Celiac Disease Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
Celiac Disease Screening in Southern and East Asia Govind K. Makharia Departments of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
Abstract Until 1970s, celiac disease (CD) was considered to be an uncommon disease except in Western Europe. The global epidemiology of CD continues to evolve with improvement in the diagnostic tests, simplification of the diagnostic criteria and increase in awareness about the disease. The Asian region is currently at the crossroads of the frontier of knowledge and awareness of CD. In many Asian nations, CD is still considered to be either nonexistent or very rare. A notable exception is India, where CD has been well recognized, especially in the northern part, and 2 population-based studies have revealed a prevalence of 0.3–1.04%. Initial reports from Malaysia, China, Japan and Singapore suggest the existence of CD in these countries. Furthermore, a meta-analysis of the predisposing factors predicts a high probability of occurrence of CD in fair numbers in China. There are no formal reports on CD from Malaysia, Indonesia, Korea, Taiwan and many other nations in this region. With the impending CD epidemic in Asia, there are many challenges. Some of the efforts which are required include determination of prevalence of CD across the region, spreading of
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0167$39.50/0 E-Mail [email protected] www.karger.com/ddi
awareness among physicians and patients, training of dieticians for proper counseling and supervision of patients, creation of gluten-free food infrastructure in the food supply and creation of patient advocacy organizations. Although the absolute number of patients with CD at present is not very large, this number is expected to increase over the next few years/decades. It is thus appropriate that the medical community across Asia define the extent of the problem and get prepared to handle the impending CD epidemic. © 2015 S. Karger AG, Basel
Introduction
Until 1970s, celiac disease (CD) was considered to be an uncommon disease, mostly affecting individuals of European origin and characterized usually by the onset of the disease during early years of life [1–3]. The global epidemiology of CD continues to evolve with improvement in the diagnostic tests, simplification of the diagnostic criteria and increase in awareness about the disease amongst health care professionals. Over the past two decades, CD has been recognized as a major public health issue in many countries. In Europe and North America, the prevalence of CD in the general population is approximately Prof. Govind K. Makharia Departments of Gastroenterology and Human Nutrition All India Institute of Medical Sciences Ansari Nagar, New Delhi 110 029 (India) E-Mail govindmakharia @ gmail.com
Downloaded by: Fudan University Library 61.129.42.15 - 5/13/2015 10:09:21 PM
Key Words Celiac disease · Epidemiology · India
Celiac Disease in Asia
Asia is a continent of diverse population, and Asians differ significantly in their ethnicity, genetic make-up, eating practices, cultural practices and economic standards, and thus susceptibility to many diseases. Realizing the emergence of an epidemic of CD in Asia, the World Gastroenterology Organization and Asia Pacific Association of Gastroenterology highlighted the issues specific to this region and have suggested a few steps to handle the impending epidemic of CD in this region [22]. Population-Based Studies from Asia India is a country with a large (1.2 billion) but diverse population. The people of India vary in their languages, eating practices and cultural practices from one region to another. Until now, CD has been more prevalent in the northern part of India, and it is believed to be uncommon in the southern and northeastern part of India. There are 2 published studies on the prevalence of CD in the general population, and both studies have come from the northern part of India. In a questionnaire-based survey of 4,347 schoolchildren (3–17 years of age) from Ludhiana, Sood et al. [13] have reported the prevalence of CD to be 1 in 310. In another recent study done in the Ballabhgarh District of Haryana State, we applied a three-step clinical/ serological screening procedure. With a large population sample (n = 2,879), the prevalence of CD was 1.04% (1 in 96) and of positive anti-transglutaminase antibodies (anti-tTG) was 1.44% (1 in 69) [14]. Based on these 2 community-based studies, 5–8 millions of Indians are expected to have CD. Of such a large pool of patients, only a few 168
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
thousands of patients have been diagnosed as having CD and the majority still remains undiagnosed. Therefore, the prevalence of CD in an Indian community is nearly the same as that reported from the European nations and United States, and CD is a much greater problem in India than has been previously thought [13–14]. Hospital-Based Studies from Asia Despite the belief that CD was rare in India, Walia et al. [23] in children and Misra et al. [24] in adults described CD in India as early as in 1960s. Most of the subsequent reports on CD came from the northern part of India (States of Punjab, Haryana, Delhi, Rajasthan, Uttar Pradesh), where wheat is the staple dietary cereal [6–14, 25–28]. During the past 5 years, a few small case series and case reports on CD have been published from China [15, 16]. These reports are of great importance and confirm occurrence of CD in China, a country where CD is thought to be nonexistent [15, 16]. In a recently published systematic review and meta-analysis, Yuan et al. [17] have predicted that CD should not be uncommon in China. While there are a few case reports on CD from Japan, Watanabe et al. [18] have reported a positive anti-tTG Ab and anti-deamidated gliadin peptide antibody (anti-DGP Ab) in 22 (12.8%) and 23 (13.4%), respectively, of 172 patients with inflammatory bowel disease and 3 (1.6%) and 1 (0.5%), respectively of 172 controls. While many had increased levels of intraepithelial lymphocytes, none had villous atrophy. Interestingly, in a subset of patients who were put on gluten-restricted diet, not only did the serum antibody titers decrease, an improvement in inflammatory bowel disease activity score was also observed. In another recently published study from Singapore, Lu et al. [19] reported evidence of a positive IgA DGP Ab in 34 (18%) of 186 patients with irritable bowel syndrome. Although small, the abovementioned studies highlight the existence of CD in certain nations of Southern and East Asia. CD in Migrant Population CD has been described in South Asian patients who had immigrated to Europe or to North America [29–32]. A recent Italian multicenter study on immigrant children with CD showed that 3 of the children that migrated to Italy were native to Pakistan and 1 to Sri Lanka [32]. Ten and 13 children of Punjabi descent were reported to have CD in the UK [33]. Recently, 3 patients with CD were observed in Canada among descendants of Japanese and Chinese immigrants [30]. With population mixing now Makharia
Downloaded by: Fudan University Library 61.129.42.15 - 5/13/2015 10:09:21 PM
1% [4]. However, there is a large intercountry variation in prevalence; for example, the prevalence of CD is as high as 2–3% in Finland and Sweden, while it is only 0.2% in Germany [5]. Despite sharing similar causal factors in these countries (level of gluten intake and frequency of HLA CD-predisposing genotypes HLA-DQ2 and -DQ8), reasons for such heterogeneity are unknown. Asia is currently at the crossroads of the frontier of knowledge and awareness of CD. Although there has been an increase in the number of publications on CD from the Asian region, there is a paucity of literature on its prevalence in most Asian nations, with the exception of India [6–14]. Additionally, few case reports and short reports are available from China, Pakistan and Japan [15– 20]. In many Asian nations, CD is still considered to be either nonexistent or very rare [21, 22].
Regional Variations in the Prevalence of CD CD in India has mostly been reported from the northern part of India, and there are only occasional reports from the southern part of India. Although rice is the staple cereal in the southern states of India, there certainly has been a change in the dietary behavior, and wheat and wheat products are often included in their diet [35–36]. In order to study the differences in the prevalence of CD in different regions of India, we have just completed a study to estimate the prevalence of CD in the three regions of India including the northern and southern parts and the northeastern region. The result of this study is expected to be released by 2015.
The Absolute Number of Patients with CD Is Likely to Increase in Asia
There are phases of evolution of disease in a particular region. In the initial years, a disease is considered uncommon/rare in a region, and this phase is based generally on beliefs and is not evidence based. In subsequent years, while a few foci/individuals start recognizing the existence of the disease, many others still refuse to accept it. With further increase in the awareness, the availability of diagnostic tests and therapeutic strategies start increasing. Ultimately, physicians even at the level of secondary and primary health care appreciate the existence of the disease, and thus the absolute number of patients starts increasing exponentially. CD has gone through such phases in the recent past in many parts of Europe and North America. CD is going through such phases in many Asian countries. While it is well recognized in the northern part of India, in other regions including China, Japan, Malaysia and Philippines, CD is still considered uncommon [22]. There are no systematic studies to confirm that CD is uncommon in these regions.
humans led a nomadic life and obtained food by hunting or collecting fruits and vegetables. One can infer, there was no CD in that era. Due to the special environmental conditions created by flooding, the cultivation first started approximately 10,000 years ago in a small region of southwestern Asia (Turkey, Lebanon, Syria, Palestine and Iraq) called the ‘Fertile Crescent’. In the Fertile Crescent, some tribes changed their lifestyle from nomadic to more stable settlement because land cultivation allowed them to store food [37]. The progressive spread of agriculture from the East to Europe took place through the migration of farmers. The successfully domesticated wheat varieties initially were einkorn and emmer wheat [1]. Based on the overall archaeological picture of the spread of agriculture in Europe, the population migrated at a rate of 1 km/year, reaching the Atlantic side of Europe (e.g. UK and Ireland) about 4,000 years ago [38–39]. There might have been patients with CD after the cultivation started; this, however, was originally described in the 19th century, principally in children, by Samuel Gee in England and by Christian Herter in the United States [40]. In the modern era, population migration is rather rapid, and there is a constant mixing of different ethnic groups all over the world. Wheat as a Preferred Cereal Wheat is a preferred cereal as it has a high protein content (8–17% by weight), and 78–85% of the total wheat endosperm protein is gluten. When wheat flour is washed with water, the insoluble protein fraction forms a viscoelastic protein mass called gluten [41–42]. Gluten is a very large protein complex composed mainly of polymeric (multiple polypeptide chains linked by disulphide bonds) and monomeric (single-chain polypeptides) proteins known as glutenins and gliadins, respectively. Glutenins confer elasticity, while gliadins mainly confer viscous flow and extensibility to the gluten complex. Because of the viscoelastic properties of wheat flour dough, wheat is commonly used in home-made food (flat breads) and food industry (varieties of bread and pasta making) [41– 42].
CD occurs because of the interaction between both environmental (gluten) and genetic factors (HLA and nonHLA genes), and the distribution of these two components can guide to identify the areas of the world at risk for CD [37]. During the very early part of the evolution,
Wheat Consumption Pattern India and China are the largest cultivators of wheat grains. The per capita consumption of wheat in India is approximately 48 kg/year [43]. Wheat consumption is higher in the northern and central parts of India and considerably less in the southern and northeastern parts of India [43]. Similarly, the national annual consumption of wheat in China is over 100 million metric tons for over 1.370 billion population [17]. Overall, the consumption
Celiac Disease Screening in Southern and East Asia
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
Risk Factors in CD
169
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becoming more common, it should not be inappropriate to consider the whole world as a global village for CD [34].
Predisposing Genetic Factors
HLA Genes CD is a multigenic disorder, in which the most dominant genetic risk factors are the genotypes encoding the HLA class II molecules HLA-DQ2 (encoded by HLADQA1*0501 and HLA-DQB1*0201) and HLA-DQ8 (encoded by HLA-DQA1*0301 and HLA-DQB1*0302) [46– 50]. Approximately 90% of individuals with CD carry the HLA-DQ2 heterodimer encoded either in cis or in trans, and practically all of the remaining patients express HLADQ8 [48]. Deamidated gliadin peptides have a high binding affinity to HLA-DQ2 and HLA-DQ8 molecules, but not to other HLA class II molecules, which explains the immunogenicity of gluten in carriers of HLA-DQ2 and HLA-DQ8 [49]. These HLA-encoding genes are associated with approximately 40% of the heritable risk of developing CD [50–51]. Furthermore, a correlation has been found between homozygosity for the genes encoding the HLA-DQ2 molecule and the development of serious complications of CD, in particular refractory CD and enteropathy-associated T cell lymphoma, which implies a gene-dose effect [50–51]. The HLA-DQ2 heterodimer is frequently found in white populations in Western Europe (20–30%), North and West Africa, the Middle East and Central Asia, whereas HLA-DQ8 is more prevalent in Latin America and Northern Europe [52–53]. One of the highest prevalences of CD that is found in the Saha170
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
rawi population of the Arab-Berber origin has been attributed to higher frequencies of HLA-DQ2 in this population [52–54]. With the second largest population in the world, India is known for its vast ethnic and cultural variability. The distribution of the genetic and environmental determinants of CD in India shows distinctive features. Recently, a case series from New Delhi showed that 38/38 local children with CD had HLA-DQ2, similar to the strength of the association found in Europe [55]. In a meta-analysis of HLA-DQ2 and -DQ8 haplotype and antigens in China, Yuan et al. [17] have reported that HLA-DQ2 antigen is more common in the northwestern than in the southeastern populations. The DQB1*0201 allele also appeared at a much higher frequency in northern China than in southern China, not only in the Han subgroups but also in the ethnic minorities. If one looks at the regional variations in China, the DQB1*0201 allele is reported to be highly prevalent in Xinjiang Uygur Autonomous Region in northwest China (22.04%), whereas this allele was least common in people living in the Yunnan province in southwest China (2.89%) [17]. Studies on the frequency of various genetic loci and on anthropological characteristics clearly show the geographical and genetic boundary between Europeans and Asians runs through northwestern China [17, 56, 57]. Additionally, the population in northwest China is related more closely to Europeans than the other populations in southern China [17, 56, 57]. Anthropological data suggest that Caucasian genes flowed particularly into northern China from the West to the East and then from the East to the South. This migratory route would explain why the DQB1*02 allele is more common in the northern populations than southern populations [17]. In other Asian countries such as Japan, Taiwan, Korea, Indonesia the frequency of predisposing HLA allele is lower (
Celiac Disease Screening in Southern and East Asia Govind K. Makharia Departments of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
Abstract Until 1970s, celiac disease (CD) was considered to be an uncommon disease except in Western Europe. The global epidemiology of CD continues to evolve with improvement in the diagnostic tests, simplification of the diagnostic criteria and increase in awareness about the disease. The Asian region is currently at the crossroads of the frontier of knowledge and awareness of CD. In many Asian nations, CD is still considered to be either nonexistent or very rare. A notable exception is India, where CD has been well recognized, especially in the northern part, and 2 population-based studies have revealed a prevalence of 0.3–1.04%. Initial reports from Malaysia, China, Japan and Singapore suggest the existence of CD in these countries. Furthermore, a meta-analysis of the predisposing factors predicts a high probability of occurrence of CD in fair numbers in China. There are no formal reports on CD from Malaysia, Indonesia, Korea, Taiwan and many other nations in this region. With the impending CD epidemic in Asia, there are many challenges. Some of the efforts which are required include determination of prevalence of CD across the region, spreading of
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0167$39.50/0 E-Mail [email protected] www.karger.com/ddi
awareness among physicians and patients, training of dieticians for proper counseling and supervision of patients, creation of gluten-free food infrastructure in the food supply and creation of patient advocacy organizations. Although the absolute number of patients with CD at present is not very large, this number is expected to increase over the next few years/decades. It is thus appropriate that the medical community across Asia define the extent of the problem and get prepared to handle the impending CD epidemic. © 2015 S. Karger AG, Basel
Introduction
Until 1970s, celiac disease (CD) was considered to be an uncommon disease, mostly affecting individuals of European origin and characterized usually by the onset of the disease during early years of life [1–3]. The global epidemiology of CD continues to evolve with improvement in the diagnostic tests, simplification of the diagnostic criteria and increase in awareness about the disease amongst health care professionals. Over the past two decades, CD has been recognized as a major public health issue in many countries. In Europe and North America, the prevalence of CD in the general population is approximately Prof. Govind K. Makharia Departments of Gastroenterology and Human Nutrition All India Institute of Medical Sciences Ansari Nagar, New Delhi 110 029 (India) E-Mail govindmakharia @ gmail.com
Downloaded by: Fudan University Library 61.129.42.15 - 5/13/2015 10:09:21 PM
Key Words Celiac disease · Epidemiology · India
Celiac Disease in Asia
Asia is a continent of diverse population, and Asians differ significantly in their ethnicity, genetic make-up, eating practices, cultural practices and economic standards, and thus susceptibility to many diseases. Realizing the emergence of an epidemic of CD in Asia, the World Gastroenterology Organization and Asia Pacific Association of Gastroenterology highlighted the issues specific to this region and have suggested a few steps to handle the impending epidemic of CD in this region [22]. Population-Based Studies from Asia India is a country with a large (1.2 billion) but diverse population. The people of India vary in their languages, eating practices and cultural practices from one region to another. Until now, CD has been more prevalent in the northern part of India, and it is believed to be uncommon in the southern and northeastern part of India. There are 2 published studies on the prevalence of CD in the general population, and both studies have come from the northern part of India. In a questionnaire-based survey of 4,347 schoolchildren (3–17 years of age) from Ludhiana, Sood et al. [13] have reported the prevalence of CD to be 1 in 310. In another recent study done in the Ballabhgarh District of Haryana State, we applied a three-step clinical/ serological screening procedure. With a large population sample (n = 2,879), the prevalence of CD was 1.04% (1 in 96) and of positive anti-transglutaminase antibodies (anti-tTG) was 1.44% (1 in 69) [14]. Based on these 2 community-based studies, 5–8 millions of Indians are expected to have CD. Of such a large pool of patients, only a few 168
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
thousands of patients have been diagnosed as having CD and the majority still remains undiagnosed. Therefore, the prevalence of CD in an Indian community is nearly the same as that reported from the European nations and United States, and CD is a much greater problem in India than has been previously thought [13–14]. Hospital-Based Studies from Asia Despite the belief that CD was rare in India, Walia et al. [23] in children and Misra et al. [24] in adults described CD in India as early as in 1960s. Most of the subsequent reports on CD came from the northern part of India (States of Punjab, Haryana, Delhi, Rajasthan, Uttar Pradesh), where wheat is the staple dietary cereal [6–14, 25–28]. During the past 5 years, a few small case series and case reports on CD have been published from China [15, 16]. These reports are of great importance and confirm occurrence of CD in China, a country where CD is thought to be nonexistent [15, 16]. In a recently published systematic review and meta-analysis, Yuan et al. [17] have predicted that CD should not be uncommon in China. While there are a few case reports on CD from Japan, Watanabe et al. [18] have reported a positive anti-tTG Ab and anti-deamidated gliadin peptide antibody (anti-DGP Ab) in 22 (12.8%) and 23 (13.4%), respectively, of 172 patients with inflammatory bowel disease and 3 (1.6%) and 1 (0.5%), respectively of 172 controls. While many had increased levels of intraepithelial lymphocytes, none had villous atrophy. Interestingly, in a subset of patients who were put on gluten-restricted diet, not only did the serum antibody titers decrease, an improvement in inflammatory bowel disease activity score was also observed. In another recently published study from Singapore, Lu et al. [19] reported evidence of a positive IgA DGP Ab in 34 (18%) of 186 patients with irritable bowel syndrome. Although small, the abovementioned studies highlight the existence of CD in certain nations of Southern and East Asia. CD in Migrant Population CD has been described in South Asian patients who had immigrated to Europe or to North America [29–32]. A recent Italian multicenter study on immigrant children with CD showed that 3 of the children that migrated to Italy were native to Pakistan and 1 to Sri Lanka [32]. Ten and 13 children of Punjabi descent were reported to have CD in the UK [33]. Recently, 3 patients with CD were observed in Canada among descendants of Japanese and Chinese immigrants [30]. With population mixing now Makharia
Downloaded by: Fudan University Library 61.129.42.15 - 5/13/2015 10:09:21 PM
1% [4]. However, there is a large intercountry variation in prevalence; for example, the prevalence of CD is as high as 2–3% in Finland and Sweden, while it is only 0.2% in Germany [5]. Despite sharing similar causal factors in these countries (level of gluten intake and frequency of HLA CD-predisposing genotypes HLA-DQ2 and -DQ8), reasons for such heterogeneity are unknown. Asia is currently at the crossroads of the frontier of knowledge and awareness of CD. Although there has been an increase in the number of publications on CD from the Asian region, there is a paucity of literature on its prevalence in most Asian nations, with the exception of India [6–14]. Additionally, few case reports and short reports are available from China, Pakistan and Japan [15– 20]. In many Asian nations, CD is still considered to be either nonexistent or very rare [21, 22].
Regional Variations in the Prevalence of CD CD in India has mostly been reported from the northern part of India, and there are only occasional reports from the southern part of India. Although rice is the staple cereal in the southern states of India, there certainly has been a change in the dietary behavior, and wheat and wheat products are often included in their diet [35–36]. In order to study the differences in the prevalence of CD in different regions of India, we have just completed a study to estimate the prevalence of CD in the three regions of India including the northern and southern parts and the northeastern region. The result of this study is expected to be released by 2015.
The Absolute Number of Patients with CD Is Likely to Increase in Asia
There are phases of evolution of disease in a particular region. In the initial years, a disease is considered uncommon/rare in a region, and this phase is based generally on beliefs and is not evidence based. In subsequent years, while a few foci/individuals start recognizing the existence of the disease, many others still refuse to accept it. With further increase in the awareness, the availability of diagnostic tests and therapeutic strategies start increasing. Ultimately, physicians even at the level of secondary and primary health care appreciate the existence of the disease, and thus the absolute number of patients starts increasing exponentially. CD has gone through such phases in the recent past in many parts of Europe and North America. CD is going through such phases in many Asian countries. While it is well recognized in the northern part of India, in other regions including China, Japan, Malaysia and Philippines, CD is still considered uncommon [22]. There are no systematic studies to confirm that CD is uncommon in these regions.
humans led a nomadic life and obtained food by hunting or collecting fruits and vegetables. One can infer, there was no CD in that era. Due to the special environmental conditions created by flooding, the cultivation first started approximately 10,000 years ago in a small region of southwestern Asia (Turkey, Lebanon, Syria, Palestine and Iraq) called the ‘Fertile Crescent’. In the Fertile Crescent, some tribes changed their lifestyle from nomadic to more stable settlement because land cultivation allowed them to store food [37]. The progressive spread of agriculture from the East to Europe took place through the migration of farmers. The successfully domesticated wheat varieties initially were einkorn and emmer wheat [1]. Based on the overall archaeological picture of the spread of agriculture in Europe, the population migrated at a rate of 1 km/year, reaching the Atlantic side of Europe (e.g. UK and Ireland) about 4,000 years ago [38–39]. There might have been patients with CD after the cultivation started; this, however, was originally described in the 19th century, principally in children, by Samuel Gee in England and by Christian Herter in the United States [40]. In the modern era, population migration is rather rapid, and there is a constant mixing of different ethnic groups all over the world. Wheat as a Preferred Cereal Wheat is a preferred cereal as it has a high protein content (8–17% by weight), and 78–85% of the total wheat endosperm protein is gluten. When wheat flour is washed with water, the insoluble protein fraction forms a viscoelastic protein mass called gluten [41–42]. Gluten is a very large protein complex composed mainly of polymeric (multiple polypeptide chains linked by disulphide bonds) and monomeric (single-chain polypeptides) proteins known as glutenins and gliadins, respectively. Glutenins confer elasticity, while gliadins mainly confer viscous flow and extensibility to the gluten complex. Because of the viscoelastic properties of wheat flour dough, wheat is commonly used in home-made food (flat breads) and food industry (varieties of bread and pasta making) [41– 42].
CD occurs because of the interaction between both environmental (gluten) and genetic factors (HLA and nonHLA genes), and the distribution of these two components can guide to identify the areas of the world at risk for CD [37]. During the very early part of the evolution,
Wheat Consumption Pattern India and China are the largest cultivators of wheat grains. The per capita consumption of wheat in India is approximately 48 kg/year [43]. Wheat consumption is higher in the northern and central parts of India and considerably less in the southern and northeastern parts of India [43]. Similarly, the national annual consumption of wheat in China is over 100 million metric tons for over 1.370 billion population [17]. Overall, the consumption
Celiac Disease Screening in Southern and East Asia
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
Risk Factors in CD
169
Downloaded by: Fudan University Library 61.129.42.15 - 5/13/2015 10:09:21 PM
becoming more common, it should not be inappropriate to consider the whole world as a global village for CD [34].
Predisposing Genetic Factors
HLA Genes CD is a multigenic disorder, in which the most dominant genetic risk factors are the genotypes encoding the HLA class II molecules HLA-DQ2 (encoded by HLADQA1*0501 and HLA-DQB1*0201) and HLA-DQ8 (encoded by HLA-DQA1*0301 and HLA-DQB1*0302) [46– 50]. Approximately 90% of individuals with CD carry the HLA-DQ2 heterodimer encoded either in cis or in trans, and practically all of the remaining patients express HLADQ8 [48]. Deamidated gliadin peptides have a high binding affinity to HLA-DQ2 and HLA-DQ8 molecules, but not to other HLA class II molecules, which explains the immunogenicity of gluten in carriers of HLA-DQ2 and HLA-DQ8 [49]. These HLA-encoding genes are associated with approximately 40% of the heritable risk of developing CD [50–51]. Furthermore, a correlation has been found between homozygosity for the genes encoding the HLA-DQ2 molecule and the development of serious complications of CD, in particular refractory CD and enteropathy-associated T cell lymphoma, which implies a gene-dose effect [50–51]. The HLA-DQ2 heterodimer is frequently found in white populations in Western Europe (20–30%), North and West Africa, the Middle East and Central Asia, whereas HLA-DQ8 is more prevalent in Latin America and Northern Europe [52–53]. One of the highest prevalences of CD that is found in the Saha170
Dig Dis 2015;33:167–174 DOI: 10.1159/000369537
rawi population of the Arab-Berber origin has been attributed to higher frequencies of HLA-DQ2 in this population [52–54]. With the second largest population in the world, India is known for its vast ethnic and cultural variability. The distribution of the genetic and environmental determinants of CD in India shows distinctive features. Recently, a case series from New Delhi showed that 38/38 local children with CD had HLA-DQ2, similar to the strength of the association found in Europe [55]. In a meta-analysis of HLA-DQ2 and -DQ8 haplotype and antigens in China, Yuan et al. [17] have reported that HLA-DQ2 antigen is more common in the northwestern than in the southeastern populations. The DQB1*0201 allele also appeared at a much higher frequency in northern China than in southern China, not only in the Han subgroups but also in the ethnic minorities. If one looks at the regional variations in China, the DQB1*0201 allele is reported to be highly prevalent in Xinjiang Uygur Autonomous Region in northwest China (22.04%), whereas this allele was least common in people living in the Yunnan province in southwest China (2.89%) [17]. Studies on the frequency of various genetic loci and on anthropological characteristics clearly show the geographical and genetic boundary between Europeans and Asians runs through northwestern China [17, 56, 57]. Additionally, the population in northwest China is related more closely to Europeans than the other populations in southern China [17, 56, 57]. Anthropological data suggest that Caucasian genes flowed particularly into northern China from the West to the East and then from the East to the South. This migratory route would explain why the DQB1*02 allele is more common in the northern populations than southern populations [17]. In other Asian countries such as Japan, Taiwan, Korea, Indonesia the frequency of predisposing HLA allele is lower (
