title: Extended LTA, TNF, LST1 and HLA gene haplotypes and their association with rubella vaccine-induced immunity.
abstract: BACKGROUND
  Recent studies have suggested the importance of HLA genes in determining immune responses following rubella vaccine. The telomeric class III region of the HLA complex harbors several genes, including lymphotoxin alpha (LTA), tumor necrosis factor (TNF) and leukocyte specific transcript -1 (LST1) genes, located between the class I B and class II DRB1 loci. Apart from HLA, little is known about the effect of this extended genetic region on HLA haplotypic backgrounds as applied to immune responses.
  
  
  RESULTS
  We examined the association between immune responses and extended class I-class II-class III haplotypes among 714 healthy children after two doses of rubella vaccination. These extended haplotypes were then compared to the HLA-only haplotypes. The most significant association was observed between haplotypes extending across the HLA class I region, ten-SNP haplotypes, and the HLA class II region (i.e. A-C-B-LTA-TNF-LST1-DRB1-DQA1-DQB1-DPA1-DPB1) and rubella-specific antibodies (global p-value of 0.03). Associations were found between both extended A*02-C*03-B*15-AAAACGGGGC-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 (p = 0.002) and HLA-only A*02-C*03-B*15-DRB1*04-DQA1*03-DQB1*03-DPA1*01-DPB1*04 haplotypes (p = 0.009) and higher levels of rubella antibodies. The class II HLA-only haplotype DRB1*13-DQA1*01-DQB1*06-DPA1*01-DPB1*04 (p = 0.04) lacking LTA-TNF-LST1 SNPs was associated with lower rubella antibody responses. Similarly, the class I-class II HLA-only A*01-C*07-B*08-DRB1*03-DQA1*05-DQB1*02-DPA1*01-DPB1*04 haplotype was associated with increased TNF-alpha secretion levels (p = 0.009). In contrast, the extended AAAACGGGGC-DRB1*01-DQA1*01-DQB1*05-DPA1*01-DPB1*04 (p = 0.01) haplotype was found to trend with decreased rubella-specific IL-6 secretion levels.
  
  
  CONCLUSIONS
  These data suggest the importance of examining both HLA genes and genes in the class III region as part of the extended haplotypes useful in understanding genomic drivers regulating immune responses to rubella vaccine.
authors.affiliation: Vaccine Research Group, Mayo Clinic, Rochester, Minnesota, United States of America. ovsyannikova.inna@mayo.edu
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: V Shane
authors.initials: VS
authors.lastname: Pankratz
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D005260:Female; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006239:Haplotypes / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics / Q000276:immunology; D056724:Immunity, Humoral / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins; D008233:Lymphotoxin-alpha / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D012411:Rubella Vaccine / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D055815:Young Adult
chemical_list: D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; C093604:LST1 protein, human; D008233:Lymphotoxin-alpha; D008565:Membrane Proteins; D012411:Rubella Vaccine; D014409:Tumor Necrosis Factor-alpha