title: Gender-specific effects of genetic variants within Th1 and Th17 cell-mediated immune response genes on the risk of developing rheumatoid arthritis.
abstract: The present study was conducted to explore whether single nucleotide polymorphisms (SNPs) in Th1 and Th17 cell-mediated immune response genes differentially influence the risk of rheumatoid arthritis (RA) in women and men. In phase one, 27 functional/tagging polymorphisms in C-type lectins and MCP-1/CCR2 axis were genotyped in 458 RA patients and 512 controls. Carriers of Dectin-2 rs4264222T allele had an increased risk of RA (OR = 1.47, 95%CI 1.10-1.96) whereas patients harboring the DC-SIGN rs4804803G, MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of developing the disease (OR = 0.66, 95%CI 0.49-0.88; OR = 0.66, 95%CI 0.50-0.89; OR = 0.73, 95%CI 0.55-0.97 and OR = 0.68, 95%CI 0.51-0.91). Interestingly, significant gender-specific differences were observed for Dectin-2 rs4264222 and Dectin-2 rs7134303: women carrying the Dectin-2 rs4264222T and Dectin-2 rs7134303G alleles had an increased risk of RA (OR = 1.93, 95%CI 1.34-2.79 and OR = 1.90, 95%CI 1.29-2.80). Also five other SNPs showed significant associations only with one gender: women carrying the MCP-1 rs1024611G, MCP-1 rs13900T and MCP-1 rs4586C alleles had a decreased risk of RA (OR = 0.61, 95%CI 0.43-0.87; OR = 0.67, 95%CI 0.47-0.95 and OR = 0.60, 95%CI 0.42-0.86). In men, carriers of the DC-SIGN rs2287886A allele had an increased risk of RA (OR = 1.70, 95%CI 1.03-2.78), whereas carriers of the DC-SIGN rs4804803G had a decreased risk of developing the disease (OR = 0.53, 95%CI 0.32-0.89). In phase 2, we genotyped these SNPs in 754 RA patients and 519 controls, leading to consistent gender-specific associations for Dectin-2 rs4264222, MCP-1 rs1024611, MCP-1 rs13900 and DC-SIGN rs4804803 polymorphisms in the pooled sample (OR = 1.38, 95%CI 1.08-1.77; OR = 0.74, 95%CI 0.58-0.94; OR = 0.76, 95%CI 0.59-0.97 and OR = 0.56, 95%CI 0.34-0.93). SNP-SNP interaction analysis of significant SNPs also showed a significant two-locus interaction model in women that was not seen in men. This model consisted of Dectin-2 rs4264222 and Dectin-2 rs7134303 SNPs and suggested a synergistic effect between the variants. These findings suggest that Dectin-2, MCP-1 and DC-SIGN polymorphisms may, at least in part, account for gender-associated differences in susceptibility to RA.
authors.affiliation: Rheumatology Department, Virgen de las Nieves University Hospital, Granada, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Cáliz
authors.forename: Luz María
authors.initials: LM
authors.lastname: Canet
authors.forename: Carmen Belén
authors.initials: CB
authors.lastname: Lupiañez
authors.forename: Helena
authors.initials: H
authors.lastname: Canhão
authors.forename: Alejandro
authors.initials: A
authors.lastname: Escudero
authors.forename: Ileana
authors.initials: I
authors.lastname: Filipescu
authors.forename: Juana
authors.initials: J
authors.lastname: Segura-Catena
authors.forename: María José
authors.initials: MJ
authors.lastname: Soto-Pino
authors.forename: Manuela
authors.initials: M
authors.lastname: Expósito-Ruiz
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Ferrer
authors.forename: Antonio
authors.initials: A
authors.lastname: García
authors.forename: Lurdes
authors.initials: L
authors.lastname: Romani
authors.forename: Alfonso
authors.initials: A
authors.lastname: González-Utrilla
authors.forename: Teresa
authors.initials: T
authors.lastname: Vallejo
authors.forename: Eva
authors.initials: E
authors.lastname: Pérez-Pampin
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Eduardo
authors.initials: E
authors.lastname: Collantes
authors.forename: João Eurico
authors.initials: JE
authors.lastname: Fonseca
authors.forename: Juan
authors.initials: J
authors.lastname: Sainz
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D015815:Cell Adhesion Molecules / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics; D003710:Demography; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007111:Immunity, Cellular / Q000235:genetics*; D037181:Lectins, C-Type / Q000235:genetics; D008297:Male; D008875:Middle Aged; D058011:Multifactor Dimensionality Reduction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054390:Receptors, CCR2 / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D012307:Risk Factors; D012727:Sex Characteristics; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; D000099181:Dectin-1
chemical_list: D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D037181:Lectins, C-Type; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C111835:CCL2 protein, human; C515334:CCR2 protein, human; C546929:CLEC7A protein, human; D000099181:Dectin-1; C445340:dectin-2, mouse
references.citation: Cell Immunol. 2011;271(1):192-6
references.pmid: 21777909
references.citation: Arthritis Res Ther. 2010;12(1):R26
references.pmid: 20158887
references.citation: Hosp Pract (1995). 1997 Apr 15;32(4):147-54
references.pmid: 9109812
references.citation: Arthritis Rheum. 2007 Jul;56(7):2111-5
references.pmid: 17599728
references.citation: Rheumatol Int. 2012 Aug;32(8):2325-30
references.pmid: 21626027
references.citation: J Autoimmun. 2005;25 Suppl:16-20
references.pmid: 16257177
references.citation: Microcirculation. 2003 Jun;10(3-4):247-57
references.pmid: 12851642
references.citation: Eur J Immunol. 2005 Jul;35(7):2163-74
references.pmid: 15940672
references.citation: Circulation. 2005 Aug 23;112(8):1113-20
references.pmid: 16116069
references.citation: Expert Rev Mol Diagn. 2004 Nov;4(6):795-803
references.pmid: 15525222
references.citation: Am J Hum Genet. 2005 Mar;76(3):449-62
references.pmid: 15700229
references.citation: J Biol Chem. 2006 Dec 15;281(50):38854-66
references.pmid: 17050534
references.citation: Eur J Immunogenet. 2002 Oct;29(5):413-6
references.pmid: 12358851
references.citation: Arthritis Res. 2001;3(4):200-6
references.pmid: 11438035
references.citation: Rheum Dis Clin North Am. 2001 May;27(2):269-81
references.pmid: 11396092
references.citation: Arthritis Rheum. 2003 Feb;48(2):360-9
references.pmid: 12571844
references.citation: Nat Clin Pract Rheumatol. 2005 Dec;1(2):102-10
references.pmid: 16932639
references.citation: Scand J Rheumatol. 2003;32(4):235-9
references.pmid: 14626631
references.citation: Curr Opin Rheumatol. 2004 May;16(3):218-22
references.pmid: 15103248
references.citation: Curr Mol Med. 2008 Sep;8(6):551-61
references.pmid: 18781962
references.citation: Arthritis Res. 2000;2(3):189-202
references.pmid: 11094428
references.citation: Arthritis Rheum. 1997 Jan;40(1):5-18
references.pmid: 9008595
references.citation: Blood. 2007 Sep 15;110(6):1933-41
references.pmid: 17505015
references.citation: Nat Genet. 2009 Dec;41(12):1313-8
references.pmid: 19898481
references.citation: Rheum Dis Clin North Am. 1992 Aug;18(3):507-15
references.pmid: 1496158
references.citation: Nat Immunol. 2009 Feb;10(2):203-13
references.pmid: 19122653
references.citation: Hum Immunol. 2003 Jul;64(7):741-4
references.pmid: 12826377
references.citation: J Rheumatol. 2004 Mar;31(3):422-5
references.pmid: 14994383
references.citation: J Rheumatol. 2009 Aug;36(8):1590-5
references.pmid: 19567623
references.citation: J Rheumatol. 2009 Mar;36(3):508-11
references.pmid: 19208610
references.citation: Arthritis Rheum. 2010 Jun;62(6):1576-82
references.pmid: 20191579
references.citation: PLoS Pathog. 2011 Jan 20;7(1):e1001259
references.pmid: 21283787
references.citation: Arthritis Rheum. 2008 Aug;58(8):2275-86
references.pmid: 18668548
references.citation: Am J Reprod Immunol. 2004 Jul;52(1):19-26
references.pmid: 15214938
references.citation: Cell Immunol. 2006 Feb;239(2):87-91
references.pmid: 16781694
references.citation: Arthritis Rheum. 1993 Jun;36(6):762-71
references.pmid: 8507217
references.citation: Ann N Y Acad Sci. 2007 Jun;1108:312-22
references.pmid: 17893995
references.citation: Immunol Lett. 2006 Jul 15;106(1):8-13
references.pmid: 16824621
references.citation: Nat Rev Immunol. 2010 Aug;10(8):594-604
references.pmid: 20651746
references.citation: Blood. 1997 Aug 1;90(3):909-28
references.pmid: 9242519
references.citation: Nat Immunol. 2007 Jun;8(6):630-8
references.pmid: 17450144
references.citation: Nucleic Acids Res. 2006 Jul 1;34(Web Server issue):W635-41
references.pmid: 16845089
references.citation: Rheumatology (Oxford). 2008 Apr;47(4):399-402
references.pmid: 18263596
references.citation: Arthritis Res Ther. 2009;11(1):R7
references.pmid: 19144159
references.citation: Biochem Biophys Res Commun. 1999 Jun 7;259(2):344-8
references.pmid: 10362511
references.citation: J Immunol. 2003 Oct 1;171(7):3801-7
references.pmid: 14500681
references.citation: Nat Genet. 2005 May;37(5):507-13
references.pmid: 15838506
references.citation: J Exp Med. 2009 Aug 31;206(9):2037-51
references.pmid: 19703985
references.citation: Arch Dermatol. 2006 Mar;142(3):371-6
references.pmid: 16549717