title: HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis.
abstract: Sarcoidosis is a multiorgan immune-mediated disease of unknown etiology with varying clinical pictures. We studied 3 genes in the major histocompatibility complex region (HLA-DRB1 and complement C4A and C4B) in patients with resolved disease after a 2-year follow-up (n = 90) and in patients whose disease was still active at that time point (n = 98) and compared them with controls (n = 150). Our primary aim was to detect genetic differences between the patient groups. We observed that the susceptibility allele for sarcoidosis was HLA-DRB1*15:01 (p = 0.011; odds ratio [OR] = 1.67) and the protective allele was HLA-DRB1*01:01 (p = 0.001; OR = 0.43). HLA-DRB1*03:01 was associated with resolving disease when compared with the persistent group (p = 0.011; OR = 2.22). The probability of having resolving disease was even greater if the patient had HLA-DRB1*03:01 and did not have extrapulmonary lesions (p = 0.001; OR = 3.39). By evaluating amino acid variants of the HLA-DRB1 gene, we determined that specific amino acids in pockets 4, 7, and 9 were associated with the prognosis of sarcoidosis. Our results support the importance of HLA-DRB1 as a predisposing gene for sarcoidosis. Particularly, HLA-DRB1*03:01 and polymorphisms of DRB1 pocket residues were associated with a favorable prognosis. Thus, accurate categorization of disease phenotype and HLA-DRB1 sequencing offer a basis for disease course estimation of sarcoidosis.
authors.affiliation: Transplantation Laboratory, Haartman Institute, University of Helsinki, 00014 Helsinki, Finland. annika.wennerstrom@helsinki.fi
authors.forename: Annika
authors.initials: A
authors.lastname: Wennerström
authors.forename: Anne
authors.initials: A
authors.lastname: Pietinalho
authors.forename: Hanna
authors.initials: H
authors.lastname: Vauhkonen
authors.forename: Laura
authors.initials: L
authors.lastname: Lahtela
authors.forename: Anil
authors.initials: A
authors.lastname: Palikhe
authors.forename: Jouni
authors.initials: J
authors.lastname: Hedman
authors.forename: Minna
authors.initials: M
authors.lastname: Purokivi
authors.forename: Essi
authors.initials: E
authors.lastname: Varkki
authors.forename: Mikko
authors.initials: M
authors.lastname: Seppänen
authors.forename: Marja-Liisa
authors.initials: ML
authors.lastname: Lokki
authors.forename: Olof
authors.initials: O
authors.lastname: Selroos
mesh_terms: D000328:Adult; D000483:Alleles; D015934:Complement C4a / Q000172:deficiency / Q000235:genetics*; D015935:Complement C4b / Q000172:deficiency / Q000235:genetics*; D056915:DNA Copy Number Variations; D005260:Female; D005387:Finland; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012507:Sarcoidosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D059811:HLA-DRB1 Chains; C487961:HLA-DRB1*01:01 antigen; C553502:HLA-DRB1*03:01 antigen; C489631:HLA-DRB1*15:01 antigen; D015934:Complement C4a; D015935:Complement C4b