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Heritability versus the role of the environment in autoimmunity
Journal of Autoimmunity 39 (2012) 249e252
Contents lists available at SciVerse ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
Review
Heritability versus the role of the environment in autoimmunity Carlo Selmi a, b, *, Qianjin Lu c, **, Michael C. Humble d, *** a
Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA Clinical Immunology, Humanitas Clinical and Research Center, Via A. Manzoni 56, Rozzano, MI 20089, Italy c Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, #139 Renmin Middle Road, Changsha, Hunan 410011, PR China d Division of Extramural Research and Training, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, PO Box 12233, MD-K3-15, Research Triangle Park, NC 27709, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 July 2012 Accepted 31 July 2012
The higher concordant occurrence of autoimmune diseases in monozygotic twins compared to dizygotic or sibling pairs supports the role for genetic susceptibility. For most conditions, however, concordance rates are considerably below 100% and lead to the estimate of the weight of genetics coined “heritability”. In the group of autoimmune diseases heritability ranges between 0.008 and 1 with median values of approximately 0.60. A complementary term coined “environmentability” represents the environmental influence on individual phenotype, and can include dietary habits, chemicals, or hygienic conditions. Genome-wide association data in complex diseases confirmed a role for the environment in disease etiology as significantly associated polymorphisms were found only in subgroups of patients and controls. Environmental links to autoimmunity range from anecdotal associations or case series to largely investigated experimental and epidemiological studies. A bibliographic analysis reveals that the number of publications dedicated to environmental factors in autoimmunity has grown on average by 7% every year since 1997. The National Institute of Environmental Health Sciences (NIEHS) convened an expert panel workshop to review the body of literature examining the role of the environment in the development of autoimmune disease and to identify conclusions, confidences, and critical knowledge gaps in this area. The results of the workshop discussion are summarized in the articles found in this issue of the Journal of Autoimmunity. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Tolerance breakdown Monozygotic twins Familiarity Environment Exposure
1. The genetic basis for autoimmune disease The etiology and pathogenesis of autoimmune diseases remain largely unknown despite our enormous progress in the technical and analytical methods crucial to clinical epidemiology and experimental laboratory research activities. In review of the factors causing tolerance breakdown we can be lured into a simplistic view exemplified by the straightforward solution found for the etiology of rheumatic fever. In this case, the logical consequence of events spanning through the known bacterial infection, the individual susceptibility, and the final tissue injury appears intuitive. Unfortunately, a similarly straightforward solution failed to apply to
* Corresponding author. Clinical Immunology, Humanitas Clinical and Research Center, Via A. Manzoni 56, Rozzano, MI 20089, Italy. Tel.: þ39 02 8224 5129; fax: þ39 02 8224 4590. ** Corresponding author. Tel.: þ86 13 7870 97676; fax: þ86 73 1553 3525. *** Corresponding author. Tel.: þ1 919 316 4621; fax: þ1 919 541 0462. E-mail addresses: [email protected] (C. Selmi), [email protected] (Q. Lu), [email protected] (M.C. Humble). 0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2012.07.011
other autoimmune diseases [1]. Thus, we are led to characterize all autoimmune diseases as complex or multifactorial, particularly considering the largely incomplete concordance between monozygotic twins. In the case of most autoimmune diseases, less than 50% (with the notable exceptions of primary biliary cirrhosis and celiac disease) of twin pairs are concordant for the disease phenotype [2]. The advent of high-throughput genomic platforms for large-scale analysis of single nucleotide polymorphisms hailed the possibility of unraveling the genomic bases of disease susceptibility but the resulting data from multicentric studies and independent recapitulation demonstrated that significant genetic associations only applied to subgroups of patients [3]. Of interest was the identification of shared genes representing the susceptibility bases of different and clinically unrelated autoimmune diseases, as in the case of STAT4 [4,5]or the IL12A receptor [6e9]. A major advantage of twin studies is the possibility to calculate the genetic heritability of each condition, i.e. the proportion of observable differences in a phenotype between individuals that is due to genetic differences. Since heritability is a proportion, its value will range from 0 (when genes do not contribute to
250
C. Selmi et al. / Journal of Autoimmunity 39 (2012) 249e252
phenotypic differences) to 1 (when the environment does not contribute to phenotypic differences). This estimate depends on numerous variables, including the prevalence of the trait in the general population and does not reflect the risk of getting a disease but the variance between twins. We may identify sources of individual variation into additive and dominant genetic effects (A, D), common environmental effects (C) and random environmental effects (E) with “heritability” defined as the proportion of the phenotypic variance attributable to genetic variance (A þ D). From a semantic standpoint, the term “environmentability” represents the proportion of phenotypic variance attributable to environmental variance (or 1-heritability). Of particular importance in the discussion of environmental factors is the fact that environmentability includes environmental influences that are sum of the common/shared environmental factors and individual environmental variance while also including the variance due to measurement errors or observation bias. In specific autoimmune diseases, genetic heritability estimates are summarized in Table 1 and demonstrate that the weight of genetic influences is maximum in some conditions (as for Crohn’s disease or ankylosing spondilitis) while being almost negligible in others (as for systemic sclerosis). 2. A growing interest for environmental factors in autoimmune diseases A PubMed search performed for each year between 1997 and 2011 using ‘autoimmune disease’ as the main search string was used as the base to determine the interest received by specific issues. The number of articles identified with this broad criterion almost doubled from 8890 in 1997 to 15,362 in 2011 with an average 3.7% yearly increase. When these denominators were used to depict the proportion of articles dedicated to ‘therapy,’ ‘genetics,’ or ‘environment,’ we observed that therapeutic studies steadily increased and represented between 60 and 75% of all publications (Fig. 1, Panel A). Manuscripts identified using the ‘environment’ or ‘genetics’ keywords represented two minority subgroups which, increased from 1.4% to 17.5% in 1997 to 2% and 18.5% in 2011, respectively (Fig. 1, Panel A). The search terms are broad and may
Table 1 Genetic heritability for specific autoimmune diseases based on available twin concordance rates and prevalence estimated. Of note, more than one estimate is provided for celiac disease (based on different prevalence rates in the general population), multiple sclerosis (the lowest and highest values are represented from multiple studies), and rheumatoid arthritis (based on the anti-citrullinated peptide antibody status). Heritability rates obtained from known variants analysis are illustrated with (*). When available, 95% confidence intervals are provided.
Acute rheumatic fever Ankylosing spondilitis Celiac disease Crohn’s disease Multiple sclerosis Psoriasis Psoriatic arthritis Rheumatoid arthritis Sarcoidosis Systemic lupus erythematosus Systemic sclerosis Type 1 diabetes
Genetic heritability
Reference
0.60 0.97 0.57 0.87 1.00 0.55 0.25 0.76 0.66 0.65 0.68 0.66 0.66 0.66
[36] [37] [38]
(0.41e0.81) (0.92e0.99) (0.32e0.93) if 1/1000 prevalence (0.49e1.00) if 1/91 prevalence (0.34e1.00) (*)
(0e0.88) (0.33e0.88) (0.52e0.77) (0.22e1.00) (0.55e0.79) if ACPA-positive (0.21e0.82) if ACPA-negative (0.52e0.80) (*)
0.008 0.88 (0.78e0.94) 0.80 (*)
[39] [40] [41] [42] [43] [44] [45] [40] [46] [47] [40]
not encompass all publications within their respective fields. Although the smallest in number, publications involving ‘environment’ grew by nearly 43% over the selected time frame, reflecting an increased interest in environmental factors contributing to autoimmune disease (Fig. 1, Panel B). With the small but growing accumulation of research data and interest in this area, the National Institute of Environmental Health Sciences (NIEHS) convened an expert panel workshop in the fall of 2010 to bring together researchers in the environmental health science and autoimmune fields. The workshop was designed to allow participants to discuss the existing evidence linking autoimmune disease and environmental exposures, and to discriminate levels of confidence between those associations. Products from the workshop include the four manuscripts included in this issue of the Journal of Autoimmunity with three providing comprehensive reviews of the available evidence in the areas of clinical epidemiology, animal models, and general mechanisms [10e12]and the fourth dedicated to defining putative criteria for environmentally-induced autoimmunity [13]. 3. Overarching questions in autoimmunity There are a number of overarching questions in the field of autoimmunity. First, are we observing an actual increase in the incidence of autoimmune diseases worldwide or is the increase due to growing physician awareness and improved diagnostic tools and criteria? The answers to these questions require rigorous population-based epidemiological studies and data mining tools, as illustrated by the diesel exhaust in miners study [14e17]. Second and relative to the first issue is the latency between exposure and phenotype [18]. Environmental factors may induce the breakdown of tolerance and the development of an autoimmune phenotype in genetically susceptible individuals, and one may hypothesize that there is a significant lapse between the exposure and the appearance of disease-associated autoantibodies and clinical manifestation of disease [19,20]. With the increase in incidence and prevalence of autoimmune diseases over the past decade, the effects of environmental exposures on epigenetic determinants such as DNA methylation and epigenetics must be taken into consideration [21] (also Refs. [23e31]). The effect of factors such as tobacco smoke or UV radiation on DNA methylation reported in cancer pathogenesis may well apply to autoimmune diseases [22]. Third, we cannot overlook the possibility that stochastic events may well underlie some of the proposed causative links. The well-established paradigm of autoantibody production in the mrl mouse model [23] is indeed based on the random expression of particular immunoglobulin variable-region genes combined with mechanisms of extensive somatic mutations. Fourth, exposure to multiple environmental factors [24e27], compounded with underlying infection and/or hormones, complicates our ability to link specific exposure to autoimmune disease etiology [28]. This hypothesis is well illustrated by the direct link between B cell mediated autoimmunity and lymphoma, as observed in the elevated risk of neoplastic transformation in patients with Sjogren’s syndrome [29e35]. 4. Concluding remarks In conclusion, as indicated above, genetics and heritability can only account for a portion of the incidence of autoimmune disease, supporting a hypothesis that the etiology of autoimmune disease involves both genetic and environmental factors. The NIEHS workshop, with the support from the American Autoimmune Related
C. Selmi et al. / Journal of Autoimmunity 39 (2012) 249e252
251
Fig. 1. Results of a PubMed search performed using ‘autoimmune disease’ in addition to ‘therapy’, ‘genetics’, or ‘environment’ search strings. The number of publications are illustrated as the proportion (%) of each subgroup out of the total ‘autoimmune disease’ articles (Panel A), while Panel B demonstrates the yearly changes (%) in the number of publications using each keyword combination.
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C. Selmi et al. / Journal of Autoimmunity 39 (2012) 249e252
Diseases Association (AARDA), enabled experts from the environmental health sciences and autoimmune research communities to review the findings from their diverse research disciplines and identify conclusions that could be drawn from existing data. In addition, the reviews identify knowledge gaps and areas of uncertainty regarding the role of environmental exposures in the development of autoimmune disease, highlighting the importance of continued research examining the role of genetics, epigenetics and environmental components in the disease manifestation. Disclaimer This article may be the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. References [1] Gershwin ME, Shoenfeld Y. Cutting-edge issues in organ-specific autoimmunity. Clin Rev Allergy Immunol 2011;41:123e5. [2] Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 2012;38:J156e69. [3] Zenewicz LA, Abraham C, Flavell RA, Cho JH. Unraveling the genetics of autoimmunity. Cell 2010;140:791e7. [4] Glas J, Seiderer J, Nagy M, Fries C, Beigel F, Weidinger M, et al. Evidence for STAT4 as a common autoimmune gene: rs7574865 is associated with colonic Crohn’s disease and early disease onset. PLoS One 2010;5:e10373. [5] Ji JD, Lee WJ, Kong KA, Woo JH, Choi SJ, Lee YH, et al. Association of STAT4 polymorphism with rheumatoid arthritis and systemic lupus erythematosus: a meta-analysis. Mol Biol Rep 2010;37:141e7. [6] Zhernakova A, Stahl EA, Trynka G, Raychaudhuri S, Festen EA, Franke L, et al. Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet 2011;7:e1002004. [7] Liu Y, Helms C, Liao W, Zaba LC, Duan S, Gardner J, et al. A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. PLoS Genet 2008;4:e1000041. [8] Bossini-Castillo L, Martin JE, Broen J, Gorlova O, Simeon CP, Beretta L, et al. A GWAS follow-up study reveals the association of the IL12RB2 gene with systemic sclerosis in Caucasian populations. Hum Mol Genet 2012;21:926e33. [9] Zhang J, Huang Z, Sun R, Tian Z, Wei H. IFN-gamma induced by IL-12 administration prevents diabetes by inhibiting pathogenic IL-17 production in NOD mice. J Autoimmun 2012;38:20e8. [10] Miller FW, Alfredsson L, Costenbader KH, Kamen DL, Nelson LM, Norris JM, et al. Epidemiology of environmental exposures and human autoimmune diseases: findings from a national institute of environmental health sciences expert panel workshop. J Autoimmun 2012;39(4):259e71. [11] Germolec D, Kono DH, Pfau JC, Pollard KM. Animal models used to examine the role of the environment in the development of autoimmune disease: findings from an NIEHS expert panel workshop. J Autoimmun 2012;39(4):285e93. [12] Selmi C, Leung PS, Sherr DH, Diaz M, Nyland JF, Monestier M, et al. Mechanisms of environmental influence on human autoimmunity: a national institute of environmental health sciences expert panel workshop. J Autoimmun 2012;39(4):272e84. [13] Miller FW, Pollard KM, Parks CG, Germolec DR, Leung PS, Selmi C, et al. Criteria for environmentally associated autoimmune diseases. J Autoimmun 2012;39(4):253e8. [14] Morfeld P. Diesel exhaust in miners study: how to understand the findings? J Occup Med Toxicol 2012;7:10. [15] Silverman DT, Samanic CM, Lubin JH, Blair AE, Stewart PA, Vermeulen R, et al. The diesel exhaust in miners study: a nested case-control study of lung cancer and diesel exhaust. J Natl Cancer Inst 2012;104:855e68. [16] Attfield MD, Schleiff PL, Lubin JH, Blair A, Stewart PA, Vermeulen R, et al. The diesel exhaust in miners study: a cohort mortality study with emphasis on lung cancer. J Natl Cancer Inst 2012;104:869e83. [17] Stewart PA, Vermeulen R, Coble JB, Blair A, Schleiff P, Lubin JH, et al. The diesel exhaust in miners study: V. Evaluation of the exposure assessment methods. Ann Occup Hyg 2012 Mar 1 [Epub ahead of print]. [18] Patel MM, Miller RL. Rapid DNA methylation changes after exposure to traffic particles: the issue of spatio-temporal factors. Am J Respir Crit Care Med 2009; 180:1030. author reply -1.
[19] Arbuckle MR, McClain MT, Rubertone MV, Scofield RH, Dennis GJ, James JA, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003;349:1526e33. [20] Arbuckle MR, James JA, Kohlhase KF, Rubertone MV, Dennis GJ, Harley JB. Development of anti-dsDNA autoantibodies prior to clinical diagnosis of systemic lupus erythematosus. Scand J Immunol 2001;54:211e9. [21] Baccarelli A, Wright RO, Bollati V, Tarantini L, Litonjua AA, Suh HH, et al. Rapid DNA methylation changes after exposure to traffic particles. Am J Respir Crit Care Med 2009;179:572e8. [22] De Santis M, Selmi C. The therapeutic potential of epigenetics in autoimmune diseases. Clin Rev Allergy Immunol 2012;42:92e101. [23] Eisenberg RA, Craven SY, Warren RW, Cohen PL. Stochastic control of anti-Sm autoantibodies in MRL/Mp-lpr/lpr mice. J Clin Invest 1987;80:691e7. [24] Cunningham M, Gilkeson G. Estrogen receptors in immunity and autoimmunity. Clin Rev Allergy Immunol 2011;40:66e73. [25] Karpuzoglu E, Zouali M. The multi-faceted influences of estrogen on lymphocytes: toward novel immuno-interventions strategies for autoimmunity management. Clin Rev Allergy Immunol 2011;40:16e26. [26] Powell JJ, Faria N, Thomas-McKay E, Pele LC. Origin and fate of dietary nanoparticles and microparticles in the gastrointestinal tract. J Autoimmun 2010;34:J226e33. [27] Chang C. The immune effects of naturally occurring and synthetic nanoparticles. J Autoimmun 2010;34:J234e46. [28] Goodnow CC. Multistep pathogenesis of autoimmune disease. Cell 2007;130: 25e35. [29] Bournia VK, Vlachoyiannopoulos PG. Subgroups of Sjogren syndrome patients according to serological profiles. J Autoimmun 2012;39:15e26. [30] Brito-Zeron P, Retamozo S, Gandia M, Akasbi M, Perez-De-Lis M, DiazLagares C, et al. Monoclonal gammopathy related to Sjogren syndrome: a key marker of disease prognosis and outcomes. J Autoimmun 2012;39: 43e8. [31] Chiorini JA, Cihakova D, Ouellette CE, Caturegli P. Sjogren syndrome: advances in the pathogenesis from animal models. J Autoimmun 2009;33:190e6. [32] Borchers AT, Gershwin ME. Sociological differences between women and men: implications for autoimmunity. Autoimmun Rev 2012;11:A413e21. [33] Khanna R, Smith MJ. Utilization and costs of medical services and prescription medications for rheumatoid arthritis among recipients covered by a state medicaid program: a retrospective, cross-sectional, descriptive, database analysis. Clin Ther 2007;29:2456e67. [34] Maynard JW, Fang H, Petri M. Low socioeconomic status is associated with cardiovascular risk factors and outcomes in systemic lupus erythematosus. J Rheumatol 2012;39:777e83. [35] Peschken CA, Katz SJ, Silverman E, Pope JE, Fortin PR, Pineau C, et al. The 1000 Canadian faces of lupus: determinants of disease outcome in a large multiethnic cohort. J Rheumatol 2009;36:1200e8. [36] Engel ME, Stander R, Vogel J, Adeyemo AA, Mayosi BM. Genetic susceptibility to acute rheumatic fever: a systematic review and meta-analysis of twin studies. PLoS One 2011;6:e25326. [37] Brown MA, Kennedy LG, MacGregor AJ, Darke C, Duncan E, Shatford JL, et al. Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. Arthritis Rheum 1997;40:1823e8. [38] Nistico L, Fagnani C, Coto I, Percopo S, Cotichini R, Limongelli MG, et al. Concordance, disease progression, and heritability of coeliac disease in Italian twins. Gut 2006;55:803e8. [39] Tysk C, Lindberg E, Jarnerot G, Floderus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29:990e6. [40] So HC, Gui AH, Cherny SS, Sham PC. Evaluating the heritability explained by known susceptibility variants: a survey of ten complex diseases. Genet Epidemiol 2011;35:310e7. [41] Hawkes CH, Macgregor AJ. Twin studies and the heritability of MS: a conclusion. Mult Scler 2009;15:661e7. [42] Grjibovski AM, Olsen AO, Magnus P, Harris JR. Psoriasis in Norwegian twins: contribution of genetic and environmental effects. J Eur Acad Dermatol Venereol 2007;21:1337e43. [43] Pedersen OB, Svendsen AJ, Ejstrup L, Skytthe A, Junker P. On the heritability of psoriatic arthritis. Disease concordance among monozygotic and dizygotic twins. Ann Rheum Dis 2008;67:1417e21. [44] van der Woude D, Houwing-Duistermaat JJ, Toes RE, Huizinga TW, Thomson W, Worthington J, et al. Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis. Arthritis Rheum 2009;60:916e23. [45] Sverrild A, Backer V, Kyvik KO, Kaprio J, Milman N, Svendsen CB, et al. Heredity in sarcoidosis: a registry-based twin study. Thorax 2008;63:894e6. [46] Feghali-Bostwick C, Medsger Jr TA, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum 2003;48:1956e63. [47] Hyttinen V, Kaprio J, Kinnunen L, Koskenvuo M, Tuomilehto J. Genetic liability of type 1 diabetes and the onset age among 22,650 young Finnish twin pairs: a nationwide follow-up study. Diabetes 2003;52:1052e5.
Contents lists available at SciVerse ScienceDirect
Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm
Review
Heritability versus the role of the environment in autoimmunity Carlo Selmi a, b, *, Qianjin Lu c, **, Michael C. Humble d, *** a
Division of Rheumatology, Allergy, and Clinical Immunology, University of California, Davis, USA Clinical Immunology, Humanitas Clinical and Research Center, Via A. Manzoni 56, Rozzano, MI 20089, Italy c Department of Dermatology, Second Xiangya Hospital, Central South University, Hunan Key Laboratory of Medical Epigenomics, #139 Renmin Middle Road, Changsha, Hunan 410011, PR China d Division of Extramural Research and Training, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, PO Box 12233, MD-K3-15, Research Triangle Park, NC 27709, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 July 2012 Accepted 31 July 2012
The higher concordant occurrence of autoimmune diseases in monozygotic twins compared to dizygotic or sibling pairs supports the role for genetic susceptibility. For most conditions, however, concordance rates are considerably below 100% and lead to the estimate of the weight of genetics coined “heritability”. In the group of autoimmune diseases heritability ranges between 0.008 and 1 with median values of approximately 0.60. A complementary term coined “environmentability” represents the environmental influence on individual phenotype, and can include dietary habits, chemicals, or hygienic conditions. Genome-wide association data in complex diseases confirmed a role for the environment in disease etiology as significantly associated polymorphisms were found only in subgroups of patients and controls. Environmental links to autoimmunity range from anecdotal associations or case series to largely investigated experimental and epidemiological studies. A bibliographic analysis reveals that the number of publications dedicated to environmental factors in autoimmunity has grown on average by 7% every year since 1997. The National Institute of Environmental Health Sciences (NIEHS) convened an expert panel workshop to review the body of literature examining the role of the environment in the development of autoimmune disease and to identify conclusions, confidences, and critical knowledge gaps in this area. The results of the workshop discussion are summarized in the articles found in this issue of the Journal of Autoimmunity. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Tolerance breakdown Monozygotic twins Familiarity Environment Exposure
1. The genetic basis for autoimmune disease The etiology and pathogenesis of autoimmune diseases remain largely unknown despite our enormous progress in the technical and analytical methods crucial to clinical epidemiology and experimental laboratory research activities. In review of the factors causing tolerance breakdown we can be lured into a simplistic view exemplified by the straightforward solution found for the etiology of rheumatic fever. In this case, the logical consequence of events spanning through the known bacterial infection, the individual susceptibility, and the final tissue injury appears intuitive. Unfortunately, a similarly straightforward solution failed to apply to
* Corresponding author. Clinical Immunology, Humanitas Clinical and Research Center, Via A. Manzoni 56, Rozzano, MI 20089, Italy. Tel.: þ39 02 8224 5129; fax: þ39 02 8224 4590. ** Corresponding author. Tel.: þ86 13 7870 97676; fax: þ86 73 1553 3525. *** Corresponding author. Tel.: þ1 919 316 4621; fax: þ1 919 541 0462. E-mail addresses: [email protected] (C. Selmi), [email protected] (Q. Lu), [email protected] (M.C. Humble). 0896-8411/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jaut.2012.07.011
other autoimmune diseases [1]. Thus, we are led to characterize all autoimmune diseases as complex or multifactorial, particularly considering the largely incomplete concordance between monozygotic twins. In the case of most autoimmune diseases, less than 50% (with the notable exceptions of primary biliary cirrhosis and celiac disease) of twin pairs are concordant for the disease phenotype [2]. The advent of high-throughput genomic platforms for large-scale analysis of single nucleotide polymorphisms hailed the possibility of unraveling the genomic bases of disease susceptibility but the resulting data from multicentric studies and independent recapitulation demonstrated that significant genetic associations only applied to subgroups of patients [3]. Of interest was the identification of shared genes representing the susceptibility bases of different and clinically unrelated autoimmune diseases, as in the case of STAT4 [4,5]or the IL12A receptor [6e9]. A major advantage of twin studies is the possibility to calculate the genetic heritability of each condition, i.e. the proportion of observable differences in a phenotype between individuals that is due to genetic differences. Since heritability is a proportion, its value will range from 0 (when genes do not contribute to
250
C. Selmi et al. / Journal of Autoimmunity 39 (2012) 249e252
phenotypic differences) to 1 (when the environment does not contribute to phenotypic differences). This estimate depends on numerous variables, including the prevalence of the trait in the general population and does not reflect the risk of getting a disease but the variance between twins. We may identify sources of individual variation into additive and dominant genetic effects (A, D), common environmental effects (C) and random environmental effects (E) with “heritability” defined as the proportion of the phenotypic variance attributable to genetic variance (A þ D). From a semantic standpoint, the term “environmentability” represents the proportion of phenotypic variance attributable to environmental variance (or 1-heritability). Of particular importance in the discussion of environmental factors is the fact that environmentability includes environmental influences that are sum of the common/shared environmental factors and individual environmental variance while also including the variance due to measurement errors or observation bias. In specific autoimmune diseases, genetic heritability estimates are summarized in Table 1 and demonstrate that the weight of genetic influences is maximum in some conditions (as for Crohn’s disease or ankylosing spondilitis) while being almost negligible in others (as for systemic sclerosis). 2. A growing interest for environmental factors in autoimmune diseases A PubMed search performed for each year between 1997 and 2011 using ‘autoimmune disease’ as the main search string was used as the base to determine the interest received by specific issues. The number of articles identified with this broad criterion almost doubled from 8890 in 1997 to 15,362 in 2011 with an average 3.7% yearly increase. When these denominators were used to depict the proportion of articles dedicated to ‘therapy,’ ‘genetics,’ or ‘environment,’ we observed that therapeutic studies steadily increased and represented between 60 and 75% of all publications (Fig. 1, Panel A). Manuscripts identified using the ‘environment’ or ‘genetics’ keywords represented two minority subgroups which, increased from 1.4% to 17.5% in 1997 to 2% and 18.5% in 2011, respectively (Fig. 1, Panel A). The search terms are broad and may
Table 1 Genetic heritability for specific autoimmune diseases based on available twin concordance rates and prevalence estimated. Of note, more than one estimate is provided for celiac disease (based on different prevalence rates in the general population), multiple sclerosis (the lowest and highest values are represented from multiple studies), and rheumatoid arthritis (based on the anti-citrullinated peptide antibody status). Heritability rates obtained from known variants analysis are illustrated with (*). When available, 95% confidence intervals are provided.
Acute rheumatic fever Ankylosing spondilitis Celiac disease Crohn’s disease Multiple sclerosis Psoriasis Psoriatic arthritis Rheumatoid arthritis Sarcoidosis Systemic lupus erythematosus Systemic sclerosis Type 1 diabetes
Genetic heritability
Reference
0.60 0.97 0.57 0.87 1.00 0.55 0.25 0.76 0.66 0.65 0.68 0.66 0.66 0.66
[36] [37] [38]
(0.41e0.81) (0.92e0.99) (0.32e0.93) if 1/1000 prevalence (0.49e1.00) if 1/91 prevalence (0.34e1.00) (*)
(0e0.88) (0.33e0.88) (0.52e0.77) (0.22e1.00) (0.55e0.79) if ACPA-positive (0.21e0.82) if ACPA-negative (0.52e0.80) (*)
0.008 0.88 (0.78e0.94) 0.80 (*)
[39] [40] [41] [42] [43] [44] [45] [40] [46] [47] [40]
not encompass all publications within their respective fields. Although the smallest in number, publications involving ‘environment’ grew by nearly 43% over the selected time frame, reflecting an increased interest in environmental factors contributing to autoimmune disease (Fig. 1, Panel B). With the small but growing accumulation of research data and interest in this area, the National Institute of Environmental Health Sciences (NIEHS) convened an expert panel workshop in the fall of 2010 to bring together researchers in the environmental health science and autoimmune fields. The workshop was designed to allow participants to discuss the existing evidence linking autoimmune disease and environmental exposures, and to discriminate levels of confidence between those associations. Products from the workshop include the four manuscripts included in this issue of the Journal of Autoimmunity with three providing comprehensive reviews of the available evidence in the areas of clinical epidemiology, animal models, and general mechanisms [10e12]and the fourth dedicated to defining putative criteria for environmentally-induced autoimmunity [13]. 3. Overarching questions in autoimmunity There are a number of overarching questions in the field of autoimmunity. First, are we observing an actual increase in the incidence of autoimmune diseases worldwide or is the increase due to growing physician awareness and improved diagnostic tools and criteria? The answers to these questions require rigorous population-based epidemiological studies and data mining tools, as illustrated by the diesel exhaust in miners study [14e17]. Second and relative to the first issue is the latency between exposure and phenotype [18]. Environmental factors may induce the breakdown of tolerance and the development of an autoimmune phenotype in genetically susceptible individuals, and one may hypothesize that there is a significant lapse between the exposure and the appearance of disease-associated autoantibodies and clinical manifestation of disease [19,20]. With the increase in incidence and prevalence of autoimmune diseases over the past decade, the effects of environmental exposures on epigenetic determinants such as DNA methylation and epigenetics must be taken into consideration [21] (also Refs. [23e31]). The effect of factors such as tobacco smoke or UV radiation on DNA methylation reported in cancer pathogenesis may well apply to autoimmune diseases [22]. Third, we cannot overlook the possibility that stochastic events may well underlie some of the proposed causative links. The well-established paradigm of autoantibody production in the mrl mouse model [23] is indeed based on the random expression of particular immunoglobulin variable-region genes combined with mechanisms of extensive somatic mutations. Fourth, exposure to multiple environmental factors [24e27], compounded with underlying infection and/or hormones, complicates our ability to link specific exposure to autoimmune disease etiology [28]. This hypothesis is well illustrated by the direct link between B cell mediated autoimmunity and lymphoma, as observed in the elevated risk of neoplastic transformation in patients with Sjogren’s syndrome [29e35]. 4. Concluding remarks In conclusion, as indicated above, genetics and heritability can only account for a portion of the incidence of autoimmune disease, supporting a hypothesis that the etiology of autoimmune disease involves both genetic and environmental factors. The NIEHS workshop, with the support from the American Autoimmune Related
C. Selmi et al. / Journal of Autoimmunity 39 (2012) 249e252
251
Fig. 1. Results of a PubMed search performed using ‘autoimmune disease’ in addition to ‘therapy’, ‘genetics’, or ‘environment’ search strings. The number of publications are illustrated as the proportion (%) of each subgroup out of the total ‘autoimmune disease’ articles (Panel A), while Panel B demonstrates the yearly changes (%) in the number of publications using each keyword combination.
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