Kickas.org Forums Ankylosing Spondylitis General Discussion #1 AS Web Support Group DNA Promethease Report and IL23R and ERAP1

Thanks, that's cool. I just took a look at the promethease website and the site and the reports have changed a lot since when I did it back in 2013. Looks much more professional now and they integrate with the 23andMe through their API so you don't have to manually upload. I might have to drop another $5 on a new report.

Hi Simply Southern,
Its hard to know what to make of Crohns Disease SNPs.
Of the ones you listed I had 8 for which CD risk was normal and 8 with slightly raised risk of CD.
Of the total of 149 CD SNPs I had 99 - Not set; 23 of Good Repute and 27 of Bad Repute.
Of the CD SNPs of Bad Repute the most interesting were those at the NOD2 locus on chromosome 16 since the NOD2 locus is considered to represent one of the strongest genetic risk factors for Crohns Disease.
They were
rs2066843 (T;T) 4.1X risk of CD
rs17221417 (G;G) 1.9X risk of CD and
rs2076756 (G;G) 1.7X risk of CD.

I don't think there are any articles which put a simple hypothesis ERAP1 bad repute SNPs -> axial disease Vs IL23R bad repute SNPs -> peripheral diseae.

You might have been thinking of this article - which is quite dated now.
http://www.sciencecodex.com/major_geneti..._treatment_hope

Understandably, most of the AS cohorts in genetic studies have in the past enrolled probably mainly classic AS cases - and very few more atypical cases - like those with an undifferientiaed spondyloarthropthy.

Recently the focus has been on IL23 and IL23R because of the discovery of a population of entheseal-resident IL23R+ T cells. It is speculated that other unique IL23R+ T cells might populate the skin, the gut, and the eyes.

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

Hi jroc and Simply Southern,

If you fit our 23andme ERAP1 data to the table in the above paper we should be able to guess what allotypes we have.

The five main SNP's in 23and me are rs2287987 (M349V); rs30187 (K528R); rs10050860 (D575N); rs17482078 (R725Q) and rs27944 (Q730E)
It's pretty simple for me and Simply Southern - we have two of the normal functioning *002 allotypes, that is amino acids MKDRQ for both our ERAP1 versions.

jroc on the other hand has one and possibly two hypofunctional alleles.

Hi David

That sounds interesting. How do I plug my data into the table to figure out my allotype - were you meaning this table? - http://www.pnas.org/content/111/49/17594/T1.expansion.html

Hi jroc,

Yeh, that's the table I was refering to.

http://www.jimmunol.org/content/191/1/35/T1.expansion.html

This table is from an earlier paper by the same authors.
The equivalent DNA bases that are reported in 23andme or Promethease are in lower case.

Let us know what you get.

Regards David