Association of extended interleukin-10 promoter haplotypes with disease susceptibility and manifestations in German patients with systemic lupus erythematosus
Restricted accessResearch articleFirst published online April, 2014
Association of extended interleukin-10 promoter haplotypes with disease susceptibility and manifestations in German patients with systemic lupus erythematosus
Associations of interleukin-10 (IL-10) promoter single nucleotide polymorphisms (SNPs) and their haplotypes with systemic lupus erythematosus (SLE) are unclear. We extended the analysis of established proximal IL-10 promoter haplotypes to a more distal SNP with functional capacity.
Methods
Two hundred and ten German caucasian SLE patients fulfilling the ACR criteria and 160 ethnically, age and sex matched controls were genotyped for IL-10 −2849 G > A, −1082 A > G, −819 T > C and −592 C > A. Haplotypes were reconstructed via a mathematical model, then allele and haplotype distributions were compared between patients and controls and patients with different disease manifestations.
Results
We detected at −2849, −1082, −819 and −592 the four predominant haplotypes GGCC (22% in patients vs. 29% in controls), AGCC (24% vs. 21%), GACC (30% vs. 25%) and GATA (24% vs. 24%). GGCC was underrepresented in SLE patients, suggesting a protective effect (odds ratio (OR) 0.67, 95% confidence interval (CI) 0.48–0.94). AGCC was found significantly more frequently in patients with pathognomonic anti-dsDNA antibodies (26% vs. 15%; OR 1.98, 95% CI 1.04–3.75). As compared to patients with glomerulonephritis type V (WHO classification), the presumptive IL-10 high producer allele −2849 G was found significantly more often in patients with GN type III/IV (93% vs. 60%; OR 8.7, 95% CI 1.59–47.15).
Conclusion
Our data confirm that the complexity of the IL-10 promoter evokes the need for a meticulous analysis of its haplotypic structure in order to specify disease associations, particularly under functional aspects, thereby shedding light on the pathophysiology of SLE.
ProkuninaLAlarcon-RiquelmeM. The genetic basis of systemic lupus erythematosus–knowledge of today and thoughts for tomorrow. Hum Mol Genet2004; 13(Suppl 1): R143–R148.
3.
TsokosGC. Systemic lupus erythematosus. N Engl J Med2011; 365: 2110–2121.
4.
ManolioTACollinsFSCoxNJ. Finding the missing heritability of complex diseases. Nature2009; 461: 747–753.
5.
SabatRGrutzGWarszawskaK. Biology of interleukin-10. Cytokine Growth Factor Rev2010; 21: 331–344.
6.
FiorentinoDFZlotnikAVieiraP. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol1991; 146: 3444–3451.
7.
de WaalMRHaanenJSpitsH. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med1991; 174: 915–924.
8.
FiorentinoDFBondMWMosmannTR. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med1989; 170: 2081–2095.
9.
WanidworanunCStroberW. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol1993; 151: 6853–6861.
10.
RoussetFGarciaEDefranceT. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A1992; 89: 1890–1893.
11.
DingLLinsleyPSHuangLYGermainRNShevachEM. IL-10 inhibits macrophage costimulatory activity by selectively inhibiting the up-regulation of B7 expression. J Immunol1993; 151: 1224–1234.
12.
De Waal MalefytRYsselHDe VriesJE. Direct effects of IL-10 on subsets of human CD4 + T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol1993; 150: 4754–4765.
13.
LlorenteLRichaud-PatinYWijdenesJ. Spontaneous production of interleukin-10 by B lymphocytes and monocytes in systemic lupus erythematosus. Eur Cytokine Netw1993; 4: 421–427.
14.
LlorenteLRichaud-PatinYFiorR. In vivo production of interleukin-10 by non-T cells in rheumatoid arthritis, Sjogren's syndrome, and systemic lupus erythematosus. A potential mechanism of B lymphocyte hyperactivity and autoimmunity. Arthritis Rheum1994; 37: 1647–1655.
15.
LlorenteLZouWLevyY. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus. J Exp Med1995; 181: 839–844.
16.
HorwitzDAGrayJDBehrendsenSC. Decreased production of interleukin-12 and other Th1-type cytokines in patients with recent-onset systemic lupus erythematosus. Arthritis Rheum1998; 41: 838–844.
HagiwaraEGourleyMFLeeSKlinmanDK. Disease severity in patients with systemic lupus erythematosus correlates with an increased ratio of interleukin-10:interferon-gamma-secreting cells in the peripheral blood. Arthritis Rheum1996; 39: 379–385.
19.
ParkYBLeeSKKimDSLeeJLeeCHSongCH. Elevated interleukin-10 levels correlated with disease activity in systemic lupus erythematosus. Clin Exp Rheumatol1998; 16: 283–88.
20.
CapperERMaskillJKGordonCBlakemoreAI. Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology?Clin Exp Immunol2004; 138: 348–356.
21.
ChunHYChungJWKimHA. Cytokine IL-6 and IL-10 as biomarkers in systemic lupus erythematosus. J Clin Immunol2007; 27: 461–466.
22.
LlorenteLRichaud-PatinYGarcia-PadillaC. Clinical and biologic effects of anti-interleukin-10 monoclonal antibody administration in systemic lupus erythematosus. Arthritis Rheum2000; 43: 1790–1800.
23.
MilesSIsenbergD. A review of serological abnormalities in relatives of SLE patients. Lupus1993; 2: 145–150.
24.
LlorenteLRichaud-PatinYCoudercJ. Dysregulation of interleukin-10 production in relatives of patients with systemic lupus erythematosus. Arthritis Rheum1997; 40: 1429–1435.
25.
LlorenteLRichaud-PatinY. The role of interleukin-10 in systemic lupus erythematosus. J Autoimmun2003; 20: 287–289.
26.
WestendorpRGLangermansJAHuizingaTW. Genetic influence on cytokine production and fatal meningococcal disease. Lancet1997; 349: 170–173.
27.
GatevaVSandlingJKHomG. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat Genet2009; 41: 1228–1233.
28.
EskdaleJKubeDTeschHGallagherG. Mapping of the human IL10 gene and further characterization of the 5' flanking sequence. Immunogenetics1997; 46: 120–128.
29.
SchotteHGaubitzMWillekeP. Interleukin-10 promoter microsatellite polymorphisms in systemic lupus erythematosus: association with the anti-Sm immune response. Rheumatology (Oxford)2004; 43: 1357–1363.
30.
TurnerDMWilliamsDMSankaranDLazarusMSinnottPJHutchinsonIV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet1997; 24: 1–8.
31.
Edwards-SmithCJJonssonJRPurdieDMBansalAShorthouseCPowellEE. Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa. Hepatology1999; 30: 526–530.
32.
LazarusMHajeerAHTurnerD. Genetic variation in the interleukin 10 gene promoter and systemic lupus erythematosus. J Rheumatol1997; 24: 2314–2317.
33.
RoodMJKeijsersVVan der LindenMW. Neuropsychiatric systemic lupus erythematosus is associated with imbalance in interleukin 10 promoter haplotypes. Ann Rheum Dis1999; 58: 85–89.
34.
LopezPGutierrezCSuarezA. IL-10 and TNFalpha genotypes in SLE. J Biomed Biotechnol2010; 2010: 838390. DOI: 10.1155/2010/838390–838390. DOI: 10.1155/2010/838390.
35.
RosadoSRua-FigueroaIVargasJA. Interleukin-10 promoter polymorphisms in patients with systemic lupus erythematosus from the Canary Islands. Int J Immunogenet2008; 35: 235–242.
36.
MokCCLanchburyJSChanDWLauCS. Interleukin-10 promoter polymorphisms in Southern Chinese patients with systemic lupus erythematosus. Arthritis Rheum1998; 41: 1090–1095.
37.
EskdaleJGallagherGVerweijCLKeijsersVWestendorpRGHuizingaTW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci U S A1998; 95: 9465–9470.
38.
MormannMRiethHHuaTD. Mosaics of gene variations in the Interleukin-10 gene promoter affect interleukin-10 production depending on the stimulation used. Genes Immun2004; 5: 246–255.
39.
WestendorpRGvan DunneFMKirkwoodTBHelmerhorstFMHuizingaTW. Optimizing human fertility and survival. Nat Med2001; 7: 873–873.
40.
De JongBAWestendorpRGEskdaleJUitdehaagBMHuizingaTW. Frequency of functional interleukin-10 promoter polymorphism is different between relapse-onset and primary progressive multiple sclerosis. Hum Immunol2002; 63: 281–285.
41.
LardLRVan GaalenFASchonkerenJJ. Association of the -2849 interleukin-10 promoter polymorphism with autoantibody production and joint destruction in rheumatoid arthritis. Arthritis Rheum2003; 48: 1841–1848.
42.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
43.
AssmannGSchulteH. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Prospective Cardiovascular Munster study. Am J Cardiol1992; 70: 733–737.
GibsonAWEdbergJCWuJWestendorpRGHuizingaTWKimberlyRP. Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus. J Immunol2001; 166: 3915–3922.
46.
HiguchiRSimple and rapid preparation of samples for PCR. In: EhrlichHA (ed). PCR-technology, principles and applications for DNA amplification, New York: Stockton Press, 1989, pp. 31–38.
47.
StephensMSmithNJDonnellyP. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet2001; 68: 978–989.
48.
StephensMDonnellyP. A comparison of Bayesian methods for haplotype reconstruction from population genotype data. Am J Hum Genet2003; 73: 1162–1169.
49.
BarrettJCFryBMallerJDalyMJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics2005; 21: 263–265.
50.
ShamPCCurtisD. Monte Carlo tests for associations between disease and alleles at highly polymorphic loci. Ann Hum Genet1995; 59: 97–105.
51.
BeebeAMCuaDJDe WaalMR. The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS). Cytokine Growth Factor Rev2002; 13: 403–412.
52.
LackiJKSamborskiWMackiewiczSH. Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins. Clin Rheumatol1997; 16: 275–278.
53.
TanEMCohenASFriesJF. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1982; 25: 1271–1277.
54.
O'NeillSCerveraR. Systemic lupus erythematosus. Best Pract Res Clin Rheumatol2010; 24: 841–855.
55.
YapDYLaiKN. Cytokines and their roles in the pathogenesis of systemic lupus erythematosus: from basics to recent advances. J Biomed Biotechnol2010; 2010: 365083–365083. DOI: 10.1155/2010/365083.
56.
EskdaleJGallagherGVerweijCLKeijsersVWestendorpRGHuizingaTW. Interleukin 10 secretion in relation to human IL-10 locus haplotypes. Proc Natl Acad Sci U S A1998; 95: 9465–9470.
57.
NossentHBerdenJSwaakT. Renal immunofluorescence and the prediction of renal outcome in patients with proliferative lupus nephritis. Lupus2000; 9: 504–510.
58.
EskdaleJKeijsersVHuizingaTGallagherG. Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin-10 (IL-10) locus. Genes Immun1999; 1: 151–155.
