Understanding and Preventing the Global Increase of Inflammatory Bowel Disease

The inflammatory bowel diseases (IBDs) are contemporary conditions of industrialized societies. The prevalence of IBD continues to increase steadily in Western countries, and newly industrialized countries have a rapidly increasing incidence. The global spread of IBD appears to associate with Westernization of diets and environments, which affects the intestinal microbiome and increases the risk of IBD in genetically susceptible individuals. It is important to increase our understanding of these events to slow progression of IBD. We present a long-term plan to develop interventions that slow or stop the global increase in the incidence of IBD. The inflammatory bowel diseases (IBDs) are contemporary conditions of industrialized societies. The prevalence of IBD continues to increase steadily in Western countries, and newly industrialized countries have a rapidly increasing incidence. The global spread of IBD appears to associate with Westernization of diets and environments, which affects the intestinal microbiome and increases the risk of IBD in genetically susceptible individuals. It is important to increase our understanding of these events to slow progression of IBD. We present a long-term plan to develop interventions that slow or stop the global increase in the incidence of IBD. Siew C. NgView Large Image Figure ViewerDownload Hi-res image Download (PPT) The evolution of the inflammatory bowel diseases (IBDs) follows the advancement of society.1Kaplan G.G. The global burden of IBD: from 2015 to 2025.Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1218) Google Scholar Systematic documentation of ulcerative colitis began in Western Europe in the 1800s, with the first case report published by Wilks and Moxon2Wilks S. Moxon W. Lectures on pathological anatomy.2nd ed. J & A Churchill, London1875Google Scholar in 1859. The emergence of ulcerative colitis in Western Europe paralleled the advent of the industrial revolution in the 1800s, a time when approximately 1 billion people lived on earth.3Mulder D.J. Noble A.J. Justinich C.J. et al.A tale of two diseases: the history of inflammatory bowel disease.J Crohns Colitis. 2014; 8: 341-348Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar The industrial revolution led to increased urbanization, with a shift in economies from rural (agricultural) to urban (manufacturing). The increasing population density within cities greatly changed diet and lifestyles—today these societal changes are called Westernization.4Crafts N. Productivity growth in the industrial revolution: a new growth accounting perspective.J Econ Hist. 2004; 64: 521-535Crossref Scopus (42) Google Scholar The incidence of ulcerative colitis slowly increased in the early 1900s in Western countries, and regional ileitis entered the medical vernacular in 1932 after the publication of a series of cases by Crohn et al.5Crohn B.B. Ginzburg L. Oppenheimer G.D. Regional ileitis: a pathologic and clinical entity.JAMA. 1932; 99: 1323-1329Crossref Scopus (1064) Google Scholar The 1950s was considered to be the start of the great acceleration of human civilization, denoted by exponential global growth in the human population.6Waters C.N. Zalasiewicz J. Summerhayes C. et al.The Anthropocene is functionally and stratigraphically distinct from the Holocene.Science. 2016; 351: aad2622Crossref PubMed Scopus (1151) Google Scholar The rapid population increase was driven by economic advancement, automation, increased food production, and profound resource and energy utilization.6Waters C.N. Zalasiewicz J. Summerhayes C. et al.The Anthropocene is functionally and stratigraphically distinct from the Holocene.Science. 2016; 351: aad2622Crossref PubMed Scopus (1151) Google Scholar Likewise, the incidence of ulcerative colitis and Crohn’s disease exploded in wealthy Westernized countries during the last 50 years of the 20th century (Figure 1).7Molodecky N.A. Panaccione R. Ghosh S. et al.Challenges associated with identifying the environmental determinants of the inflammatory bowel diseases.Inflamm Bowel Dis. 2011; 17: 1792-1799Crossref PubMed Scopus (72) Google Scholar Many factors contributed to the increase in the incidence of IBD, including increased awareness, improved access to medical technology and health care providers, development of sophisticated disease surveillance systems, and environmental exposures associated with Westernization of society.1Kaplan G.G. The global burden of IBD: from 2015 to 2025.Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1218) Google Scholar We define Westernized countries as high-income countries of dominantly Western European cultural heritage: Western Europe, the United States, Canada, Australia, and New Zealand. These countries have a shared industrial history with the industrial revolution that began in Great Britain in the 18th century before spreading to the rest of Western Europe and to Western European colonies in North America and Oceania. For brevity, we use the terms industrializing and newly industrialized to describe countries that are developing or have developed, respectively, qualities similar to the wealthy Westernized countries and regions (eg, industrialization, diet, health care, urbanization). We also use the terms Western countries and industrialized countries to refer to wealthy Westernized countries. The end of the 20th century is recognized as the onset of globalization whereby certain industrializing countries in Asia, the Middle East, and South America became more Westernized. During this time, newly industrialized countries experienced rapid population growth, urbanization, industrialization, and Westernization of culture.8Zwi A.B. Mills A. Health policy in less developed countries: past trends and future directions.J Int Dev. 1995; 7: 299-328Crossref PubMed Scopus (40) Google Scholar In comparison with Western countries, the pace of these changes was accelerated dramatically, even when compared with the Western Industrial Revolution. Nearly 100 years after Sir Wilks case report of IBD,2Wilks S. Moxon W. Lectures on pathological anatomy.2nd ed. J & A Churchill, London1875Google Scholar the first case of ulcerative colitis was recognized in 1956 in China.9Jiang X.-L. Cui H.-F. An analysis of 10218 ulcerative colitis cases in China.World J Gastroenterol. 2002; 8: 158-161Crossref PubMed Scopus (179) Google Scholar Systematic analyses confirmed that the incidence of ulcerative colitis, followed by that of Crohn’s disease, was increasing in Asia at the turn of the 21st century, similar to that observed in Western countries during the 20th century (Figure 1).10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar In 2017, IBD is a global disease with the highest prevalence in Western countries, but with newly industrialized countries documenting the greatest increases in incidence. The peak in the incidence of IBD in newly industrialized countries is unknown. However, despite this, with population sizes of countries such as India and China each exceeding 1 billion, the future global impact of IBD simply cannot be ignored. We review the global epidemiologic features of IBD, discuss what these tell us about the pathogenesis of IBD, and recommend future directions for research. Based on this information we will propose a moonshot to cut the global incidence of IBD by 50% by 2032. The diagnosis of IBD is made in every inhabitable continent, among all ethnicities and socioeconomic classes. Although IBD is most prevalent among individuals of European descent living in wealthy Western countries, newly industrialized countries in Asia, the Middle East, Africa, and South America have reported rapid increases in incidence.10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar As incidence increases, the prevalence of IBD also is increasing in many of these countries. IBD care will be required for an older population in the Western countries and a younger population in newly industrialized countries.1Kaplan G.G. The global burden of IBD: from 2015 to 2025.Nat Rev Gastroenterol Hepatol. 2015; 12: 720-727Crossref PubMed Scopus (1218) Google Scholar This information is required to develop a global strategy for handling the future burden of IBD. Since 2000, the prevalence of IBD has ranged from 0.3% to 0.5% in North America.11Benchimol E.I. Manuel D.G. Guttmann A. et al.Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends.Inflamm Bowel Dis. 2014; 20: 1761-1769Crossref PubMed Scopus (131) Google Scholar, 12Kappelman M.D. Moore K.R. Allen J.K. et al.Recent trends in the prevalence of Crohn's disease and ulcerative colitis in a commercially insured US population.Dig Dis Sci. 2013; 58: 519-525Crossref PubMed Scopus (330) Google Scholar Similar high prevalence values have been reported in Northern Europe (eg, United Kingdom and Scandinavia),13Busch K. Ludvigsson J.F. Ekstrom-Smedby K. et al.Nationwide prevalence of inflammatory bowel disease in Sweden: a population-based register study.Aliment Pharmacol Ther. 2014; 39: 57-68Crossref PubMed Scopus (98) Google Scholar, 14Stone M.A. Mayberry J.F. Baker R. Prevalence and management of inflammatory bowel disease: a cross-sectional study from central England.Eur J Gastroenterol Hepatol. 2003; 15: 1275-1280Crossref PubMed Scopus (82) Google Scholar Western Europe (eg, Spain and Germany),15Hein R. Koster I. Bollschweiler E. et al.Prevalence of inflammatory bowel disease: estimates for 2010 and trends in Germany from a large insurance-based regional cohort.Scand J Gastroenterol. 2014; 49: 1325-1335Crossref PubMed Scopus (38) Google Scholar, 16Lucendo A.J. Hervias D. Roncero O. et al.Epidemiology and temporal trends (2000-2012) of inflammatory bowel disease in adult patients in a central region of Spain.Eur J Gastroenterol Hepatol. 2014; 26: 1399-1407Crossref PubMed Scopus (10) Google Scholar and Oceania (eg, New Zealand).17Gearry R.B. Richardson A. Frampton C.M.A. et al.High incidence of Crohn's disease in Canterbury, New Zealand: results of an epidemiologic study.Inflamm Bowel Dis. 2006; 12: 936-943Crossref PubMed Scopus (222) Google Scholar What began as a handful of cases of ulcerative colitis, followed by Crohn’s disease, in the early 1900s in Western countries has grown to millions of individuals afflicted with IBD in North America, Europe, and Oceania.18Burisch J. Jess T. Martinato M. et al.The burden of inflammatory bowel disease in Europe.J Crohns Colitis. 2013; 7: 322-337Abstract Full Text Full Text PDF PubMed Scopus (647) Google Scholar, 19Kappelman M.D. Rifas-Shiman S.L. Kleinman K. et al.The prevalence and geographic distribution of Crohn's disease and ulcerative colitis in the United States.Clin Gastroenterol Hepatol. 2007; 5: 1424-1429Abstract Full Text Full Text PDF PubMed Scopus (744) Google Scholar The steady increase in the prevalence of IBD coincided with the great acceleration of the human population in the last half of the 20th century.6Waters C.N. Zalasiewicz J. Summerhayes C. et al.The Anthropocene is functionally and stratigraphically distinct from the Holocene.Science. 2016; 351: aad2622Crossref PubMed Scopus (1151) Google Scholar During this time the incidence of Crohn’s disease and ulcerative colitis sharply increased; a finding consistently shown by more than 200 epidemiologic studies investigating IBD in Western countries during the 20th century (Figure 1).10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar Since the start of the 21st century, the incidence of IBD has been changing in Western countries. Some contemporary population-based studies have shown stabilization, and some have reported a decreasing incidence of IBD, although pediatric-onset IBD continues to increase steadily in incidence.11Benchimol E.I. Manuel D.G. Guttmann A. et al.Changing age demographics of inflammatory bowel disease in Ontario, Canada: a population-based cohort study of epidemiology trends.Inflamm Bowel Dis. 2014; 20: 1761-1769Crossref PubMed Scopus (131) Google Scholar, 20Benchimol E.I. Guttmann A. Griffiths A.M. et al.Increasing incidence of paediatric inflammatory bowel disease in Ontario, Canada: evidence from health administrative data.Gut. 2009; 58: 1490-1497Crossref PubMed Scopus (294) Google Scholar, 21Bitton A. Vutcovici M. Patenaude V. et al.Epidemiology of inflammatory bowel disease in Quebec: recent trends.Inflamm Bowel Dis. 2014; 20: 1770-1776Crossref PubMed Scopus (48) Google Scholar, 22Leddin D. Tamim H. Levy A.R. Decreasing incidence of inflammatory bowel disease in Eastern Canada: a population database study.BMC Gastroenterol. 2014; 14: 140Crossref PubMed Scopus (46) Google Scholar Nonetheless, population-based studies of Western countries have shown consistently that since 2000, the incidence of IBD has not accelerated at the same rates observed at the end of the 20th century. Despite the easing of the incidence rates in some regions, the prevalence of IBD continues to increase substantially throughout the world.10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar IBD is a chronic disease with relatively low mortality that is diagnosed primarily in young individuals. Consequently, the prevalence of IBD increases over time such that new diagnoses add to the base population at a rate significantly higher than the loss of patients from a clinical practice. The net effect is a steady increase in the prevalence of IBD over time. For example, in Olmsted County, Minnesota, the prevalence of Crohn’s disease was only 28 cases per 100,000 in 1965,23Sedlack R.E. Nobrega F.T. Kurland L.T. et al.Inflammatory colon disease in Rochester, Minnesota, 1935-1964.Gastroenterology. 1972; 62: 935-941Abstract Full Text PDF PubMed Scopus (68) Google Scholar increasing to 90.5 per 100,000 in 1980,24Sedlack R.E. Whisnant J. Elveback L.R. et al.Incidence of Crohn's disease in Olmsted County, Minnesota, 1935-1975.Am J Epidemiol. 1980; 112: 759-763Crossref PubMed Scopus (69) Google Scholar 132.7 per 100,000 in 1991,25Loftus Jr., E.V. Silverstein M.D. Sandborn W.J. et al.Crohn's disease in Olmsted County, Minnesota, 1940-1993: incidence, prevalence, and survival.Gastroenterology. 1998; 114: 1161-1168Abstract Full Text Full Text PDF PubMed Scopus (523) Google Scholar 213.9 per 100,000 in 2001,26Loftus C.G. Loftus Jr., E.V. Harmsen W.S. et al.Update on the incidence and prevalence of Crohn's disease and ulcerative colitis in Olmsted County, Minnesota, 1940-2000.Inflamm Bowel Dis. 2007; 13: 254-261Crossref PubMed Scopus (544) Google Scholar and 246.7 per 100,000 in 2011.27Shivashankar R. Tremaine W. Harmsen S. et al.Updated incidence and prevalence of Crohn’s disease and ulcerative colitis in Olmsted County, Minnesota (1970-2010).Am J Gastroenterol. 2014; 109: S499Google Scholar The increase in the prevalence of IBD in Western countries poses a significant challenge to gastroenterologists. For example, the prevalence of IBD in the United States was estimated to be slightly more than 0.5% in 2015, and is forecasted to increase to more than 0.6% in a decade, which equates to approximately 2.2 million Americans living with IBD in 2025.28Coward S. Clement F. Williamson T. et al.The rising burden of inflammatory bowel disease in North America from 2015 to 2025: a predictive model.Am J Gastroenterol. 2015; 110: S835Crossref Scopus (21) Google Scholar Naturally, the average age of patients with established IBD increases each year, which in turn affects the complexity of care because older patients have more comorbidities and complications. Over the next decade, the number of patients with IBD may overwhelm gastroenterology clinics, necessitating innovations in health care delivery to meet the increasing demand. In contrast, newly industrialized countries in Asia, the Middle East, Africa, and South America have a low prevalence of IBD.10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar Studies recording the prevalence of IBD in newly industrialized countries are relatively sparse because of a lack of infrastructure for routine population-based disease surveillance. The prevalence of IBD in Japan was 76 cases per 100,000 in 2005,29Asakura K. Nishiwaki Y. Inoue N. et al.Prevalence of ulcerative colitis and Crohn's disease in Japan.J Gastroenterol. 2009; 44: 659-665Crossref PubMed Scopus (199) Google Scholar whereas in South Korea the prevalence of IBD was 42 per 100,000,30Yang S.-K. Yun S. Kim J.-H. et al.Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986-2005: a KASID study.Inflamm Bowel Dis. 2008; 14: 542-549Crossref PubMed Scopus (345) Google Scholar and the prevalence in Hong Kong was 43 per 100,000 in 2014.31Niu J. Miao J. Tang Y. et al.Identification of environmental factors associated with inflammatory bowel disease in a southwestern highland region of China: a nested case-control study.PLoS One. 2016; 11: e0153524Crossref PubMed Scopus (29) Google Scholar Fortunately, studies on the incidence of IBD in newly industrialized countries are becoming more common because several inception cohorts have been coordinated by gastroenterologists. The most noted inception cohort outside of Western countries is the Asia–Pacific Crohn’s and Colitis Epidemiologic Study—a population-based cohort of newly diagnosed patients with IBD (2011–2013) from 13 countries in the Asia–Pacific region.32Ng S.C. Tang W. Ching J.Y. et al.Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study.Gastroenterology. 2013; 145: 158-165.e152Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar The incidence of IBD in Asia is 1.4 cases per 100,000 and climbing.32Ng S.C. Tang W. Ching J.Y. et al.Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study.Gastroenterology. 2013; 145: 158-165.e152Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar The highest incidence of IBD among the Asia–Pacific Crohn’s and Colitis Epidemiologic Study countries is in India at 9.3 per 100,000 person-years.33Ng S. Kaplan G.G. Banerjee R. et al.Incidence and phenotype of inflammatory bowel disease from 13 countries in Asia-pacific: results from the Asia-Pacific Crohn's and colitis epidemiologic study 2011-2013.Gastroenterology. 2016; 150: S21Abstract Full Text PDF Google Scholar Overall, the incidence of IBD in China is 3.3 per 100,000; however, variation is high across China, with the highest incidence rates observed, tellingly, in regions with the greatest urbanization and the most economic advancement.33Ng S. Kaplan G.G. Banerjee R. et al.Incidence and phenotype of inflammatory bowel disease from 13 countries in Asia-pacific: results from the Asia-Pacific Crohn's and colitis epidemiologic study 2011-2013.Gastroenterology. 2016; 150: S21Abstract Full Text PDF Google Scholar, 34Ng S.C. Bernstein C.N. Vatn M.H. et al.Geographical variability and environmental risk factors in inflammatory bowel disease.Gut. 2013; 62: 630-649Crossref PubMed Scopus (399) Google Scholar In Asia, ulcerative colitis is 2-fold more likely to be diagnosed than Crohn’s disease, although this ratio has been decreasing over time.32Ng S.C. Tang W. Ching J.Y. et al.Incidence and phenotype of inflammatory bowel disease based on results from the Asia-pacific Crohn's and colitis epidemiology study.Gastroenterology. 2013; 145: 158-165.e152Abstract Full Text Full Text PDF PubMed Scopus (560) Google Scholar The incidence of IBD also is increasing rapidly in newly industrialized countries outside of Asia.10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar For example, the incidence of Crohn’s disease and ulcerative colitis substantially increased in Piaui, Brazil, from 1988 to 2012.35Parente J.M. Coy C.S. Campelo V. et al.Inflammatory bowel disease in an underdeveloped region of Northeastern Brazil.World J Gastroenterol. 2015; 21: 1197-1206Crossref PubMed Scopus (57) Google Scholar Furthermore, in Sao Paulo, Brazil, the incidence of IBD doubled from 4.5 per 100,000 (1991–1995) to 9.7 per 100,000 (2001–2005).36Victoria C.R. Sassak L.Y. Nunes H.R. Incidence and prevalence rates of inflammatory bowel diseases, in midwestern of Sao Paulo State, Brazil.Arq Gastroenterol. 2009; 46: 20-25Crossref PubMed Scopus (99) Google Scholar Data from Uruguay37Buenavida G. Casanas A. Vasquez C. et al.Incidence of inflammatory bowel disease in five geographical areas of Uruguay in the biennial 2007-2008.Acta Gastroenterol Latinoam. 2011; 41: 281-287PubMed Google Scholar and Barbados38Edwards C.N. Griffith S.G. Hennis A.J. et al.Inflammatory bowel disease: incidence, prevalence, and disease characteristics in Barbados, West Indies.Inflamm Bowel Dis. 2008; 14: 1419-1424Crossref PubMed Scopus (25) Google Scholar have shown patterns similar to those of Brazil, indicating that the incidence of IBD is increasing in Central and South America. However, the greatest gap in our understanding of the epidemiologic features of IBD comes from the lack of data from most newly industrialized countries—especially from developing nations. Our interactive global map of IBD incidence and prevalence can be found at: https://people.ucalgary.ca/∼ggkaplan/IBDG2016.html. In addition, see the Supplementary Appendix for a static global map with an accompanying table describing the incidence and prevalence by country. The current incidence rates and prevalence values reported from newly industrialized countries are akin to rates published in Western countries in the 1970s and 1980s.10Molodecky N.A. Soon I.S. Rabi D.M. et al.Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review.Gastroenterology. 2012; 142 (quiz e30): 46-54.e42Abstract Full Text Full Text PDF PubMed Scopus (3358) Google Scholar If the increase of IBD in newly industrialized countries parallels those of Western countries 30–40 years ago, then the global prevalence of IBD will climb steadily, affecting tens of millions of people throughout the world over the next generation. In 2027, newly industrialized countries almost certainly will be caring for considerably more patients with IBD, most diagnosed as they enter the work force. Young individuals with IBD living in poorer countries may face barriers in access to care and their ability to afford costly drugs such as biologics. The net effect is a global IBD community with a wide variation in health outcomes, resulting not from differences in disease pathogenesis but rather from economic disparities. Increasing our understanding of the pathogenesis of IBD with the goal of using our knowledge to prevent disease should be a top priority. Pathogenesis of Crohn’s disease and ulcerative colitis involves a dysregulated immune response to commensal microbiota in genetically susceptible individuals. The lifetime risk of IBD in first-degree relatives is at least 2-fold higher in Ashkenazi Jews than in non-Jews.39Roth M.P. Petersen G.M. McElree C. et al.Familial empiric risk estimates of inflammatory bowel disease in Ashkenazi Jews.Gastroenterology. 1989; 96: 1016-1020Abstract Full Text PDF PubMed Scopus (154) Google Scholar Twin studies have supported the heritable component of Crohn’s disease and ulcerative colitis.40Brant S.R. Update on the heritability of inflammatory bowel disease: the importance of twin studies.Inflamm Bowel Dis. 2011; 17: 1-5Crossref PubMed Scopus (89) Google Scholar Crohn’s disease has 20%–50% concordance between monozygotic twins and 10% concordance in dizygotic twins; concordance values for ulcerative colitis are estimated to be lower, at 15% and 5%, respectively. This observation indicates a weaker heritable component for ulcerative colitis.41Halfvarson J. Jess T. Magnuson A. et al.Environmental factors in inflammatory bowel disease: a co-twin control study of a Swedish-Danish twin population.Inflamm Bowel Dis. 2006; 12: 925-933Crossref PubMed Scopus (132) Google Scholar In 2001, linkage analyses identified variants in the NOD2 gene (also called CARD15) that increased risk for Crohn’s disease. This observation supported the model that alterations in innate immunity and the immune response to bacteria contributed to the pathogenesis of Crohn’s disease.42Hampe J. Cuthbert A. Croucher P.J. et al.Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations.Lancet. 2001; 357: 1925-1928Abstract Full Text Full Text PDF PubMed Scopus (1016) Google Scholar, 43Hugot J.P. Chamaillard M. Zouali H. et al.Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4688) Google Scholar, 44Ogura Y. Bonen D.K. Inohara N. et al.A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.Nature. 2001; 411: 603-606Crossref PubMed Scopus (4171) Google Scholar Since then, genome-wide association studies within genetics consortia have identified more variants associated with IBD.45Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3255) Google Scholar There are now more than 200 IBD risk loci, which indicate the involvement of innate immune response, adaptive immunity, autophagy, endoplasmic reticulum stress, intestinal epithelial barrier function, and microbial defense pathways in IBD.45Jostins L. Ripke S. Weersma R.K. et al.Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.Nature. 2012; 491: 119-124Crossref PubMed Scopus (3255) Google Scholar, 46Khor B. Gardet A. Xavier R.J. Genetics and pathogenesis of inflammatory bowel disease.Nature. 2011; 474: 307-317Crossref PubMed Scopus (1707) Google Scholar, 47Liu J.Z. van Sommeren S. Huang H. et al.Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015; 47: 979-986Crossref PubMed Scopus (1302) Google Scholar Furthermore, approximately 70% of IBD risk loci are shared with other immune-mediated disorders such as type 1 diabetes mellitus, celiac disease, rheumatoid arthritis, ankylosing spondylitis, and psoriasis.48Zhernakova A. van Diemen C.C. Wijmenga C. Detecting shared pathogenesis from the shared genetics of immune-related diseases.Nat Rev Genet. 2009; 10: 43-55Crossref PubMed Scopus (412) Google Scholar Genetic risk for IBD varies among different populations; individuals of African-American and Asian ancestry have a lower familial risk.49Huang C. Haritunians T. Okou D.T. et al.Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.Gastroenterology. 2015; 149: 1575-1586Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar A meta-analysis of genetic studies of different ethnic groups13Busch K. Ludvigsson J.F. Ekstrom-Smedby K. et al.Nationwide prevalence of inflammatory bowel disease in Sweden: a population-based register study.Aliment Pharmacol Ther. 2014; 39: 57-68Crossref PubMed Scopus (98) Google Scholar found most IBD risk loci to be shared among diverse ancestry groups (eg, African Americans, Caucasians, and Asians). There were only a few population-specific risk loci, with heterogeneity in effect size (such as in TNF-SF15 and ATG16L) or risk-allele frequency (such as in NOD2).47Liu J.Z. van Sommeren S. Huang H. et al.Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015; 47: 979-986Crossref PubMed Scopus (1302) Google Scholar This was reported in a transethnic association study of Crohn’s disease and ulcerative colitis, comprising 86,640 Europeans and 9846 individuals of East Asian, Iranian, and Indian descent, which identified 38 new risk loci.47Liu J.Z. van Sommeren S. Huang H. et al.Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015; 47: 979-986Crossref PubMed Scopus (1302) Google Scholar Analyses of the functions of the products of the genes at these loci associated risk of IBD, in Western and Eastern populations, with an abnormal immune response to gut microbes. Genetic studies have gre