographic events within the Bufo bufo species complex. The allozyme study included sixteen protein systems, corresponding to 21 presumptive loci. Finally, the distribution models were based on maximum entropy. Our distribution models show that Eastern and Western species complexes are greatly isolated by the Central Asian Deserts, and our dating estimates place this divergence during the Middle Miocene, a moment in which different sources of evidence document a major upturn of the aridification rate of Central Asia. This climate-driven process likely separated the Eastern and Western species. At the level of the Western Palearctic, our dating estimates place most of the deepest phylogenetic structure before the Pleistocene, indicating that Pleistocene glaciations did not have a major role in splitting the major lineages. At a shallow level, the glacial dynamics contributed unevenly to the genetic structuring of populations, with a strong influence in the European–Caucasian populations, and a more relaxed effect in the Iberian populations.

The prevalence of neuromyelitis optica in South East Wales

Neuromyeltis optica (NMO) is a neuroinflammatory disorder considered rare in Caucasian populations. However, accurate population-based epidemiological data for NMO and NMO spectrum disorder (NMO-SD) from Western populations employing validated diagnostic criteria remain limited. We sought therefore to estimate the prevalence and clinical features of NMO in a north European Caucasian population in South East Wales. Patients were identified by a comprehensive, multistage ascertainment strategy employing a regional neuroinflammatory disease register, hospital diagnostic databases personal physician referrals and regional requests for anti-aquaporin-4 antibodies (anti-AQP4). Fourteen Caucasian patients (11 patients with NMO and three with NMO-SD) were identified in a population of 712,572 (19.6/million; 95% CIs: 12.2-29.7). There was an excess of females (female:male 12:2), 11/14 were anti-AQP4 positive and 5/14 had disease onset under the age of 20 years. This study suggests that NMO and related spectrum disorders are at least as frequent in Northern European populations as in non-Caucasian populations and that the demographic profile of prevalent patients differs from clinic-based cohorts.

Risk of venous thromboembolism in first- and second-generation immigrants in Sweden

Background There are ethnic differences in the incidence of venous thromboembolism. This is the first nationwide study to examine whether there is an association between country of birth in first-generation immigrants and first hospitalisation for venous thrombosis (VT) and pulmonary embolism (PE), and to study whether a similar association exists in second-generation immigrants. Methods The study is a nationwide follow-up study. The study subjects were first- and second-generation immigrants residing in Sweden between January 1, 1964 and December 31, 2007. The reference population comprised first- and second-generation Swedish-born individuals. Standardised incidence ratios (SIRs) for VT and PE, standardised with regard to age, geographic region of residence, time period, and socioeconomic status, were estimated by sex in first- and second-generation immigrants. Results First-generation male and/or female immigrants from Greece, Italy, Spain, Finland, Baltic countries, Central Europe, Eastern Europe, Russia, Latin America, Turkey, Iran, and Iraq had a lower risk of VT and/or PE than Swedish-born individuals. The lower risk of VT and/or PE in some first-generation immigrant groups was not replicated in the second generation. However, in certain second-generation immigrant groups, the risk of VT/PE was similar to that in the corresponding parental groups. Conclusions Country of birth affects the risk of VT and PE in several immigrant groups. Our study indicates that ethnicity-related inherited and acquired venous thromboembolism risk factors play a role in the aetiology of venous thromboembolism. Ethnic differences in thromboembolism risk even exist in Caucasian European populations, and may thus be important to consider in genetic studies.

Metabolic Syndrome, Cardiovascular Disease, and Risk for Chronic Kidney Disease in an Italian Cohort: Analysis of the INCIPE Study

Metabolic syndrome is a frequent condition that has been linked to cardiovascular disease (CVD) and mortality. Metabolic syndrome has been extensively shown to increase the risk of chronic nephropathies in Americans and Asians, but not in European populations. Renal disease increases the risk of CVD and mortality. However, the chronic nephropathy-CVD liaison has not been analyzed in the framework of the possible role of metabolic syndrome in both. We analyzed data from 3,757 subjects participating in the INCIPE survey (Initiative on Nephropathy, of relevance to public health, which is Chronic, possibly in its Initial stages, and carries a Potential risk of major clinical End-points), a cross-sectional study enrolling subjects from the general population in the Veneto region in Italy, and calculated the odds ratio (OR) and 95% confidence interval (CI) of the association between metabolic syndrome, and/or chronic kidney disease (CKD) and albuminuria, and/or previous CVD after adjustment for confounding factors. Metabolic syndrome is associated with CKD (OR 2.17; P<0.001) and albuminuria (OR 2.28; P<0.001) and CVD (OR 1.58; P=0.002). There is a direct correlation between number of metabolic syndrome traits and nephropathy and CVD. CVD and nephropathies are associated even after adjustment for metabolic syndrome (OR 2.30; P<0.001). In a homogeneous Caucasian European population, metabolic syndrome is associated with CKD and albuminuria, and CVD. Although metabolic syndrome is a risk factor for both CVD and nephropathy, it does not entirely explain the dangerous CVD-nephropathy liaison.

Functional Variants inNOS1andNOS2AAre Not Associated with Progressive Hearing Loss in Ménière's Disease in a European Caucasian Population

Hearing loss in Ménière's disease (MD) is associated with loss of spiral ganglion neurons and hair cells. In a guinea pig model of endolymphatic hydrops, nitric oxide synthases (NOS) and oxidative stress mediate loss of spiral ganglion neurons. To test the hypothesis that functional variants of NOS1 and NOS2A are associated with MD, we genotyped three functional variants of NOS1 (rs41279104, rs2682826, and a cytosine-adenosine microsatellite repeat in exon 1f) and the CCTTT repeat in the promoter of NOS2A gene (rs3833912) in two independent MD sets (273 patients in total) and 550 controls. A third cohort of American patients was genotyped as replication cohort for the CCTTT repeat. Neither allele nor genotype frequencies of rs41279104 and rs2682826 were associated with MD, although longer alleles of the cytosine-adenosine microsatellite repeat were marginally significant (corrected p = 0.05) in the Mediterranean cohort but not in a second Galicia cohort. Shorter numbers of the CCTTT repeat in NOS2A were significantly more frequent in Galicia controls (OR = 0.37 [CI, 0.18-0.76], corrected p = 0.04), but this finding could not be replicated in Mediterranean or American case-control populations. Meta-analysis did not support an association between CCTTT repeats and risk for MD. Severe hearing loss (>75 dB) was also not associated with any functional variants studied. Functional variants of NOS1 and NOS2A do not confer susceptibility for MD.

No association between polymorphisms and haplotypes of COL1A1 and COL1A2 genes and osteoporotic fracture in postmenopausal Chinese women

To study whether genetic polymorphisms of COL1A1 and COL1A2 genes affected the onset of fracture in postmenopausal Chinese women. SNPs in COL1A1 and COL1A2 genes were identified via direct sequencing in 32 unrelated postmenopausal Chinese women. Ten SNPs were genotyped in 1252 postmenopausal Chinese women. The associations were examined using both single-SNP and haplotype tests using logistic regression. Twenty four (4 novel) and 28 (7 novel) SNPs were identified in COL1A1 and COL1A2 gene, respectively. The distribution frequencies of 2 SNPs in COL1A1 (rs2075554 and rs2586494) and 3 SNPs in COL1A2 (rs42517, rs1801182, and rs42524) were significantly different from those documented for the European Caucasian population. No significant difference was observed between fracture and control groups with respect to allele frequency or genotype distribution in 9 selected SNPs and haplotype. No significant association was found between fragility fracture and each SNP or haplotype. The results remained the same after additional corrections for other risk factors such as weight, height, and bone mineral density. Our results show no association between common genetic variations of COL1A1 and COL1A2 genes and fracture, suggesting the complex genetic background of osteoporotic fractures.

A Novel NYX Mutation Associated with X-Linked Congenital Stationary Night Blindness in a New Zealand Family

Background: Complete Congenital Stationary Night Blindness (CSNB) type 1A is an X-linked condition associated with reduced scotopic vision, myopia, nystagmus and mutations in the NYX (nyctalopin) gene. This paper reports a novel mutation identified in this gene associated with X-linked CSNB in a New Zealand Caucasian family. Methods: A 16 year old male, presenting with night blindness, underwent detailed phenotypic assessment including pedigree construction and electrophysiology testing. Genetic analysis was performed in the Division of Medical Molecular Genetics, University of Zurich, Switzerland. Other family members also underwent clinical examination and genetic testing. Results: Electrodiagnostic testing has confirmed the diagnosis of Type 1 (complete) CSNB in the proband and his maternal grandfather by identifying a 'negative' rod-mediated waveform and near normal cone responses. NYX gene testing revealed a novel missense sequence alteration c.425T>G (p.Leu142Arg) in the proband. This has not been detected in control European and New Zealand Caucasian populations and segregates with the disease in this family. Conclusion: Missense changes account for the majority of the mutations reported in the NYX gene so far. A novel missense sequence variant causing complete CSNB has been identified in a New Zealand family. This expands the known mutation spectrum of the NYX gene.

Association of the CD226 Ser307 variant with systemic sclerosis: Evidence of a contribution of costimulation pathways in systemic sclerosis pathogenesis

The nonsynonymous polymorphism rs763361 of the CD226 gene, which encodes DNAX accessory molecule 1, which is involved in T cell costimulation pathways, has recently been identified as a genetic risk factor for autoimmunity. The purpose of this study was to test for association of the CD226 rs763361 polymorphism with systemic sclerosis (SSc) in European Caucasian populations. CD226 rs763361 was genotyped in 3,632 individuals, consisting of a discovery sample (991 SSc patients and 1,008 controls) and a replication sample (999 SSc patients and 634 controls). All study subjects were of European Caucasian origin. Expression of CD226 was assessed on peripheral blood mononuclear cells obtained from 21 healthy donors genotyped for CD226 rs763361. The CD226 rs763361 T allele was found to be associated with SSc in both the discovery and the replication samples, showing the following results in the combined populations: odds ratio (OR) 1.22 (95% confidence interval [95% CI] 1.10-1.34), P = 5.69 × 10(-5) . The CD226 T allele was also associated with various SSc subsets, highlighting a potential contribution to disease severity. The most remarkable associations of the CD226 TT risk genotype were observed with the diffuse cutaneous SSc subtype, the anti-topoisomerase I antibody-positive, and SSc-related fibrosing alveolitis subsets: OR 1.86 (95% CI 1.42-2.43), P = 5.15 × 10(-6) , OR 1.82 (95% CI 1.38-2.40), P = 2.16 × 10(-5) , and OR 1.61 (95% CI 1.25-2.08), P = 2.73 × 10(-4) , respectively. CD226 expression was not significantly influenced by CD226 rs763361 genotypes whatever the T cell subtype investigated. Our results establish CD226 as a new SSc genetic susceptibility factor underlying the contribution of costimulation pathways in the pathogenesis of SSc. Further work is nevertheless needed to define the causal variant at the CD226 locus as well as the functional consequences.

P02-452 - Dystonia and acute psychotic episode complicated by neuroleptic malignant syndrome in an adolescent with CYP2D6 deficiency

IntroductionCYP2D6 gene encodes an isozyme of the P450 cytochrome mono-oxygenase family, responsible for hepatic metabolism of the majority of neuroleptics. Phenotypes of CYP2D6 activity are ultrarapid, extensive, intermediate, and poor metabolizers. Prevalence of poor metabolizers is relatively high in European Caucasian population and ranges between 5–10%. The subjects with such phenotype are more likely to manifest adverse reactions and toxicity following administration of drugs in standard doses.ObjectiveWe describe a case report of a 16 year old male patient with dystonia and acute psychotic episode who developed neuroleptic malignant syndrome (NMS) associated with antipsychotic medication and a non-functional CYP2D6*4 allele.MethodsThe patient's clinical course is a case report.ResultsThe patient developed NMS after treatment with standard doses of antipsychotics. Genotyping revealed that this patient was homozygous for non-functional CYP2D6*4 allele. Ziprasidone was used for a follow-up treatment after recovery from the NMS. Persistent neuropsychiatric impairment was noted after 9-months.ConclusionsInitial symptoms developed by this patient may be explained by overuse OTC cough medication. This case suggest that as in adult population, non-functional CYP2D6 allele could be associated with NMS in pediatric population. This means that screening for CYP2D6*4 allele in pediatric patients with NMS and history of adverse drug reactions could be helpful in the treatment of residual state after NMS.