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Gene–environment interaction in autoimmune disease

Published online by Cambridge University Press:  07 March 2014

Justine A Ellis ,
Andrew S Kemp  and
Anne-Louise Ponsonby
Justine A Ellis*
Affiliation:
Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, Victoria, Australia Department of Paediatrics, University of Melbourne, Victoria, Australia
Andrew S Kemp
Affiliation:
Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
Anne-Louise Ponsonby
Affiliation:
Department of Paediatrics, University of Melbourne, Victoria, Australia Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, Victoria, Australia
*
*Corresponding author: Dr Justine Ellis, Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Royal Children's Hospital, 50 Flemington Road, Parkville, Victoria 3052, Australia. E-mail: justine.ellis@mcri.edu.au
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Abstract

Autoimmune disease manifests in numerous forms, but as a disease group is relatively common in the population. It is complex in aetiology, with genetic and environmental determinants. The involvement of gene variants in autoimmune disease is well established, and evidence for significant involvement of the environment in various disease forms is growing. These factors may act independently, or they may interact, with the effect of one factor influenced by the presence of another. Identifying combinations of genetic and environmental factors that interact in autoimmune disease has the capacity to more fully explain disease risk profile, and to uncover underlying molecular mechanisms contributing to disease pathogenesis. In turn, such knowledge is likely to contribute significantly to the development of personalised medicine, and targeted preventative approaches. In this review, we consider the current evidence for gene–environment (G–E) interaction in autoimmune disease. Large-scale G–E interaction research efforts, while well-justified, face significant practical and methodological challenges. However, it is clear from the evidence that has already been generated that knowledge on how genes and environment interact at a biological level will be crucial in fully understanding the processes that manifest as autoimmunity.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 16 , 2014 , e4
Copyright
Copyright © Cambridge University Press 2014 

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References

1Cooper, G.S., Bynum, M.L. and Somers, E.C. (2009) Recent insights in the epidemiology of autoimmune diseases: improved prevalence estimates and understanding of clustering of diseases. Journal of Autoimmunity 33, 197-207Google Scholar
2Cotsapas, C. et al. (2011) Pervasive sharing of genetic effects in autoimmune disease. PLoS Genetics 7, e1002254Google Scholar
3Javierre, B.M., Hernando, H. and Ballestar, E. (2011) Environmental triggers and epigenetic deregulation in autoimmune disease. Discovery Medicine 12, 535-545Google Scholar
4Richard-Miceli, C. and Criswell, L.A. (2012) Emerging patterns of genetic overlap across autoimmune disorders. Genome Medicine 4, 6CrossRefGoogle ScholarPubMed
5Ellis, J.A., Munro, J.E. and Ponsonby, A.L. (2010) Possible environmental determinants of juvenile idiopathic arthritis. Rheumatology (Oxford) 49, 411-425Google Scholar
6Davidson, A. and Diamond, B. (2001) Autoimmune diseases. New England Journal of Medicine 345, 340-350CrossRefGoogle ScholarPubMed
7Doria, A. et al. (2012) Autoinflammation and autoimmunity: bridging the divide. Autoimmunity Reviews 12, 22-30Google Scholar
8Hayter, S.M. and Cook, M.C. (2012) Updated assessment of the prevalence, spectrum and case definition of autoimmune disease. Autoimmunity Reviews 11, 754-765CrossRefGoogle ScholarPubMed
9Cho, J.H. and Gregersen, P.K. (2011) Genomics and the multifactorial nature of human autoimmune disease. New England Journal of Medicine 365, 1612-1623CrossRefGoogle ScholarPubMed
10Tsokos, G.C. (2011) Systemic lupus erythematosus. New England Journal of Medicine 365, 2110-2121CrossRefGoogle ScholarPubMed
11McInnes, I.B. and Schett, G. (2011) The pathogenesis of rheumatoid arthritis. New England Journal of Medicine 365, 2205-2219Google Scholar
12Ramagopalan, S.V. et al. (2010) Multiple sclerosis: risk factors, prodromes, and potential causal pathways. Lancet Neurology 9, 727-739Google Scholar
13Bluestone, J.A., Herold, K. and Eisenbarth, G. (2010) Genetics, pathogenesis and clinical interventions in type 1 diabetes. Nature 464, 1293-1300Google Scholar
14Behr, M.A., Divangahi, M. and Lalande, J.D. (2010) What's in a name? The (mis)labelling of Crohn's as an autoimmune disease. Lancet 376, 202-203CrossRefGoogle Scholar
15Somers, E.C. et al. (2006) Autoimmune diseases co-occurring within individuals and within families: a systematic review. Epidemiology 17, 202-217Google Scholar
16Thorsby, E. and Lie, B.A. (2005) HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transplant Immunology 14, 175-182CrossRefGoogle ScholarPubMed
17Manolio, T.A. et al. (2009) Finding the missing heritability of complex diseases. Nature 461, 747-753Google Scholar
18Eichler, E.E. et al. (2010) Missing heritability and strategies for finding the underlying causes of complex disease. Nature Reviews Genetics 11, 446-450Google Scholar
19Miller, F.W. et al. (2012) Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. Journal of Autoimmunity 39, 259-271Google Scholar
20Arnson, Y., Shoenfeld, Y. and Amital, H. (2010) Effects of tobacco smoke on immunity, inflammation and autoimmunity. Journal of Autoimmunity 34, J258-J265CrossRefGoogle Scholar
21Sugiyama, D. et al. (2010) Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Annals of the Rheumatic Diseases 69, 70-81Google Scholar
22Antonovsky, A. et al. (1965) Epidemiologic study of multiple sclerosis in Israel. I. An overall review of methods and findings. Archives of Neurology 13, 183-193Google Scholar
23Costenbader, K.H. et al. (2004) Cigarette smoking and the risk of systemic lupus erythematosus: a meta-analysis. Arthritis Rheumatology 50, 849-857CrossRefGoogle ScholarPubMed
24Wiersinga, W.M. (2013) Smoking and thyroid. Clinical Endocrinology (Oxf) 79, 145-151CrossRefGoogle ScholarPubMed
25Hart, P.H., Gorman, S. and Finlay-Jones, J.J. (2011) Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nature Reviews Immunology 11, 584-596CrossRefGoogle ScholarPubMed
26Hammond, S.R. et al. (1988) The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart. Brain 111(Pt 1), 1-25Google Scholar
27Kurtzke, J.F., Beebe, G.W. and Norman, J.E. Jr. (1979) Epidemiology of multiple sclerosis in U.S. veterans: 1. Race, sex, and geographic distribution. Neurology 29(9 Pt 1), 1228-1235CrossRefGoogle ScholarPubMed
28Taylor, B.V. et al. (2010) MS prevalence in New Zealand, an ethnically and latitudinally diverse country. Multiple Sclerosis 16, 1422-1431Google Scholar
29Vukusic, S. et al. (2007) Regional variations in the prevalence of multiple sclerosis in French farmers. Journal of Neurology, Neurosurgery and Psychiatry 78, 707-709CrossRefGoogle ScholarPubMed
30van der Mei, I.A. et al. (2003) Past exposure to sun, skin phenotype, and risk of multiple sclerosis: case–control study. BMJ 327, 316Google Scholar
31Dobson, R., Giovannoni, G. and Ramagopalan, S. (2012) The month of birth effect in multiple sclerosis: systematic review, meta-analysis and effect of latitude. Journal of Neurology, Neurosurgery and Psychiatry 84, 427-32CrossRefGoogle ScholarPubMed
32Staples, J., Ponsonby, A.L. and Lim, L. (2010) Low maternal exposure to ultraviolet radiation in pregnancy, month of birth, and risk of multiple sclerosis in offspring: longitudinal analysis. BMJ 340, c1640Google ScholarPubMed
33van der Mei, I.A. et al. (2007) Vitamin D levels in people with multiple sclerosis and community controls in Tasmania, Australia. Journal of Neurology 254, 581-590Google Scholar
34Munger, K.L. et al. (2006) Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 296, 2832-2838CrossRefGoogle ScholarPubMed
35Munger, K.L. et al. (2004) Vitamin D intake and incidence of multiple sclerosis. Neurology 62, 60-65CrossRefGoogle ScholarPubMed
36Diabetes Epidemiology Research International Group (1988) Geographic patterns of childhood insulin-dependent diabetes mellitus. Diabetes Epidemiology Research International Group. Diabetes 37, 1113-1119Google Scholar
37EURODIAB ACE Study Group (2000) Variation and trends in incidence of childhood diabetes in Europe. EURODIAB ACE Study Group. Lancet 355, 873-876Google Scholar
38Armitage, E.L. et al. (2004) Incidence of juvenile-onset Crohn's disease in Scotland: association with northern latitude and affluence. Gastroenterology 127, 1051-1057Google Scholar
39Ramos-Remus, C. et al. (2007) Latitude gradient influences the age of onset in rheumatoid arthritis patients. Clinical Rheumatology 26, 1725-1728Google Scholar
40Vieira, V.M. et al. (2010) Association between residences in U.S. northern latitudes and rheumatoid arthritis: a spatial analysis of the Nurses’ Health Study. Environmental Health Perspectives 118, 957-961Google Scholar
41Disanto, G. et al. (2012) Month of birth, vitamin D and risk of immune mediated disease: a case control study. BMC Medicine 10, 69Google Scholar
42Kahn, H.S. et al. (2009) Association of type 1 diabetes with month of birth among U.S. youth: the SEARCH for Diabetes in Youth Study. Diabetes Care 32, 2010-2015Google Scholar
43Rothwell, P.M. et al. (1996) Seasonality of birth of patients with childhood diabetes in Britain. BMJ 312, 1456-1457Google Scholar
44Bener, A. et al. (2009) High prevalence of vitamin D deficiency in type 1 diabetes mellitus and healthy children. Acta Diabetologia 46, 183-189Google Scholar
45EURODIAB Substudy 2 Study Group (1999) Vitamin D supplement in early childhood and risk for Type I (insulin-dependent) diabetes mellitus. The EURODIAB Substudy 2 Study Group. Diabetologia 42, 51-54Google Scholar
46Hypponen, E. et al. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500-1503Google Scholar
47Kroger, H., Penttila, I.M. and Alhava, E.M. (1993) Low serum vitamin D metabolites in women with rheumatoid arthritis. Scandinavian Journal of Rheumatology 22, 172-177Google Scholar
48Merlino, L.A. et al. (2004) Vitamin D intake is inversely associated with rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheumatology 50, 72-77Google Scholar
49Oelzner, P. et al. (1999) Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis. Rheumatology (Oxford) 38, 841-847Google Scholar
50Stene, L.C. et al. (2000) Use of cod liver oil during pregnancy associated with lower risk of Type I diabetes in the offspring. Diabetologia 43, 1093-1098CrossRefGoogle ScholarPubMed
51Lucas, R.M. et al. (2011) Epstein-Barr virus and multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry 82, 1142-1148Google Scholar
52Handel, A.E. et al. (2010) An updated meta-analysis of risk of multiple sclerosis following infectious mononucleosis. PLoS One 5, e12496CrossRefGoogle ScholarPubMed
53Ascherio, A. and Munch, M. (2000) Epstein-Barr virus and multiple sclerosis. Epidemiology 11, 220-224Google Scholar
54Wagner, H.J. et al. (2000) Altered prevalence and reactivity of anti-Epstein-Barr virus antibodies in patients with multiple sclerosis. Viral Immunology 13, 497-502Google Scholar
55Draborg, A.H., Duus, K. and Houen, G. (2012) Epstein-Barr virus and systemic lupus erythematosus. Clinical and Developmental Immunology 2012, 370516CrossRefGoogle ScholarPubMed
56Meron, M.K. et al. (2010) Infectious aspects and the etiopathogenesis of rheumatoid arthritis. Clinical Reviews in Allergy and Immunology 38, 287-291Google Scholar
57Chen, Y.S. et al. (2006) Parvovirus B19 infection in patients with rheumatoid arthritis in Taiwan. Journal of Rheumatology 33, 887-891Google Scholar
58Kozireva, S.V. et al. (2008) Incidence and clinical significance of parvovirus B19 infection in patients with rheumatoid arthritis. Journal of Rheumatology 35, 1265-1270Google Scholar
59Peterlana, D. et al. (2003) The presence of parvovirus B19 VP and NS1 genes in the synovium is not correlated with rheumatoid arthritis. Journal of Rheumatology 30, 1907-1910Google Scholar
60Chen, H.H. et al. (2013) Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case–control study. Annals of the Rheumatic Diseases 72, 1206-1211Google Scholar
61Mikuls, T.R. et al. (2009) Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. International Immunopharmacology 9, 38-42Google Scholar
62Mikuls, T.R. et al. (2012) Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheumatology 64, 3522-3530Google Scholar
63Hasni, S., Ippolito, A. and Illei, G.G. (2011) Helicobacter pylori and autoimmune diseases. Oral Diseases 17, 621-627Google Scholar
64Yeung, W.C., Rawlinson, W.D. and Craig, M.E. (2011) Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies. BMJ 342, d35Google Scholar
65Strachan, D.P. (1989) Hay fever, hygiene, and household size. BMJ 299, 1259-1260Google Scholar
66Okada, H. et al. (2010) The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update. Clinical and Experimental Immunology 160, 1-9Google Scholar
67Ponsonby, A.L. et al. (2005) Exposure to infant siblings during early life and risk of multiple sclerosis. JAMA 293, 463-469Google Scholar
68Cardwell, C.R. et al. (2011) Birth order and childhood type 1 diabetes risk: a pooled analysis of 31 observational studies. International Journal of Epidemiology 40, 363-374Google Scholar
69Selmi, C. and Tsuneyama, K. (2010) Nutrition, geoepidemiology, and autoimmunity. Autoimmunity Reviews 9, A267-A270Google Scholar
70Strickland, F.M. et al. (2013) Diet influences expression of autoimmune associated genes and disease severity by epigenetic mechanisms in a transgenic lupus model. Arthritis Rheumatology 65, 1872-1881Google Scholar
71Brown, K. et al. (2012) Diet-induced dysbiosis of the intestinal microbiota and the effects on immunity and disease. Nutrients 4, 1095-1119CrossRefGoogle ScholarPubMed
72Wu, C. et al. (2013) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496, 513-517Google Scholar
73Kleinewietfeld, M. et al. (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496, 518-522Google Scholar
74Virtanen, S.M. et al. (2012) Food consumption and advanced beta cell autoimmunity in young children with HLA-conferred susceptibility to type 1 diabetes: a nested case–control design. American Journal of Clinical Nutrition 95, 471-478CrossRefGoogle ScholarPubMed
75Fasano, A. and Catassi, C. (2012) Clinical practice. Celiac disease. New England Journal of Medicine 367, 2419-2426Google Scholar
76Klareskog, L. et al. (2011) Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis. Seminars in Immunology 23, 92-98Google Scholar
77Rothman, K.J. (1976) Causes. American Journal of Epidemiology 104, 587-592Google Scholar
78Lanctot, C. et al. (2007) Dynamic genome architecture in the nuclear space: regulation of gene expression in three dimensions. Nature Reviews Genetics 8, 104-115Google Scholar
79Wang, X., Elston, R.C. and Zhu, X. (2010) The meaning of interaction. Human Heredity 70, 269-277Google Scholar
80de Mutsert, R. et al. (2009) The effect of joint exposures: examining the presence of interaction. Kidney International 75, 677-681Google Scholar
81Vandenbroucke, J.P. et al. (2007) Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Medicine 4, e297Google Scholar
82Knol, M.J. et al. (2009) When one depends on the other: reporting of interaction in case–control and cohort studies. Epidemiology 20, 161-166Google Scholar
83Dwyer, T. et al. (2004) Measuring environmental factors can enhance the search for disease causing genes? Journal of Epidemiology and Community Health 58, 613-615Google Scholar
84Khoury, M.J. and Wacholder, S. (2009) Invited commentary: from genome-wide association studies to gene-environment-wide interaction studies – challenges and opportunities. American Journal of Epidemiology 169, 227-230; discussion 34–5Google Scholar
85Lindstrom, S. et al. (2009) The impact of gene-environment dependence and misclassification in genetic association studies incorporating gene-environment interactions. Human Heredity 68, 171-181Google Scholar
86Williamson, E. et al. (2010) Effect of including environmental data in investigations of gene-disease associations in the presence of qualitative interactions. Genetic Epidemiology 34, 552-560Google Scholar
87Hancock, D.B. et al. (2012) Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genetics 8, e1003098Google Scholar
88Boffetta, P. et al. (2012) Recommendations and proposed guidelines for assessing the cumulative evidence on joint effects of genes and environments on cancer occurrence in humans. International Journal of Epidemiology 41, 686-704Google Scholar
89Foley, D.L. et al. (2009) Prospects for epigenetic epidemiology. American Journal of Epidemiology 169, 389-400CrossRefGoogle ScholarPubMed
90Breitling, L.P. et al. (2011) Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. American Journal of Human Genetics 88, 450-457Google Scholar
91Wan, E.S. et al. (2012) Cigarette smoking behaviors and time since quitting are associated with differential DNA methylation across the human genome. Human Molecular Genetics 21, 3073-3082Google Scholar
92Feil, R. and Fraga, M.F. (2012) Epigenetics and the environment: emerging patterns and implications. Nature Reviews Genetics 13, 97-109Google Scholar
93Gregersen, P.K., Silver, J. and Winchester, R.J. (1987) The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheumatology 30, 1205-1213Google Scholar
94Padyukov, L. et al. (2004) A gene-environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheumatology 50, 3085-3092Google Scholar
95Kallberg, H. et al. (2007) Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. American Journal of Human Genetics 80, 867-875Google Scholar
96Karlson, E.W. et al. (2010) Gene-environment interaction between HLA-DRB1 shared epitope and heavy cigarette smoking in predicting incident rheumatoid arthritis. Annals of the Rheumatic Diseases 69, 54-60Google Scholar
97Mahdi, H. et al. (2009) Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nature Genetics 41, 1319-1324Google Scholar
98Morgan, A.W. et al. (2009) Reevaluation of the interaction between HLA-DRB1 shared epitope alleles, PTPN22, and smoking in determining susceptibility to autoantibody-positive and autoantibody-negative rheumatoid arthritis in a large UK Caucasian population. Arthritis Rheumatology 60, 2565-2576Google Scholar
99Pedersen, M. et al. (2007) Strong combined gene–environment effects in anti-cyclic citrullinated peptide-positive rheumatoid arthritis: a nationwide case–control study in Denmark. Arthritis Rheumatology 56, 1446-1453Google Scholar
100Too, C.L. et al. (2012) Smoking interacts with HLA-DRB1 shared epitope in the development of anti-citrullinated protein antibody-positive rheumatoid arthritis: results from the Malaysian Epidemiological Investigation of Rheumatoid Arthritis (MyEIRA). Arthritis Research and Therapy 14, R89Google Scholar
101van der Helm-van Mil, A.H. et al. (2007) The HLA-DRB1 shared epitope alleles differ in the interaction with smoking and predisposition to antibodies to cyclic citrullinated peptide. Arthritis Rheumatology 56, 425-432Google Scholar
102van der Woude, D. et al. (2010) Gene-environment interaction influences the reactivity of autoantibodies to citrullinated antigens in rheumatoid arthritis. Nature Genetics 42, 814-816; author reply 16Google Scholar
103Willemze, A. et al. (2011) The interaction between HLA shared epitope alleles and smoking and its contribution to autoimmunity against several citrullinated antigens. Arthritis Rheumatology 63, 1823-1832Google Scholar
104Hill, J.A. et al. (2003) Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. Journal of Immunology 171, 538-541Google Scholar
105Klareskog, L. et al. (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheumatology 54, 38-46Google Scholar
106Wegner, N. et al. (2010) Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunological Reviews 233, 34-54Google Scholar
107Klareskog, L. et al. (2006) Mechanisms of disease: Genetic susceptibility and environmental triggers in the development of rheumatoid arthritis. Nature Clinical Practice Rheumatology 2, 425-433Google Scholar
108Rhee, I. and Veillette, A. (2012) Protein tyrosine phosphatases in lymphocyte activation and autoimmunity. Nature Immunology 13, 439-447Google Scholar
109Criswell, L.A. et al. (2006) Smoking interacts with genetic risk factors in the development of rheumatoid arthritis among older Caucasian women. Annals of the Rheumatic Diseases 65, 1163-1167Google Scholar
110Keenan, B.T. et al. (2010) Effect of interactions of glutathione S-transferase T1, M1, and P1 and HMOX1 gene promoter polymorphisms with heavy smoking on the risk of rheumatoid arthritis. Arthritis Rheumatology 62, 3196-3210CrossRefGoogle ScholarPubMed
111Mikuls, T.R. et al. (2012) Impact of interactions of cigarette smoking with NAT2 polymorphisms on rheumatoid arthritis risk in African Americans. Arthritis Rheumatology 64, 655-664Google Scholar
112Kochi, Y. et al. (2011) PADI4 polymorphism predisposes male smokers to rheumatoid arthritis. Annals of the Rheumatic Diseases 70, 512-515Google Scholar
113Costenbader, K.H. et al. (2008) Genetic polymorphisms in PTPN22, PADI-4, and CTLA-4 and risk for rheumatoid arthritis in two longitudinal cohort studies: evidence of gene-environment interactions with heavy cigarette smoking. Arthritis Research and Therapy 10, R52Google Scholar
114Saevarsdottir, S. et al. (2011) Mannan Binding Lectin (MBL) genotypes coding for high MBL serum levels are associated with rheumatoid factor negative rheumatoid arthritis in never smokers. Arthritis Research and Therapy 13, R65Google Scholar
115Karouzakis, E. et al. (2009) DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheumatology 60, 3613-3622Google Scholar
116Nile, C.J. et al. (2008) Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheumatology 58, 2686-2693Google Scholar
117Takami, N. et al. (2006) Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheumatology 54, 779-787Google Scholar
118Liu, Y. et al. (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnology 31, 142-147Google Scholar
119Nakano, K. et al. (2013) DNA methylome signature in rheumatoid arthritis. Annals of the Rheumatic Diseases 72, 110-117Google Scholar
120De Jager, P.L. et al. (2008) Integrating risk factors: HLA-DRB1*1501 and Epstein-Barr virus in multiple sclerosis. Neurology 70(13 Pt 2), 1113-1118Google Scholar
121Nielsen, T.R. et al. (2009) Effects of infectious mononucleosis and HLA-DRB1*15 in multiple sclerosis. Multiple Sclerosis 15, 431-436Google Scholar
122van der Mei, I.A. et al. (2010) Human leukocyte antigen-DR15, low infant sibling exposure and multiple sclerosis: gene-environment interaction. Annals of Neurology 67, 261-265Google Scholar
123Sundqvist, E. et al. (2012) Epstein-Barr virus and multiple sclerosis: interaction with HLA. Genes and Immunity 13, 14-20Google Scholar
124Ramagopalan, S.V. et al. (2010) HLA-DRB1*15, low infant sibling exposure, and multiple sclerosis gene-environment interaction. Annals of Neurology 67, 694-695Google Scholar
125Mechelli, R. et al. (2013) A “candidate-interactome” aggregate analysis of genome-wide association data in multiple sclerosis. PLoS One 8, e63300CrossRefGoogle Scholar
126Ramagopalan, S.V. et al. (2009) HLA-DRB1 and month of birth in multiple sclerosis. Neurology 73, 2107-2111CrossRefGoogle ScholarPubMed
127Ramagopalan, S.V. et al. (2009) Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1*1501 is regulated by vitamin D. PLoS Genetics 5, e1000369Google Scholar
128Nolan, D. et al. (2012) Contributions of vitamin D response elements and HLA promoters to multiple sclerosis risk. Neurology 79, 538-546Google Scholar
129Saastamoinen, K.P., Auvinen, M.K. and Tienari, P.J. (2012) Month of birth is associated with multiple sclerosis but not with HLA-DR15 in Finland. Multiple Sclerosis 18, 563-568Google Scholar
130International Multiple Sclerosis Genetics Consortium et al. (2011) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476, 214-219Google Scholar
131Dickinson, J.L. et al. (2009) Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 vitamin D receptor variant in this interaction. Multiple Sclerosis 15, 563-570Google Scholar
132Simon, K.C. et al. (2010) Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk. Neurology 74, 1365-1371Google Scholar
133Hedstrom, A.K. et al. (2011) Smoking and two human leukocyte antigen genes interact to increase the risk for multiple sclerosis. Brain 134(Pt 3), 653-664Google Scholar
134Kiyohara, C. et al. (2009) Cigarette smoking, N-acetyltransferase 2 polymorphisms and systemic lupus erythematosus in a Japanese population. Lupus 18, 630-638Google Scholar
135Kiyohara, C. et al. (2009) Cigarette smoking, STAT4 and TNFRSF1B polymorphisms, and systemic lupus erythematosus in a Japanese population. Journal of Rheumatology 36, 2195-2203Google Scholar
136Kiyohara, C. et al. (2012) Risk modification by CYP1A1 and GSTM1 polymorphisms in the association of cigarette smoking and systemic lupus erythematosus in a Japanese population. Scandinavian Journal of Rheumatology 41, 103-109Google Scholar
137Griffiths, H.R. (2008) Is the generation of neo-antigenic determinants by free radicals central to the development of autoimmune rheumatoid disease? Autoimmunity Reviews 7, 544-549Google Scholar
138Fraser, P.A. et al. (2003) Glutathione S-transferase M null homozygosity and risk of systemic lupus erythematosus associated with sun exposure: a possible gene-environment interaction for autoimmunity. Journal of Rheumatology 30, 276-282Google Scholar
139Zhang, Y. et al. (2013) Impaired DNA methylation and its mechanisms in CD4(+)T cells of systemic lupus erythematosus. Journal of Autoimmunity 41, 92-99Google Scholar
140Richardson, B. et al. (1990) Evidence for impaired T cell DNA methylation in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheumatology 33, 1665-1673Google Scholar
141Lu, Q. et al. (2002) Demethylation of ITGAL (CD11a) regulatory sequences in systemic lupus erythematosus. Arthritis Rheumatology 46, 1282-1291Google Scholar
142Kaplan, M.J. et al. (2004) Demethylation of promoter regulatory elements contributes to perforin overexpression in CD4+ lupus T cells. Journal of Immunology 172, 3652-3661Google Scholar
143Javierre, B.M. et al. (2010) Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Research 20, 170-179Google Scholar
144Jeffries, M. et al. (2011) Genome-wide DNA methylation patterns in CD4+ T cells from patients with systemic lupus erythematosus. Epigenetics 6, 593-601Google Scholar
145Wang, G.S. et al. (2009) Ultraviolet B exposure of peripheral blood mononuclear cells of patients with systemic lupus erythematosus inhibits DNA methylation. Lupus 18, 1037-1044Google Scholar
146Wysenbeek, A.J., Block, D.A. and Fries, J.F. (1989) Prevalence and expression of photosensitivity in systemic lupus erythematosus. Annals of the Rheumatic Diseases 48, 461-463Google Scholar
147Helbig, K.L. et al. (2012) A case-only study of gene-environment interaction between genetic susceptibility variants in NOD2 and cigarette smoking in Crohn's disease aetiology. BMC Medical Genetics 13, 14Google Scholar
148van der Heide, F. et al. (2010) Differences in genetic background between active smokers, passive smokers, and non-smokers with Crohn's disease. American Journal of Gastroenterology 105, 1165-1172Google Scholar
149Nimmo, E.R. et al. (2012) Genome-wide methylation profiling in Crohn's disease identifies altered epigenetic regulation of key host defense mechanisms including the Th17 pathway. Inflammatory Bowel Disease 18, 889-899Google Scholar
150Zeilinger, S. et al. (2013) Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLoS One 8, e63812Google Scholar
151Skorka, A. et al. (2005) Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and Graves’ disease in a Polish population: association and gene dose-dependent correlation with age of onset. Clinical Endocrinology (Oxf) 62, 679-682Google Scholar
152Jurecka-Lubieniecka, B. et al. (2013) Association between age at diagnosis of Graves’ disease and variants in genes involved in immune response. PLoS One 8, e59349Google Scholar
153Hasham, A. and Tomer, Y. (2012) Genetic and epigenetic mechanisms in thyroid autoimmunity. Immunology Research 54, 204-213Google Scholar
154Badenhoop, K. et al. (2009) MHC-environment interactions leading to type 1 diabetes: feasibility of an analysis of HLA DR-DQ alleles in relation to manifestation periods and dates of birth. Diabetes, Obesity and Metabolism 11(Suppl 1), 88-91Google Scholar
155Rakyan, V.K. et al. (2011) Identification of type 1 diabetes-associated DNA methylation variable positions that precede disease diagnosis. PLoS Genetics 7, e1002300Google Scholar
156Sollid, L.M. and Jabri, B. (2011) Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Current Opinion in Immunology 23, 732-738Google Scholar
157Vader, W. et al. (2003) The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proceedings of the National Academy of Sciences of the United States of America 100, 12390-12395Google Scholar
158Lu, Q. (2013) The critical importance of epigenetics in autoimmunity. Journal of Autoimmunity 41, 1-5Google Scholar
159Yu, Q. and Huang, J.F. (2013) The DEER database: a bridge connecting drugs, environmental effects, and regulations. Gene 520, 98-105Google Scholar
160Kelly, T.K., De Carvalho, D.D. and Jones, P.A. (2010) Epigenetic modifications as therapeutic targets. Nature Biotechnology 28, 1069-1078Google Scholar
161Song, M., Lee, K.M. and Kang, D. (2011) Breast cancer prevention based on gene-environment interaction. Molecular Carcinogenesis 50, 280-290Google Scholar
162Bookman, E.B. et al. (2011) Gene-environment interplay in common complex diseases: forging an integrative model-recommendations from an NIH workshop. Genetic Epidemiology 35, 217-225Google Scholar
163Ioannidis, J.P., Thomas, G. and Daly, M.J. (2009) Validating, augmenting and refining genome-wide association signals. Nature Reviews Genetics 10, 318-329Google Scholar
164Cornelis, M.C. et al. (2010) The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genetic Epidemiology 34, 364-372Google Scholar
165Lin, R. et al. (2013) Novel modulating effects of PKC family genes on the relationship between serum vitamin D and relapse in multiple sclerosis. Journal of Neurology, Neurosurgery and Psychiatry. Published online first July 18, doi:10.1136/jnnp-2013-305245Google Scholar
166Aschard, H. et al. (2012) Challenges and opportunities in genome-wide environmental interaction (GWEI) studies. Human Genetics 131, 1591-1613Google Scholar