1 / 28

Coeliac disease

Coeliac disease. Can genotyping help to diagnose coeliac disease?. Difficult diagnosis. Asymptomatic patients: relatives Moderate histological lesions (Marsh 1-2) Positive Ab without histological lesion: not perfectly specific Gluten free diet before intestinal biopsy

usoa
Download Presentation

Coeliac disease

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Coeliac disease Can genotyping help to diagnose coeliac disease?

  2. Difficult diagnosis • Asymptomatic patients: relatives • Moderate histological lesions (Marsh 1-2) • Positive Ab without histological lesion: not perfectly specific • Gluten free diet before intestinal biopsy • Usefulness of HLA genotyping?

  3. Genetic origins • Ethnic differences in disease incidence/prevalence • Familial aggregation: • 5–15% first-degree relatives • 30% HLA identical sibs • Monozygotic twins 83–86% • Dizygotic twins 11% Greco. Gut. 02 Sollid. J Exp Med 89

  4. Genes involvement • Susceptibility loci: chromosomes 2, 5, 6, 9, 15, 19 • Genetic association studies of functional candidate genes: • CTLA4 • MYO1XB • Association with genetic syndromes: • Down syndrome • Turner syndrome • Williams syndrome

  5. MHC Class II Wolters. Am J Gastroenterol. 08

  6. HLA • Major histocompatibility complex (MHC): 6p21 • MHC class II : • Loci HLA-DQ, HLA-DP and HLA-DR, • Expressed on professional antigen presenting cells • HLA-DQ2: • Alleles DQA1*0501 and DQB1*0201 • DQ2 (DR3 or DR5/7): 90-95% of CD patients vs 15-20% of controls • 3% of HLA-DQ2 positive population will develop a CD • Risk effect: 38-53% • DQ8: • 5-10% of CD patients vs 20% of controls Sollid. J Exp Med. 89 Petronzelli. Ann Hum Genet. 97

  7. HLA-DQ2 alleles: a gene dosage effect • Highest risk if: • 2 alleles (DQA1*0501 and DQB1*0201) • In cis or in trans • Further increased if: • Homozygous for the DQ2.5cis • A second DQB1*02 on the 2nd chromosome Vader. Proc Natl Acad Sci USA. 03

  8. Sollid. Nat Rev Immunol. 02

  9. HLA DQ2/DQ8 are more frequent in female • Female: 94% vs 85% in males (P = 1.6 × 10−3) • NPV: 99.1% in female and 90.5% in males • Majority of the DQ2/DQ8 negative cases were male • DQ2/DQ8 transmission is more frequent from fathers to daughters (P = 0.02): • 61% of female patients • 42% of male patients Megiorni. Am J Gastroenterol. 08

  10. HLA: an excellent NPV Kaukinen. AM J Gastroenterol. 02

  11. HLA genotyping in practice Kaukinen. AM J Gastroenterol. 02

  12. Kaukinen. AM J Gastroenterol. 02

  13. When diagnosis still remains uncertain • Borderline small bowel mucosal finding • Positive serology without villous atrophy • Gluten-free diet before biopsy

  14. Familial screening Srivastava. J Gastroenterol Hepatol. 10

  15. first-degree relatives • 2.8-12% CD prevalence in relatives • 5.8% to 14% of serology positive relatives • Higher prevalence in siblings vs parents? • 59%-85% HLA DQ2/DQ3 DQ2-positive relatives • 14.3% HLA negative relatives Srivastava. J Gastroenterol Hepatol. 10 Bonamico. JPGN. 06

  16. Cost/effectiveness Srivastava. J Gastroenterol Hepatol. 10

  17. tTG + Total IgA NEGATIVE: 2 years later HLA genotyping tTG screening POSITIVE : Intestinal biopsy Ab POSITIVE Ab NEGATIVE HLA + Serologic follow-up HLA - Clinical follow-up Bonamico. JPGN. 06

  18. HLA genotyping • Non specific: only NPV • Long-life information • Diagnosis remained uncertain: • Borderline intestinal lesions, • Positive serological diagnosis without villous atrophy • If gluten free diet: • Surveillance for HLA positive cases • Role of: • Positive EmA? • Increased g/d IELs?

  19. First coeliac disease GWAS • 778 patients, 1422 controls, 310 605 SNP • 4q27 SNP rs13119723: • English, dutch and irish populations: p=2x10-7 • Meta-analysis: p=4.8x10-11 • Replication in UK and scandinavian populations Van Heel. Nat Genet. 07

  20. First coeliac disease GWAS • Several genes in high level of linkage disequilibrium: • KIAA1109: unknown function • Adenosine deaminase domain containing 1 (ADAD1) • Interleukin2 (IL2): T cell activation and proliferation • IL21: B, T and NK cells proliferation and IFNg production • Also linked to type 1 diabetes and rheumatoid arthritis Van Heel. Nat Genet. 07

  21. Follow-up of Coeliac GWAS • Genotyping of 1020 non-HLA SNP • In Dutch, Irish and UK collections • Meta-analysis of 2410 cases vs 4828 controls • 7 new significant regions Hunt. Nat Genet. 08

  22. Regions of the coeliac GWAS • In 5’ region of regulator of G protein signalling 1 (RGS1): • Regulation of G protein signalling activity • 3p21: CCR3 and CCR5 • 3q25–2: IL12A cytokine subunit • 6q25: TAGAP: a T cell activation GTPase activating protein • 3q28: Lim domain containing preferred translocation partner in lipoma (LPP): not immune? • 2q11–12: IL1RL1, IL18R1, IL18RAP and solute carrier SLC9A4 • 12q23: SH2B3 • TNFAIP3 • REL Hunt. Nat Genet. 08 Trynka. Gut. 09

  23. Non-HLA genes: a new diagnostic tool? Romanos. Gastroenterology. 09

  24. 3 risk groups • Low risk: • HLA-DQ2 negative (DQ2.5 and DQ2.2) • Intermediate risk: • Homozygous for HLA-DQ2.2 • Heterozygous for HLA-DQ2.5 • Heterozygous for HLA-DQ2.2 • High risk for: • Homozygous for HLA-DQ2.5 • Composite heterozygote HLA-DQ2.5/DQ2.2

  25. The tested SNPs Romanos. Gastroenterology. 09

  26. Non HLA genes increase CD risk 7.5% of HLA DQ2 positive cases are reclassified if ≥ 13 non HLA alleles Sensitivity increases from 46.6 to 49.5% Specificity decreases from 93.6% to 92.8% Romanos. Gastroenterology. 09

  27. Romanos. Gastroenterology. 09 What changes?

  28. Conclusive remarks • HLA: • Good NPV, especially in female • Long-life information • Can avoid repeted exams in: • Asymptomatic DQ2/DQ8 negative cases (screening) • Serology negative patients with atypical symptoms • Cost/effectiveness? • Non-HLA genotypes: • Slight increasing of diagnostic effectiveness • Will evoluate with new susceptibility SNPs • Cost as to be evaluated!

More Related