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34 COELIAC DISEASE IN THE SAHARAWI DQB1 genes and dot blot analysis of amplified DNA with sequence specific 19-21 oligonucleotide probes (SSO) were carried out as previously reported . The DQA1 alleles were inferred using the known patterns of linkage disequilibrium from the DRB1-DQB1 haplotypes. Parental haplotypes were reconstructed using a program written by Frank Dudbridge available at ftp://ftp-gene.cimr.cam.ac.uk/pub/software/. A possible drawback of case-control analyses is their sensitivity to problems related to genetic stratification. In order to circumvent this problem, 82 affected family-based control, (AFBAC) DQA1-DQB1 haplotypes have been selected from all the families in 22 which the parents were available, as described for single alleles by Thomson . The AFBAC frequencies are based on the chromosomes that are never transmitted from the parents to affected children and provide a source of controls which is not sensitive to population stratification unless very recent. The control frequencies were also enriched by 18 chromosomes deriving from 9 unaffected and unrelated Saharawi individuals. The pseudo-controls (AFBAC) and control frequencies were nearly identical and therefore were merged (total controls equal to 100 chromosomes). Using these control haplotype frequencies and assuming Hardy-Weinberg equilibrium, we also established 23 the control genotype frequencies as previously described . The frequencies of the HLA class II haplotypes and genotypes obtained in patients and in controls, were then compared using a 2 x 2 chi-squared Pearson test. The odds ratios ORs) were calculated using the Wolf formula [a x d)/(b x c)]; when one element of this equation was 0 we used the Haldane formula: RR=[2a + 1) 2d +1)]/[2b +1) 2c +1)], where a is the number of patients possessing the HLA antigen; d is the number of controls lacking the particular HLA antigen; b the number of patients lacking the particular antigen; c the number of controls possessing the particular HLA antigen. In the association analyses performed in this study, we considered only the probands in the 8 families with more than one affected sibling. A correction for number of tests performed was applied by multiplying the P values for the tested markers present in more than 1 patient or 1 control (respectively 10 haplotypes and 8 genotypes). We also evaluated the evolutionary relationship between the Saharawis and the 24 other human groups. To this aim we performed a multi-dimensional scaling analysis carried out using the correlation matrix of the haplotype frequencies reported in the various populations and determined with a gene counting procedure. Who are the Saharawis? In order to obtain a visual output of the DRB1-DQA1-DQB1 haplotype distribution worldwide and obtain information about the evolutionary relationships between the various human groups we performed a multi-dimensional scaling analysis. The results of this analysis are shown in Fig.1. The first dimension splits Eastern and Western world populations. The Asian and the African appear to be the most differentiated human groups, with the Kogi and Cayapa native American populations as the most differentiated within the Asian group. The Caucasians are closely grouped and are located between the African and the Asian range of variability. The second dimension explains the diversity of the Caucasian group, which includes the North-African and the Saharawi samples. More specifically, the Saharawi population appears to be located in
COELIAC DISEASE IN THE SAHARAWI 35 the border between the European and the African range of variability. Thus, the genetic structure of this population is consistent with its geographical location. The association of the DQ molecules with CD in the Saharawi population We first established the sibling lifetime risk/population prevalence ratio, ls in our Saharawi sample set, that was equal to 3 (16.7%/5.6%). Because of the high disease prevalence, the degree of familial clustering was lower in the Saharawi than in Caucasian populations ls = ~30). Next, we established the association of the haplotypes and genotypes at the main disease superlocus HLA-DQB1-DQA1 in this population. The distribution of the various haplotypes among the Saharawi CD patients and controls is shown in Tab. 1. The DQA1*0501-DQB1*0201 haplotype was positively associated with CD (OR: -6 4.5, Pc = 1.4x10 ) while the DQA1*0102-DQB1*0604, haplotype showed some -3 degree of negative association with the disease (OR: 0.4, Pc = 4.7x10 ). To our knowledge the latter finding has been never reported in other populations and therefore needs confirmation in independent sample sets. Tab. 2 shows the distribution of the genotypes among patients and controls. The (DR3)DQA1*0501-DQB1*0201/(DR3)DQA1*0501-DQB1*0201 encoding two putative a*0501 - b*0201 heterodimers was positively associated with CD (OR: 6.4, -2 P= 2.4x10 ). The (DR3)DQA1*0501-DQB1*0201/(DR4)DQA1*0301-DQB1*0302 and the (DR3)DQA1*0501-DQB1*0201/(DR7)DQA1*0201-DQB1*0201 genotypes showed a trend toward a positive association (OR: 8.6 and 2.4 respectively) without reaching the level of significance. Overall, 91.3% of the patients, but only 38.9% of the controls were found to be positive for the combined presence of the DQA1*0501 and DQB1*0201 alleles encoding in cis or in trans at least one putative a*0501 - b*0201 heterodimer. The patients positive for the DQA1*0501-DQB1*0201 or DQA1*03-0302 heterodimer HAPLOTYPES Patients Controls DQA1 DQB1 N N OR 95% C.I. P
Page 1: Perspectives on Coeliac Disease Vol
Page 4: The AIC Meeting was held in the Aul
Page 8 and 9: Italian Coeliac Society, Via Picott
Page 11 and 12: Preface Coeliac disease (CD) is a u
Page 13: Contents Current understanding of t
Page 16 and 17: 2 THE BASIS OF COELIAC DISEASE hapl
Page 18 and 19: 4 THE BASIS OF COELIAC DISEASE 1 pr
Page 20 and 21: 6 THE BASIS OF COELIAC DISEASE spre
Page 22 and 23: 8 THE BASIS OF COELIAC DISEASE Ackn
Page 24 and 25: 10 THE BASIS OF COELIAC DISEASE glu
Page 27 and 28: Catassi C, Fasano A, Corazza GR (ed
Page 29: T CELL RESPONSES TO GLUTEN PEPTIDES
Page 32 and 33: 18 A DOMINANT EPITOPE IN GLUTEN PEP
Page 42 and 43: 28 ROLE OF A-GLIADIN 31-49 PEPTIDE
Page 47: COELIAC DISEASE IN THE SAHARAWI 33
Page 51 and 52: COELIAC DISEASE IN THE SAHARAWI 37
Page 53 and 54: COELIAC DISEASE IN THE SAHARAWI 39
Page 55: COELIAC DISEASE IN THE SAHARAWI 41
Page 58 and 59: 44 INFANT FEEDING PRACTICES AND COE
Page 66 and 67: Age (years) 52 INFANT FEEDING PRACT
Page 76 and 77: 62 MECHANISMS OF ORAL TOLERANCE the
Page 78 and 79: 64 MECHANISMS OF ORAL TOLERANCE pot
Page 80 and 81: 66 MECHANISMS OF ORAL TOLERANCE Epi
Page 82 and 83: 68 MECHANISMS OF ORAL TOLERANCE typ
Page 84 and 85: 70 MECHANISMS OF ORAL TOLERANCE 51
Page 86 and 87: 72 MECHANISMS OF ORAL TOLERANCE 23.
Page 91 and 92: GENETICALLY DETOXIFIED GRAINS 77 to
Page 93 and 94: • • GENETICALLY DETOXIFIED GRAI
Page 95 and 96: GENETICALLY DETOXIFIED GRAINS 81 3.
Page 99 and 100:
IMMUNOTHERAPY OF COELIAC DISEASE 85
Page 101 and 102:
IMMUNOTHERAPY OF COELIAC DISEASE 87
Page 103 and 104:
Catassi C, Fasano A, Corazza GR (ed
Page 105 and 106:
RECENT ADVANCES ON GLUTEN TOXICITY
Page 107 and 108:
Index A Antiendomysium antibodies (
Page 109:
INDEX 95 W Wheat, 7, 23, 27, 31, 53
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