HLA-DRB1 allele frequencies and C4 copy number variation in Finnish sarcoidosis patients and associations with disease prognosis

Hum Immunol. 2012 Jan;73(1):93-100. doi: 10.1016/j.humimm.2011.10.016. Epub 2011 Oct 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Complement C4a / deficiency
  • Complement C4a / genetics*
  • Complement C4b / deficiency
  • Complement C4b / genetics*
  • DNA Copy Number Variations
  • Female
  • Finland
  • Gene Frequency
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • HLA-DRB1 Chains / genetics*
  • Haplotypes
  • Humans
  • Linkage Disequilibrium
  • Logistic Models
  • Male
  • Middle Aged
  • Prognosis
  • Sarcoidosis / genetics*
  • Sarcoidosis / metabolism
  • Sarcoidosis / pathology
  • Young Adult

Substances

  • HLA-DRB1 Chains
  • HLA-DRB1*01:01 antigen
  • HLA-DRB1*03:01 antigen
  • HLA-DRB1*15:01 antigen
  • Complement C4a
  • Complement C4b