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Do MYO9B genetic variants predispose to coeliac disease? An association study in a cohort of South Italian children
Digestive and Liver Disease 39 (2007) 228–231
Alimentary Tract
Do MYO9B genetic variants predispose to coeliac disease? An association study in a cohort of South Italian children G. Cirillo, M.R. Di Domenico, I. Corsi, T. Gagliardo, E.M. del Giudice, L. Perrone, C. Tolone ∗ Department of Pediatrics “F. Fede”, Second University of Naples, Via Luigi De Crecchio 2, 80138 Naples, Italy Received 20 July 2006; accepted 11 December 2006
Abstract Background. Coeliac disease is a complex disorder influenced by environmental and genetic factors. A genome wide linkage study identified the myosin IXB (MYO9B) as a gene possibly associated with coeliac disease. Recently, a Dutch study reported a strong association of a single SNP, rs 2305764, of MYO9B with coeliac disease. However, two successive studies carried out on British and Swedish/Norwegian cohorts reported lack of association of the MYO9B variant with coeliac disease. Aims. The aim of the present study is to verify the effects of the MYO9B rs 2305764 polymorphism on disease risk in a Mediterranean population of coeliac children. Patients and methods. To address this issue, an association study was performed in 223 (127 females) Italian coeliac children and adolescents and in 600 controls. Results. The allelic frequencies of the MYO9B rs 2305764 polymorphism found in our patients and in the population control were not statistically different (P = 0.46). Conclusion. The MYO9B gene rs 2305764 polymorphism is not associated to coeliac disease in coeliac children from Southern Italy. This is in accordance with the most recent reports. Ethnic differences or a false positive result might explain the discrepancy with the Dutch study. © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Association study; Children; Coeliac disease; MYO9B polymorphism
1. Introduction Once considered an uncommon disorder, coeliac disease (CD) is one of the most widespread food intolerance, with an estimated prevalence of the disease of about 1%, as demonstrated by large studies in western populations [1]. It is a complex enteropathy influenced both by environmental and genetic factors [2]. It is characterized by small bowel hypersensitivity to gluten ingestion resulting in villous atrophy, crypt hyperplasia and lymphocytic infiltration in the epithelium and lamina propria [3]. This, in turn, may lead to a chronic autoimmune disease with production of antibody directed against tissue transglutaminase, the endomysial anti∗
Corresponding author. Tel.: +39 081 5665429; fax: +39 081 5665427. E-mail address: [email protected] (C. Tolone).
gen [4]. Different studies on siblings and identical twins underline the presence of a strong genetic susceptibility [5]. The major CD predisposing gene encodes for specific class II human leukocyte antigens (HLA). CD has a strong HLA association, with more than 90% of cases in Caucasian populations being associated with the HLA DQ2 haplotype. In Southern European populations, where the overall prevalence of DQ2 is low, there is an additional association with the HLA DR4-DQ8 haplotype [6,7]. However, these variants were found also in healthy population suggesting that the expression of HLA DQ2/DQ8 molecules is necessary but not sufficient to develop the disease [8]. In the mean time, several studies have been performed to identify non-HLA genes involved in CD; a genome wide linkage study in a Dutch population and a meta analysis of European linkage studies suggested the myosin
1590-8658/$30 © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2006.12.009
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231
229
Table 1 Case–control association study of MYO9B rs 2305764 polymorphism in Italian coeliac children
Individuals (n) Female (%) Median age and range (years) Median age at diagnosis and range (years) Homozygous AA (%) Heterozygous AG (%) Homozygous GG (%) Minor allelic (A) frequency (%) P value vs. population control
Italian coeliac patients
Dutch coeliac patients
UK coeliac patients
Swedish/Norwegian coeliac patients
223 57% 11.5 (1–17) 2.91 (1–17) 14% (18%)a 52% (51%)a 34% (31%)a 40.1% (43.5%)a 0.5
463 69% 44 35 N.A. N.A. N.A. 46.5% (37.9%)a 0.000002
375 73% 55 42 15% (18.2%)a 48% (46%)a 37% (35.8%)a 38.7% (41.1%)a 0.3
273 N.A. Children N.A. N.A. N.A. N.A. 41.6% (42.6%)a 0.7
N.A.: not available. a In brackets are indicated the frequencies (%) referred to the respective population controls.
IXB (MYO9B) as a gene which may be implicated in the predisposition to CD [9,10]. Recently, Monsuur et al. [11] analysed two independent Dutch case–control cohorts reporting a strong association of the 3 region of MYO9B with CD. In particular, the presence of the allele A of a single SNP, rs 2305764, located within the intron 28, alone explained this association and, therefore, it was considered as a marker for CD risk [11]. Allele A homozygous individuals showed a higher risk to develop CD (odds ratio = 2.27, P = 1.55 × 10−5 ) than the heterozygous (odds ratio = 1.66, P = 5.3 × 10−4 ), suggesting a codominant allele-dose effect [11]. However, two successive studies carried out on two different cohorts of British and Swedish/Norwegian coeliac patients were not able to confirm this association [12,13]. On the basis of these discordant results, the aim of the present study is to assess the effects of the MYO9B rs 2305764 polymorphism in determining susceptibility to CD in coeliac children from South Italy.
2. Materials and methods The study was carried out on 223 (127 female) unrelated South Italian coeliac children and adolescents (median age 11.5 years; range 1.3–17.1) (Table 1) referred from March 2001 to April 2004 to the Department of Pediatrics of the Second University of Naples. Diagnosis of CD was performed according to the ESPGHAN criteria (typical histological findings on small bowel biopsy and positive serological test specific for CD). Small bowel biopsy specimens were obtained by upper gastrointestinal endoscopy with 2–3 specimens from the distal duodenum. Six hundred Italian healthy controls (325 female, median age 10.7 years; range 1.8–16.8) belonging to the same geographic area, were randomly recruited. Informed consent from parents and assent from children were obtained. Genomic DNA was extracted from peripheral whole blood and stored at −20 ◦ C. Detection of the rs 2305764
polymorphism was performed by polymerase chain reactionrestriction-fragment length polymorphism (PCR-RFLP). A couple of primers covering the intron 28 of MYO9B gene (MYO9B F: TGA GTA GGC TGC ACA TAG AT and MYO9B R: AGA GGA AGG CGC TGG GCA GG) were designed according to the published genomic sequence (acc. N.NC-000019). Polymerase chain reaction, generating a fragment of 263 bp, was performed as follow: an initial denaturation at 95 ◦ C for 5 min followed by 30 cycles consisting of 94 ◦ C for 30 s, 59 ◦ C for 30 s and 72 ◦ C for 30 s. Ten microliters of PCR products were incubated with 1 unit of MspI (New England Biolabs) at 37 ◦ C overnight. Digestion products were resolved in 2.5% (w/v) agarose gel and visualized with ethidium bromide. Samples showing a 263 bp band were assigned genotype AA, samples showing two bands of 139 bp and 124 bp were assigned genotype GG, whereas heterozygotes were identified by the co-presence of the three bands. Some samples, randomly chosen, were also analysed by direct sequence using an ABI PRISM 310 automated sequencer (Applied Biosystem, Foster City, CA) and the relative genotypes were confirmed. To test the significance of differences in genotype and allele frequencies a χ2 test was used. Power calculations were performed using the genetic power calculator (http://pngu.mgh.harvard.edu∼purcell/gpc/).
3. Results Prior to analyse the association of SNP rs 2305764 with CD we calculated that the statistical power in the proband-control data set had 99.6% at P = 0.05 to detect an association, using the control frequencies and odds ratios (OR) shown in the Dutch population (allele frequency 0.379 and OR = 1.66 for AG genotype, OR = 2.27 for AA genotype, respectively). Comparison between cases and controls did not show any statistically significant difference concerning the rs 2305764 polymorphism distribution, since the genotype frequencies
230
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231
found were: 14% versus 18% (P = 0.344) for the minor allele homozygous (AA), 34% versus 31% (P = 0.6) for the major allele homozygous (GG) and 52% versus 51% (P = 0.988) for heterozygous coeliac patients compared to the control subjects, respectively. No significant association between the minor allele A and CD (P = 0.46) was found. In Table 1 the MYO9B genotypic and allelic frequencies are summarized and results compared to the other published data.
4. Discussion Multiple factors, both environmental (wheat gluten) and genetic contribute to the pathogenesis of CD. Although the role of HLA genes is well known, few data are available for non HLA-linked genes. Recently, different studies seems to indicate MYO9B as a good non-HLA candidate gene for CD since the encoded protein myosin IXB, a single motor protein containing a Rho-GTPase activating domain, is particularly important in the epithelial permeability, being involved in cytoskeleton remodelling and tight junction assembly [14,15]. This suggestion has been supported by a Dutch report showing a strong association between the allelic variant carrying an adenine (A) at the rs 2305764 A/G polymorphism localized in the MYO9B intron 28 and CD [9]. In our case–control study we have assessed the frequency of the MYO9B rs 2305764 polymorphic variant in Italian coeliac children. No significant differences in the allele frequencies were found between coeliac patients and population control, in contrast with the strong association previously reported (P = 0.000002) [11]. Furthermore, the lack of association we have shown is in agreement to the data reported in two different studies carried out on a British and a Swedish/Norwegian coeliac population (P = 0.3 and P = 0.7, respectively) [12,13] and with a more recent report on North Italian CD patients [16]. The discrepancy between our and Dutch data might be due to differences in the phenotypic feature between the two populations (i.e.; median age at diagnosis 2.91 versus 35 years in the South Italian and Dutch patients, respectively) or, more likely, the Dutch study might be considered a false positive, probably due to a type I error. Finally, the present study helps to shed more lights on the contrasting results concerning the association between MYO9B variants and CD. This because (i) the lack of association has been demonstrated in a group of patients ethnically different (i.e.; South Italian coeliac children) from the North European populations till now investigated and (ii) Italian CD patients at diagnosis are younger than the other cohorts analysed. This latter feature represents a characteristic that usually should enhance the possibility to find susceptibility gene variants, since it has been shown that the genetic influence of single gene defects is more penetrating in childhood than in the adult life [17].
Practice points • The principal factors responsible for CD are environmental (wheat gluten) and genetic (HLA-linked genes) features. • Analysis of a genetic variant localized in the intron 28 of MYO9B indicated this gene as a good non-HLA candidate gene for CD. • No significant differences in the MYO9B allele frequencies were found between Italian coeliac patients and population control. • MYO9B does not appear as a susceptibility gene in CD.
Research agenda • Searching for other genetic variants involved in CD. • Analysis of genes coding for proteins affecting small bowel epithelial permeability.
Conflict of interest statement None declared.
References [1] Alaedini A, Green PH. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Intern Med 2005;142:289–98. [2] Ascher H. Paediatric aspects of coeliac disease: old challenges and new ones . . .. Dig Liver Dis 2002;34:216–24. [3] Walker-Smith J, Guandalini S, Schmitz J, Schmerling D, Visakorpi J. Report of working group of European Society of Paediatric Gastroenterology and Nutrition: revised criteria for diagnosis of coeliac disease. Arch Dis Child 1991;65:909–11. [4] Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disese. Nat Med 1997;3:797–801. [5] Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, et al. The first large population based twin study of coeliac disease. Gut 2002;50:624–8. [6] Boniotto M, Braida L, Ventura A, Percopo S, Amoroso A, Crovella S. Promoter polymorphisms of the CD14 gene in Italian patients with coeliac disease. J Med Genet 2003;40:e108. [7] Martucci S, Biagi F, Di Sabatino A, Corazza GR. Coeliac disease. Dig Liver Dis 2002;34(Suppl. 2):S150–3. [8] van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:323–39. [9] Van Belzen MJ, Meijer JW, Sandkuijl LA, Bardoel AF, Mulder CJ, Pearson PL, et al. A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–41. [10] Babron MC, Nilsson S, Adamovic S, Naluai AT, Wahlstrom J, Ascher H, et al. European Genetics Cluster on Coeliac Disease. Meta and pooled analysis of European coeliac disease data. Eur J Hum Genet 2003;11:828–34.
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231 [11] Monsuur AJ, de Bakker PI, Alizadeh BZ, Zhernakova A, Bevova MR, Strengman E, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defects. Nat Genet 2005;37:1341–4. [12] Hunt KA, Monsuur AJ, McArdle WL, Kumar PJ, Travis SP, Walters JR, et al. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut 2006;55:969–72. [13] Amundsen SS, Monsuur AJ, Wapenaar MC, Lie BA, Ek J, Gudj´onsd´ottir AH, et al. Association analysis of MYO9B gene polymorphism with celiac disease in a Swedish/Norwegian cohort. Hum Immunol 2006;67:341–5.
231
[14] Post PL, Tyska MJ, O’Connell CB, Johung K, Hayward A, Mooseker MS. Myosin-IXb is a single-headed and processive motor. J Biol Chem 2002;277:11679–83. [15] Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol 2003;4:225–36. [16] Giordano M, Marano C, Mellai M, Limongelli MG, Bolognesi E, Clerget-Darpoux F, et al. A family-based study does not confirm the association of MYO9B with celiac disease in the Italian population. Genes Immun 2006;7:606–8. [17] Hebebrand J, Friedel S, Sch¨auble N, Geller F, Hinney A. Perspectives: molecular genetic research in human obesity. Obesity 2003;4:139–46.
Alimentary Tract
Do MYO9B genetic variants predispose to coeliac disease? An association study in a cohort of South Italian children G. Cirillo, M.R. Di Domenico, I. Corsi, T. Gagliardo, E.M. del Giudice, L. Perrone, C. Tolone ∗ Department of Pediatrics “F. Fede”, Second University of Naples, Via Luigi De Crecchio 2, 80138 Naples, Italy Received 20 July 2006; accepted 11 December 2006
Abstract Background. Coeliac disease is a complex disorder influenced by environmental and genetic factors. A genome wide linkage study identified the myosin IXB (MYO9B) as a gene possibly associated with coeliac disease. Recently, a Dutch study reported a strong association of a single SNP, rs 2305764, of MYO9B with coeliac disease. However, two successive studies carried out on British and Swedish/Norwegian cohorts reported lack of association of the MYO9B variant with coeliac disease. Aims. The aim of the present study is to verify the effects of the MYO9B rs 2305764 polymorphism on disease risk in a Mediterranean population of coeliac children. Patients and methods. To address this issue, an association study was performed in 223 (127 females) Italian coeliac children and adolescents and in 600 controls. Results. The allelic frequencies of the MYO9B rs 2305764 polymorphism found in our patients and in the population control were not statistically different (P = 0.46). Conclusion. The MYO9B gene rs 2305764 polymorphism is not associated to coeliac disease in coeliac children from Southern Italy. This is in accordance with the most recent reports. Ethnic differences or a false positive result might explain the discrepancy with the Dutch study. © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. Keywords: Association study; Children; Coeliac disease; MYO9B polymorphism
1. Introduction Once considered an uncommon disorder, coeliac disease (CD) is one of the most widespread food intolerance, with an estimated prevalence of the disease of about 1%, as demonstrated by large studies in western populations [1]. It is a complex enteropathy influenced both by environmental and genetic factors [2]. It is characterized by small bowel hypersensitivity to gluten ingestion resulting in villous atrophy, crypt hyperplasia and lymphocytic infiltration in the epithelium and lamina propria [3]. This, in turn, may lead to a chronic autoimmune disease with production of antibody directed against tissue transglutaminase, the endomysial anti∗
Corresponding author. Tel.: +39 081 5665429; fax: +39 081 5665427. E-mail address: [email protected] (C. Tolone).
gen [4]. Different studies on siblings and identical twins underline the presence of a strong genetic susceptibility [5]. The major CD predisposing gene encodes for specific class II human leukocyte antigens (HLA). CD has a strong HLA association, with more than 90% of cases in Caucasian populations being associated with the HLA DQ2 haplotype. In Southern European populations, where the overall prevalence of DQ2 is low, there is an additional association with the HLA DR4-DQ8 haplotype [6,7]. However, these variants were found also in healthy population suggesting that the expression of HLA DQ2/DQ8 molecules is necessary but not sufficient to develop the disease [8]. In the mean time, several studies have been performed to identify non-HLA genes involved in CD; a genome wide linkage study in a Dutch population and a meta analysis of European linkage studies suggested the myosin
1590-8658/$30 © 2007 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l. doi:10.1016/j.dld.2006.12.009
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231
229
Table 1 Case–control association study of MYO9B rs 2305764 polymorphism in Italian coeliac children
Individuals (n) Female (%) Median age and range (years) Median age at diagnosis and range (years) Homozygous AA (%) Heterozygous AG (%) Homozygous GG (%) Minor allelic (A) frequency (%) P value vs. population control
Italian coeliac patients
Dutch coeliac patients
UK coeliac patients
Swedish/Norwegian coeliac patients
223 57% 11.5 (1–17) 2.91 (1–17) 14% (18%)a 52% (51%)a 34% (31%)a 40.1% (43.5%)a 0.5
463 69% 44 35 N.A. N.A. N.A. 46.5% (37.9%)a 0.000002
375 73% 55 42 15% (18.2%)a 48% (46%)a 37% (35.8%)a 38.7% (41.1%)a 0.3
273 N.A. Children N.A. N.A. N.A. N.A. 41.6% (42.6%)a 0.7
N.A.: not available. a In brackets are indicated the frequencies (%) referred to the respective population controls.
IXB (MYO9B) as a gene which may be implicated in the predisposition to CD [9,10]. Recently, Monsuur et al. [11] analysed two independent Dutch case–control cohorts reporting a strong association of the 3 region of MYO9B with CD. In particular, the presence of the allele A of a single SNP, rs 2305764, located within the intron 28, alone explained this association and, therefore, it was considered as a marker for CD risk [11]. Allele A homozygous individuals showed a higher risk to develop CD (odds ratio = 2.27, P = 1.55 × 10−5 ) than the heterozygous (odds ratio = 1.66, P = 5.3 × 10−4 ), suggesting a codominant allele-dose effect [11]. However, two successive studies carried out on two different cohorts of British and Swedish/Norwegian coeliac patients were not able to confirm this association [12,13]. On the basis of these discordant results, the aim of the present study is to assess the effects of the MYO9B rs 2305764 polymorphism in determining susceptibility to CD in coeliac children from South Italy.
2. Materials and methods The study was carried out on 223 (127 female) unrelated South Italian coeliac children and adolescents (median age 11.5 years; range 1.3–17.1) (Table 1) referred from March 2001 to April 2004 to the Department of Pediatrics of the Second University of Naples. Diagnosis of CD was performed according to the ESPGHAN criteria (typical histological findings on small bowel biopsy and positive serological test specific for CD). Small bowel biopsy specimens were obtained by upper gastrointestinal endoscopy with 2–3 specimens from the distal duodenum. Six hundred Italian healthy controls (325 female, median age 10.7 years; range 1.8–16.8) belonging to the same geographic area, were randomly recruited. Informed consent from parents and assent from children were obtained. Genomic DNA was extracted from peripheral whole blood and stored at −20 ◦ C. Detection of the rs 2305764
polymorphism was performed by polymerase chain reactionrestriction-fragment length polymorphism (PCR-RFLP). A couple of primers covering the intron 28 of MYO9B gene (MYO9B F: TGA GTA GGC TGC ACA TAG AT and MYO9B R: AGA GGA AGG CGC TGG GCA GG) were designed according to the published genomic sequence (acc. N.NC-000019). Polymerase chain reaction, generating a fragment of 263 bp, was performed as follow: an initial denaturation at 95 ◦ C for 5 min followed by 30 cycles consisting of 94 ◦ C for 30 s, 59 ◦ C for 30 s and 72 ◦ C for 30 s. Ten microliters of PCR products were incubated with 1 unit of MspI (New England Biolabs) at 37 ◦ C overnight. Digestion products were resolved in 2.5% (w/v) agarose gel and visualized with ethidium bromide. Samples showing a 263 bp band were assigned genotype AA, samples showing two bands of 139 bp and 124 bp were assigned genotype GG, whereas heterozygotes were identified by the co-presence of the three bands. Some samples, randomly chosen, were also analysed by direct sequence using an ABI PRISM 310 automated sequencer (Applied Biosystem, Foster City, CA) and the relative genotypes were confirmed. To test the significance of differences in genotype and allele frequencies a χ2 test was used. Power calculations were performed using the genetic power calculator (http://pngu.mgh.harvard.edu∼purcell/gpc/).
3. Results Prior to analyse the association of SNP rs 2305764 with CD we calculated that the statistical power in the proband-control data set had 99.6% at P = 0.05 to detect an association, using the control frequencies and odds ratios (OR) shown in the Dutch population (allele frequency 0.379 and OR = 1.66 for AG genotype, OR = 2.27 for AA genotype, respectively). Comparison between cases and controls did not show any statistically significant difference concerning the rs 2305764 polymorphism distribution, since the genotype frequencies
230
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231
found were: 14% versus 18% (P = 0.344) for the minor allele homozygous (AA), 34% versus 31% (P = 0.6) for the major allele homozygous (GG) and 52% versus 51% (P = 0.988) for heterozygous coeliac patients compared to the control subjects, respectively. No significant association between the minor allele A and CD (P = 0.46) was found. In Table 1 the MYO9B genotypic and allelic frequencies are summarized and results compared to the other published data.
4. Discussion Multiple factors, both environmental (wheat gluten) and genetic contribute to the pathogenesis of CD. Although the role of HLA genes is well known, few data are available for non HLA-linked genes. Recently, different studies seems to indicate MYO9B as a good non-HLA candidate gene for CD since the encoded protein myosin IXB, a single motor protein containing a Rho-GTPase activating domain, is particularly important in the epithelial permeability, being involved in cytoskeleton remodelling and tight junction assembly [14,15]. This suggestion has been supported by a Dutch report showing a strong association between the allelic variant carrying an adenine (A) at the rs 2305764 A/G polymorphism localized in the MYO9B intron 28 and CD [9]. In our case–control study we have assessed the frequency of the MYO9B rs 2305764 polymorphic variant in Italian coeliac children. No significant differences in the allele frequencies were found between coeliac patients and population control, in contrast with the strong association previously reported (P = 0.000002) [11]. Furthermore, the lack of association we have shown is in agreement to the data reported in two different studies carried out on a British and a Swedish/Norwegian coeliac population (P = 0.3 and P = 0.7, respectively) [12,13] and with a more recent report on North Italian CD patients [16]. The discrepancy between our and Dutch data might be due to differences in the phenotypic feature between the two populations (i.e.; median age at diagnosis 2.91 versus 35 years in the South Italian and Dutch patients, respectively) or, more likely, the Dutch study might be considered a false positive, probably due to a type I error. Finally, the present study helps to shed more lights on the contrasting results concerning the association between MYO9B variants and CD. This because (i) the lack of association has been demonstrated in a group of patients ethnically different (i.e.; South Italian coeliac children) from the North European populations till now investigated and (ii) Italian CD patients at diagnosis are younger than the other cohorts analysed. This latter feature represents a characteristic that usually should enhance the possibility to find susceptibility gene variants, since it has been shown that the genetic influence of single gene defects is more penetrating in childhood than in the adult life [17].
Practice points • The principal factors responsible for CD are environmental (wheat gluten) and genetic (HLA-linked genes) features. • Analysis of a genetic variant localized in the intron 28 of MYO9B indicated this gene as a good non-HLA candidate gene for CD. • No significant differences in the MYO9B allele frequencies were found between Italian coeliac patients and population control. • MYO9B does not appear as a susceptibility gene in CD.
Research agenda • Searching for other genetic variants involved in CD. • Analysis of genes coding for proteins affecting small bowel epithelial permeability.
Conflict of interest statement None declared.
References [1] Alaedini A, Green PH. Narrative review: celiac disease: understanding a complex autoimmune disorder. Ann Intern Med 2005;142:289–98. [2] Ascher H. Paediatric aspects of coeliac disease: old challenges and new ones . . .. Dig Liver Dis 2002;34:216–24. [3] Walker-Smith J, Guandalini S, Schmitz J, Schmerling D, Visakorpi J. Report of working group of European Society of Paediatric Gastroenterology and Nutrition: revised criteria for diagnosis of coeliac disease. Arch Dis Child 1991;65:909–11. [4] Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disese. Nat Med 1997;3:797–801. [5] Greco L, Romino R, Coto I, Di Cosmo N, Percopo S, Maglio M, et al. The first large population based twin study of coeliac disease. Gut 2002;50:624–8. [6] Boniotto M, Braida L, Ventura A, Percopo S, Amoroso A, Crovella S. Promoter polymorphisms of the CD14 gene in Italian patients with coeliac disease. J Med Genet 2003;40:e108. [7] Martucci S, Biagi F, Di Sabatino A, Corazza GR. Coeliac disease. Dig Liver Dis 2002;34(Suppl. 2):S150–3. [8] van Heel DA, Hunt K, Greco L, Wijmenga C. Genetics in coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:323–39. [9] Van Belzen MJ, Meijer JW, Sandkuijl LA, Bardoel AF, Mulder CJ, Pearson PL, et al. A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–41. [10] Babron MC, Nilsson S, Adamovic S, Naluai AT, Wahlstrom J, Ascher H, et al. European Genetics Cluster on Coeliac Disease. Meta and pooled analysis of European coeliac disease data. Eur J Hum Genet 2003;11:828–34.
G. Cirillo et al. / Digestive and Liver Disease 39 (2007) 228–231 [11] Monsuur AJ, de Bakker PI, Alizadeh BZ, Zhernakova A, Bevova MR, Strengman E, et al. Myosin IXB variant increases the risk of celiac disease and points toward a primary intestinal barrier defects. Nat Genet 2005;37:1341–4. [12] Hunt KA, Monsuur AJ, McArdle WL, Kumar PJ, Travis SP, Walters JR, et al. Lack of association of MYO9B genetic variants with coeliac disease in a British cohort. Gut 2006;55:969–72. [13] Amundsen SS, Monsuur AJ, Wapenaar MC, Lie BA, Ek J, Gudj´onsd´ottir AH, et al. Association analysis of MYO9B gene polymorphism with celiac disease in a Swedish/Norwegian cohort. Hum Immunol 2006;67:341–5.
231
[14] Post PL, Tyska MJ, O’Connell CB, Johung K, Hayward A, Mooseker MS. Myosin-IXb is a single-headed and processive motor. J Biol Chem 2002;277:11679–83. [15] Matter K, Balda MS. Signalling to and from tight junctions. Nat Rev Mol Cell Biol 2003;4:225–36. [16] Giordano M, Marano C, Mellai M, Limongelli MG, Bolognesi E, Clerget-Darpoux F, et al. A family-based study does not confirm the association of MYO9B with celiac disease in the Italian population. Genes Immun 2006;7:606–8. [17] Hebebrand J, Friedel S, Sch¨auble N, Geller F, Hinney A. Perspectives: molecular genetic research in human obesity. Obesity 2003;4:139–46.