ERAP1 is known to be highly polymorphic with at least 70 nsSNPs, although the majority are rare. Considering the more common SNPs, at least 15 SNPs in ERAP1 are known to be associated with AS. Until recently it was not known whether they acted independently or as disease associated haplotypes. Recent studies have shown the latter, that SNPs occur as distinct haplotypes (hereafter called allotypes) in the human population and that these allotypes encode functionally distinct ERAP1 molecules. Using a range of substrates researchers have demonstrated that each allotype has a trend bias toward ‘normal’, ‘hypofunctional’ or ‘hyperfunctional’ ERAP1.
The prevalence of specific ERAP1 allotypes is different in AS cases and healthy controls, although, at this stage the exact frequency of each allotype has not yet been accurately established for the general population or for AS cohorts. Each person has a pair of ERAP1 allotypes (one from each parent) and each of the chromosomal copies of ERAP1 are co-dominantly expressed. Most healthy controls have at least one ‘normal’ ERAP1 allotype compared with AS patients, who in general have two ‘hypoactive’ allotypes (and sometimes hyperactive allotypes). The disease associated ERAP1 allotype combinations have a reduced ability to generate peptides for presentation at the cell surface by MHC class I molecules, including HLA-B27. Hence, an ERAP1 pair composed of a ‘normal’ and a ‘hypoactive’ allotype will still produce sufficient peptide ligands, and of sufficient quality, as to allow for the normal biochemical functioning of HLA-B27.
Increased disease risk is potentially manifested in two ways. Firstly, aberrant ERAP1 activity, either hypo-functional of hyper-functional, might result in increased misfolding of HLAB-27 in the ER and the generation of B27 homodimers and an unfolded protein response; and secondly, aberrant ERAP1 activity might generate unstable peptide ligands and result in elevated cell surface B27 homodimers which could activate NK cells (through KIR3DL2 engagement) and/or Th17cells.
I have presented here only a simplified summary of a paper entitled “Functionally distinct ERAP1 allotype combinations distinguish individuals with Ankylosing Spondylitis†by Reeves, Colebatch-Bourn, Elliot, Edwards and James – 2014.
Regards to all – David.
http://www.pnas.org/content/111/49/17594.short
