Hi jroc and Simply Southern,
Naturally occurring ERAP1 molecules are polymorphic, existing as haplotypes (also referred to as allotypes) which consist of multiple combinations of AS-associated SNPs, and that they have functional differences resulting from the different amino acid specificities. Indeed, naturally occurring ERAP1 allotypes have been shown to alter the repertoire of peptides presented by HLA-B27 and that in general ‘hypoactive’ ERAP1 allotypes (and on occasion ‘hyperactive’ allotypes) are preferentially associated with the diseased state.
Just to show that, even in scientific research, nothing is set in concrete.
Bettencourt et al. (2103) showed that haplotype analysis of four SNPs in ERAP1 identified two haplotypes of variants encoding residues 349-528-575-725 that significantly affected AS risk: V349-R528-N575-Q725 (VRNQ) was an AS protective haplotype and M349-K528-D575-R725 (MKDR) was an AS-risk haplotype. They also confirmed that the strongest association was with the AS-risk variant K528. By comparison the functional studies of the protein products of ERAP1 allotypes by Reeves et al. (2014) showed the opposite, VRNQE (349-528-575-275-730) was a risk allotype and MKDRQ was protective, and according to Ombrello, Kastner and Reimmers (2015), and quoting from the latter’s paper
“... allotypes within their collection of 17 AS cases and 19 healthy controls were surprisingly inconsistent with existing AS literature. Specifically, the AS-risk allele K528 and risk allotype (*002) were more common among their controls than cases, whereas the AS-protective allele (E730) and protective allotype (*001) were more common among their cases than controls. The source of this discrepancy is unclear, and this issue is unlikely to be resolved without an analogous, sequencing-base study of the ERAP1 locus in a substantially larger AS case-control collection.
It has also been hypothesized that AS-associated variants or allotypes may influence disease risk by affecting ERAP1 expression. Constantino et al. (2015) recently reported that the K528-D575-R725 AS-risk haplotype was strongly correlated with reduced ERAP1 mRNA levels, more so than was any individual AS-associated variant. This raises the possibility that AS-associated ERAP1 allotypes may contain both coding variants that influence AS risk through changes in enzymatic function and non-coding variants that influence AS risk through alterations in gene expression.â€
Earlier researchers also found that the results of imputation analysis showed a group of six SNPs in the 5'-upstream region and two SNPs in intron 19 of ERAP1 that reached a higher level of significance than rs30187 or any of the other single SNP. Researchers were perplexed because these novel SNPs, when considered individually, did not achieve AS-association and they appeared to localise to parts of the molecule unlikely to have any functional impact. It became apparent that the role of ERAP1 SNPs associated with AS work at a level more complex than individual SNPs.
Reeves et al. (2014), when considering SNPs relating to amino acid positions 82, 102, 115, 199, 581 and 737 found two distinct sequences that seemed to be co-inherited (along with positions 349, 528, 575, 725 and 730); and phylogenetic analysis confirmed that these positions (82, 102, 115, 199, 581 and 737) formed a backbone in almost all allotypes, either VILFLV or ILPLSA, the first being more likely to be disease-associated than the second; and this suggested of an earlier (more ancient) evolutionary branching. The SNPs that caused altered ERAP1 function (349, 528, 575, 725 and 730) originated at some later times, but nevertheless, remain in strong linkage disequilibrium with the older backbone SNPs.
Regards David
