An investigation of polymorphisms in the 4q13.3-21.1 CXC chemokine gene cluster for association with multiple sclerosis in Australians

Abstract

Susceptibility to multiple sclerosis (MS) is believed to result from the complex interaction of a number of genes, each with modest effect. Vital to the migration of cells to sites of inflammation, including the central nervous system, are chemokines, many of which are implicated in MS pathogenesis. Most of the CXC chemokine genes are encoded in a cluster on chromosome 4q13.3-21.1, which has been identified in several genome-wide screens as being potentially associated with MS. We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. Initially, we sequenced the chemokine genes in several DNA pools to identify common polymorphisms, and then genotyped selected SNPs in 373 Australian MS trio families. We found no evidence that the CXC chemokine gene cluster is genetically associated with MS. However, the existence of common variants conferring small risk factors or rare variants with significant risk cannot be excluded.

Keywords

autoimmune disease Caucasians CXC chemokines DNA pool sequencing genetics multiple sclerosis

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References

Ewing C , Bernard CC. Insights into the aetiology and pathogenesis of multiple sclerosis . Immunol Cell Biol 1998; 76: 47-54 .

Dyment DA , Sadovnick AD , Ebers GC , Sadnovich AD. Genetics of multiple sclerosis . Hum Mol Genet 1997; 6: 1693-1698 .

Sawcer S , Compston A. The Genetic Analysis of Multiple sclerosis in EuropeanS: concepts and design . J Neuroimmunol 2003; 143: 13-16 .

Stewart GJ. Multiple sclerosis, multiple genes . Med J Aus 1997; 166: 573-574 .

Brown KD , Zurawski SM , Mosmann TR , Zurawski G. A family of small inducible proteins secreted by leukocytes are members of a new superfamily that includes leukocyte and fibroblast-derived inflammatory agents, growth factors, and indicators of various activation processes . J Immunol 1989; 142: 679-687 .

Baggiolini M. Chemokines and leukocyte traffic . Nature 1998; 392: 565-568 .

Gale LM , McColl SR.

Chemokines: extracellular messengers for all occasions?

Bioessays 1999; 21: 17-28 .

Taub DD , Turcovski-Corrales SM , Key ML , Longo DL , Murphy WJ. Chemokines and T lymphocyte activation: I. Beta chemokines costimulate human T lymphocyte activation in vitro . J Immunol 1996; 156: 2095-2103 .

Molon B , Gri G , Bettella M , Gomez-Mouton C , Lanzavecchia A , Martinez AC et al. T cell costimulation by chemokine receptors . Nat Immunol 2005; 6: 465-471 .

10.

Cappello P , Caorsi C , Bosticardo M , De Angelis S , Novelli F , Forni G et al. CCL16/LEC powerfully triggers effector and antigen-presenting functions of macrophages and enhances T cell cytotoxicity . J Leukoc Biol 2004; 75: 135-142 .

11.

Taub DD , Sayers TJ , Carter CR , Ortaldo JR. Alpha and beta chemokines induce NK cell migration and enhance NK-mediated cytolysis . J Immunol 1995; 155: 3877-3888 .

12.

Karpus WJ , Lukacs NW , Kennedy KJ , Smith WS , Hurst SD , Barrett TA. Differential CC chemokine-induced enhancement of T helper cell cytokine production . J Immunol 1997; 158: 4129-4136 .

13.

Ransohoff RM , Hamilton TA , Tani M , Stoler MH , Shick HE , Major JA et al. Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis . FASEB J 1993; 7: 592-600 .

14.

Fife BT , Kennedy KJ , Paniagua MC , Lukacs NW , Kunkel SL , Luster AD et al. CXCL10 (IFN-gammainducible protein-10) control of encephalitogenic CD4/T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis . J Immunol 2001; 166: 7617-7624 .

15.

Magliozzi R , Columba-Cabezas S , Serafini B , Aloisi F. Intracerebral expression of CXCL13 and BAFF is accompanied by formation of lymphoid follicle-like structures in the meninges of mice with relapsing experimental autoimmune encephalomyelitis . J Neuroimmunol 2004; 148: 11-23 .

16.

Glabinski AR , Tuohy VK , Ransohoff RM. Expression of chemokines RANTES, MIP-1alpha and GRO-alpha correlates with inflammation in acute experimental autoimmune encephalomyelitis . Neuroimmunomodulation 1998; 5: 166-171 .

17.

Simpson JE , Newcombe J , Cuzner ML , Woodroofe MN. Expression of the interferon-gamma-inducible chemokines IP-10 and Mig and their receptor, CXCR3, in multiple sclerosis lesions . Neuropathol Appl Neurobiol 2000; 26: 133-142 .

18.

Sorensen TL , Tani M , Jensen J , Pierce V , Lucchinetti C , Folcik VA et al. Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients . J Clin Invest 1999; 103: 807-815 .

19.

Balashov KE , Rottman JB , Weiner HL , Hancock WW. CCR5(/) and CXCR3(/) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions . Proc Natl Acad Sci USA 1999; 96: 6873-6878 .

20.

Franciotta D , Martino G , Zardini E , Furlan R , Bergamaschi R , Andreoni L et al. Serum and CSF levels of MCP-1 and IP-10 in multiple sclerosis patients with acute and stable disease and undergoing immunomodulatory therapies . J Neuroimmunol 2001; 115: 192-198 .

21.

Lund BT , Ashikian N , Ta HQ , Chakryan Y , Manoukian K , Groshen S et al. Increased CXCL8 (IL-8) expression in multiple sclerosis . J Neuroimmunol 2004; 155: 161-171 .

22.

Nomiyama H , Mera A , Ohneda O , Miura R , Suda T , Yoshie O. Organization of the chemokine genes in the human and mouse major clusters of CC and CXC chemokines: diversification between the two species . Genes Immunol 2001; 2: 110-113 .

23.

Sawcer S , Maranian M , Setakis E , Curwen V , Akesson E , Hensiek A et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility . Brain 2002; 125: 1337-1347 .

24.

Akesson E , Oturai A , Berg J , Fredrikson S , Andersen O , Harbo HF et al. A genome-wide screen for linkage in Nordic sib-pairs with multiple sclerosis . Genes Immunol 2002; 3: 279-285 .

25.

Ross OA , O’Neill C , Rea IM , Lynch T , Gosal D , Wallace A et al. Functional promoter region polymorphism of the proinflammatory chemokine IL-8 gene associates with Parkinson’s disease in the Irish . Hum Immunol 2004; 65: 340-346 .

26.

Van Der Kuyl AC , Polstra AM , Weverling GJ , Zorgdrager F , Van Den Burg R , Cornelissen M. An IL-8 gene promoter polymorphism is associated with the risk of the development of AIDS-related Kaposi’s sarcoma: a case-control study . AIDS 2004; 18: 1206-1208 .

27.

Helbig KJ , George J , Beard MR. A novel I-TAC promoter polymorphic variant is functional in the presence of replicating HCV in vitro . J Clin Virol 2005; 32: 137-143 .

28.

Poser CM , Paty DW , Scheinberg L , McDonald WI , Davis FA , Ebers GC et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols . Ann Neurol 1983; 13: 227-231 .

29.

Lahiri DK , Nurnberger JI Jr. A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies . Nucleic Acids Res 1991; 19: 5444-5444 .

30.

Teutsch SM , Booth DR , Bennetts BH , Heard RN , Stewart GJ. Identification of 11 novel and common single nucleotide polymorphisms in the interleukin-7 receptor-alpha gene and their associations with multiple sclerosis . Eur J Hum Genet 2003; 11: 509-515 .

31.

Ban M , Sawcer SJ , Heard RN , Bennetts BH , Adams S , Booth D et al. A genome-wide screen for linkage disequilibrium in Australian HLA-DRB1*1501 positive multiple sclerosis patients . J Neuroimmunol 2003; 143: 60-64 .

32.

den Dunnen JT , Antonarakis E. Nomenclature for the description of human sequence variations . Hum Genet 2001; 109: 121-124 .

33.

Spielman RS , McGinnis RE , Ewens WJ. Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM) . Am J Hum Genet 1993; 52: 506-516 .

34.

Kruglyak L , Daly MJ , Reeve-Daly MP , Lander ES. Parametric and nonparametric linkage analysis: a unified multipoint approach . Am J Hum Genet 1996; 58: 1347-1363 .

35.

Zhang K , Jin L. HaploBlockFinder: haplotype block analyses . Bioinformatics 2003; 19: 1300-1301 .

36.

Clayton D. A generalization of the transmission/dis-equilibrium test for uncertain-haplotype transmission . Am J Hum Genet 1999; 65: 1170-1177 .

37.

Abecasis GR , Cherny SS , Cookson WO , Cardon LR. MERLIN rapid analysis of dense genetic maps using sparse gene flow trees . Nat Genet 2002; 30: 97-101 .

38.

Hull J , Ackerman H , Isles K , Usen S , Pinder M , Thomson A et al. Unusual haplotypic structure of IL8, a susceptibility locus for a common respiratory virus . Am J Hum Genet 2001; 69: 413-419 .

39.

Sawcer S , Ban M , Maranian M , Yeo TW , Compston A , Kirby A et al. A high-density screen for linkage in multiple sclerosis . Am J Hum Genet 2005; 77: 454-467 .

40.

Germer S , Holland MJ , Higuchi R. High-throughput SNP allele-frequency determination in pooled DNA samples by kinetic PCR . Genome Res 2000; 10: 258-266 .

41.

Giordano M , Mellai M , Hoogendoorn B , Momigliano-Richiardi P. Determination of SNP allele frequencies in pooled DNAs by primer extension genotyping and denaturing high-performance liquid chromatography . J Biochem Biophys Methods 2001; 47: 101-110 .

42.

Harada A , Sekido N , Akahoshi T , Wada T , Mukaida N , Matsushima K. Essential involvement of interleukin-8 (IL-8) in acute inflammation . J Leukoc Biol 1994; 56: 559-564 .

43.

Petering H , Gotze O , Kimmig D , Smolarski R , Kapp A , Elsner J. The biologic role of interleukin-8: functional analysis and expression of CXCR1 and CXCR2 on human eosinophils . Blood 1999; 93: 694-702 .

44.

Magazin M , Vita N , Cavrois E , Lefort S , Guillemot JC , Ferrara P. The biological activities of gro beta and IL-8 on human neutrophils are overlapping but not identical . Eur Cytokine Netw 1992; 3: 461-467 .

45.

Broxmeyer HE , Sherry B , Cooper S , Lu L , Maze R , Beckmann MP et al. Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression . J Immunol 1993; 150: 3448-3458 .

46.

Robinson S , Tani M , Strieter RM , Ransohoff RM , Miller RH. The chemokine growth-regulated oncogene-alpha promotes spinal cord oligodendrocyte precursor proliferation . J Neurosci 1998; 18: 10457-10463 .