Celiac disease by MikeJenny

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									   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

• Usefulness of HLA genotyping?
            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
          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
MHC Class II




               Wolters. Am J Gastroenterol. 08
                                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
            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
Sollid. Nat Rev Immunol. 02
           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
HLA: an excellent NPV




                  Kaukinen. AM J Gastroenterol. 02
HLA genotyping in practice




                     Kaukinen. AM J Gastroenterol. 02
Kaukinen. AM J Gastroenterol. 02
          When diagnosis still
          remains uncertain


• Borderline small bowel mucosal finding

• Positive serology without villous atrophy

• Gluten-free diet before biopsy
Familial screening




                Srivastava. J Gastroenterol Hepatol. 10
        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
Cost/effectiveness




                Srivastava. J Gastroenterol Hepatol. 10
              tTG + Total IgA




                                                 NEGATIVE: 2 years later
  POSITIVE :
                           Ab POSITIVE               HLA genotyping
Intestinal biopsy
                                                     tTG screening



                                                     Ab NEGATIVE




                                         HLA +                       HLA -
                                   Serologic follow-up       Clinical follow-up


                                                                     Bonamico. JPGN. 06
                 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?
  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
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
   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
    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
   Non-HLA genes:
a new diagnostic tool?




                     Romanos. Gastroenterology. 09
                   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
The tested SNPs




                  Romanos. Gastroenterology. 09
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
What changes?




                Romanos. Gastroenterology. 09
          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!

								
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