CD originally thought to almost exclusively affect white Europeans, is now known to be widely distributed worldwide[8
]. Epidemiological studies conducted in areas supposedly free of CD, including Africa, the Middle East, Asia, and South America, show that the disease was previously underdiagnosed[9
]. This provides evidence that CD is one of the most common genetic diseases, resulting from both environmental (gluten) and genetic (HLA and non-HLA genes) factors.
The world distribution of CD seems to have followed the mankind wheat consumption and the migratory flows. Man originally fed on meat, fruit and vegetables, with no exposer to gluten-containing cereals. It was only about 10 000 years ago in a small region called the “Fertile Crescent” of the Middle-East (including Anatolia (Southern Turkey), Lebanon, Syria, Palestine and Iraq) where wild wheat and barley grains successfully cultivated due to favorable environmental conditions. In the Fertile Crescent some tribes changed from nomadic to stable settlement style of living because land cultivation permitted food storage, and later migrated westwards to obtain new lands for cultivation. These persons spread through the Mediterranean area (Northern Africa, Southern Europe) and Central Europe. The expansion continued from 9000 to 4000 BC by which time the cultivation of wheat and barley had spread all over the Old Continent, also reaching Northern Europe (Ireland, Denmark and the Scandinavian countries). This expansion in farming was due to the diffusion of agricultural practices and replacement of local inhabitants by descendants from the Middle-East[10
]. Hence, the European and North-African populations share genetic background with the peoples of Middle-East origin.
In the last few years a number of studies in different populations have been carried out using molecular genetics methods to identify genes causing CD. CD-predisposing genetic loci are CELIAC1
on chromosome 6, CELIAC2
on chromosome 5q31-33[11
on chromosome 2q33[12
], and CELIAC4
on chromosome 19p13.1[13
tight junction genes associations have also been reported in Dutch CD or ulcerative colitis patients, suggesting a common intestinal defect in these two conditions[14
]. Another gene expressed in major histocompatibility complex (MHC)
antigen presenting cell is HLA B8
, was found to be associated with CD in Algeria[15
] and Turkey[18
]. Moreover, atypical CD Saharawi patients were found to over-express the MHC class
chain-related gene A (MICA) allele 5.1[15
], which have also been reported in Western countries[19
]. Increased prevalence of HLA-A25 in Turkish children with CD was also reported, suggesting that this genotype is particularly encountered among this population[18
], with no association described in Western countries.
Useful Background: Genes causing CD CELIAC1 on chromosome 6 (HLA-DQ2
); CELIAC2 on chromosome 5q31-33[11
]; CELIAC3 on chromosome 2q33 (containing T lymphocyte regulatory genes CD28
]; and CELIAC4 (myosin IXB gene, MYO9XB
) on chromosome 19p13.1[13
HLA genotype contributes to the genetic risk for CD at 30%-50%[20,21
]. Non-HLA genes contribute more evidence to the CD genetic background than the HLA genes, but each by itself contributes only a modest to the disease development. Hence, it is reasonable to assume that the susceptibility to CD involves with polymorphic genes that influence the immune response to gluten, as shown for the HLA-linked genes[22
Ninety percent of European patients with CD carry the HLA-DQ2 molecule, encoded either in cis on the HLA-DQA1*0501-DQB1*0201 haplotype (HLA-DQ2.5cis) or in trans on the HLA-DQA1*0505 DQB1*0301/DQA1*0201-DQB1*0202 haplotypes (HLA-DQ2.5trans). Approximately 5% express HLA-DQ8, encoded by HLA-DQA1*0301-DQB1*0302. The majority of the remainder carry the HLA-DQA1*0201-DQB1*0202 haplotype[20
]. With genetic testing, DQ2 is almost synonymous with DQB1*02, a gene with two common alleles designated DQB1*0201 and DQB1*0202. The DQ2 frequency in Caucasian in Western Europe populations has been estimated at 20%-30%, and relatively high frequencies also occur in Northern and Western Africa, the Middle East and central Asia[23
]. Thereafter, the overall frequency of DQ2 declines from West to East with low frequencies in populations in South-East Asia and the virtual absence of DQ2 in Japan (Table ). DQ8 frequency has a worldwide distribution, whereas DQ2.5, is common in South and Central America; approximately 90% of Amerindian populations carry DQ8 and may display the celiac phenotype[24,25
]. The frequency of DQ8 population is shown in Table .
Frequency of human leukocyte antigen-DQ2, encoded by human leukocyte antigen-DQB1*02 and human leukocyte antigen-DQ8, encoded by human leukocyte antigen-DQA1*0301-DQB1*0302
In the past, the prevalence of CD had been underestimated, but it is now regarded one of the most common genetic disorders in the West with 1% prevalence[26-28
]. Interestingly, there is increased prevalence of CD amongst women compared to men with male:female ratio of 1:2.8[29
]. This could be due to the finding that men with CD were diagnosed at an older age[30
]. Indeed, there have been reported CD cases among immigrant children native of Eastern Europe, Northern, West and East Africa, the Middle East and Southern Asia, according to their acquisition of Western dietary practices (i.e., short period or lack of breast feeding and early weaning with a great amount of gluten intake)[31
]. This suggests that many persons may have the genetic predisposition to CD but the clinical presentation only occurs when there is sufficient gluten in the diet.
Normal at-risk persons
In several parts of the world, the presence of the combination of antibody (serum tissue transglutaminase and endomysial autoantibodies) positivity and an HLA haplotype associated with CD is predictive of small-bowel abnormalities indicative of CD. For the majority of countries, the CD prevalence is unknown. Figure shows a range of estimated normal at-risk CD prevalence in continents and nations around the globe. It must be noted that some studies report prevalence of CD based on serology, others on celiac compatible small bowel biopsies and a few on serology, biopsy and response to gluten challenge.
Prevalence of celiac disease worldwide. N/A: Not available.
CD prevalence in North American and Europe were found to be similar in symptomatic patients and not-at-risk subjects. In the United States, CD is believed to affect 0.5%-1.0% of the general population[32
]. The study by Fasano et al[28
] on serum antibody and biopsy screening were performed for a total of 13 145 United States subjects: first-degree (n
= 4508) and second-degree relatives of patients (n
= 1275) with biopsy-proven CD, symptomatic patients (n
= 3236) (with either gastrointestinal symptoms or a disorder associated with CD), and not-at-risk individuals (n
= 4126). The overall CD prevalence is 1:133 in the not-at-risk groups, whereas in the at-risk group, the prevalence is 1:22 in first-degree relatives, 1:39 in second-degree relatives, and 1:56 in symptomatic patients[28
In South America, CD had been historically considered a rare disorder and the prevalence investigations have not been extensively studied. However, during the last few years studies in Brazil disclosed a prevalence of 1:681 in healthy blood donors[33
] and 1:473 among adult outpatients attending a clinical laboratory for routine blood testing[34
]. In an urban area of Argentina, the overall prevalence of CD, among 2000 adults from the general population (996 women; median age 29 year, range 16-79 year) was 1:167, with prevalence in women double that for men[35
]. The high CD prevalence in Argentina could be correlated with HLA DQ8 (> 20%) in the Argentina population.
The overall prevalence of CD in Western populations is close to 1% (1:100) and may be higher in Northern European countries (Table )[36-38
]. The Scandinavian countries, Ireland, and the United Kingdom population tended to show a higher prevalence of CD of approximately 1.0%-1.5%, although there also were studies that showed a lower prevalence in these countries. A study of small-intestinal biopsy obtained from healthy Dutch blood donors at Arnhem and Nijmegen Blood Donation Centers shows that the prevalence of CD-compatible biopsies of 1:330[39
]. The prevalence of CD among 3654 children (age range, 7-16 years) in Finland was at least 1:99 based on serum autoantibodies and small-bowel abnormalities[40
]. The prevalence of CD in Northern Spain in the general population was 1:389[41
], 1:132 (0.75%) in Eastern Switzerland adolescents[42
Table 2 Prevalence of celiac disease in Europeans based on unselected population serological screenings[36-38] (adapted)
In Northern African populations (including Morocco, Algeria, Tunisia, Libya and Egypt) higher incidences of 0.28%-5.6% of CD have recently been reported in the general population[43-46
]. The prevalence of CD in asymptomatic Tunisian school children was estimated to be about 1:157, which is close to the European prevalence. In this respect, the highest world frequency of 16.4% is reported in the CD associated with Insulin Dependent Diabetes Mellitus[47
], in Oran (Algeria). A recent serological screening in 2500 Tunisian healthy blood donors[45
], showed similar that the prevalence of anti-endomysium antibodies in the general population of 1:355, to that of Europeans. Due to high wheat and barley consumption in the North American countries[45
], as well as high frequency of CD predisposing DR3-DQ2 haplotypes in these populations[48-50
], these high CD frequencies are not surprising.
Saharawi population in North Africa, who are of Arabian and Berberian origin, having a high degree of cognation and live as refugees in the Sahara desert (Algeria), has the highest prevalence of CD (5.6%) known in the world today[43,49
]. This elevated prevalence in this population may be explained both by genetic factors: very high frequency of the DR3-DQ2 haplotype, and by environmental factors: changed of dietary habits in the last few decades. The reduced rates and duration of breast-feeding and increased consumption of gluten in early life as part of the staple diet, supplied by Western countries as humanitarian aids[51
], may have played a role in this elevated CD prevalence. However, there are other unknown genetic and environmental factors that explain such a high frequency of CD in the Saharawi people, because there is a much lower prevalence of CD in Sardinia population with similar staple diet consumption and frequencies of DR3-DQ2[52
Australia and New Zealand
Australia and New Zealand are the two countries having the highest proportion of individuals from Caucasian background, with high prevalence of HLA DQ2 and per capita wheat consumption of > 150 and 75-150 kg per person per year, respectively[23
]. Only two prevalence studies have been carried out in these two countries. From a random population of 1064 adults in Christchurch, New Zealand (96% Caucasian), CD was confirmed histologically in all patients with positive serology giving an overall prevalence of 1:82 (1.2%)[53
]. A larger study in 3011 adults from a large Caucasian community in Western Australia, revealed an overall prevalence of CD of 1:251 (0.4%) of the population[54
CD is likely to be rare in Indonesia, South Korea, Philippines and many smaller Pacific islands because of their low wheat consumption and a low frequency of HLA-DQB1*02. In South-East Asia, HLA-DQB1*02 is often present in more than 5% of the population but CD is predicted to be rare, as staple diets are based on rice. In contrast, prevalence rates that are similar to those in Europe are likely to apply from Pakistan in the South to Kazakhstan in the North. Ancient migration patterns that determine the frequency of DQB1*02 would also predict more patients with CD in Western China than in Eastern China[23
]. Interestingly, there is one report of CD in three adult descendants of Chinese and Japanese families who migrated to Canada[55
In genetic studies of CD in India, the appearance of HLA associations is similar to those in Western countries with a frequency of HLA-DQB1*02 of close to 100%[56
]. This association is more frequent in the population of Northern and North-Eastern India (16%-27%)[57
], than in groups of adults in the Southern state of Tamil Nadu (9%-14%)[58
]. The prevalence of CD in India is nearly the same as that in Western Caucasian populations[59
]. In Punjab (North-west India) school children, CD frequency was estimated to be 0.3%[60
]. This prevalence is probably an underestimation. A retrospective analysis of confirmed cases of CD between 1995 and 2000 in Dayanand Medical College and Hospital (Ludhiana, Punjab) from a total of 202 cases showed an initial of 10 positive cases with a significant growth rate of 79.43% annually with a trend equation increase of 15.49 cases/year[61
]. These studies showed that CD is relatively common in Northern India where there has been a history of wheat cultivation from before 1000 BC[62
]. Hence, the relative rarity of CD in Southern India reflects the effect of both genetic and environmental factors.
The prevalence in first-degree relatives of North Indian children with CD diagnosed as per the European Society for Pediatric Gastroenterology and Nutrition criteria is 4.4% of the first-degree relatives (85% positive for HLA DQ2/DQ8), which is 14 times higher than that of the general population[63
]. There have been reports on clinical experience of biopsy-defined CD in 10 North Indian Immigrants or descendants born in Canada out of 14 Asians diagnosed since 1988 in a single Canadian teaching hospital[55
]. Several studies, particularly from Northern and North-West India, have also documented the presence of CD in children presenting with chronic diarrhea[64
It seems likely that the prevalence of CD in the Middle East is similar to that of Europe[65
]. CD is a relatively common cause of chronic diarrhea in Iran, Iraq and Kuwait and has been diagnosed in 2%-8% of patients with type 1 diabetes in Iran, Israel and Saudi Arabia[39
]. Many of these countries have a per capita wheat consumption that ranks among the highest in the world (> 150 kg per person per year)[23
]. Although only a limited number of genetic studies have been carried out, the population of countries such as Iran, Israel, Saudi Arabia and Turkey have a high frequency of HLA-DQB1*02. The prevalence of CD in adult blood donors in Iran, Israel, Syria, Turkey and Anatolia are 1:166[66
], respectively. Similar prevalence rates were determined in surveys of Iranian children (1:165, 0.6%)[71
], and Turkish children (1:115, 0.9%)[72
The prevalence of CD is approximately 0.5%-1% in all parts of the world, except for populations with very low and very high intake of gluten in their diet.
High at-risk persons
In the general celiac population (without classical CD symptoms, e.g., diarrhea or weight loss), there are high risk groups that may have higher CD prevalence rates (Table ). Among factors that denote a higher risk for CD, the most important factor is familial history of biopsy proven CD with an estimate of 20% or more of first-degree relatives having CD[73
]. Some authors observed a higher prevalence in CD siblings as compared to parents[74-76
]. A study in Swedish youth (< 20 years old) diagnosed with type 1 diabetes (T1D) confirmed the low prevalence (0.7%) of diagnosed symptomatic CD at initial onset of clinical diagnosis, but document by screening an increasing prevalence of silent CD during a 5-year follow-up to reached an overall prevalence of 10%[77
]. Thus, the prevalence of an association with CD in high risk groups may increase over time.
Table 3 High risk populations for celiac disease (adapted)
The overall prevalence of CD is highly dependent on the HLA DQ2/DQ8 typing and gluten consumption. The population with positive HLA typing for celiac have high chances of developing celiac symptoms when on high gluten consumption. However, the population with diabetes, autoimmune disorder or relatives of CD individuals) have even higher risk for the development of CD, since they share the same HLA typing.