The Turkish Journal of Pediatrics
[Mail to Editor ]
HLA types in Turkish children with celiac disease
Zarife Kuloğlu1, Tümay Doğancı2, Aydan Kansu1, Fulya Demirçeken1, Murat Duman3, Hüseyin Tutkak3, Arzu Ensari4, Nurten Girgin1
1Departments of Pediatric Gastroenterology, Ankara University Faculty of Medicine, Ankara, Turkey
2Department of Pediatric Gastroenterology, Dışkapı Social Security Hospital, Ankara, Turkey
3Departments of Immunology Ankara University Faculty of Medicine, Ankara, Turkey
4Departments of Pathology, Ankara University Faculty of Medicine, Ankara, Turkey
|Kuloğlu Z, Doğancı T, Kansu A, Demirçeken F, Duman M, Tutkak
H, Ensari A, Girgin N. HLA types in Turkish children with celiac disease.
Turk J Pediatr 2008; 50: 515-520.|
The aim of this study was to assess the distribution of human leukocyte
antigen (HLA) groups in Turkish children with celiac disease (CD) and to
investigate the association of HLA types and clinical manifestations of CD.
Seventy-five children with CD were evaluated in two groups: Group I consisted
of 45 classical celiac patients (15 males, 6.7±3.8 years); Group II consisted
of 30 atypical celiac patients (9 males, 9.3±4.3 years). The control group
consisted of 100 healthy renal transplantation donors. HLA typing was made
serologically using standard lymphocytotoxicity techniques.
HLA A29, B51, CW5, DR14, DR16, and DQ1 were the most common antigens
in the control group. Frequency of HLA B13, CW7, B8, DR7, DR17 and
DQ2 was higher in CD patients than in the control group (p<0.005, <0.05,
<0.001, <0.001 and <0.001, respectively). The relative risks for HLA DQ2,
B8, DR17 and B13 were 14.9, 13.6, 7.1 and 3.6, respectively. Frequency of
HLA B35, DR11 and DQ7 was higher in classical CD than atypical CD, while
a positive association was found between HLA B8 and atypical CD.
A positive association was found between HLA B13, CW7 and DR17 in
Turkish celiac patients in addition to HLA B8, DR7 and DQ2. This study
also suggested that a correlation may exist between genotype and clinical
celiac disease, HLA antigens
|Celiac disease (CD) or gluten sensitive enteropathy
is a disease of the proximal small
intestine, and is characterized by abnormal
small intestinal mucosae and associated with
permanent intolerance to dietary gluten. Genetic
predisposition is an essential factor in the
development of CD. Gluten sensitive enteropathy
has often been used to refer to the condition
of every individual with gluten sensitivity
regardless of clinical findings or degree of
mucosal involvement. CD can present at any age
and in different clinical forms such as classical,
atypical, silent, or latent CD[2,3]. Classical CD is
characterized by chronic diarrhea, abdominal
distention, vomiting, muscle wasting and failure
to thrive. The timing of presentation of CD may
be dependent on the amount and timing of
gluten introduction to the diet. Within weeks to
months of starting to ingest gluten, stool becomes larger, softer, paler and more frequent than usual,
and abdominal distention develops and growth
is impaired. Secondary to impaired absorption,
anemia, hypoalbuminemia, hypocalcemia,
hypomagnesemia, hypoprothrombinemia and
zinc deficiency may occur. Atypical CD presents
with extraintestinal manifestations such as
unexplained iron deficiency anemia, short stature,
osteoporosis, pubertal delay, dental enamel
defects, and abnormalities in liver function
tests[4,5]. The symptoms in patients are variable.
At present, there is not yet an explanation as
to why some patients with CD are symptomatic
while others remain asymptomatic.|
Genetic, environmental and immunological
factors may play important roles in the
pathogenesis of the disease[3,5]. A significant
association between CD and human leukocyte
antigen (HLA) types was shown both in family and population studies. CD was first found
to be associated with HLA B8. Later, it was
shown that the disease is associated with
expression of HLA DQ2 and HLA DQ8[6-8]. The
frequency of HLA groups varies significantly
in different populations. Although association
of HLA group and CD has been reported in
numerous studies, the influence of HLA type
on the clinical manifestations of CD has not
yet been investigated. The aim of this study
was to assess the distribution of HLA groups
in Turkish children with CD and to investigate
the association of HLA type and clinical
manifestations of CD.
|Material and Methods |
Seventy-five children (51 girls, 24 boys) diagnosed
as CD according to the European Society of
Pediatric Gastroenterology and Nutrition criteria
were included in our study. The mean age
of the study population was 7.3±4.09 years
(range: 1 to 16 years). They were divided into
two groups according to clinical manifestations
at diagnosis: Group I consisted of 45 patients
with classical CD (15 boys, mean age: 6.7±3.8
years, range: 1-14 years); Group II consisted of
30 patients with atypical CD (9 boys, mean age:
9.3±4.3 years, range: 2-16 years). One hundred
(54 M, 46 F) randomly selected individuals
from among renal transplant donors served as
healthy control subjects.
Human leukocyte antigen class I and II typing
was studied serologically by the standard
The distribution of HLA types in the groups
of patients was compared using χ2 test. When
frequency of HLA types was below 2%, Fisher’s
exact test was used. P<0.05 was considered
significant. In order to estimate relative risk,
the odds ratio method was also used.
|The distribution of HLA groups/types in CD
patients and controls is shown in Tables I
and II. In the control group, HLA A29 (8%),
B51 (22%), CW5 (10%), DR1 (17%), DR14 (15%), DR16 (11%), and DQ1 (38%) were
the most common HLA types observed in
HLA groups A, B, DR and DQ, respectively. In
CD patients, HLA B8 (41.9%), B13 (14.9%),
CW7 (48.6%) (p<0.05), DR7 (43.1%), DR17
(17.7%) and DQ2 (84.7%) (p<0.001) were the
most common HLA types observed in HLA
groups A, B, C, DR and DQ, respectively.|
| ||Table I: The Frequency of HLA-A, B and C in Celiac Disease Patients and Control Group|
| ||Table II: The Frequency of HLA-DR and DQ in Celiac Disease Patients and Control Group|
In odds ratio test, HLA DQ2, B8, DR17 and
B13 were demonstrated to have higher risk
for development of CD (14.9, 13.6, 7.1 and
3.6, respectively) (Table III).
| ||Table III: HLA Types Associated with Celiac Disease|
Classical CD was significantly associated with
HLA B35 (24.4%) (p<0.05), DR11 (36.7%)
(p<0.01) and DQ7 (31.8%) (p<0.05). In
atypical CD, HLA B8 (58.6%) was the most
common HLA type in HLA groups (p<0.05)
(Tables IV, V).
| ||Table IV: The Frequency of HLA-A, B and C in Classical and Atypical CD|
| ||Table V: The Frequency of HLA-DR and DQ in Classical and Atypical CD|
|The observations that CD may occur in firstdegree
relatives of children with CD and
association between some HLA groups and
CD indicate the influence of genetic factors in
the disease predisposition. It is demonstrated
in both patients and family studies that the
genetic feature of CD is multifactorial[3-5].|
Exposure to gluten in genetically susceptible
individuals is the major factor of development
of CD. A gluten molecule contains two
fractions: gliadin and glutenin. Gliadin fraction
is known to be the main cause of CD. The
possible interactions of gliadin (and/or its
peptide derivates) with intestinal epithelia and
the mechanism through which it crosses the
epithelial barrier to reach the submucosa are
not yet completely explained. After passage
of gliadin into the subepithelial compartment,
toxic gliadin derivates are deaminated by tissue
transglutaminase. Deaminated gliadin epitopes
are taken up by antigen presenting cells and
are presented by MHC class II molecules
HLA DQ2 and/or DQ8 to CD4+ helper T
lymphocytes. Activation of T cells results in
release of proinflammatory mediators causing
damage of enterocytes resulting in villous
atrophy[9-11]. It is thought that class II HLAs
are efficient to present peptides produced
from digestion of gliadin in the lamina propria
of the small bowel mucosa to T cells[11,12]. It
is known that most celiac patients (>90%)
carry a particular DQ heterodimer encoded by DQ2 (DQA1*0501/DQB 1*0201) alleles[12,13].
Association of HLA DQ alleles with CD can
explain the immunological concept of the disease
pathogenesis; however, it does not explain the
wide range of disease manifestations.
Our results showed that HLA B8, B13, CW7,
DR7, DR17 and DQ2 were found in higher
frequencies in celiac patients. Firstly, frequency
of HLA B8 in celiac patients has been reported as
45-88%. Later, it was observed that frequency
of HLA DR3 is also increased and that the
association with HLA B8 simply reflected the
linkage disequilibrium between the alleles
that coded for these antigens. In our study,
frequency of HLA B8 in CD was 41.9%, which
is similar to other reports. Our study confirmed
the strong association of CD and HLA DQ2.
However, HLA DQ8, which is known as one of
the most common antigens in CD, was not found
to be frequent among our celiac patients.
The association between HLA DR3/DR7 and
CD is explained by the linkage disequilibrium
of these alleles with DQ2 allele. Although
in our study, frequency of HLA DR7 in celiac
patients was significantly increased, we did
not demonstrate an association between DR3
and CD. Difference of HLA distribution may
be associated with genetic heterogeneity and
geographic region. While in northern Europe,
frequency of HLA DR3 is 95%, in southern
Europe, HLA DR3 and DR7 are the most
common HLAs[17,18]. It was previously reported
in Turkish children by Erkan et al. and Altuntaş et al. that HLA A2, A9, B35, B4,
DR2, DR4, DR53, CW4 and DQ4 were the
most common antigens among celiac patients.
According to these data, we may conclude that
the HLA groups that are found to be strongly
associated with CD are not seen in high
frequency in the general Turkish population.
Based on recent epidemiological data, prevalence
of CD is similar in Europe and North America,
but clinical presentation is different. Early
onset classical form is more commonly seen
in Europe than in North America. It is unclear
why presentation of CD differs from country
to country or person to person. It is suggested
that the difference in clinical presentations
may be due to HLA-related predisposing
genes or gluten intake. Genotype-phenotype
association was reported by Vogelsang et al.,
who found that HLA B8 and CW7 might lead to
late onset of CD. To our knowledge, association
of HLA types and clinical manifestations has
not been studied previously. In our study, an
association was found between HLA types and
different forms of CD. While in classical CD
patients with chronic diarrhea, weight loss,
abdominal distention and malnutrition, HLA
B35, DR11 and DQ7 were the most frequent
antigens, HLA B8 was the most frequent
antigen in atypical CD patients who presented
with extraintestinal manifestations.
In conclusion, this study demonstrated that
HLA types are important in the development
of CD, and HLA B8, CW7, DR7, DQ2, B13 and DR17 were the most frequent antigens
in Turkish children with CD. Our study also
showed that a relation may exist between HLA
types and clinical presentations.
1. Branski D, Fasono A, Troncone R. Latest developments
in the pathogenesis and treatment of celiac disease.
J Pediatr 2006; 149: 295-300.
2. Treem WR. Emerging concepts in celiac disease. Curr
Opin Pediatr 2004; 16: 552-559.
3. Madani S, Kamat D. Clinical guidelines for celiac disease
in children: what does it mean to the pediatrician/
family practitioner? Clin Pediatr 2006; 45: 213-219.
4. Guideline for the diagnosis and treatment of celiac
disease in children: recommendations of the North
American Society for Pediatric Gastroenterology,
Hepatology and Nutrition. J Pediatr Gastroenterol
Nutr 2005; 40: 1-19.
5. Waker-Smith JA. Celiac disease. In: Walker WA, Durie
PR, Hamilton JR, Walker-Smith JA, Wetkins JB (eds).
Pediatric Gastrointestinal Disease (3rd ed). Ontario:
B.C. Decker; 2004: 932-934.
6. Ludvig M, Sollid LM, Thorsby E. HLA susceptibility
genes in coeliac disease: genetic mapping and role in
pathogenesis. Gastroenterology 1993; 105: 910-922.
7. Falchuck ZM, Katz AJ, Schachman H, Rogetine GN,
Strober W. Gluten sensitive enteropathy: genetic
analysis and organ culture study in 35 families. Scand
J Gastroenterol 1978; 13: 839-843.
8. Tosi R, Vismara D, Tanigaki N. Evidence that celiac
disease is primarily associated with a DC locus
allelic specificity. Clin Immunol Immunopathol 1983;
9. Robbins G, Howdle PD. Advances in celiac disease.
Curr Opin Gastroenterol 2004; 21: 152-161.
10. Matysiak-Budnik T, Candalh C, Dugave C, et al.
Alterations of the intestinal transport and processing
of gliadin peptides in celiac disease. Gastroenterology
2003; 125: 696-707.
11. Molberg O, Kett K, Scott H, Thorsby E, Sollid LM,
Lundin KE. Gliadin specific HLA-DQ–restricted T cells
are commonly found in small intestinal biopsies from
coeliac disease patients, but not from controls. Scand
J Immunol 1997; 46: 103-109.
12. Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F,
Thorsby E. Evidence for primary association of celiac
disease to a particular HLA-DQ α/β heterodimer.
J Exp Med 1989; 169: 345-350.
13. Clot F, Babron MC. Genetics of celiac disease. Mol
Genet Metab 2000; 71: 76-80.
14. Mackintosh P, Asquitth P. HLA and coeliac disease.
Br Med Bull 1978; 34: 291-294.
15. Pena AS, Mann DL, Hague NE. Genetic basis of
gluten sensitive enteropathy. Gastroenterology 1978;
16. Corazza GR, Tabacchi P, Frisoni M, Prati C, Gasbarrini G.
DR and non-DR allotypes are associated with susceptibility
to coeliac disease. Gut 1985; 26: 1210-1213.
17. Tighe R, Ciclitera PJ. Molecular biology of coeliac
disease. Arch Dis Child 1995; 73: 189-191.
18. Tighe MR, Hall MA, Barbado M, Cardi E, Welsh
KI, Ciclitera PJ. HLA class II alleles associated with
celiac disease susceptibility in a southern European
population. Tissue Antigens 1992; 40: 90-97.
19. Erkan T, Kutlu T, Yılmaz E, Çullu F, Tümay G. Human
leukocyte antigens in Turkish pediatric celiac patients.
Turk J Pediatr 1999; 41: 181-188.
20. Altuntaş B, Hasanoğlu A, Söylemezoğlu O, Arınsoy T.
Pattern of human leukocyte antigen in Turkish children
with celiac disease. Pediatr Int 2000; 42: 678-681.
21. Fasano A, Catassi C. Coeliac disease in children. Best
Pract Res Clin Gastroenterol 2005; 19: 467-478.
22. Vogelsang H, Panzer S, Mayr WR, et al. Distribution of
HLA class I alleles differs in celiac disease patients according
to age of onset. Dig Dis Sci 2003; 48: 611-614.
[Mail to Editor ]