KINESIOL 1Y03 Chapter 11: Genetics of Coeliac Disease
22 Jun 2018
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Genetics of Coeliac Disease
- Concordance of CD in MZ twins = 80%
-This may be incomplete due to DZ twins being included, and asymptomatic disease
not being recognized
- Concordance of Coeliac in HLA-matched siblings = 30% (The HLA-DQ2 genotype is
important in Coeliac)
- Overall risk to siblings = around 10% -Macdonald et al, NEJM 1965
- I.e. sibling relative risk (sibling risk / prevalence) = Δ s = 10
HLA Associations
HLA is coded for in a region of chromosome 6
HLA class 1 associations with Coeliac include HLA-A1 and HLAB8
HLA-DQ2(1*0501, 1*02) is a heterodimeric cell surface receptor molecule on
lymphocytes. It can be encoded in DNA in a cis form (both polypeptide subunits encoded on
the same chromosome) or a trans form (polypeptide subunits encoded on different
chromosomes).
-Those who have the cis form are HLA-DR3 (65-95% of N European patients)
-Those who have the trans form are HLA-DR5 / DR7 (Mediterranean patients)
The HLA-DQ2 binds the de-amidated DQ2--1 epitope, leading to pathogenesis…
About 5% of Coeliacs are DR4-DQ8 (DQA1*0301, DQB1*0302)
- However, as only 30% concordance in HLA-matched siblings, there must be other genes
implicated.
Strategies to map non-HLA genes
1) Genome wide linkage studies (1990s)
-Sharing by siblings of markers throughout the entire genome, markers in linkage
disequilibrium more frequently shared
-There were 13 studies with variable, often non-confirmed findings. Many genes
were implicated:
-2q33 (CD28-CTLA-ICOS region)
-6p23 = distinct from HLA
-19p13.1 = myosin 9B
Candidate Gene analysis
-went on to research the implicated candidate genes
-overall there is some evidence for these but the association wasn’t clear
CTLA4/CD28
-binding regulates T cell activation when antigen is presented.
-An A/G polymorphism in CTLA4 exon 1 +49 is associated with: T1DM and Graves
disease
-Hunt et al, Eur J. Hum Genet. 2005 found definite linkages across entire region with
common haplotypes identified in CD however though alleles at 2q33 may predispose
to CD, the CTLA4 (+49 A/G) polymorphism is unlikely to be implicated
Non-HLA loci within MHC on chr.6
-Strong linkage disequilibrium in the region of extended haplotypes (B8/DR3/DQ2),
most of this due to HLA-DQ2
-Studies of TNF, TAP1, TAP2 has shown weak evidence
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Concordance of cd in mz twins = 80% This may be incomplete due to dz twins being included, and asymptomatic disease not being recognized. Concordance of coeliac in hla-matched siblings = 30% (the hla-dq2 genotype is important in coeliac) Overall risk to siblings = around 10% -macdonald et al, nejm 1965. I. e. sibling relative risk (sibling risk / prevalence) = s = 10. Hla is coded for in a region of chromosome 6. Hla class 1 associations with coeliac include hla-a1 and hlab8. Hla-dq2( 1*0501, 1*02) is a heterodimeric cell surface receptor molecule on lymphocytes. It can be encoded in dna in a cis form (both polypeptide subunits encoded on the same chromosome) or a trans form (polypeptide subunits encoded on different chromosomes). Those who have the cis form are hla-dr3 (65-95% of n european patients) Those who have the trans form are hla-dr5 / dr7 (mediterranean patients) The hla-dq2 binds the de-amidated dq2- -1 epitope, leading to pathogenesis .
