Association of IRF5 polymorphisms with increased risk for systemic lupus erythematosus in population of Crete, a southern-eastern European Greek island

Interferon regulatory factor 5 (IRF5) regulates type I interferon (IFN)-responsive genes, and has been one of the most consistently associated genes with systemic lupus erythematosus (SLE). We sought to investigate whether IRF5 haplotypes are associated with risk for SLE in the genetically homogeneous Greek population of the island of Crete, as well as whether these haplotypes are associated with increased type I IFN. 322 SLE patients and 247 healthy controls from Crete were genotyped for rs2004640, rs3807306, rs10488631 and rs2280714 SNPs of IRF5 gene by using Taqman primer-probe sets. Type I IFN levels were measured using a functional reporter cell assay. All IRF5 SNPs examined were found to be associated with SLE in univariate case-control analysis. The 4 SNPs formed 5 major haplotypes and the Neanderthal-derived TACA risk haplotype was present in Crete and enriched in the SLE cases (OR = 2.01, P = 0.0003). Serum IFN levels were measured in a subset of the SLE patients, and carriage of the TACA haplotype was associated with higher circulating type I IFN levels (P = 0.037). This study demonstrates the association of IRF5 with an increased susceptibility for SLE in the population of Crete and emphasizes the association of the Neanderthal-derived IRF5 haplotype with SLE susceptibility. Patients carrying allele the Neanderthal allele C had greater type I IFN, supporting a functional consequence of this polymorphism. © 2017 Elsevier B.V

TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus erythematosus in Turkey

Pathophysiology and treatment of rheumatic disease

Investigation of the genetic overlap between rheumatoid arthritis and psoriatic arthritis in a Greek population

Objectives: Several rheumatoid arthritis (RA) susceptibility loci have also been found to be associated with psoriatic arthritis (PsA), demonstrating that there is a degree of genetic overlap between various autoimmune diseases. We sought to investigate whether single nucleotide polymorphisms (SNPs) mapping to previously reported RA and/or PsA susceptibility loci, including PLCL2, CCL21, REL, STAT4, CD226, PTPN22, and TYK2, are associated with risk for the two diseases in a genetically homogeneous Greek population. Method: This study included 392 RA patients, 126 PsA patients, and 521 healthy age- and sex-matched controls from Greece. Genotyping of the SNPs was performed with Taqman primer/probe sets. Bioinformatic analysis was performed using BlastP, PyMOL, and Maestro and Desmond. Results: A significant association was detected between the GC genotype of rs34536443 (TYK2) in both the PsA and RA cohorts. The C allele of this SNP was associated with PsA only. Evidence for association with PsA was also found for the GG genotype and G allele of the rs10181656 SNP of STAT4. The TC genotype of the rs763361 SNP of CD226 was associated with PsA only. Conclusions: Genetic overlap between PsA and RA was detected for the rs34536443 SNP of the TYK2 gene within a Greek population. An association of STAT4 (rs10181656) with PsA was confirmed whereas CD226 (rs763361) was associated with PsA but not with RA, in contrast to previous reports. The different findings of this study compared to previous ones highlights the importance of comparative studies that include various ethnic or racial populations. © 2017 Informa Healthcare on license from Scandinavian Rheumatology Research Foundation

Identification and characterization of a rare variant in apolipoprotein A-IV, p.(V336M), and evaluation of HDL functionality in a Greek cohort with extreme HDL cholesterol levels

High-Density Lipoprotein cholesterol (HDL-C) levels do not correlate well with Coronary Artery Disease (CAD) risk, while HDL functionality affects atherogenesis and is a better prognostic marker for CAD. Often, the extreme HDL-C levels have a multigenic origin. Here, we searched for single-nucleotide polymorphisms (SNPs) in ten genes of HDL metabolism in a Greek cohort with very low (<10th percentile, n = 13) or very high (>90th percentile, n = 21) HDL-C. We also evaluated the association between HDL-C levels, HDL functionality (anti-oxidant capacity) and CAD in the subjects of this cohort. Individuals with low HDL-C levels had higher triglyceride levels, lower apoA-I levels, decreased HDL anti-oxidant capacity and higher incidence of CAD compared with individuals with control or high HDL-C levels. With next generation sequencing we identified 18 exonic SNPs in 6 genes of HDL metabolism and for selected amino acid changes we performed computer-aided structural analysis and modeling. A previously uncharacterized rare apolipoprotein A-IV variant, apoA-IV [V336M], present in a subject with low HDL-C (14 mg/dL) and CAD, was expressed in recombinant form and structurally and functionally characterized. ApoA-IV [V336M] had similar α-helical content to WT apoA-IV but displayed a small thermodynamic stabilization by chemical unfolding analysis. ApoA-IV [V336M] was able to associate with phospholipids but presented reduced kinetics compared to WT apoA-IV. Overall, we identified a rare apoA-IV variant in a subject with low HDL levels and CAD with altered biophysical and phospholipid binding properties and showed that subjects with very low HDL-C presented with HDL dysfunction and higher incidence of CAD in a Greek cohort. © 2020 Elsevier Inc

Lack of Association of Variants Previously Associated with Anti-TNF Medication Response in Rheumatoid Arthritis Patients: Results from a Homogeneous Greek Population

Treatment strategies blocking tumor necrosis factor (anti-TNF) have proven very successful in patients with rheumatoid arthritis (RA), showing beneficial effects in approximately 50-60% of the patients. However, a significant subset of patients does not respond to anti-TNF agents, for reasons that are still unknown. The aim of this study was to validate five single nucleotide polymorphisms (SNPs) of PTPRC, CD226, AFF3, MyD88 and CHUK gene loci that have previously been reported to predict anti-TNF outcome. In addition, two markers of RA susceptibility, namely TRAF1/C5 and STAT4 were assessed, in a cohort of anti-TNF-treated RA patients, from the homogeneous Greek island of Crete, Greece. The RA patient cohort consisted of 183 patients treated with either of 3 anti-TNF biologic agents (infliximab, adalimumab and etanercept) from the Clinic of Rheumatology of the University Hospital of Crete. The SNPs were genotyped by TaqMan assays or following the Restriction Fragments Length Polymorphisms (RFLPs) approach. Disease activity score in 28 joints (DAS28) at baseline and after 6 months were available for all patients and analysis of good versus poor response at 6 months was performed for each SNP. None of the 7 genetic markers correlated with treatment response. We conclude that the gene polymorphisms under investigation are not strongly predictive of anti-TNF response in RA patients from Greece. © 2013 Zervou et al

Replication of a distinct psoriatic arthritis risk variant at IL23R

Background: Psoriatic arthritis (PsA) is an inflammatory arthritis that is associated with psoriasis. Although the majority of PsA genetic risk loci identified also confer risk for psoriasis, we have recently reported evidence of loci that are associated with PsA and not psoriasis, including an association at the IL23R locus which is also independent of a psoriasis variant at the same locus. Methods: The PsA-specific SNP rs12044149, and the psoriasis SNP rs9988642 at the IL23R locus were genotyped in a cohort of 914 PsA cases and 6,945 controls from Spain, Crete, Germany and the UK, with the Life Technologies QuantStudio genotyping platform. Association testing was carried out using PLINK, and a meta-analysis was performed with PsA Immunochip data (1,962 cases, 8,923 controls). Genotype data was also available from the psoriasis WTCCC2 study (excluding known PsA, n=1,784) to compare effect sizes between PsA and psoriasis using multinomial logistic regression in Stata, and to directly compare PsA and psoriasis genotypes. Credible SNP sets were calculated for the PsA and psoriasis IL23R associations using the Bayesian refinement method, and functionally annotated. Results: We replicated the association rs12044149 with PsA (P=4.03x10–6), which remained significant when conditioning upon the psoriasis variant, rs9988642 (Pcond=4.86x10–6), and reached genome-wide significance during meta-analysis of the combined PsA dataset (Pmeta=4.76x10–20). Only a modest association was found for rs9988642 (P=0.04), with no genome-wide significance found during meta-analysis (P=4.61x10–4). Within the psoriasis dataset, this association remained significant when conditioning upon rs12044149 (P=1.0x10–07 vs. Pcond=1.63x10–5). Effect estimates for rs12044149 were significantly different between PsA and psoriasis (P=2.0x10–3), and direct comparison of genotypes for PsA and psoriasis found the risk allele to be significantly increased in PsA (P=4.52x10–4, OR=1.3). Credible SNPs for rs12044149 mapped to promoter and enhancer regions within memory CD8+ T cells, which we have previously reported to be critical for PsA. Conclusions: We have successfully replicated a PsA-specific (associated with PsA but not psoriasis) risk variant at the IL23R locus in an independent cohort, confirming rs12044149 to be distinct from rs9988642 (r2=0.02). This gives five PsA-specific associations that have now been identified

Validation of a distinct psoriatic arthritis risk variant at IL23R

Background: PsA is an inflammatory arthritis that is associated with psoriasis and is estimated to present in ∼14% of psoriasis patients in the UK. PsA is a complex disease that is influenced by both genetic and environmental factors. Genetic studies have aided the discovery of PsA risk loci, the majority of which also confer a risk for psoriasis. We have recently reported evidence of specific loci that confer a risk for PsA and not psoriasis, including a variant at IL23R that was also found to be independent of a psoriasis variant reported at the same locus. Methods: In this study we attempted to identify additional PsA-specific risk variants by genotyping 32 single nucleotide polymorphisms (SNPs), which included those found to have nominal significance in our recent Immunochip study (P < 1.0 × 10−4). These were analysed in 914 PsA cases and 6945 controls from the UK, Crete, Spain and Germany, which were independent from those genotyped as part of the Immunochip study. Genotyping was performed using the Life Technologies QuantStudio genotyping platform and association testing was carried out using PLINK. Genotype data were also available from the psoriasis WTCCC2 study (excluding known PsA, n = 1784). Multinomial logistic regression was carried out in Stata to compare effect estimates in PsA and psoriasis using PsA Immunochip data (n = 1962). A direct comparison of PsA and psoriasis genotypes was also performed. Results: We found a significant association for the SNP rs12044149 mapping to IL23R (P = 4.03 × 10−6). A weak association was found with the psoriasis risk variant rs9988642, which has been reported at the same locus (P = 0.04). The association with rs12044149 remained significant when conditioning upon rs9988642 (Pcond = 4.86 × 10−6). Likewise, rs9988642 remained significantly associated with psoriasis when conditioning upon rs12044149 (P = 1.0 × 10−7 vs Pcond 1.63 × 10−5), indicating that they represent independent effects. Effect estimates for rs12044149 were significantly different between PsA and psoriasis (P = 2.0 × 10−3). When genotypes for rs12044149 were directly compared between PsA and psoriasis, the risk allele was significantly increased in PsA (P = 1.91 × 10−3, odds ratio = 1.2). Conclusion: For the first time we have been able to successfully validate a PsA-specific (associated with PsA but not psoriasis) risk variant at the IL23R locus in an independent cohort, confirming rs12044149 to be independent of rs9988642 (r2 = 0.01). This now gives a total of four PsA-specific associations that have been identified. Such variants could potentially provide markers to identify psoriasis patients who are prone to developing PsA. IL-23 is a target for the psoriasis drug ustekinumab, which has also shown efficacy in PsA during clinical trials. Therefore it would be interesting to explore the role of disease-specific risk variants in treatment response. Disclosure statement: The authors have declared no conflicts of interest

The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune diseases.

Item does not contain fulltextOBJECTIVES: The TRAF1-C5 locus has recently been identified as a genetic risk factor for rheumatoid arthritis (RA). Since genetic risk factors tend to overlap with several autoimmune diseases, a study was undertaken to investigate whether this region is associated with type 1 diabetes (TID), celiac disease (CD), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). METHODS: The most consistently associated SNP, rs10818488, was genotyped in a total of 735 patients with T1D, 1049 with CD, 367 with SSc, 746 with SLE and 3494 ethnically- and geographically-matched healthy individuals. The replication sample set consisted of 99 patients with T1D, 272 with SLE and 482 healthy individuals from Crete. RESULTS: A significant association was detected between the rs10818488 A allele and T1D (OR 1.14, p=0.027) and SLE (OR 1.16, p=0.016), which was replicated in 99 patients with T1D, 272 with SLE and 482 controls from Crete (OR 1.64, p=0.002; OR 1.43, p=0.002, respectively). Joint analysis of all patients with T1D (N=961) and all patients with SLE (N=1018) compared with 3976 healthy individuals yielded an allelic common OR of 1.19 (p=0.002) and 1.22 (p=2.6 x 10(-4)), respectively. However, combining our dataset with the T1D sample set from the WTCCC resulted in a non-significant association (OR 1.06, p=0.087). In contrast, previously unpublished results from the SLEGEN study showed a significant association of the same allele (OR 1.19, p=0.0038) with an overall effect of 1.22 (p=1.02 x 10(-6)) in a total of 1577 patients with SLE and 4215 healthy individuals. CONCLUSION: A significant association was found for the TRAF1-C5 locus in SLE, implying that this region lies in a pathway relevant to multiple autoimmune diseases.1 april 201