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1. Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients

Author

Jo, Yun Gun, Ortiz-Fernández, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentür, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Düzgün, Nursen, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Kısacık, Bünyamin, Kötter, Ina, Henes, Jörg, Çınar, Muhammet, Schaefer, Arne, Nohutcu, Rahime M., Takeuchi, Fujio, Harihara, Shinji, Kaburaki, Toshikatsu, Messedi, Meriam, Song, Yeong-Wook, Kaşifoğlu, Timuçin, Martin, Javier, González Escribano, María Francisca, Saruhan-Direskeneli, Güher, Direskeneli, Haner, and Sawalha, Amr H.

Published
2022
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2. Sex-specific analysis in Behçet's disease reveals higher genetic risk in male patients

Author

National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Jo, Yun Gun, Ortiz-Fernández, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentür, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Düzgün, Nursen, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Kısacık, Bünyamin, Kötter, Ina, Henes, Jörg, Çınar, Muhammet, Schaefer, Arne, Nohutcu, Rahime M., Takeuchi, Fujio, Harihara, Shinji, Kaburaki, Toshikatsu, Messedi, Meriam, Song, Yeong-Wook, Kaşifoğlu, Timuçin, Martin, Javier, González-Escribano, María Francisca, Saruhan-Direskeneli, Güher, Direskeneli, Haner, Sawalha, Amr H., National Institute of Arthritis and Musculoskeletal and Skin Diseases (US), Jo, Yun Gun, Ortiz-Fernández, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentür, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Düzgün, Nursen, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Kısacık, Bünyamin, Kötter, Ina, Henes, Jörg, Çınar, Muhammet, Schaefer, Arne, Nohutcu, Rahime M., Takeuchi, Fujio, Harihara, Shinji, Kaburaki, Toshikatsu, Messedi, Meriam, Song, Yeong-Wook, Kaşifoğlu, Timuçin, Martin, Javier, González-Escribano, María Francisca, Saruhan-Direskeneli, Güher, Direskeneli, Haner, and Sawalha, Amr H.

Abstract

[Objectives] Behçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease., [Methods] A total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients., [Results] Genetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10−8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10−8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10−7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients., [Conclusions] Male patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease.

Published
2022

3. Genetic Association of a Gain-of-Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet's Disease

Author

Ortiz-Fernández, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentür, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Düzgün, Nursen, Kese, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Casali, Bruno, Bünyamin, Kısacık, Kötter, Ina, Henes, Jörg, Muhammet, Çınar, Schaefer, Arne, Nohutcu, Rahime M., Zhernakova, Alexandra, Wijmenga, Cisca, Takeuchi, Fujio, Harihara, Shinji, Kaburak, Toshikatsu, Messedi, Meriam, Song, Y. W., Kaşifoğlu, Timuçin, Carmona, F.D., Guthridge, Joel M., James, Judith A., Martín, J., González-Escribano, María Francisca, Saruhan-Direskeneli, Güher, Direskeneli, Haner, Sawalha, Amr H., Ortiz-Fernández, Lourdes, Coit, Patrick, Yilmaz, Vuslat, Yentür, Sibel P., Alibaz-Oner, Fatma, Aksu, Kenan, Erken, Eren, Düzgün, Nursen, Kese, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Casali, Bruno, Bünyamin, Kısacık, Kötter, Ina, Henes, Jörg, Muhammet, Çınar, Schaefer, Arne, Nohutcu, Rahime M., Zhernakova, Alexandra, Wijmenga, Cisca, Takeuchi, Fujio, Harihara, Shinji, Kaburak, Toshikatsu, Messedi, Meriam, Song, Y. W., Kaşifoğlu, Timuçin, Carmona, F.D., Guthridge, Joel M., James, Judith A., Martín, J., González-Escribano, María Francisca, Saruhan-Direskeneli, Güher, Direskeneli, Haner, and Sawalha, Amr H.

Abstract

Objective. Behçet’s disease is a complex systemic inflammatory vasculitis of incompletely understood etiology. This study was undertaken to investigate genetic associations with Behçet’s disease in a diverse multiethnic population.Methods. A total of 9,444 patients and controls from 7 different populations were included in this study. Genotyping was performed using an Infinium ImmunoArray- 24 v.1.0 or v.2.0 BeadChip. Analysis of expression data from stimulated monocytes, and epigenetic and chromatin interaction analyses were performed.Results. We identified 2 novel genetic susceptibility loci for Behçet’s disease, including a risk locus in IFNGR1(rs4896243) (odds ratio [OR] 1.25; P = 2.42 × 10−9) and within the intergenic region LNCAROD/DKK1 (rs1660760) (OR 0.78; P = 2.75 × 10−8). The risk variants in IFNGR1 significantly increased IFNGR1 messenger RNA expression in lipopolysaccharide- stimulated monocytes. In addition, our results replicated the association (P < 5 × 10−8) of 6 previously identified susceptibility loci in Behçet’s disease: IL10, IL23R, IL12A- AS1, CCR3, ADO, and LACC1, reinforcing the notion that these loci are strong genetic factors in Behçet’s disease shared across ancestries. We also identified >30 genetic susceptibility loci with a suggestive level of association (P < 5 × 10−5), which will require replication. Finally, functional annotation of genetic susceptibility loci in Behçet’s disease revealed their possible regulatory roles and suggested potential causal genes and molecular mechanisms that could be further investigated.Conclusion. We performed the largest genetic association study in Behçet’s disease to date. Our findings reveal novel putative functional variants associated with the disease and replicate and extend the genetic associations in other loci across multiple ancestries.

Published
2021

4. Genetic Association of a Gain‐of‐Function IFNGR1 Polymorphism and the Intergenic Region LNCAROD/DKK1 With Behçet’s Disease

Author

Ortiz Fernández, Lourdes, primary, Coit, Patrick, additional, Yilmaz, Vuslat, additional, Yentür, Sibel P., additional, Alibaz‐Oner, Fatma, additional, Aksu, Kenan, additional, Erken, Eren, additional, Düzgün, Nursen, additional, Keser, Gokhan, additional, Cefle, Ayse, additional, Yazici, Ayten, additional, Ergen, Andac, additional, Alpsoy, Erkan, additional, Salvarani, Carlo, additional, Casali, Bruno, additional, Kısacık, Bünyamin, additional, Kötter, Ina, additional, Henes, Jörg, additional, Çınar, Muhammet, additional, Schaefer, Arne, additional, Nohutcu, Rahime M., additional, Zhernakova, Alexandra, additional, Wijmenga, Cisca, additional, Takeuchi, Fujio, additional, Harihara, Shinji, additional, Kaburaki, Toshikatsu, additional, Messedi, Meriam, additional, Song, Yeong‐Wook, additional, Kaşifoğlu, Timuçin, additional, Carmona, F. David, additional, Guthridge, Joel M., additional, James, Judith A., additional, Martin, Javier, additional, González Escribano, María Francisca, additional, Saruhan‐Direskeneli, Güher, additional, Direskeneli, Haner, additional, and Sawalha, Amr H., additional

Published
2021
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5. Serum lipid, lipoprotein and oxidatively modified low density lipoprotein levels in active or inactive patients with behcet's disease

Author

Cimen, Fuat, Yildirmak, Sembol, Ergen, Andac, Cakmak, Mustafa, Dogan, Serkan, Yenice, Necati, and Sezgin, Funda

Subjects
Diagnosis, Care and treatment, Usage, Measurement, Health aspects, Behcet's syndrome -- Diagnosis -- Care and treatment, Low density lipoproteins -- Measurement -- Health aspects, Statistical methods -- Usage, Behcet's disease -- Diagnosis -- Care and treatment
Published
2012

6. Dense Genotyping of Immune Related Loci in a Multi-Ethnic Behcet's Disease Cohort Identifies Genetic Associations in a Long Noncoding RNA Near QSOX2, RASIP1/FUT2, and IL12A-AS1

Author

Renauer, Paul, Coit, Patrick, Hughes, Travis, Ognenovski, Mikhail, Adler, Adam, Ortiz-Fernandez, Lourdes, Yilmaz, Vuslat, Aksu, Kenan, Duzgun, Nursen, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alpsoy, Erkan, Salvarani, Carlo, Casali, Bruno, Koetter, Ina, Zhernakova, Alexandra, Wijmenga, Cisca, Takeuchi, Fujio, Harihara, Shinji, Kaburaki, Toshikatsu, Song, Yeong Wook, David Carmona, Francisco, Alarcon Riquelme, Marta E., Martin, Javier, Saruhan-Direskeneli, Guher, Gonzalez Escribano, Maria Francisca, Direskeneli, Haner, Sawalha, Amr H., Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), and Translational Immunology Groningen (TRIGR)

Published
2016

7. A putative functional variant within the ubiquitin-associated domain-containing protein 2 gene (UBAC2) is associated with increased risk of Behçet’s disease

Author

Sawalha, Amr H, Hughes, Travis, Nadig, Ajay, YıImaz, Vuslat, Aksu, Kenan, Keser, Gokhan, Cefle, Ayse, Yazıcı, Ayten, Ergen, Andac, Alarcón-Riquelme, Marta E., Salvarani, Carlo, Casali, Bruno, Direskeneli, Haner, and Saruhan-Direskeneli, Güher

Subjects
Adult, Gene Frequency, Genotype, Haplotypes, Behcet Syndrome, Case-Control Studies, Intracellular Signaling Peptides and Proteins, Humans, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Article, Alleles
Abstract

Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behçet's disease. We undertook this study to establish the genetic effect within the UBAC2 gene, in the course of which we replicated this genetic association and identified a functional variant within this locus.We studied a total of 676 Behçet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls from Turkey and 144 patients and 560 controls from Italy. Genotyping of 14 single-nucleotide polymorphisms (SNPs) within and around UBAC2 was performed using TaqMan SNP genotyping assays.The genetic association between Behçet's disease and UBAC2 was established, replicated, and confirmed (meta-analysis odds ratio 1.84, P = 1.69 × 10(-7) ). Haplotype analysis identified both a disease-risk haplotype and a protective haplotype (P = 0.00014 and P = 0.0075, respectively). Using conditional haplotype analysis, we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrated that rs7999348 tags a functional variant associated with increased messenger RNA expression of a UBAC2 transcript variant in peripheral blood mononuclear cells of individuals homozygous for the Behçet's disease-associated "G" allele. Further, our data suggested the possibility of multiple genetic effects that increase susceptibility to Behçet's disease in the UBAC2 locus.We established and confirmed the genetic association between UBAC2 and Behçet's disease in 3 independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression.

Published
2011

8. Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease

Author

Hughes, Travis, primary, Coit, Patrick, additional, Adler, Adam, additional, Yilmaz, Vuslat, additional, Aksu, Kenan, additional, Düzgün, Nursen, additional, Keser, Gokhan, additional, Cefle, Ayse, additional, Yazici, Ayten, additional, Ergen, Andac, additional, Alpsoy, Erkan, additional, Salvarani, Carlo, additional, Casali, Bruno, additional, Kötter, Ina, additional, Gutierrez-Achury, Javier, additional, Wijmenga, Cisca, additional, Direskeneli, Haner, additional, Saruhan-Direskeneli, Güher, additional, and Sawalha, Amr H, additional

Published
2013
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11. A putative functional variant within the UBAC2 gene is associated with increased risk of Behçet's disease

Author

Andac Ergen, Ayten Yazici, Vuslat Yilmaz, Gökhan Keser, Carlo Salvarani, Travis K. Hughes, Marta E. Alarcón-Riquelme, Ajay Nadig, Güher Saruhan-Direskeneli, Kenan Aksu, Bruno Casali, Haner Direskeneli, Ayse Cefle, Amr H. Sawalha, Ege Üniversitesi, Sawalha, Amr H., Hughes, Travis, Nadig, Ajay, Yilmaz, Vuslat, Aksu, Kenan, Keser, Gokhan, Cefle, Ayse, Yazici, Ayten, Ergen, Andac, Alarcon-Riquelme, Marta E., Salvarani, Carlo, Casali, Bruno, Direskeneli, Haner, and Saruhan-Direskeneli, Guher

Subjects
Adult, SUSCEPTIBILITY LOCI, Genotype, Immunology, Locus (genetics), Biology, Alleles, Behcet Syndrome, Case-Control Studies, Gene Frequency, Genetic Predisposition to Disease, Haplotypes, Humans, Intracellular Signaling Peptides and Proteins, Polymorphism, Single Nucleotide, AGE, Rheumatology, Genetic predisposition, Immunology and Allergy, Pharmacology (medical), Allele, GENOME-WIDE ASSOCIATION, Polymorphism, Allele frequency, Gene, Genetic association, Genetics, Haplotype, ComputerSystemsOrganization_COMPUTER-COMMUNICATIONNETWORKS, Single Nucleotide, PREVALENCE, IL23R-IL12RB2, ComputingMilieux_MANAGEMENTOFCOMPUTINGANDINFORMATIONSYSTEMS, SEVERITY, ComputingMethodologies_PATTERNRECOGNITION, VISUALIZATION, InformationSystems_MISCELLANEOUS, IL10
Abstract

WOS: 000297221100049, PubMed ID: 21918955, Objective. Using a genome-wide association scan and DNA pooling, we previously identified 5 novel genetic susceptibility loci for Behc,et's disease. We undertook this study to establish the genetic effect within the UBAC2 gene, in the course of which we replicated this genetic association and identified a functional variant within this locus. Methods. We studied a total of 676 Behcet's disease patients and 1,096 controls. The discovery set included 156 patients and 167 controls from Turkey, and the replication sets included 376 patients and 369 controls from Turkey and 144 patients and 560 controls from Italy. Genotyping of 14 single-nucleotide polymorphisms (SNPs) within and around UBAC2 was performed using TaqMan SNP genotyping assays. Results. The genetic association between Behc, et's disease and UBAC2 was established, replicated, and confirmed (meta-analysis odds ratio 1.84, P = 1.69 x 10(-7)). Haplotype analysis identified both a disease-risk haplotype and a protective haplotype (P = 0.00014 and P = 0.0075, respectively). Using conditional haplotype analysis, we identified the SNP rs7999348 (A/G) within UBAC2 as the most likely SNP with a genetic effect independent of the haplotypic effect formed by the remaining associated SNPs in this locus. Indeed, we demonstrated that rs7999348 tags a functional variant associated with increased messenger RNA expression of a UBAC2 transcript variant in peripheral blood mononuclear cells of individuals homozygous for the Behc, et's disease-associated "G" allele. Further, our data suggested the possibility of multiple genetic effects that increase susceptibility to Behc, et's disease in the UBAC2 locus. Conclusion. We established and confirmed the genetic association between UBAC2 and Behcet's disease in 3 independent sets of patients and controls. We identified the minor allele in rs7999348 as a disease-risk allele that tags altered UBAC2 expression., American College of Rheumatology Research and Education Foundation; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R03-AI-076729, P20-RR-020143, P30-AR-053483], Supported by the American College of Rheumatology Research and Education Foundation (Rheumatology Investigator Award to Dr. Sawalha) and by the NIH (grants R03-AI-076729, P20-RR-020143, and P30-AR-053483).

Published
2011

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