title: Association of tumour necrosis factor-alpha, lymphotoxin-alpha and HLA-DRB1 gene polymorphisms with Löfgren's syndrome in Czech patients with sarcoidosis.
abstract: Sarcoidosis is a granulomatous disorder showing a clear association with MHC (HLA) class I and class II genes. In order to investigate whether polymorphisms of nearby pro-inflammatory genes located within the MHC class III region may also contribute to susceptibility to sarcoidosis or to its clinical manifestation, tumour necrosis factor-alpha (TNF-alpha) and lymphotoxin-alpha (LT-alpha) genes were chosen for analysis in a case-control association study. In order to evaluate the findings on the TNF-alpha and LT-alpha genes in connection with the closely linked MHC class II region, 'classical' HLA-DRB1 locus was also investigated. Polymerase chain reaction-based methodologies were used in order to characterize two single-nucleotide polymorphisms (TNF-308*G/A and LTAlpha+252*A/G) and HLA-DRB1 allele groups in 114 Czech patients with pulmonary sarcoidosis and 425 healthy controls. LTA+252*G and HLA-DRB1*13 allele carriers were more frequent in patients, compared to those in controls. By contrast, HLA-DRB1*07 carriers were less frequent among sarcoidosis patients. The overrepresentation of TNF-308*A, LTAlpha+252*G and HLA-DRB1*03 allele carriers was found in a subgroup of sarcoidosis patients presenting with Lofgren's syndrome (LS) by comparison with the subgroup of patients without LS (NLS; phenotype frequency LS vs NLS: 68.8 vs 37.1% for TNF-308*A, 93.8 vs 66.3% for LTA+252*G and 68.8 vs 21.3% for DRB1*03). The data suggest that the LTAlpha and HLA-DRB1 genes themselves or a gene located nearby contributes to the susceptibility to sarcoidosis and that TNF-308*A, LTA+252*G and HLA-DRB1*03 alleles are associated (directly or via linkage with unknown causative locus) with LS as a specific manifestation of the disease.
authors.affiliation: Department of Immunology, Medical Faculty, Palacky University, I.P Pavlova Str. 6, CZ-775 20 Olomouc, Czech Republic. petrekm@fnol.cz
authors.forename: F
authors.initials: F
authors.lastname: Mrazek
authors.forename: L I
authors.initials: LI
authors.lastname: Holla
authors.forename: B
authors.initials: B
authors.lastname: Hutyrova
authors.forename: V
authors.initials: V
authors.lastname: Znojil
authors.forename: A
authors.initials: A
authors.lastname: Vasku
authors.forename: V
authors.initials: V
authors.lastname: Kolek
authors.forename: K I
authors.initials: KI
authors.lastname: Welsh
authors.forename: J
authors.initials: J
authors.lastname: Vacha
authors.forename: R M
authors.initials: RM
authors.lastname: du Bois
authors.forename: M
authors.initials: M
authors.lastname: Petrek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D018153:Czech Republic; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017565:Sarcoidosis, Pulmonary / Q000150:complications / Q000235:genetics*; D013577:Syndrome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
chemical_list: D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D008233:Lymphotoxin-alpha; D014409:Tumor Necrosis Factor-alpha