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Hi jroc and Simply Southern,

It's difficult to work backward from the amino acid change, to the antisense mRNA codon, then to the sense DNA strand - sometimes the DNA quoted in 23andme is FWD, other times Reversed.

By convention M349V stands for M being the major allele amino acid and V the minor allele amino acid.

M349V is equivalent M=T and V=C where M and V are a.a.'s and T and C are the DNA bases quoted in Promethease.
K528R K=C and R=T
D575N D=C and N=T
R725Q R=C and Q=T
Q730E Q=C and E=G

For me Promethease gives
rs2287987 (349) T;T -> M;M
rs30187 (528) C;C -> K;K
rs10050860 (575) C;C -> D;D
rs17482078 (725) C;C -> R;R
rs27044 (730) C;C -> Q;Q

Put another way I have two allotypes MKDRQ and MKDRQ - that is two of the wild type or normal functioning ERAP1 allotypes

By the way, 23andme gives only the main nsSNPs in ERAP1 - the papers quoted give a few extras which help to delineate their 13 allotypes but not necessarily being disease causing?


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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It helps if you put a highlighter down each of the columns 349, 528, 575, 725, and 730 and mentally block out the rest.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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DavidP

I knew my products and customers but science and chemistry were not my forte'....lol

Based on the break down to figure it out, here are my results:

rs2287987(C;T) 349 V;M
rs30187(C;C) 528 K;K
rs10050860(C;T) 575 D;N
rs17482078(C;T) 725 R;Q
rs27044(C;C) 730 Q;Q

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Hi Simply Southern,
Based on your results the most likely combination of allotypes for you would be MKDRQ and VKNQQ
That would correspond with the *002 allotype which is an 'efficient' trimmer and the other as *010 allotype which is one of the disease associated 'hypoactive' trimmers.

That combination of allotypes, because of their codominant expression, would most likely not develop AS - but you would probably have a greater risk of AS than me with my two *002 allotypes.

Interestingly, you have one of the minor alleles at rs10050860 -> the N amino acid at 575 - which, at least on it's own, is considered protective against AS.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Ah I see, I think I get it now. These are my results:

rs2287987 (CT) > VV
rs30187 ( CT) > KR
rs10050860 (CT) > DN
rs17482078 (CT) > RQ
rs27044 (CG) > QE

And if I've understood correctly that would mean:

Allotypes: VKDRQ (*012) & VRNQE (*001)

Haplotypes: M349V & 5SNP

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Hi jroc,

Did you really mean you were heterozygote C;T at rs2287987 because that would correspond with M;V

For sure you are going to have the *001 allotype, which is fairly common in controls (21%) and even more abundant in AS cases (44%), bearing in mind that their sampled groups contained just 19 controls and 17 AS patients.

If you are homozygote C;C at rs2287987 then your analysis as *001 and *012 allotype pair is correct - which is a disease associated allotype pair.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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If you search on the term ERAP1 allotypes you can come up with some references to Behcet’s disease. Behcet’s Disease (sometimes called Behcet’s Syndrome or Silk Road Disease) is an immune-mediated small-vessel systemic vasculitis that often presents with recurrent mucous membrane ulceration and ocular lesions. It is described as a triple-symptom complex of recurrent oral aphthous (stomatitis) ulcers, genital ulcers, and uveitis. The disease can also involve visceral organs such as the gastrointestinal tract, pulmonary, musculoskeletal, cardiovascular and neurological systems. Skin lesions include erythema-nodosum-like lesions, erythema multiforme-like lesions and Sweet’s Syndrome-like lesions and the inflammatory infiltrating cells are predominantly macrophages.

Behcet’s disease, like the spondyloarthropathies, has a strong contribution to disease by variants of the ERAP1 gene, in fact, the very same ERAP1 allotypes that are linked to AS are seemingly involved in Behcet’s Disease. But whereas AS is associated with the MHC class I molecule HLA-B27, Behcet’s disease is associated with HLA-B51 and HLA-B5. Whilst HLA-B51 is generally below 1% in Caucasians its prevalence can be up to 20% in Turkish populations, for instance.

Why do AS and Behcet’s present so differently – presumably B27 and B51/5 activate and polarise the innate immune system in aberrant, but, different directions. AS is polarised toward the Th17/IL23 axis whilst traditionally BD is regarded as a predominantly Th1-mediated inflammatory disease (with possibly Th17 as well?).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597260/

http://journals.lww.com/co-rheumatology/...tidase_1.6.aspx

https://www.kickas.org/ubbthreads/ubbthre...lat&fpart=7


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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Magical_AS_Kicker
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Originally Posted By DavidP

Did you really mean you were heterozygote C;T at rs2287987 because that would correspond with M;V

Nice catch, yes I did mean CT for rs2287987 but then I screwed up and put VV instead of MV. So it would actually be:

Allotypes: MKDRQ (*002) & VRNQE (*001)

Haplotypes: WT & 5SNP

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Hi jroc,

Allotypes *001 and *002 (previously referred by the authors of the earlier paper as 5SNP and WT haplotypes) would be the most common allotypes (*002 more than *001) for healthy controls, remembering of course the tiny sample sizes. The combination *001 and *002 allotype pair would normally not be associated with AS, but clearly you are an exception.

Usually *002, being an efficient trimmer would nullify the effects of *001 which is a 'hypoactive' trimmer.

Regards David

PS. I think the same concept when applied to IL23R will yield useful results. In the case of ERAP1 allotype pairs, cumulative loss of function is a risk factor for AS; whereas for IL23R, loss of function is protective against AS, because if IL23 can't engage functionally or properly with IL23R then inflammation will be shut down?


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
Joined: Sep 2007
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Hi jroc and Simply Southern,

At this point it's worth mentioning that 23andme only measure a small proportion of the quoted SNPs using SNP microarrays then use computer programs to impute (a sophisticated form of guessing) the rest. That's why the price has come down from $1000 to $150. They do state up front that their results can't reliably be used for research, for that, more exact and detailed fine mapping might be required.

I did send them an email asking which of the SNPs rs2287987, rs30187, rs10050860, rs17482078 and rs27044, was actually 'read' and which was imputed - don't know if I'll get a reply?


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
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