The Experts below are selected from a list of 711 Experts worldwide ranked by ideXlab platform
Robert Haesler - One of the best experts on this subject based on the ideXlab platform.
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Corrigendum: Sarcoidosis is associated with a truncating splice site mutation in the gene BTNL2
Nature Genetics, 2005Co-Authors: Ruta Valentonyte, Klaus Huse, Mario Albrecht, Annette Stenzel, Marion Nagy, Karoline I. Gaede, Andre Franke, Philip Rosenstiel, Jochen Hampe, Robert HaeslerAbstract:Corrigendum: Sarcoidosis is associated with a truncating splice site mutation in the gene BTNL2
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sarcoidosis is associated with a truncating splice site mutation in BTNL2
Nature Genetics, 2005Co-Authors: Ruta Valentonyte, Klaus Huse, Mario Albrecht, Annette Stenzel, Marion Nagy, Karoline I. Gaede, Andre Franke, Philip Rosenstiel, Jochen Hampe, Robert HaeslerAbstract:Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; PTDT = 3 × 10−6, Pcase-control = 1.1 × 10−8; replication PTDT = 0.0018, Pcase-control = 1.8 × 10−6) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G → A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.
John Trowsdale - One of the best experts on this subject based on the ideXlab platform.
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analysis of the BTNL2 truncating splice site mutation in tuberculosis leprosy and crohn s disease
Tissue Antigens, 2007Co-Authors: Chris Johnson, James A Traherne, Sarra E Jamieson, Mark Tremelling, Sheila Bingham, Miles Parkes, Jenefer M Blackwell, John TrowsdaleAbstract:: The region on chromosome 6 encoding the major histocompatibility complex (MHC) is associated with a number of autoimmune and infectious diseases. Primary susceptibility to many of these has been localized to a region containing the human leukocyte antigen (HLA)-DR and -DQ genes. A recent study of sarcoidosis has provided evidence of an independent effect, associated with a truncating single nucleotide polymorphism (SNP) of a nearby gene, BTNL2. This gene may encode an immune receptor involved in costimulation. Sarcoidosis, tuberculoid leprosy, tuberculosis (TB) and Crohn's disease all have similar immunological features, including a Th1 response with granuloma formation. In addition mycobacteria have been identified or suggested to be causative pathogens in such conditions. We genotyped the truncating BTNL2 SNP in 92 TB and 72 leprosy families from Brazil and carried out family-based association studies. We could not find evidence of overtransmission of the truncating allele in TB. There was an association with susceptibility to leprosy (P=0.04), however, this is most likely due to linkage disequilibrium with HLA-DR. We also genotyped 476 UK Caucasian cases of Crohn's disease with 760 geographically matched controls and found no evidence of a disease association. We conclude that the truncating BTNL2 SNP is not important in this group of Th1 dominated granulomatous diseases.
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association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to hla drb1 15
Human Molecular Genetics, 2006Co-Authors: James A Traherne, Lisa F Barcellos, Stephen Sawcer, Alastair Compston, Patricia P Ramsay, Stephen L Hauser, Jorge R Oksenberg, John TrowsdaleAbstract:: The major histocompatibility complex human leukocyte antigen (HLA)-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis (MS). The primary susceptibility has been localized to only approximately 200 kb encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated inflammatory condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and myelin oligodendrocyte glycoprotein, an autoantigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to MS, we genotyped 1136 well-characterized MS families from the UK and the USA, as well as an African-American case-control data set, making this among the largest genetic studies in MS. Family-based and case-control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family data sets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined data sets: global P=2.4x10(-11)). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15-negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association.
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Association of the truncating splice site mutation in BTNL2 with multiple sclerosis is secondary to HLA-DRB1*15.
Human molecular genetics, 2005Co-Authors: James A Traherne, Lisa F Barcellos, Stephen Sawcer, Alastair Compston, Patricia P Ramsay, Stephen L Hauser, Jorge R Oksenberg, John TrowsdaleAbstract:The major histocompatibility complex human leukocyte antigen (HLA)-DRB1*15 (DR2) haplotype is strongly associated with risk of multiple sclerosis (MS). The primary susceptibility has been localized to only approximately 200 kb encompassing the HLA-DR and -DQ loci. Further dissection of disease association with this region is demanding because of the high levels of linkage disequilibrium (LD). Recently, evidence was obtained for the involvement of a gene, potentially encoding an immune co-receptor, in another DR2-associated inflammatory condition, sarcoidosis. The implicated gene, BTNL2, is adjacent to DR and is in strong LD with HLA-DRB1. This fact, combined with a sequence relationship between BTNL2 and myelin oligodendrocyte glycoprotein, an autoantigen associated with MS, makes the gene an attractive candidate. To determine whether BTNL2 contributes to MS, we genotyped 1136 well-characterized MS families from the UK and the USA, as well as an African-American case-control data set, making this among the largest genetic studies in MS. Family-based and case-control association studies were performed for the BTNL2 and HLA-DRB1 loci. In all family data sets, the protein-truncating allele of BTNL2, implicated in sarcoidosis, was significantly over-transmitted to cases (combined data sets: global P=2.4x10(-11)). Given that the protein-truncating allele of BTNL2 virtually always occurred with DRB1*15, an effect could only be tested in DRB1*15-negative individuals or pedigrees. However, despite adequate power to detect an independent association, no difference in transmission of BTNL2 alleles or genotypes was observed in DRB1*15-negative individuals with MS. Conditional logistic regression modeling also strongly supported the conclusion that BTNL2 does not confer additional disease risk. The association of BTNL2 with MS observed in the African-American data set was also secondary to the primary DRB1*15 association.
Ruta Valentonyte - One of the best experts on this subject based on the ideXlab platform.
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Identification of sarcoidosis susceptibility genes by association mapping and candidate gene approaches
2006Co-Authors: Ruta ValentonyteAbstract:Identification of a sarcoidosis susceptibility gene on chromosome 6 in this study has been performed using the association mapping approach.Here, a systematic three-stage single nucleotide polymorphism (SNP) scan of 16.4 Mb on chromosome 6p21 was performed in up to 947 independent cases of familial and sporadic sarcoidosis. Using TDT and case-control analyses, a 15 kb segment located at the 3-prime end of the BTNL2 gene could be identified as being strongly associated with sarcoidosis. The major disease-associated variant, rs2076530, represents a risk factor that is entirely independent of the previously reported association between sarcoidosis and alleles of the DRB1 gene, located within ~200kb of BTNL2. BTNL2 is a member of the immunoglobulin superfamily. Homology to B7-1 implicates the BTNL2 as a co-stimulatory molecule. The risk allele A of rs2076530 leads to alternative splicing of the BTNL2 transcript, which introduces a premature stop. The resulting truncated protein lacks the C-terminal IgC domain and transmembrane helix, thereby disturbing the putative co-stimulatory function of this molecule.
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Corrigendum: Sarcoidosis is associated with a truncating splice site mutation in the gene BTNL2
Nature Genetics, 2005Co-Authors: Ruta Valentonyte, Klaus Huse, Mario Albrecht, Annette Stenzel, Marion Nagy, Karoline I. Gaede, Andre Franke, Philip Rosenstiel, Jochen Hampe, Robert HaeslerAbstract:Corrigendum: Sarcoidosis is associated with a truncating splice site mutation in the gene BTNL2
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sarcoidosis is associated with a truncating splice site mutation in BTNL2
Nature Genetics, 2005Co-Authors: Ruta Valentonyte, Klaus Huse, Mario Albrecht, Annette Stenzel, Marion Nagy, Karoline I. Gaede, Andre Franke, Philip Rosenstiel, Jochen Hampe, Robert HaeslerAbstract:Sarcoidosis is a polygenic immune disorder with predominant manifestation in the lung. Genome-wide linkage analysis previously indicated that the extended major histocompatibility locus on chromosome 6p was linked to susceptibility to sarcoidosis. Here, we carried out a systematic three-stage SNP scan of 16.4 Mb on chromosome 6p21 in as many as 947 independent cases of familial and sporadic sarcoidosis and found that a 15-kb segment of the gene butyrophilin-like 2 (BTNL2) was associated with the disease. The primary disease-associated variant (rs2076530; PTDT = 3 × 10−6, Pcase-control = 1.1 × 10−8; replication PTDT = 0.0018, Pcase-control = 1.8 × 10−6) represents a risk factor that is independent of variation in HLA-DRB1. BTNL2 is a member of the immunoglobulin superfamily and has been implicated as a costimulatory molecule involved in T-cell activation on the basis of its homology to B7-1. The G → A transition constituting rs2076530 leads to the use of a cryptic splice site located 4 bp upstream of the affected wild-type donor site. Transcripts of the risk-associated allele have a premature stop in the spliced mRNA. The resulting protein lacks the C-terminal IgC domain and transmembrane helix, thereby disrupting the membrane localization of the protein, as shown in experiments using green fluorescent protein and V5 fusion proteins.
Michael C. Iannuzzi - One of the best experts on this subject based on the ideXlab platform.
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Advances in the genetics of sarcoidosis
Proceedings of the American Thoracic Society, 2007Co-Authors: Michael C. IannuzziAbstract:Familial aggregation and racial differences in incidence support the notion that sarcoidosis occurs in genetically susceptible hosts. Siblings of those affected with sarcoidosis have a modestly increased disease risk, with an odds ratio of about 5. HLA genes have been the most extensively studied susceptibility genes in sarcoidosis. Many other attractive candidate genes have been evaluated using the case-control study design, but few have been confirmed. Confounding by population stratification likely explains much of the failure to replicate initial findings. A genomewide scan performed in German families with follow-up fine mapping studies has yielded a highly attractive candidate gene, BTNL2 in the MHC II region on chromosome 6. BTNL2, a member of the B7 family of costimulatory molecules, likely functions to down-regulate T-cell activation. A BTNL2 single-nucleotide polymorphism associated with sarcoidosis is predicted to result in a truncated nonfunctioning protein. Association of BTNL2 with sarcoidosis has been confirmed in both white and African Americans. A genomewide scan with follow-up fine mapping studies in African American families has identified chromosome 5 as potentially harboring candidate genes. Additional linkage analysis in the African American families stratified according to genetic ancestry demonstrated that linkage signals varied according to degree of admixture. Certain chromosomal regions were also found linked to specific phenotypes. Follow-up fine mapping studies of the linked regions are underway.
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the BTNL2 gene and sarcoidosis susceptibility in african americans and whites
American Journal of Human Genetics, 2005Co-Authors: Benjamin A. Rybicki, José L. Walewski, Mary J. Maliarik, Hamed Kian, Michael C. IannuzziAbstract:The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations—one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P<.0001). The A allele of rs2076530 results in a premature exon-splice site and increases risk for sarcoidosis (odds ratio=2.03; 95% confidence interval 1.32–3.12). Although rs2076530 was not associated with sarcoidosis in either African American sample, a three-locus haplotype that included rs2076530 was associated with sarcoidosis across all three study samples. Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans. Our results underscore the complexity of genetic risk for sarcoidosis emanating from the MHC region.
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The BTNL2 Gene and Sarcoidosis Susceptibility in African Americans and Whites
American journal of human genetics, 2005Co-Authors: Benjamin A. Rybicki, José L. Walewski, Mary J. Maliarik, Hamed Kian, Michael C. IannuzziAbstract:The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations—one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P
Yves Pacheco - One of the best experts on this subject based on the ideXlab platform.
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BTNL2 gene polymorphism and sarcoid uveitis.
The British journal of ophthalmology, 2019Co-Authors: Mayeul Chaperon, Yves Pacheco, Laurent Pérard, Yvan Jamilloux, Delphine Maucort-boulch, Jean Iwaz, Christiane Broussolle, Carole Burillon, Laurent Kodjikian, Alain CalenderAbstract:Background Uveitis is a frequent and early feature of sarcoidosis. As BTNL2 (butyrophilin-like 2) gene polymorphism was found linked with the susceptibility to sarcoidosis, we investigated whether a specific genotype of BTNL2 gene G16071A (or rs2076530) single-nucleotide polymorphism (SNP) would be associated with the risk of sarcoid uveitis in all patient subgroups. Methods The study compared the genotype frequencies of SNP G16071A of 135 patients with sarcoid uveitis (Sa+Uv+) with those of 196 patients with sarcoidosis without uveitis (Sa+Uv−), 81 patients with uveitis without sarcoidosis (Sa−Uv+), and 271 controls with no sarcoidosis nor uveitis (Sa−Uv−). Three hypothetical subgroups of patients with sarcoid uveitis (Sa+Uv+ cases) were considered: (1) subgroup I: patients aged 45 years; and (3) subgroup III: all other patients. Results A statistically significant difference in genotype frequencies was found between the groups Sa+Uv− and Sa−Uv− (p=3.2×10−6) and between the groups Sa+Uv+ and Sa+Uv− (p=7.1×10−3). There was no difference between the three subgroups of Sa+Uv+ patients. There was a statistically significant difference in genotype frequencies between Sa+Uv− and Sa+Uv+ subgroup II (p=0.005) but no difference between Sa+Uv− and Sa+Uv+ subgroup I. Conclusion No association was found between G16071A and the susceptibility to sarcoid uveitis. BTNL2 gene G16071A SNP seems to be a predisposing factor for sarcoidosis except in Caucasian postmenopausal women with sarcoid uveitis in whom the GG genotype prevails. These and future results will help in understanding differences between particular subgroups of patients with sarcoid uveitis.
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Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort
Orphanet journal of rare diseases, 2016Co-Authors: Yves Pacheco, Alain Calender, Dominique Israël-biet, Pascal Roy, Serge Lebecque, Vincent Cottin, Diane Bouvry, Hilario Nunes, Pascal Sève, Laurent PérardAbstract:The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated. The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32–3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome. Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.
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Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort
Orphanet Journal of Rare Diseases, 2016Co-Authors: Yves Pacheco, Alain Calender, Dominique Israël-biet, Pascal Roy, Serge Lebecque, Vincent Cottin, Diane Bouvry, Hilario Nunes, Pascal Sève, Laurent PérardAbstract:Background: The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.Results: The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome.Conclusion: Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.
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Comparative phenotype and BTNL2 polymorphism in familial and sporadic sarcoidosis in the French SARCFAM cohort
European Respiratory Journal, 2014Co-Authors: Yves Pacheco, Alain Calender, Dominique Israël-biet, Pascal Roy, Serge Lebecque, Vincent Cottin, Dominique Valeyre, Claire Bardel, Mad Hélénie ElsensohnAbstract:Familial clustering and epidemiologic studies suggest a genetic susceptibility to sarcoidosis that may be associated with a difference in phenotype. The objective of the study was to compare the phenotype and the polymorphisms of the BTNL2 gene in familial and sporadic sarcoidosis. The cohort included 485 patients with histologically proved sarcoidosis (274 women, 211 men), with 267 sporadic cases (SC), and 218 familial cases (FC) from 142 families with at least two first-degree relatives with documented sarcoidosis. The clinical phenotype was studied retrospectively, and the polymorphisms of the BTNL2 gene were analysed. The sex ratio and ethnicity (77% Caucasian, 20% African/Caribbean and 3% from Asia) did not differ between FC and SC. The mean age at diagnosis was 38+1.9 yr in FC and 43+1.9 in SC (p=0.001). At the date of diagnosis the number of affected organs was significantly greater in FC than in SC (OR=1.29, p=0.01). The mean clinical severity score (range, 0-106) based on the number of affected organs and the clinical/biological manifestations was 17.2 at baseline, with no difference between FC and SC. Lofgren syndrome was present in 57 patients. Radiological stages were I (41%), II (41%), III (12.33%) and IV (5.4%), respectively. A total of 333 patients were treated, with no difference between groups. The frequency of the rs 2076530 polymorphism in BTNL2 was similar in FC and SC. In conclusion, familial sarcoidosis differs from sporadic disease only by earlier onset and higher number of affected organs. SARCFAM is an interesting tool for a study on natural history and the identification of new genetic loci in this disease.
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Lack of correlation of BTNL2 polymorphism and cancer risk in sarcoidosis. BTNL2 and cancer risk in sarcoidosis.
Sarcoidosis vasculitis and diffuse lung diseases : official journal of WASOG, 2014Co-Authors: Maud Gaillot-drevon, Alain Calender, Dominique Israël-biet, Pascal Roy, Jean Yves Blay, Dominique Valeyre, Yves PachecoAbstract:Background: Sarcoidosis is a polygenic immune disorder disease with predominant manifestations in the lung. BTNL2 gene polymorphisms were previously linked to susceptibility to sarcoidosis. Relationships between sarcoidosis and cancers have been suspected for a long time but little evidence has been reported until now, and recent works show a link between butyrophilin family proteins and anti tumor immunity. Methods: We studied the polymorphism of the rs2076530 SNP of BTNL2 gene in 35 patients with sarcoidosis and cancer compared to 340 sarcoidosis without cancer, 271 controls and 32 cancer matched controls. Results: We found no association between BTNL2 genotype and cancer risk in sarcoidosis (OR: 2,34; CI95%: 1,30 – 4,20; p = 0,15). Sarcoidosis is associated with the rs2076530SNP of BTNL2 gene. The AA genotype is significantly associated with a 3 more increased risk of sarcoidosis compared to the GG genotype in a co-dominant model (OR: 3,22; CI95%: 2,58 – 4,06; p < 0.0001). The AG genotype is associated with a 1,8 more increased risk (OR: 1,79; CI95%: 1,42 – 2,26). Conclusions: These results confirm the association of BTNL2 rs2076530SNP with the susceptibility to develop sarcoidosis, but not with an increased risk of cancer in these patients.
