Influence of genetic polymorphisms (IL-10/CXCL8/CXCR2/
               NFκB) on the susceptibility of autoimmune rheumatic diseases

Salim, Patricia Hartstein; Xavier, Ricardo Machado

doi:10.1016/j.rbr.2013.10.006

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Revista Brasileira de Reumatologia

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Review articles • Rev. Bras. Reumatol. 54 (4) • Jul-Aug 2014 • https://doi.org/10.1016/j.rbr.2013.10.006 copy

Influence of genetic polymorphisms (IL-10/CXCL8/CXCR2/ NFκB) on the susceptibility of autoimmune rheumatic diseases

Authorship SCIMAGO INSTITUTIONS RANKINGS

The autoimmune rheumatologic disorders mostly have a common genetic path to the autoimmunity. Several genes have been associated with rheumatologic disorders; therefore, we are analyzing just the ones in those containing several evidences of the existence of association with the risk or protection from autoimmune disorder. The nuclear factor kappa beta (NF-kappa B), which regulates the autoimmune and anti-inflammatory responses, is associated with systemic sclerosis (SS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), just as the CXCR2 e CXCL8 genes. On the other hand, the interleukin-10 (IL-10), which is an anti-inflammatory cytokine, is associated with almost all rheumatologic disorders. In this article, we are reviewing the potential roles of these genes in the immune system and in several rheumatologic disorders. In relation to IL-10, several studies have been carried out, but most of them are controversial - some detected the absence of association, and others found association in different genetic polymorphisms. Conversely, in relation to NF-kappa B, it was studied just in RA and SLE, and no relevant significant analyses were observed. The genetic polymorphisms of the CXCR2 gene were associated with SS, but not with RA e SLE. On the other side, the genetic polymorphisms of the CXCL8 gene are not associated with SS, but with RA.

Rheumatologic diseases; Cytokine; Chemokine; NF-kB

Gene	Disease	Polymorphism	Results	Number (N)		Study (Ref.)
				Patients	Controls
CXCL8
	Systemic sclerosis
		(+)293 G/T	no association	128	194	Renzoni et al. 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
		(+)678 T/C	no association	128	194	Renzoni et al. 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
		(-)353 A/T	association with gene CCL5-403 G/A (p=0.039)	99	198	Lee et al. 2007⁴¹41 Lee EB, Zhao J, Kim JY, Xiong M, Song YW. Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis. Arthritis Rheum. 2007 Jul;56:2443-8.
			no association	128	194	Renzoni et al. 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
		(-)251T/A	association with gene/cxcr2+1208 C/T (p<0.001)	151	147	Emonts et al. 2011⁴³43 Emonts M, Hazes MJ, Houwing-Duistermaat JJ, van der Gaastde Jongh CE, de Vogel L, Han HK et al. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study. BMC Med Genet. 2011;7:12-36.
	Rheumatoid arthritis
		(+)781 C/T	CC homozygote (p<0.0001; rs2227306)	376	463
		3'UTR 2767 A/G	AA homozygote (p=0.02; rs10938092)	199	130	Lo et al. 2008⁴⁴44 Lo SF, Huang CM, Lin HC, Chen WC, Tsai CH, Tsai FJ. Cytokine (IL-6) and chemokine (IL-8) gene polymorphisms among rheumatoid arthritis patients in Taiwan. Clin Exp Rheumatol. 2008;26:632-7.
	Systemic lupus erythematosus
		rs46941 78 C/A	C allele (OR=1.26; P<0.001)	826	1310	Sendling et al. 2011⁴⁵45 Sandling JK, Garnier S, Sigurdsson S, Wang C, Nordmark G, Gunnarsson I et al. A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE. Eur J Hum Genet. 2011;19:479-84.
			no association	150	130	Hang et al. 2006⁴⁶46 Huang CM, Huo AP, Tsai CH, Chen CL, Tsai FJ. Lack of association of interleukin-6 and interleukin-8 gene polymorphisms in Chinese patients with systemic lupus erythematosus. J Clin Lab Anal. 2006;20:255-9.
		(-)353 A/T; (+)781 C/T	no association	500	481	Sanchez et al. 2006⁴⁷47 Sánchez E, Sabio JM, Callejas JL, de Ramón E, Garcia-Portales R, García-Hernández FJ et al. Association study of genetic variants of pro-inflammatory chemokine and cytokine genes in systemic lupus erythematosus. BMC Med Genet. 2006;7:48.

Gene	Disease	Polymorphism	Results	Number (N)		Study (Ref.)
				Patients	Controls
CXCR2
	Systemic sclerosis
		(-)786 C/T	no association	14	242	Kato et al., 2000⁴⁸48 Kato H, Tsuchiya N, Tokunaga K. Single nucleotide polymorphisms in the coding regions of human CXCchemokine receptors CXCR1, CXCR2 and CXCR3. Genes and Immunity. 2000;1:330-337.
			CC homozygote (OR=1.7; p=0.04)	99	198	Lee et al., 2007⁴¹41 Lee EB, Zhao J, Kim JY, Xiong M, Song YW. Evidence of potential interaction of chemokine genes in susceptibility to systemic sclerosis. Arthritis Rheum. 2007 Jul;56:2443-8.
		(+)785 C/T	CC homozygote (OR=2.33; p=0.01)	128	194	Renzoni et al., 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
		(+)1208 C/T	TT homozygote (OR=2.67; p=0.003)	128	194	Renzoni et al., 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
			CC homozygote (or=2.76; p=0.001)	151	147	Salim et al., 2012⁴²42 Salim PH, Jobim M, Bredemeier M, Chies JA, Brenol JC, Jobim LF, Xavier RM. Combined effects of CXCL8 and CXCR2 gene polymorphisms on susceptibility to systemic sclerosis. Cytokine. 2012;60:473-477.
		(+)1440 G/A	no association	128	194	Renzoni et al., 2000⁴⁰40 Renzoni E, Lympany P, Sestini P, Pantelidis P, Wells A, Black C et al. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis. Arthritis Rheum. 2000;43:1633-40.
	Rheumatoid arthritis
		(-)786 C/T	no association	146	242	Kato et al., 2000⁴⁸48 Kato H, Tsuchiya N, Tokunaga K. Single nucleotide polymorphisms in the coding regions of human CXCchemokine receptors CXCR1, CXCR2 and CXCR3. Genes and Immunity. 2000;1:330-337.
	Systemic lupus erythematosus
		(-)786 C/T	no association	80	242	Kato et al., 2000⁴⁸48 Kato H, Tsuchiya N, Tokunaga K. Single nucleotide polymorphisms in the coding regions of human CXCchemokine receptors CXCR1, CXCR2 and CXCR3. Genes and Immunity. 2000;1:330-337.
	Sjogren syndrome
		(-)786 C/T	no association	12	242	Kato et al., 2000⁴⁸48 Kato H, Tsuchiya N, Tokunaga K. Single nucleotide polymorphisms in the coding regions of human CXCchemokine receptors CXCR1, CXCR2 and CXCR3. Genes and Immunity. 2000;1:330-337.

Gene	Disease	Results	Number (N)		Study (Ref.)
			Patients	Controls
NFKB1-94 ins/del ATTG (rs28362491)


	Systemic sclerosis
		association of ATTG (homozygous) insertion with gene IL-10 (-819)CC and (-592)CC	151	147	Salim et al., 2013⁵⁰50 Salim PH, Jobim M, Bredemeier M, Chies JA, Brenol JC, Jobim LF et al. Interleukin-10 Gene Promoter and NFKB1 Promoter Insertion/Deletion Polymorphisms in Systemic Sclerosis. Scand J Immunol. 2013;77:162-8.

	Rheumatoid arthritis
	Rheumatoid arthritis
		no association	272	264	Orozco et al., 2009⁵¹51 Orozco G, Sánchez E, Collado MD, López-Nevot MA, Paco L, García A et al. Analysis of the functional NFKB1 promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus. Tissue Antigens. 2005;65:183-6.
		no association	458	657	Dieguez-Gonzalez et al., 2009⁵²52 Dieguez-Gonzalez R, Akar S, Calaza M, Perez-Pampin E, Costas J, Torres M, Vicario JL et al. Genetic variation in the nuclear factor kappaB pathway in relation to susceptibility to rheumatoid arthritis. Ann Rheum Dis. 2009;68:579-83.
		association of heterozygous gene (ins/Del) with gene FCRL3 (-169)GG (p=0.003)	592	646	Martinez et al., 2006⁵³53 Martínez A, Sánchez E, Valdivia A, Orozco G, López-Nevot MA, Pascual-Salcedo D et al. Epistatic interaction between FCRL3 and NFkappaB1 genes in Spanish patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1188-91.

		association of homozygous gene for deletion (Del/Del) with risk for cardiovascular events (OR=1.76; p=0.03)	1437	^* * The study only accessed the interaction among patients	Lopez-Mejias et al., 2002⁵⁴54 López-Mejías R, García-Bermúdez M, González-Juanatey C, Castañeda S, Miranda-Filloy JA, Gómez-Vaquero C et al. NFKB1-94ATTG ins/del polymorphism (rs28362491) is associated with cardiovascular disease in patients with rheumatoid arthritis. Atherosclerosis. 2012 Oct;224:426-9.


	Systemic lupus erythematosus
		protection with heterozygote gene (Ins/del) (OR=0,52; P=0,012)	224	256	Gao et al., 2012⁵⁵55 Gao M, Wang CH, Sima X, Han XM. NFKB1 -94 insertion/ deletion ATTG polymorphism contributes to risk of systemic lupus erythematosus. DNA Cell Biol. 2012;31:611-5.

		No association	181	264	Orozco et al., 2009⁵²52 Dieguez-Gonzalez R, Akar S, Calaza M, Perez-Pampin E, Costas J, Torres M, Vicario JL et al. Genetic variation in the nuclear factor kappaB pathway in relation to susceptibility to rheumatoid arthritis. Ann Rheum Dis. 2009;68:579-83.
	Ankylosing spondilitis
		no association	205	200	Kim et al., 2005⁵⁶56 Kim TH, Stone MA, Rahman P, Yoo DH, Park YW, Payne U et al. Interleukin 1 and nuclear factor-kappaB polymorphisms in ankylosing spondylitis in Canada and Korea. J Rheumatol. 2005:32:1907-10.

Gene	Disease	Polymorphism	Results	Number (N)		Study (Ref.)
				Patients	Controls
IL-10
	Systemic sclerosis
		(-)1082 G/A; (-)819 C/T; (-)592 C/A	association of GCC haplotype with diffuse form (OR=1.84; p=0.04)	161	94	Beretta et al., 2007³⁶36 Beretta L, Bertolotti F, Cappiello F, Barili M, Masciocchi M, Toussoun K et al. Interleukin-1 gene complex polymorphisms in systemic sclerosis patients with severe restrictive lung physiology. Hum Immunol. 2007;68:603-9.
			GCC/GCC genotype (OR=1.87; p=0.019	151	147	Salim et al., 2013⁴⁸48 Kato H, Tsuchiya N, Tokunaga K. Single nucleotide polymorphisms in the coding regions of human CXCchemokine receptors CXCR1, CXCR2 and CXCR3. Genes and Immunity. 2000;1:330-337.
			protection of GCC/GCC genotype with	51	94	Crilly et al., 2003³⁴34 Crilly A, Hamilton J, Clark CJ, Jardine A, Madhok R. Analysis of the 5' flanking region of the interleukin 10 gene in patients with systemic sclerosis. Rheumatology (Oxford). 2003;42:1295-8.
			diffuse form (OR=0.10; p=0.005)
			association of GCC/GCC genotype	45	150	Ates et al., 2008⁵⁷57 Ates O, Müsellim B, Ongen G, Topal-Sarikaya A. Association between 'interleukin' 10 gene (IL10) polymorphisms and systemic sclerosis with interstitial lung involvement. Rheumatol Int. 2008;28:1123-6.
			(OR=5.07; p=0.002)			Peng et al., 2012⁵⁸58 Peng WJ, Wang BX, Pan HF, Tao JH, Zhang JQ, He Q et al. Association of the interleukin-10 1082G/A, 819C/T and 3575T/A gene polymorphisms with systemic sclerosis: a meta-analysis. Mol Biol Rep. 2012;39:6851-5.
		(-)590 A/C	no association	242	242	Beretta et al., 2007³⁶36 Beretta L, Bertolotti F, Cappiello F, Barili M, Masciocchi M, Toussoun K et al. Interleukin-1 gene complex polymorphisms in systemic sclerosis patients with severe restrictive lung physiology. Hum Immunol. 2007;68:603-9.
		(-)3575 A/T	association of AA haplotype with limited	105	143	Hudson et al., 2005⁶⁰60 Hudson LL, Rocca KM, Kuwana M, Pandey JP. Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses .Genes and Immunity. 2005;6:274-278.
			form (OR=3.60; p=0.0002)
			no association	78	692	Matuzzi et al., 2007³³33 Mattuzzi S, Barbi S, Carletto A, Ravagnani V, Moore PS, Bambara LM et al. Association of polymorphisms in the IL1B and IL2 genes with susceptibility and severity of systemic sclerosis. J Rheumatol. 2007;34:997-1004.
		(-)2849 A/G	association of GG haplotype with limited	105	143	Hudson et al. 2005⁶⁰60 Hudson LL, Rocca KM, Kuwana M, Pandey JP. Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses .Genes and Immunity. 2005;6:274-278.
			form (OR=0.53; p=0.03)
		(-)2763 A/C	association of AA haplotype with limited	105	143	Hudson et al., 2005⁶⁰60 Hudson LL, Rocca KM, Kuwana M, Pandey JP. Interleukin-10 genotypes are associated with systemic sclerosis and influence disease-associated autoimmune responses .Genes and Immunity. 2005;6:274-278.
			form (OR=3.50; p=0.003) and diffuse
			form (OR=3.0; p=0.03)
	Rheumatoid arthritis
		(-)1082 G/A; (-)819 C/T; (-)592 C/A	association of GCC (OR=1.46; p=0.006) and ACC (OR=1.43; p=0.011) haplotypes	98	122	Ates et al., 2008⁵⁷57 Ates O, Müsellim B, Ongen G, Topal-Sarikaya A. Association between 'interleukin' 10 gene (IL10) polymorphisms and systemic sclerosis with interstitial lung involvement. Rheumatol Int. 2008;28:1123-6.
			association of ACC haplotype in patients positive for rheumatoid factor IgA (OR=1.6; p=0.05)	234	238	Hajeer et al., 1998⁶¹61 Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P et al. IL-10 gene promoter polymorphisms in rheumatoid arthritis. Scand J Rheumatol. 1998;27:142-5.
			association of GCC/GCC genotype (OR=2.18; P<0.005)	95	104	Pawlik et al., 2005⁶²62 Pawlik A, Kurzawski M, Szklarz BG, Herczynska M, Drozdzik M. Interleukin-10 promoter polymorphism in patients with rheumatoid arthritis. Clin Rheumatol 2005;24:480-484.
			no association	222	398	Gambhir et al., 2010⁶³63 Gambhir D, Lawrence A, Aggarwal A, Misra R, Mandal SK, Naik S. Association of tumor necrosis factor alpha and IL-10 promoter polymorphisms with rheumatoid arthritis in North Indian population. Rheumatol Int. 2010;30:1211-1217.
		(-)1087 G/A; (-)824 C/T; (-)597 C/A	ATA haplotype associated with low production of IL-10 (P<0.05)	84	95	Hee et al., 2007⁶⁴64 Hee CS, Gun SC, Naidu R, Gupta E, Somnath SD, Radhakrishnan AK. Comparison of single nucleotide polymorphisms in the human interleukin-10 gene promoter between rheumatoid arthritis patients and normal subjects in Malaysia. Mod Rheumatol. 2007;17:429-35.
		(-)2849 A/G	association of G allele in patients positive for rheumatoid factor IgG (P<0.001)	283	1220	Lard et al., 2003⁶⁵65 Lard LR, van Gaalen FA, Schonkeren JJ, Pieterman EJ, Stoeken G, Vos K, Nelissen RG, Westendorp RG et al. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. Arthritis Rheum. 2003;48:1841-8.
		(-)1082 G/A	no association (rs1800896)	376	463	Emonts et al., 2011⁴³43 Emonts M, Hazes MJ, Houwing-Duistermaat JJ, van der Gaastde Jongh CE, de Vogel L, Han HK et al. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study. BMC Med Genet. 2011;7:12-36.
			no association	108	128	Cantagrel et al., 1999⁶⁶66 Cantagrel A, Navaux F, Loubet-Lescoulié P, Nourhashemi F, Enault G, Abbal M et al. Interleukin-1beta, interleukin-1 receptor antagonist, interleukin-4, and interleukin-10 gene polymorphisms: relationship to occurrence and severity of rheumatoid arthritis. Arthritis Rheum. 1999;42:1093-100.
			protection with AA genotype (OR=0.56; p=0.006)	162	373	de Paz et al., 2010⁶⁷67 de Paz B, Alperi-López M, Ballina-García FJ, Prado C, Mozo L, Gutiérrez C et al. Interleukin 10 and tumor necrosis factor-alpha genotypes in rheumatoid arthritis-association with clinical response to glucocorticoids. J Rheumatol. 2010;37:503-11.
		(-)819 C/T	no association (rs3021097)	376	463	Emonts et al., 2011⁴³43 Emonts M, Hazes MJ, Houwing-Duistermaat JJ, van der Gaastde Jongh CE, de Vogel L, Han HK et al. Polymorphisms in genes controlling inflammation and tissue repair in rheumatoid arthritis: a case control study. BMC Med Genet. 2011;7:12-36.
		(-)592 C/A	association of A allele (OR=1.31; p=0.008)	164	196	Ying et al., 2011⁶⁸68 Ying B, Shi Y, Pan X, Song X, Huang Z, Niu Q, Cai B, Wang L. Association of polymorphisms in the human IL-10 and IL- 18 genes with rheumatoid arthritis. Mol Biol Rep. 2011;38:379-385.
			association of CA genotype (OR=46.34; P<0.001)	244	106	Paradowska-Gorycka et al., 2008⁶⁹69 Paradowska-Gorycka A, Trefler J, Maciejewska-Stelmach J, Lacki JK. Interleukin-10 gene promoter polymorphism in Polish rheumatoid arthritis patients. Int J Immunogenet. 2010;37:225- 231.

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[1] * Corresponding author. E-mail: rmaxavier@hcpa.ufrgs.br (R.M. Xavier).