Coeliac disease
description
Transcript of 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
• 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. 02Sollid. 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. 89Petronzelli. 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. 10Bonamico. JPGN. 06
Cost/effectiveness
Srivastava. J Gastroenterol Hepatol. 10
tTG + Total IgA
POSITIVE :
Intestinal biopsy
NEGATIVE: 2 years later
HLA genotyping
tTG screening
Ab POSITIVE
Ab NEGATIVE
HLA +
Serologic follow-up
HLA -
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 / 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 IFN
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
• RELHunt. 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
Romanos. Gastroenterology. 09
7.5% of HLA DQ2 positive cases are reclassified if ≥ 13 non HLA allelesSensitivity increases from 46.6 to 49.5%
Specificity decreases from 93.6% to 92.8%
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!