FCGR3A-V158F polymorphism is a disease-specific pharmacogenetic marker for the treatment of psoriasis with Fc-containing TNFα inhibitors.

Psoriasis is a multifactorial skin disease affecting ~2% of world's population, causing a dramatic decrease in patients' quality of life and a significant increase in health-care expenses. Biological agents such as the anti-TNFα ones had an enormous impact in patients' therapy; however, a significant proportion of them do not respond well, an outcome attributed mainly to genetic factors. Recently, in a large European cohort of rheumatoid arthritis patients we have shown association with variation in the receptors that correspond to the Fc portion of the biological agents. As both diseases share common immunological fingerprints, we examined the hypothesis that they share common pharmacogenetic markers. Analysis of FCGR2A-H131R and FCGR3A-V158F polymorphisms in 100 psoriasis patients showed association only with respect to FCGR3A-V158F and response to etanercept (P=0.018). Interestingly, no association was found between FCGR2A-H131R and response to anti-TNFα therapy (P=0.882). This study suggests a role for FCGR3A-V158F polymorphism unique for psoriasis.

Replication of PTPRC as genetic biomarker of response to TNF inhibitors in patients with rheumatoid arthritis.

Genetic biomarkers could be useful for orienting treatment of patients with rheumatoid arthritis (RA), but none has been convincingly validated yet. Putative biomarkers include 14 single nucleotide polymorphisms that have shown association with response to TNF inhibitors (TNFi) in candidate gene studies and that we assayed here in 755 RA patients. Three of them, in the PTPRC, IL10 and CHUK genes, were significantly associated with response to TNFi. The most significant result was obtained with rs10919563 in PTPRC, which is a confirmed RA susceptibility locus. Its RA risk allele was associated with improved response (B=0.33, P=0.006). This is the second independent replication of this biomarker (P=9.08 × 10(-8) in the combined 3003 RA patients). In this way, PTPRC has become the most replicated genetic biomarker of response to TNFi. In addition, the positive but weaker replication of IL10 and CHUK should stimulate further validation studies.

A pharmacogenetic study of ABCB1 polymorphisms and cyclosporine treatment response in patients with psoriasis in the Greek population.

Psoriasis affects 2-3% of the population, causing significant morbidity and financial burden. Immunosuppressive drugs such as cyclosporine are first line systemic therapies for moderate-to-severe forms. However, patients exhibit heterogeneity in their response to therapy, possibly due to genetic factors. The aim of the present study was to assess the ABCB1 T-129C, G1199A, C1236T, G2677T and C3435T single-nucleotide polymorphisms (SNPs) as candidate predictive markers of response to cyclosporine treatment in 84 psoriasis patients. 62% of the patients were defined as responders and 38% as nonresponders. All SNPs complied with Hardy-Weinberg equilibrium. SNP and haplotype analyses were performed to access responsiveness to treatment. Association analysis revealed statistically significant association of SNP 3435 T with negative response (P=0.0075), a result that was further validated in haplotype analysis. This study is the first in the field of the pharmacogenetics of cyclosporine in psoriasis whose results merit further exploitation in larger independent cohorts.

Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-α response in rheumatoid arthritis.

OBJECTIVES: To investigate the possible influence of tumour necrosis factor-alpha (TNF), TNF receptor I (TNFRI) and TNF receptor II (TNFRII) gene polymorphisms on anti-TNF treatment responsiveness, stratified by autoantibody status. METHODS: A Greek multi-centre collaboration was established to recruit a cohort of patients (n=100) with active RA treated with anti-TNF drugs. TNF g.-238G>A (rs361525), g.-308G>A (rs1800629), g.-857C>T (rs1799724), TNFRI c.36A>G (rs4149584) and TNFRII c.676T>G (rs1061622) polymorphisms were genotyped by PCRRFLP assays. Serum RF and anti-CCP antibody status were determined using commercially available kits. Single-SNP, haplotype and stratification by autoantibody status analyses were performed in predicting response to treatment by 6 months, defined as the absolute change in DAS28. RESULTS: 31 patients (31%) were defined as non-responders due to failure to fulfill the DAS28 criteria. 79% and 66% were RF and anti-CCP positive, respectively. None of the genotyped SNPs was alone associated with responsiveness to drug treatment. However, after stratification by autoantibody status, carriage of TNFRII c.676G allele was associated with poorer response to drug treatment in anti-CCP positive patients (p=0.03), after 6 months of anti-TNF therapy. CONCLUSIONS: In concordance with previous studies, genetic polymorphisms alone cannot be used to safely predict clinical response to anti-TNF therapy however the combination of genetic factors and autoantibody status warrants further investigation in larger independent cohorts.

Major histocompatibility complex variation at class II DQA locus in the brown hare (Lepus europaeus).

The major histocompatability complex (MHC) is a multigene family of receptors that bind and present antigenic peptides to T-cells. Genes of the MHC are characterized by an outstanding genetic polymorphism, which is considered to be maintained by positive selection. Sites involved in peptide binding form binding pockets (P) that are collectively termed the peptide-binding region (PBR). In this study, we examined the level of MHC genetic diversity within and among natural populations of brown hare (Lepus europaeus) from Europe and Anatolia choosing for analysis of the second exon of the DQA locus, one of the most polymorphic class II loci. We aimed at an integrated population genetic analysis of L. europeaus by (i) correlating MHC polymorphism to genetic variability and phylogenetic status estimated previously from maternally (mtDNA) and biparentally (allozymes, microsatellites) inherited loci; and (ii) comparing full-length exon amino acid polymorphism with functional polymorphism in the PBR and the binding pockets P1, P6 and P9. A substantial level of DQA exon 2 polymorphism was detected with two completely different set of alleles between the Anatolian and European populations. However, the phylogeny of full-length exon 2 Leeu-DQA alleles did not show a strong phylogeographic signal. The presence of balancing selection was supported by a statistically significant excess of nonsynonymous substitutions over synonymous in the PBR and a trans-species pattern of evolution detected after phylogenetic reconstruction. The differentiating patterns detected between genetic and functional polymorphism, i.e. the number and the distribution of pocket variants within and among populations, indicated a hierarchical action of selection pressures.

Genetic analysis of the LGI/Epitempin gene family in sporadic and familial lateral temporal lobe epilepsy.

Mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE), a partial epilepsy characterized by the presence of auditory seizures. However, not all the pedigrees with a phenotype consistent with ADLTE show mutations in LGI1/Epitempin, or evidence for linkage to the 10q24 locus. Other authors as well as ourselves have found an internal repeat (EPTP, pfam# PF03736) that allowed the identification of three other genes sharing a sequence and structural similarity with LGI1/Epitempin. In this work, we present the sequencing of these genes in a set of ADLTE families without mutations in both LGI1/Epitempin and sporadic cases. No analyzed polymorphisms modified susceptibility in either the familial or sporadic forms of this partial epilepsy.

Identification and characterization of a novel human brain-specific gene, homologous to S. scrofa tmp83.5, in the chromosome 10q24 critical region for temporal lobe epilepsy and spastic paraplegia.

We describe the structure, genomic organization, and some transcription features of a human brain-specific gene previously localized to the genomic region involved in temporal lobe epilepsy and spastic paraplegia on chromosome 10q24. The gene, which consists of six exons disseminated over 16 kb of genomic DNA, is highly homologous to the porcine tmp83.5 gene and encodes a putative transmembrane protein of 141 amino acids. Unlike its porcine homolog, from which two mRNAs with different 5'-sequences are transcribed, the human gene apparently encodes three mRNA species with 3'-untranslated regions of different sizes. Mutation analysis of its coding sequence in families affected with temporal lobe epilepsy or spastic paraplegia linked to 10q24 do not support the involvement of this gene in either diseases.

ZNF232: structure and expression analysis of a novel human C(2)H(2) zinc finger gene, member of the SCAN/LeR domain subfamily.

We have identified a novel zinc finger gene, ZNF232, mapped to human chromosome 17p12. The coding region of the gene is organized in three exons corresponding to a 417 amino acid long polypeptide containing a SCAN/LeR domain and five C(2)H(2)-type zinc fingers. ZNF232 is possibly a nuclear protein, as suggested by expression analysis of GFP/ZNF232 chimeric constructs. ZNF232 transcripts were detected in a wide collection of adult human tissues. The gene is possibly subjected to tissue-specific post-transcriptional regulation by means of alternative splicing.

Map integration at human chromosome 10: molecular and cytogenetic analysis of a chromosome-specific somatic cell hybrid panel and genomic clones, based on a well-supported genetic map.

Well-characterized, chromosome-specific somatic cell hybrid panels are powerful tools for the analysis of the human genome. We have characterized a panel of human x hamster somatic cell hybrids retaining fragments of human chromosome 10 by fluorescence in situ hybridization and associated them to genetic markers. Most of the hybrids were generated by the radiation-reduction method, starting from a chromosome 10-specific monochromosomal hybrid, whereas some were collected from hybrids retaining chromosome 10-specific fragments as a result of spontaneous in vitro rearrangements. PCR was used to score the retention of 57 microsatellite markers evenly distributed along a well-supported framework genetic map containing 149 loci uniquely placed at 69 anchor points (odds exceeding 1,000:1), with an average spacing of 2.8 cM. As an additional resource for genomic studies involving human chromosome 10, we report the cytogenetic localization of a series of YAC and PAC clones recognized by at least one genetic marker. Somatic cell hybrids provide a powerful source of partial chromosome paints useful for detailed clinical cytogenetic and primate chromosome evolution investigations. Furthermore, correlation of the above physical, genetic, and cytogenetic data contribute to an emerging consensus map of human chromosome 10.