title: Effects of vitamin A and D receptor gene polymorphisms/haplotypes on immune responses to measles vaccine.
abstract: OBJECTIVE
  Vitamins A and D, and their receptors, are important regulators of the immune system, including vaccine immune response. We assessed the association between polymorphisms in the vitamin A receptors [retinoic acid receptor α, retinoic acid receptor β (RARB), and retinoic acid receptor γ] and vitamin D receptor (VDR)/retinoid X receptor α (RXRA) genes and interindividual variations in immune responses after two doses of measles vaccine in 745 children.
  
  
  METHODS
  Using a tag single nucleotide polymorphism (SNP) approach, we genotyped 745 healthy children for the 391 polymorphisms in vitamin A receptor and VDR genes.
  
  
  RESULTS
  The RARB haplotype (rs6800566/rs6550976/rs9834818) was significantly associated with variations in both measles antibody (global, P=0.013) and cytokine secretion levels, such as interleukin (IL)-10 (global, P=0.006), interferon (IFN)-α (global, P=0.008), and tumor necrosis factor-α (global, P=0.039) in the Caucasian subgroup. Specifically, the RARB haplotype, AAC, was associated with higher (t-statistic: 3.27, P=0.001) measles antibody levels. At the other end of the spectrum, haplotype GG for rs6550978/rs6777544 was associated with lower antibody levels (t-statistic: -2.32, P=0.020) in the Caucasian subgroup. In a sensitivity analysis, the RARB haplotype, CTGGGCAA, remained marginally significant (P<0.02) when the single SNP rs12630816 was included in the model for IL-10 secretion levels. A significant association was found between lower measles-specific IFN-γ Enzyme-linked immunosorbent spot responses and haplotypes rs11102986/rs11103473/rs11103482/rs10776909/rs12004589/rs35780541/rs2266677/rs875444 (global, P=0.004) and rs6537944/rs3118571 (global, P<0.001) in the RXRA gene for Caucasians. We also found associations between multiple RARB, VDR, and RXRA SNPs/haplotypes and measles-specific IL-2, IL-6, IL-10, IFN-α, IFN-γ, IFNλ-1, and TNF-α cytokine secretions.
  
  
  CONCLUSIONS
  Our results suggest that specific allelic variations and haplotypes in the vitamin A receptor and VDR genes may influence adaptive immune responses to measles vaccine.
authors.affiliation: Mayo Clinic Vaccine Research Group, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Inna G
authors.initials: IG
authors.lastname: Ovsyannikova
authors.forename: Iana H
authors.initials: IH
authors.lastname: Haralambieva
authors.forename: Robert A
authors.initials: RA
authors.lastname: Vierkant
authors.forename: Megan M
authors.initials: MM
authors.lastname: O'Byrne
authors.forename: Robert M
authors.initials: RM
authors.lastname: Jacobson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Poland
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics*; D000914:Antibodies, Viral / Q000097:blood; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008457:Measles / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008458:Measles Vaccine / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha / Q000235:genetics; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000914:Antibodies, Viral; D008458:Measles Vaccine; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047490:Retinoid X Receptor alpha; D000097768:Retinoic Acid Receptor gamma; C000607071:RARA protein, human; C082925:retinoic acid receptor beta
references.citation: Am J Hum Genet. 2002 Feb;70(2):425-34
references.pmid: 11791212
references.citation: BMC Med Genet. 2010 Mar 02;11:37
references.pmid: 20196868
references.citation: Lancet. 1997 Jul 12;350(9071):101-5
references.pmid: 9228962
references.citation: Nat Rev Immunol. 2008 Sep;8(9):685-98
references.pmid: 19172691
references.citation: J Infect Dis. 2007 Jan 1;195(1):21-9
references.pmid: 17152005
references.citation: J Rheumatol Suppl. 2005 Sep;76:11-20
references.pmid: 16142846
references.citation: Bioinformatics. 2005 Jan 15;21(2):263-5
references.pmid: 15297300
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9440-5
references.pmid: 12883005
references.citation: J Hyg (Lond). 1981 Feb;86(1):35-47
references.pmid: 7462597
references.citation: J Infect Dis. 2008 Feb 1;197(3):405-10
references.pmid: 18205531
references.citation: Hum Genet. 2010 Feb;127(2):207-21
references.pmid: 19902255
references.citation: J Hepatol. 2006 May;44(5):856-63
references.pmid: 16545485
references.citation: J Cell Biochem. 1994 Aug;55(4):435-44
references.pmid: 7962175
references.citation: Novartis Found Symp. 1998;217:3-13; discussion 13-23
references.pmid: 9949798
references.citation: Annu Rev Biochem. 2003;72:291-336
references.pmid: 12626338
references.citation: Virology. 2007 Jul 20;364(1):87-94
references.pmid: 17397893
references.citation: Am J Hum Genet. 2004 Jan;74(1):106-20
references.pmid: 14681826
references.citation: Br J Nutr. 2011 Jun 28;105(12):1819-22
references.pmid: 21294931
references.citation: Clin Vaccine Immunol. 2008 Jul;15(7):1054-9
references.pmid: 18463223
references.citation: J Immunol. 2002 Feb 1;168(3):1181-9
references.pmid: 11801653
references.citation: Hum Hered. 2011;72(3):206-23
references.pmid: 22086389
references.citation: Methods Mol Biol. 2005;302:207-18
references.pmid: 15937354
references.citation: J Immunol. 2000 Mar 1;164(5):2405-11
references.pmid: 10679076
references.citation: Hum Genet. 2011 Oct;130(4):547-61
references.pmid: 21424379
references.citation: J Endocrinol. 1996 May;149(2):277-85
references.pmid: 8708539
references.citation: Hum Immunol. 2010 Apr;71(4):383-91
references.pmid: 20079393
references.citation: J Allergy Clin Immunol. 2007 Sep;120(3):666-72
references.pmid: 17560639
references.citation: J Infect Dis. 2010 Jan 15;201(2):207-13
references.pmid: 20001730
references.citation: Epidemiol Infect. 2006 Dec;134(6):1129-40
references.pmid: 16959053
references.citation: Cytokine. 2010 Apr;50(1):24-9
references.pmid: 20117947
references.citation: J Immunol Methods. 2009 Feb 28;341(1-2):97-105
references.pmid: 19038260
references.citation: J Infect Dis. 1999 Mar;179(3):721-4
references.pmid: 9952386
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W635-41
references.pmid: 16845089
references.citation: Eur J Clin Nutr. 2002 Apr;56(4):321-5
references.pmid: 11965508
references.citation: J Infect Dis. 2006 Mar 1;193(5):655-63
references.pmid: 16453260
references.citation: Vaccine. 2011 Oct 19;29(45):7883-95
references.pmid: 21875636
references.citation: J Neurol Sci. 2005 May 15;232(1-2):29-35
references.pmid: 15850579