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doi:10.1111/jgh.12859
SOLICITED REVIEW
Emerging leadership lecture: Inflammatory bowel disease in Asia: Emergence of a “Western” disease Siew C Ng Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Chinese University of Hong Kong, Hong Kong
Key words IBD, epidemiology, genetics, risk factors. Accepted for publication 28 November 2014. Correspondence Professor Siew C Ng, Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Chinese University of Hong Kong, Hong Kong. Email: [email protected] Statement of interests: I have served as a speaker for Ferring, Janssen, and Abbvie pharmaceuticals. Unrestricted educational grants from Ferring, Abbvie, and Jessie and Thomas Tam Charity Foundation have been used to support our epidemiology studies and IBD Registry.
Abstract More than a decade ago, inflammatory bowel disease (IBD) is rare in Asia. Today, the importance of IBD in Asia is exemplified by its rapidly increasing incidence, complicated disease behavior, and substantial morbidity. In the first large-scale population-based epidemiologic study in Asia, the incidence of IBD varied from 0.60 to 3.44 per 100 000. There has been a twofold to threefold increase in the incidence of IBD in several countries in Asia. Ulcerative colitis (UC) is more prevalent than Crohn’s disease (CD), although CD incidence is rapidly increasing. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. Complicated and penetrating CD are common in Asia. These epidemiologic changes may relate to increased contact with the West, westernization of diet, improved hygiene, increasing antibiotics use, or changes in the gut microbiota. Asian patients with CD have altered gut microbiota compared with their healthy counterparts and Caucasian CD subjects. Mucosa-associated microbiota in IBD may differ geographically. In a population-based case–control study, breast-feeding, having pets, and better sanitary conditions were protective of IBD, suggesting that childhood environment plays an important role in modulating disease development. Genetic factors also differ between Asians and Caucasians. Nucleotide oligomerization domain-2 (NOD2) and autophagy variants were not associated with CD, but tumor necrosis factor superfamily gene-15 polymorphisms were strongly associated with CD in East Asians. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD.
Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. The pathophysiology of IBD relates to the mucosal immune response to antigenic stimulation from the gut microbiota secondary to environmental influence, on a background of genetic susceptibility. Over the last 20 years, significant advances have been achieved in our understanding of IBD. One of the greatest scientific advances, enabled by high-throughput sequencing and other new technologies, have been a deeper understanding of the genetic factors that are associated with IBD susceptibility in conjunction with alterations in the intestinal microbiome.1,2 Secondly, the changing epidemiology of IBD has provided a unique opportunity for investigators in areas of emerging disease incidence to study disease evolution and etiology.3 For almost 20 years, I lived and worked in London, whereby IBD is common. I had the privilege to work with two inspiring figures in the field of IBD and mucosal immunology, Professor Michael Kamm and Professor Stella Knight, at St. Mark’s 440
Hospital in London. There I completed a Ph.D. in immunology and bacteriology in intestinal inflammation. In 2009, I joined the Division of Gastroenterology and Hepatology of the Chinese University of Hong Kong and witnessed the emergence of this “Western” disease in the Asian population, which mirrored what took place in the West 50 years ago. Professor Joseph Sung, my mentor, once told me that when he was a medical student, IBD almost does not exist. If he encounters a case of suspected IBD, investigations will be performed to prove that it is not IBD. More likely than not, the patient will be treated as infectious colitis or tuberculosis. Today, IBD is increasingly been recognized as an important disease with major health-care implications not just in developed, but also in developing countries. Although incidence and prevalence may have stabilized in high-incidence areas such as North America and Europe, they continue to rise in previously low-incidence areas such as Eastern Europe, Asia, and much of the developing world. This epidemiological shift likely relates to westernization of lifestyle, changes in diet, and improved hygiene as part of socioeconomic development in developing countries.
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It is a great honor for me to receive and deliver the Emerging Leadership Lecture 2014. Through a series of population-based and longitudinal studies and collaborative research with friends around the globe, we have studied the genetic susceptibility, epidemiology, and environmental risk factors associated with IBD in Asia. This paper summarizes our work in the past 5 years aimed to further enhance our understanding of the pathogenesis, characteristics, and evolution of IBD in this part of the world. Studying the epidemiology of IBD in an area of rapidly increasing incidence may lead to discovery of important etiologic factors associated with disease development.
What do we know about epidemiology of IBD in Asia? To date, most data on epidemiology and the natural history of IBD have been taken from population-based studies performed in Scandinavia and Olmsted County, Minnesota, during the years 1950– 1970 whereby data have been collected and maintained using reliable and accurate means.3 Until recently, there have been very few population-based studies of IBD in Asia.4 In most studies, the incidence and/or prevalence rates have been derived from hospitalbased database, which can potentially result in an underestimation of the true incidence and an overestimation of disease severity. There are several reasons why conducting an inception cohort study in Asia can be challenging. First, there is a lack of national registries in most Asian countries. Second, there is a diversity of medical and alternative practice; third, population is mobile in certain areas with high population flux from rural to urban areas; and lastly, the high background prevalence of infections and tuberculosis make accurate disease diagnosis difficult. Nonetheless, time trend studies have shown a rise in disease incidence in Hong Kong, Japan, and Korea. In Asia, Japan is the only country that has a national IBD registry maintained by the Ministry of Health, Labour and Welfare since 1975 now consisting of over 150 000 UC patients and 37 000 CD patients. In Korea, there has been a steady rise in the mean annual incidence of CD and UC in the Songpa-Kangdong district of Seoul from 0.05 and 0.34, respectively, to 1.34 and 3.08 per 100 000 inhabitants, respectively, over one decade.5 In India, a community-based survey 10 years ago reported a crude incidence for UC of 6.02 cases per 100 000 inhabitants.6 In 2011, together with investigators in mainland China (Professor P. J. Hu, M. H. Chen, B. Xia, J. M. Qian), we reported in population-based settings the incidence of IBD to be 1.77, 1.96, and 3.14 in Daqing (Northern China), Wuhan, and Guangzhou (Southern China), respectively.7–9 We were curious as of the true disease burden of IBD in the rest of Asia. Professor Francis Chan once told me that a research area is important if the problem is common or emerging and if it has serious consequence. To this end, we initiated the Asia-Pacific Crohn’s and Colitis Epidemiology Study (ACCESS) in 2011 across eight countries in Asia and Australia. We strived to conduct an inception cohort study that needs to be prospective and performed in a welldescribed geographical area with a stable population using uniform diagnostic criteria, strict case definitions, and complete case ascertainment. In the ACCESS, the crude annual overall incidence for IBD per 100 000 individuals in 2011–2012 was 1.37 in Asia and 23.67 in Australia.10 Hong Kong and China have among the highest disease incidences in Asia while Australia has
IBD in Asia
Table 1
Incidence rates of IBD from population-based studies in Asia
Country 10
Hong Kong Macau10 Mainland China7–9 Guangzhou8 Wuhan7 Chengdu10 Xian10 Daqing9 Malaysia10 Singapore10 Thailand10 Indonesia10 Sri Lanka10 India6 Seoul5 Taiwan12
Time
IBD
CD
UC
2011–2012 2011–2012
2.62 2.24
1.25 0.89
1.30 0.93
2011–2012 2010–2011 2011–2012 2011–2012 2012–2013 2011–2012 2011–2012 2011–2012 2011–2012 2011–2012 2006 1986–2005 1998–2008
3.14 1.96 0.56 0.50 1.77 1.01 0.97 0.58 0.83 1.55 — — —
1.09 0.51 0.15 0.05 0.13 0.18 0.39 0.34 0.27 0.56 — 1.7 0.27
2.05 1.45 0.42 0.41 1.64 0.71 0.51 0.24 0.56 0.94 6.02 3.60 1.07
CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis.
Table 2
Prevalence of IBD in East Asia
Country 5
Seoul Japan13 Hong Kong (unpublished)
Time
CD
UC
2005 2003–2005 2011–2013
11.2 18.6 21.0
30.9 57.3 34.0
CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis.
the equal highest incidence of these diseases in the world.10,11 The incidence of IBD in Hong Kong/China has risen by threefold in the past decade. Although still lower than the West, disease incidence varies across Asia. UC is the predominant disease in Asia although the ratio of UC to CD is narrowing. Marked differences in incidence are found in various geographic areas, and ethnic differences have been observed in multi-racial Asian countries. We validated these findings in a second independent inception cohort from 2012 to 2013 and found little variation reflecting that these data represent true disease incidence in Asia. In 2013, we developed the Nixon-TAM Hong Kong IBD Registry covering 13 hospitals in Hong Kong, which allow us to delineate the prevalence and disease course of IBD in the Chinese population. Tables 1 and 2 summarize population-based studies in Asia assessing the incidence and prevalence of IBD.
Is the disease phenotype and evolution similar to the West? Clinical manifestation of IBD in Asia is relatively similar to that of the West but with some differences, including a higher prevalence of males with CD, ileo-colonic CD, less familial clustering, lower surgical rates, and less extra-intestinal manifestations.14–17 We found in Asia that CD is as if not more severe than Australia. There was a higher rate of penetrating disease and perianal disease in Asia even at diagnosis,10,16 which suggest that complicated disease
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is unlikely to be accounted by delayed diagnosis. The mean duration to disease diagnosis is around 4–6 months. The peak age of disease onset in Asia is 20–50 years, and a second peak after 50 years old is less common in Asian patients.18 A family history of IBD has been reported in up to 3% and 10% of UC and CD patients in Asian studies.15,16 This lower rate of familial aggregration in Asia most likely relates to the overall low disease prevalence, and as disease prevalence increases with time, the attributable risk of a positive family history will be similar in Asian and Caucasian patients.19 Differences in disease, severity, and complications may relate to genetic background, environmental factors such as diet and intestinal flora, and the duration of disease.4 When we followed up our incident cohort, early disease course in Asian IBD patients appeared comparable with that of Western patients. Progression to complicated behavior and accelerated use of immunosuppressants is common in CD. Furthermore, cumulative probability of behavior change from inflammatory to stricturing or penetrating disease was 18%, and cumulative rate of colectomy was 8% at 1 year. In contrast, early surgical rate for UC in Asia remains lower (1% at 1 year), which could relate to a milder disease or a higher threshold for colectomy.20 Understanding the natural history of IBD in our population can help optimize therapeutic interventions
Genetics To date, 163 independent genetic susceptibility loci have been associated with IBD via large-scale genome-wide association studies (GWAS) in European cohorts.2 Smaller GWAS performed in non-European populations from Japan and Korea have reported six novel genome-wide significant non-human leukocyte antigen associations.21–23 In our meta-analysis, we found that susceptibility genes differ between IBD patients in Asia and the West.24 For instance, nucleotide oligomerization domain-2 (NOD2) variants which account for approximately 20% of CD in white and Jewish populations25,26 have not been detected in studies of IBD subjects of East Asian descent.27–30 In addition, interleukin-23 receptor and autophagy-related 16-like 1 (ATG16L1) genes that have been firmly associated with CD in the Caucasian population31,32 were reported to have no or little associations with CD in Japanese33 and Korean patients.34 In contrast, novel genetic variants in the coding regions of DLG1 represent a novel potential susceptibility gene for CD in Chinese patients,35 and ATG16L2 and/or FCHSD2 are novel susceptibility genes for CD in Koreans.23 Tumor necrosis factor superfamily gene-15 (TNF-SF15) polymorphisms were strongly associated with CD odds ratio (OR 2.68) in East Asians, while TNF-308 polymorphisms (OR 1.82) and cytotoxic T-lymphocyte antigen-4 (OR 2.75) were associated with UC in Asians.24 Recent GWAS in Koreans with UC has also shown extensive overlapping of genetic loci with Caucasians.36 In one of the largest studies to date of genetic risk factors underlying non-European IBD from the International IBD Genetics Consortium Trans-Ethnic Working Party, we have identified several additional novel IBD loci. There appears to be pervasive sharing of genetic risk factors between different ethnicities, and the amount of phenotypic variance explained by some of the genetic loci is clearly heterogeneous between populations mainly driven by a combination of differences in effect size and allele frequency.37 442
Environmental risk factors The changing epidemiology of IBD across time and geography suggests that environmental factors play a major role in modifying disease expression.38 Changes in lifestyle in Asia during the last two decades have resulted in a more “westernized” standard way of living, with increased consumption of refined sugar, fatty acids, and fast food, and reduced consumption of fruit, vegetables, and fibers. Urbanization of societies, associated with changes in antibiotic use, hygiene status, microbial exposures, and pollution, have been implicated as potential environmental risk factors for IBD. The strongest environmental associations identified are cigarette smoking and appendectomy. Studies in the West have shown that smoking is a risk factor for the development of CD but is protective for the development of UC.39 However, smoking rates in IBD subjects appeared to be lower in Asia than the West. At a population level, countries with high CD incidence have a low prevalence of smoking in the adult populations whereas Asia and Africa have high rates of smoking (> 65% of adult males) but a low incidence of CD. This observation suggests that smoking influences CD course but may not influence population trends of IBD.16 Preliminary data showed lower rates of smoking among patients with CD in Asia. Exposure to environmental factors during childhood appears to be critical. The precise environmental factors that account for changing IBD prevalence have not been defined; downstream effect on the intestinal microbial milieu from dietary changes probably plays an important pathogenic role in CD and UC. In case–control studies and systematic review, a high dietary intake of fats, fatty acids, sweeteners, sugars, and meat increased the risk for developing CD and UC, while increased intake of fiber, fruit, and vegetables decreased the risk for development of CD and UC.40,41 In our case–control population-based study in Asia-Pacific consisting of 442 IBD cases and 940 matched controls, we found that breast-feeding had a marked protective effect on development of CD and UC; the beneficial effect was most prominent when breast-feeding was continued for 12 months or longer. On the other hand, a more “Westernized” diet was a risk factor whereas tea or coffee consumption was a protective factor for IBD. Contact with childhood pets was also a novel protective factor. In contrast to the literature, there was an inverse association between antibiotic use and the development of CD, suggesting that antibiotics may not be a contributing factor to the rising incidence in Asia. Overall, our data support the importance of childhood immunologic, hygiene, and dietary factors in development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.42 Compelling evidence suggests that gut microbes participate in an important way in disease pathogenesis. Geographical and genetic backgrounds impact the composition of the intestinal microbiota. Furthermore, a decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii appears to define dysbiosis in patients with IBD in Asia. In collaboration with Professor Michael Kamm and Professor Mark Morrison in Australia, we have shown that bacterial composition in healthy subjects differed between regions and between ethnicities within the same country.43 The variation in microbial diversity and composition among diseases, ethnicities, and geographies may be related to genetic and environmental factors.
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Furthermore, genetic factors play a critical role in shaping the microbiota in health and IBD.44
Current challenges and future directions To date, IBD epidemiologic studies have been limited by disease misclassification of exposure and outcomes, incomplete capture of events longitudinally (or long enough), and challenges to accurately measure or account for gene–environment interactions. Larger epidemiological data over time are necessary to describe the true incidence of IBD and further characterize the clinical features and risk factors of IBD in different geographical areas in Asia-Pacific. Such studies will better define the burden of illness, explore the mechanism of association with environmental factors, as well as identify new risk factors. Three major areas of epidemiologic research deserve more attention. First, studies of disease etiology are needed, with a specific focus on diet and gene– environmental interactions. The role of diet cannot be understated; changing dietary patterns is one of the most rapidly evolving phenomena observed in Asia. We need to understand which and how environmental factors enhance the risk of IBD through effects on epigenetic, microbial, and immunologic functions. Second, studies in natural history of disease are necessary to better understand the role of environmental factors on disease perpetuation, progression, and complications. Third, pharmacoepidememiologic studies of available therapy can help refine our treatment algorithms in real-life settings in diverse populations. A major clinical challenges in Asia relates to the accurate diagnosis of IBD in countries with a high background prevalence of infections.45 The diagnosis of CD in geographical areas where tuberculosis is common continues to pose a diagnostic challenge. Infections may mimic IBD and can complicate the course of existing IBD. Screening for latent infections specifically for tuberculosis and hepatitis B deserve special consideration in Asia given the high prevalence of these diseases. Furthermore, one of the major research questions in IBD diagnostic includes development of better ways to classify our patients for prediction of disease course, response to therapy, and adverse effects. Differences in genetic loci and microbial composition/functions in diverse populations may influence prognosis and response to treatment. Defining clinically relevant subsets of IBD patients using genetic, microbial, immunological, and metabolite profiling to predict disease outcome will lead to a personalized strategy in our patients. In the genetics front, translation of genetic advances into the bedside will involve the use of genomic-based diagnostic formula, risk prediction model, and development of novel therapeutics strategies. Accumulating data showed an overlap of susceptibility loci between diverse populations and other immune-mediated diseases. However, data remain limited in non-European cohorts and very early-onset pediatric subjects. Studies of longitudinal cohort and genome-wide analyses in non-European cohorts may help to identify novel Asian IBD-associated genes; such a study will require collaborative efforts between various centers in Asia to collect large number of samples. Studies from trans-ethnic cohort can provide new insights into different linkage disequilibrium structure, genetic architecture, allele frequencies, and also pharmacogenomic characteristics distinct to our population. The
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next phase of genetics discovery will require centralized and structured biobanking consisting of serum, urine, stool and tissue repositories in IBD individuals (at diagnosis, before, and after therapy), and characterization of large robustly phenotyped, prospective cohort in order to have an integrative human investigation. More likely than not, the incidence of IBD will continue to surge in Asia in the next 10 years. Effective research and development of IBD therapies will require network and collaboration between multiple centers in Asia. Although yet incorporated into practice in Asia, optimal patient management will need to move towards multidisciplinary approach, including the active involvement of specialist dietitians, radiologists, surgeons, IBD nurse specialists, and psychologists and social workers. New systems and opportunities for education in IBD should be incorporated into training of specialists. In the past decade, there has been remarkable progress in our understanding of the epidemiology, pathogenesis, and therapeutics of IBD. Through ambitious research goals and collaborative efforts, we hope to move a step closer to understanding and managing the “epidemic of IBD” in Asia.
Acknowledgments I am very fortunate to have several role models in my career. Professor Michael Kamm, a friend and a mentor, showed me the meaning and direction of research. Professor Joseph Sung, an exceptional researcher and leader, took me into his unit and gave me the opportunity and support in all that I have achieved today. Professor Francis Chan taught me how to go from “good to great.” Professor Henry Chan’s skill and vision in people management and development of an outstanding team inspired me. Professor Justin Wu, humble as he may, is an excellent clinician and educator, who has guided me in every aspect of my career. I would like to thank Professors Vincent Wong and Grace Wong for the support, positivity, and team spirit they have created, and Professor Jun Yu for laboratory advice and support. The support and help from our fellows and trainees make clinical and research work enjoyable. I am ever so grateful to my efficient and dedicated research team and Ph.D. students (Jessica Ching, Whitney Tang, Tiffany Chung, Y. K. Tse, Kitty Cheung, Joey Chan, Alfa Bai, Lani Prideaux, and Haiyun Shi). I am also thankful to all my collaborators from the ACCESS group and HK IBD Registry—I value the friendship, trust, and generosity built from our collaboration. Last but not least, dedication goes to my wonderful family, Graham, Olivia, and Oscar who mean the world to me—where would I be without their love and support.
References 1 Lepage P, Leclerc MC, Joossens M et al. A metagenomic insight into our gut’s microbiome. Gut 2013; 62: 146–58. 2 Jostins L, Ripke S, Weersma RK et al. Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. Nature 2012; 491: 119–24. 3 Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012; 142: 46–54.
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4 Thia KT, Loftus EV, Jr, Sandborn WJ, Yang SK. An update on the epidemiology of inflammatory bowel disease in Asia. Am. J. Gastroenterol. 2008; 103: 3167–82. 5 Yang SK, Yun S, Kim JH et al. Epidemiology of inflammatory bowel disease in the Songpa-Kangdong district, Seoul, Korea, 1986–2005: a KASID study. Inflamm. Bowel Dis. 2008; 14: 542–9. 6 Sood A, Midha V, Sood N, Bhatia AS, Avasthi G. Incidence and prevalence of ulcerative colitis in Punjab, North India. Gut 2003; 52: 1587–90. 7 Zhao J, Ng SC, Lei Y et al. First prospective, population-based inflammatory bowel disease incidence study in mainland of China: the emergence of “western” disease. Inflamm. Bowel Dis. 2013; 19: 1839–45. 8 Zeng Z, Zhu Z, Yang Y et al. Incidence and clinical characteristics of inflammatory bowel disease in a developed region of Guangdong Province, China: a prospective population-based study. J. Gastroenterol. Hepatol. 2013; 28: 1148–53. 9 Yang H, Li Y, Wu W et al. The incidence of inflammatory bowel disease in Northern China: a prospective population-based study. PLoS ONE 2014; 9: e101296. 10 Ng SC, Tang W, Ching JY 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: 158–65. 11 Wilson J, Hair C, Knight R et al. High incidence of inflammatory bowel disease in Australia: a prospective population-based Australian incidence study. Inflamm. Bowel Dis. 2010; 16: 1550–6. 12 Wei SC, Lin MH, Tung CC et al. A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan. BMC Gastroenterol. 2013; 13: 166. 13 Asakura K, Nishiwaki Y, Inoue N, Hibi T, Watanabe M, Takebayashi T. Prevalence of ulcerative colitis and Crohn’s disease in Japan. J. Gastroenterol. 2009; 44: 659–65. 14 Ng SC. Epidemiology of inflammatory bowel disease: focus on Asia. Best Pract. Res. Clin. Gastroenterol. 2014; 28: 363–72. 15 Prideaux L, Kamm MA, De Cruz PP, Chan FK, Ng SC. Inflammatory bowel disease in Asia: a systematic review. J. Gastroenterol. Hepatol. 2012; 27: 1266–80. 16 Prideaux L, Kamm MA, De CP et al. Comparison of clinical characteristics and management of inflammatory bowel disease in Hong Kong versus Melbourne. J. Gastroenterol. Hepatol. 2012; 27: 919–27. 17 Hou JK, El-Serag H, Thirumurthi S. Distribution and manifestations of inflammatory bowel disease in Asians, Hispanics, and African Americans: a systematic review. Am. J. Gastroenterol. 2009; 104: 2100–9. 18 Ouyang Q, Tandon R, Goh KL et al. Management consensus of inflammatory bowel disease for the Asia-Pacific region. J. Gastroenterol. Hepatol. 2006; 21: 1772–82. 19 Park JB, Yang SK, Byeon JS et al. Familial occurrence of inflammatory bowel disease in Korea. Inflamm. Bowel Dis. 2006; 12: 1146–51. 20 Ng SC, Tang W, de Silva J. Natural history of inflammatory bowel disease in Asia: a follow-up population-based cohort study. Gastroenterology 2014; (Suppl. 1): 1012. 21 Anderson CA, Boucher G, Lees CW et al. Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. Nat. Genet. 2011; 43: 246–52. 22 Asano K, Matsushita T, Umeno J et al. A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat. Genet. 2009; 41: 1325–9.
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23 Yang SK, Hong M, Zhao W et al. Genome-wide association study of Crohn’s disease in Koreans revealed three new susceptibility loci and common attributes of genetic susceptibility across ethnic populations. Gut 2014; 63: 80–7. 24 Ng SC, Tsoi KK, Kamm MA et al. Genetics of inflammatory bowel disease in Asia: systematic review and meta-analysis. Inflamm. Bowel Dis. 2012; 18: 1164–76. 25 Hugot JP. CARD15/NOD2 mutations in Crohn’s disease. Ann. N. Y. Acad. Sci. 2006; 1072: 9–18. 26 Ogura Y, Bonen DK, Inohara N et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature 2001; 411: 603–6. 27 Guo QS, Xia B, Jiang Y, Qu Y, Li J. NOD2 3020insC frameshift mutation is not associated with inflammatory bowel disease in Chinese patients of Han nationality. World J. Gastroenterol. 2004; 10: 1069–71. 28 Croucher PJ, Mascheretti S, Hampe J et al. Haplotype structure and association to Crohn’s disease of CARD15 mutations in two ethnically divergent populations. Eur. J. Hum. Genet. 2003; 11: 6–16. 29 Inoue N, Tamura K, Kinouchi Y et al. Lack of common NOD2 variants in Japanese patients with Crohn’s disease. Gastroenterology 2002; 123: 86–91. 30 Leong RW, Armuzzi A, Ahmad T et al. NOD2/CARD15 gene polymorphisms and Crohn’s disease in the Chinese population. Aliment. Pharmacol. Ther. 2003; 17: 1465–70. 31 Tremelling M, Cummings F, Fisher SA et al. IL23R variation determines susceptibility but not disease phenotype in inflammatory bowel disease. Gastroenterology 2007; 132: 1657–64. 32 Van LJ, Russell RK, Nimmo ER et al. IL23R Arg381Gln is associated with childhood onset inflammatory bowel disease in Scotland. Gut 2007; 56: 1173–4. 33 Yamazaki K, Onouchi Y, Takazoe M, Kubo M, Nakamura Y, Hata A. Association analysis of genetic variants in IL23R, ATG16L1 and 5p13.1 loci with Crohn’s disease in Japanese patients. J. Hum. Genet. 2007; 52: 575–83. 34 Yang SK, Park M, Lim J et al. Contribution of IL23R but not ATG16L1 to Crohn’s disease susceptibility in Koreans. Inflamm. Bowel Dis. 2009; 15: 1385–90. 35 Xu S, Zhou F, Tao J et al. Exome sequencing identifies DLG1 as a novel gene for potential susceptibility to Crohn’s disease in a Chinese family study. PLoS ONE 2014; 9: e99807. 36 Yang SK, Hong M, Zhao W et al. Genome-wide association study of ulcerative colitis in Koreans suggests extensive overlapping of genetic susceptibility with Caucasians. Inflamm. Bowel Dis. 2013; 19: 954–66. 37 Sommeren SV, International IBD Genetics Consortium. Trans-Ethnic Association Study of IBD identifies 14 new disease loci and demonstrates pervasive sharing of genetic risk factors and phenotypic features between Europeans and non-Europeans. supplement ed. 2014. 38 Ng SC, Bernstein CN, Vatn MH et al. Geographical variability and environmental risk factors in inflammatory bowel disease. Gut 2013; 62: 630–49. 39 Lakatos PL, Vegh Z, Lovasz BD, David G, Pandur T, Erdelyi Z. Is current smoking still an important environmental factor for inflammatory bowel disease? Results from a population-based incident cohort. 2012:in press. 40 Hou JK, Abraham B, El-Serag H. Dietary intake and risk of developing inflammatory bowel disease: a systematic review of the literature. Am. J. Gastroenterol. 2011; 106: 563–73. 41 Sakamoto N, Kono S, Wakai K et al. Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. Inflamm. Bowel Dis. 2005; 11: 154–63.
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42 Ng SC, Tang W, Leong RW et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut 2014; [Epub ahead of print]. 43 Prideaux L, Kang S, Wagner J et al. Impact of ethnicity, geography, and disease on the microbiota in health and inflammatory bowel disease. Inflamm. Bowel Dis. 2013; 19: 2906–18.
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44 De CP, Prideaux L, Wagner J et al. Characterization of the gastrointestinal microbiota in health and inflammatory bowel disease. Inflamm. Bowel Dis. 2012; 18: 372–90. 45 Ng SC, Chan FK. Infections and inflammatory bowel disease: challenges in Asia. J. Dig. Dis. 2013; 14: 567–73.
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doi:10.1111/jgh.12859
SOLICITED REVIEW
Emerging leadership lecture: Inflammatory bowel disease in Asia: Emergence of a “Western” disease Siew C Ng Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Chinese University of Hong Kong, Hong Kong
Key words IBD, epidemiology, genetics, risk factors. Accepted for publication 28 November 2014. Correspondence Professor Siew C Ng, Department of Medicine and Therapeutics, Institute of Digestive Disease, State Key Laboratory of Digestive Diseases, Chinese University of Hong Kong, Hong Kong. Email: [email protected] Statement of interests: I have served as a speaker for Ferring, Janssen, and Abbvie pharmaceuticals. Unrestricted educational grants from Ferring, Abbvie, and Jessie and Thomas Tam Charity Foundation have been used to support our epidemiology studies and IBD Registry.
Abstract More than a decade ago, inflammatory bowel disease (IBD) is rare in Asia. Today, the importance of IBD in Asia is exemplified by its rapidly increasing incidence, complicated disease behavior, and substantial morbidity. In the first large-scale population-based epidemiologic study in Asia, the incidence of IBD varied from 0.60 to 3.44 per 100 000. There has been a twofold to threefold increase in the incidence of IBD in several countries in Asia. Ulcerative colitis (UC) is more prevalent than Crohn’s disease (CD), although CD incidence is rapidly increasing. A positive family history is much less common than in the West, as are extra-intestinal disease manifestations. Complicated and penetrating CD are common in Asia. These epidemiologic changes may relate to increased contact with the West, westernization of diet, improved hygiene, increasing antibiotics use, or changes in the gut microbiota. Asian patients with CD have altered gut microbiota compared with their healthy counterparts and Caucasian CD subjects. Mucosa-associated microbiota in IBD may differ geographically. In a population-based case–control study, breast-feeding, having pets, and better sanitary conditions were protective of IBD, suggesting that childhood environment plays an important role in modulating disease development. Genetic factors also differ between Asians and Caucasians. Nucleotide oligomerization domain-2 (NOD2) and autophagy variants were not associated with CD, but tumor necrosis factor superfamily gene-15 polymorphisms were strongly associated with CD in East Asians. Research in Asia, an area of rapidly changing IBD epidemiology, may lead to the discovery of critical etiologic factors that lead to the development of IBD.
Background Crohn’s disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. The pathophysiology of IBD relates to the mucosal immune response to antigenic stimulation from the gut microbiota secondary to environmental influence, on a background of genetic susceptibility. Over the last 20 years, significant advances have been achieved in our understanding of IBD. One of the greatest scientific advances, enabled by high-throughput sequencing and other new technologies, have been a deeper understanding of the genetic factors that are associated with IBD susceptibility in conjunction with alterations in the intestinal microbiome.1,2 Secondly, the changing epidemiology of IBD has provided a unique opportunity for investigators in areas of emerging disease incidence to study disease evolution and etiology.3 For almost 20 years, I lived and worked in London, whereby IBD is common. I had the privilege to work with two inspiring figures in the field of IBD and mucosal immunology, Professor Michael Kamm and Professor Stella Knight, at St. Mark’s 440
Hospital in London. There I completed a Ph.D. in immunology and bacteriology in intestinal inflammation. In 2009, I joined the Division of Gastroenterology and Hepatology of the Chinese University of Hong Kong and witnessed the emergence of this “Western” disease in the Asian population, which mirrored what took place in the West 50 years ago. Professor Joseph Sung, my mentor, once told me that when he was a medical student, IBD almost does not exist. If he encounters a case of suspected IBD, investigations will be performed to prove that it is not IBD. More likely than not, the patient will be treated as infectious colitis or tuberculosis. Today, IBD is increasingly been recognized as an important disease with major health-care implications not just in developed, but also in developing countries. Although incidence and prevalence may have stabilized in high-incidence areas such as North America and Europe, they continue to rise in previously low-incidence areas such as Eastern Europe, Asia, and much of the developing world. This epidemiological shift likely relates to westernization of lifestyle, changes in diet, and improved hygiene as part of socioeconomic development in developing countries.
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It is a great honor for me to receive and deliver the Emerging Leadership Lecture 2014. Through a series of population-based and longitudinal studies and collaborative research with friends around the globe, we have studied the genetic susceptibility, epidemiology, and environmental risk factors associated with IBD in Asia. This paper summarizes our work in the past 5 years aimed to further enhance our understanding of the pathogenesis, characteristics, and evolution of IBD in this part of the world. Studying the epidemiology of IBD in an area of rapidly increasing incidence may lead to discovery of important etiologic factors associated with disease development.
What do we know about epidemiology of IBD in Asia? To date, most data on epidemiology and the natural history of IBD have been taken from population-based studies performed in Scandinavia and Olmsted County, Minnesota, during the years 1950– 1970 whereby data have been collected and maintained using reliable and accurate means.3 Until recently, there have been very few population-based studies of IBD in Asia.4 In most studies, the incidence and/or prevalence rates have been derived from hospitalbased database, which can potentially result in an underestimation of the true incidence and an overestimation of disease severity. There are several reasons why conducting an inception cohort study in Asia can be challenging. First, there is a lack of national registries in most Asian countries. Second, there is a diversity of medical and alternative practice; third, population is mobile in certain areas with high population flux from rural to urban areas; and lastly, the high background prevalence of infections and tuberculosis make accurate disease diagnosis difficult. Nonetheless, time trend studies have shown a rise in disease incidence in Hong Kong, Japan, and Korea. In Asia, Japan is the only country that has a national IBD registry maintained by the Ministry of Health, Labour and Welfare since 1975 now consisting of over 150 000 UC patients and 37 000 CD patients. In Korea, there has been a steady rise in the mean annual incidence of CD and UC in the Songpa-Kangdong district of Seoul from 0.05 and 0.34, respectively, to 1.34 and 3.08 per 100 000 inhabitants, respectively, over one decade.5 In India, a community-based survey 10 years ago reported a crude incidence for UC of 6.02 cases per 100 000 inhabitants.6 In 2011, together with investigators in mainland China (Professor P. J. Hu, M. H. Chen, B. Xia, J. M. Qian), we reported in population-based settings the incidence of IBD to be 1.77, 1.96, and 3.14 in Daqing (Northern China), Wuhan, and Guangzhou (Southern China), respectively.7–9 We were curious as of the true disease burden of IBD in the rest of Asia. Professor Francis Chan once told me that a research area is important if the problem is common or emerging and if it has serious consequence. To this end, we initiated the Asia-Pacific Crohn’s and Colitis Epidemiology Study (ACCESS) in 2011 across eight countries in Asia and Australia. We strived to conduct an inception cohort study that needs to be prospective and performed in a welldescribed geographical area with a stable population using uniform diagnostic criteria, strict case definitions, and complete case ascertainment. In the ACCESS, the crude annual overall incidence for IBD per 100 000 individuals in 2011–2012 was 1.37 in Asia and 23.67 in Australia.10 Hong Kong and China have among the highest disease incidences in Asia while Australia has
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Table 1
Incidence rates of IBD from population-based studies in Asia
Country 10
Hong Kong Macau10 Mainland China7–9 Guangzhou8 Wuhan7 Chengdu10 Xian10 Daqing9 Malaysia10 Singapore10 Thailand10 Indonesia10 Sri Lanka10 India6 Seoul5 Taiwan12
Time
IBD
CD
UC
2011–2012 2011–2012
2.62 2.24
1.25 0.89
1.30 0.93
2011–2012 2010–2011 2011–2012 2011–2012 2012–2013 2011–2012 2011–2012 2011–2012 2011–2012 2011–2012 2006 1986–2005 1998–2008
3.14 1.96 0.56 0.50 1.77 1.01 0.97 0.58 0.83 1.55 — — —
1.09 0.51 0.15 0.05 0.13 0.18 0.39 0.34 0.27 0.56 — 1.7 0.27
2.05 1.45 0.42 0.41 1.64 0.71 0.51 0.24 0.56 0.94 6.02 3.60 1.07
CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis.
Table 2
Prevalence of IBD in East Asia
Country 5
Seoul Japan13 Hong Kong (unpublished)
Time
CD
UC
2005 2003–2005 2011–2013
11.2 18.6 21.0
30.9 57.3 34.0
CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis.
the equal highest incidence of these diseases in the world.10,11 The incidence of IBD in Hong Kong/China has risen by threefold in the past decade. Although still lower than the West, disease incidence varies across Asia. UC is the predominant disease in Asia although the ratio of UC to CD is narrowing. Marked differences in incidence are found in various geographic areas, and ethnic differences have been observed in multi-racial Asian countries. We validated these findings in a second independent inception cohort from 2012 to 2013 and found little variation reflecting that these data represent true disease incidence in Asia. In 2013, we developed the Nixon-TAM Hong Kong IBD Registry covering 13 hospitals in Hong Kong, which allow us to delineate the prevalence and disease course of IBD in the Chinese population. Tables 1 and 2 summarize population-based studies in Asia assessing the incidence and prevalence of IBD.
Is the disease phenotype and evolution similar to the West? Clinical manifestation of IBD in Asia is relatively similar to that of the West but with some differences, including a higher prevalence of males with CD, ileo-colonic CD, less familial clustering, lower surgical rates, and less extra-intestinal manifestations.14–17 We found in Asia that CD is as if not more severe than Australia. There was a higher rate of penetrating disease and perianal disease in Asia even at diagnosis,10,16 which suggest that complicated disease
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is unlikely to be accounted by delayed diagnosis. The mean duration to disease diagnosis is around 4–6 months. The peak age of disease onset in Asia is 20–50 years, and a second peak after 50 years old is less common in Asian patients.18 A family history of IBD has been reported in up to 3% and 10% of UC and CD patients in Asian studies.15,16 This lower rate of familial aggregration in Asia most likely relates to the overall low disease prevalence, and as disease prevalence increases with time, the attributable risk of a positive family history will be similar in Asian and Caucasian patients.19 Differences in disease, severity, and complications may relate to genetic background, environmental factors such as diet and intestinal flora, and the duration of disease.4 When we followed up our incident cohort, early disease course in Asian IBD patients appeared comparable with that of Western patients. Progression to complicated behavior and accelerated use of immunosuppressants is common in CD. Furthermore, cumulative probability of behavior change from inflammatory to stricturing or penetrating disease was 18%, and cumulative rate of colectomy was 8% at 1 year. In contrast, early surgical rate for UC in Asia remains lower (1% at 1 year), which could relate to a milder disease or a higher threshold for colectomy.20 Understanding the natural history of IBD in our population can help optimize therapeutic interventions
Genetics To date, 163 independent genetic susceptibility loci have been associated with IBD via large-scale genome-wide association studies (GWAS) in European cohorts.2 Smaller GWAS performed in non-European populations from Japan and Korea have reported six novel genome-wide significant non-human leukocyte antigen associations.21–23 In our meta-analysis, we found that susceptibility genes differ between IBD patients in Asia and the West.24 For instance, nucleotide oligomerization domain-2 (NOD2) variants which account for approximately 20% of CD in white and Jewish populations25,26 have not been detected in studies of IBD subjects of East Asian descent.27–30 In addition, interleukin-23 receptor and autophagy-related 16-like 1 (ATG16L1) genes that have been firmly associated with CD in the Caucasian population31,32 were reported to have no or little associations with CD in Japanese33 and Korean patients.34 In contrast, novel genetic variants in the coding regions of DLG1 represent a novel potential susceptibility gene for CD in Chinese patients,35 and ATG16L2 and/or FCHSD2 are novel susceptibility genes for CD in Koreans.23 Tumor necrosis factor superfamily gene-15 (TNF-SF15) polymorphisms were strongly associated with CD odds ratio (OR 2.68) in East Asians, while TNF-308 polymorphisms (OR 1.82) and cytotoxic T-lymphocyte antigen-4 (OR 2.75) were associated with UC in Asians.24 Recent GWAS in Koreans with UC has also shown extensive overlapping of genetic loci with Caucasians.36 In one of the largest studies to date of genetic risk factors underlying non-European IBD from the International IBD Genetics Consortium Trans-Ethnic Working Party, we have identified several additional novel IBD loci. There appears to be pervasive sharing of genetic risk factors between different ethnicities, and the amount of phenotypic variance explained by some of the genetic loci is clearly heterogeneous between populations mainly driven by a combination of differences in effect size and allele frequency.37 442
Environmental risk factors The changing epidemiology of IBD across time and geography suggests that environmental factors play a major role in modifying disease expression.38 Changes in lifestyle in Asia during the last two decades have resulted in a more “westernized” standard way of living, with increased consumption of refined sugar, fatty acids, and fast food, and reduced consumption of fruit, vegetables, and fibers. Urbanization of societies, associated with changes in antibiotic use, hygiene status, microbial exposures, and pollution, have been implicated as potential environmental risk factors for IBD. The strongest environmental associations identified are cigarette smoking and appendectomy. Studies in the West have shown that smoking is a risk factor for the development of CD but is protective for the development of UC.39 However, smoking rates in IBD subjects appeared to be lower in Asia than the West. At a population level, countries with high CD incidence have a low prevalence of smoking in the adult populations whereas Asia and Africa have high rates of smoking (> 65% of adult males) but a low incidence of CD. This observation suggests that smoking influences CD course but may not influence population trends of IBD.16 Preliminary data showed lower rates of smoking among patients with CD in Asia. Exposure to environmental factors during childhood appears to be critical. The precise environmental factors that account for changing IBD prevalence have not been defined; downstream effect on the intestinal microbial milieu from dietary changes probably plays an important pathogenic role in CD and UC. In case–control studies and systematic review, a high dietary intake of fats, fatty acids, sweeteners, sugars, and meat increased the risk for developing CD and UC, while increased intake of fiber, fruit, and vegetables decreased the risk for development of CD and UC.40,41 In our case–control population-based study in Asia-Pacific consisting of 442 IBD cases and 940 matched controls, we found that breast-feeding had a marked protective effect on development of CD and UC; the beneficial effect was most prominent when breast-feeding was continued for 12 months or longer. On the other hand, a more “Westernized” diet was a risk factor whereas tea or coffee consumption was a protective factor for IBD. Contact with childhood pets was also a novel protective factor. In contrast to the literature, there was an inverse association between antibiotic use and the development of CD, suggesting that antibiotics may not be a contributing factor to the rising incidence in Asia. Overall, our data support the importance of childhood immunologic, hygiene, and dietary factors in development of IBD, suggesting that markers of altered intestinal microbiota may modulate risk of IBD later in life.42 Compelling evidence suggests that gut microbes participate in an important way in disease pathogenesis. Geographical and genetic backgrounds impact the composition of the intestinal microbiota. Furthermore, a decrease of the butyrate-producing species Roseburia hominis and Faecalibacterium prausnitzii appears to define dysbiosis in patients with IBD in Asia. In collaboration with Professor Michael Kamm and Professor Mark Morrison in Australia, we have shown that bacterial composition in healthy subjects differed between regions and between ethnicities within the same country.43 The variation in microbial diversity and composition among diseases, ethnicities, and geographies may be related to genetic and environmental factors.
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Furthermore, genetic factors play a critical role in shaping the microbiota in health and IBD.44
Current challenges and future directions To date, IBD epidemiologic studies have been limited by disease misclassification of exposure and outcomes, incomplete capture of events longitudinally (or long enough), and challenges to accurately measure or account for gene–environment interactions. Larger epidemiological data over time are necessary to describe the true incidence of IBD and further characterize the clinical features and risk factors of IBD in different geographical areas in Asia-Pacific. Such studies will better define the burden of illness, explore the mechanism of association with environmental factors, as well as identify new risk factors. Three major areas of epidemiologic research deserve more attention. First, studies of disease etiology are needed, with a specific focus on diet and gene– environmental interactions. The role of diet cannot be understated; changing dietary patterns is one of the most rapidly evolving phenomena observed in Asia. We need to understand which and how environmental factors enhance the risk of IBD through effects on epigenetic, microbial, and immunologic functions. Second, studies in natural history of disease are necessary to better understand the role of environmental factors on disease perpetuation, progression, and complications. Third, pharmacoepidememiologic studies of available therapy can help refine our treatment algorithms in real-life settings in diverse populations. A major clinical challenges in Asia relates to the accurate diagnosis of IBD in countries with a high background prevalence of infections.45 The diagnosis of CD in geographical areas where tuberculosis is common continues to pose a diagnostic challenge. Infections may mimic IBD and can complicate the course of existing IBD. Screening for latent infections specifically for tuberculosis and hepatitis B deserve special consideration in Asia given the high prevalence of these diseases. Furthermore, one of the major research questions in IBD diagnostic includes development of better ways to classify our patients for prediction of disease course, response to therapy, and adverse effects. Differences in genetic loci and microbial composition/functions in diverse populations may influence prognosis and response to treatment. Defining clinically relevant subsets of IBD patients using genetic, microbial, immunological, and metabolite profiling to predict disease outcome will lead to a personalized strategy in our patients. In the genetics front, translation of genetic advances into the bedside will involve the use of genomic-based diagnostic formula, risk prediction model, and development of novel therapeutics strategies. Accumulating data showed an overlap of susceptibility loci between diverse populations and other immune-mediated diseases. However, data remain limited in non-European cohorts and very early-onset pediatric subjects. Studies of longitudinal cohort and genome-wide analyses in non-European cohorts may help to identify novel Asian IBD-associated genes; such a study will require collaborative efforts between various centers in Asia to collect large number of samples. Studies from trans-ethnic cohort can provide new insights into different linkage disequilibrium structure, genetic architecture, allele frequencies, and also pharmacogenomic characteristics distinct to our population. The
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next phase of genetics discovery will require centralized and structured biobanking consisting of serum, urine, stool and tissue repositories in IBD individuals (at diagnosis, before, and after therapy), and characterization of large robustly phenotyped, prospective cohort in order to have an integrative human investigation. More likely than not, the incidence of IBD will continue to surge in Asia in the next 10 years. Effective research and development of IBD therapies will require network and collaboration between multiple centers in Asia. Although yet incorporated into practice in Asia, optimal patient management will need to move towards multidisciplinary approach, including the active involvement of specialist dietitians, radiologists, surgeons, IBD nurse specialists, and psychologists and social workers. New systems and opportunities for education in IBD should be incorporated into training of specialists. In the past decade, there has been remarkable progress in our understanding of the epidemiology, pathogenesis, and therapeutics of IBD. Through ambitious research goals and collaborative efforts, we hope to move a step closer to understanding and managing the “epidemic of IBD” in Asia.
Acknowledgments I am very fortunate to have several role models in my career. Professor Michael Kamm, a friend and a mentor, showed me the meaning and direction of research. Professor Joseph Sung, an exceptional researcher and leader, took me into his unit and gave me the opportunity and support in all that I have achieved today. Professor Francis Chan taught me how to go from “good to great.” Professor Henry Chan’s skill and vision in people management and development of an outstanding team inspired me. Professor Justin Wu, humble as he may, is an excellent clinician and educator, who has guided me in every aspect of my career. I would like to thank Professors Vincent Wong and Grace Wong for the support, positivity, and team spirit they have created, and Professor Jun Yu for laboratory advice and support. The support and help from our fellows and trainees make clinical and research work enjoyable. I am ever so grateful to my efficient and dedicated research team and Ph.D. students (Jessica Ching, Whitney Tang, Tiffany Chung, Y. K. Tse, Kitty Cheung, Joey Chan, Alfa Bai, Lani Prideaux, and Haiyun Shi). I am also thankful to all my collaborators from the ACCESS group and HK IBD Registry—I value the friendship, trust, and generosity built from our collaboration. Last but not least, dedication goes to my wonderful family, Graham, Olivia, and Oscar who mean the world to me—where would I be without their love and support.
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42 Ng SC, Tang W, Leong RW et al. Environmental risk factors in inflammatory bowel disease: a population-based case-control study in Asia-Pacific. Gut 2014; [Epub ahead of print]. 43 Prideaux L, Kang S, Wagner J et al. Impact of ethnicity, geography, and disease on the microbiota in health and inflammatory bowel disease. Inflamm. Bowel Dis. 2013; 19: 2906–18.
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