banners
Kickas Main Page | Rights and Responsibilities | Donate to Kickas
Forum Statistics
Forums30
Topics43,792
Posts518,796
Members13,839
Most Online1,568
Jun 29th, 2016
Newest Members
AshleyB, Dori, Mel_Sigman, wle2, Ur4n1cD34Th6488
13,839 Registered Users
KickAs Team
Administrator/owner:
John (Dragonslayer)
Administrator:
Melinda (mig)
WebAdmin:
Timo (Timo)
Administrator:
Brad (wolverinefan)

Moderators:
· Tim (Dotyisle)
· Chelsea (Kiwi)
· Megan (Megan)
· Wendy (WendyR)
· John (Cheerful)
· Chris (fyrfytr187)

QR Code
If you want to use this QR code (Quick Response code) just save the image and paste it where you want. You can even print it and use it that way. Coffee cups, T-Shirts etc would all be good for the QR code.

KickAS QR Code
Previous Thread
Next Thread
Print Thread
Page 8 of 8 1 2 3 4 5 6 7 8
Joined: Apr 2013
Posts: 372
Fifth_Degree_AS_Kicker
OP Offline
Fifth_Degree_AS_Kicker
Joined: Apr 2013
Posts: 372
Originally Posted By DavidP
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?


Based on my results, the ERAP1 is not my strong suit but lends more 'bad' rupute towards IL23R. Do you have a method for the IL23R?

Joined: Sep 2007
Posts: 608
D
Master_Sergeant_AS_Kicker
Offline
Master_Sergeant_AS_Kicker
D
Joined: Sep 2007
Posts: 608
At this stage I don't think anyone has attempted to define any IL23 haplotype associations with AS - not sure if it is even possible.

Regards again.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
Joined: Apr 2013
Posts: 372
Fifth_Degree_AS_Kicker
OP Offline
Fifth_Degree_AS_Kicker
Joined: Apr 2013
Posts: 372
DavidP

So IYO (in your opinion), what are the results really saying about a person's results?

Joined: Oct 2008
Posts: 758
Magical_AS_Kicker
Offline
Magical_AS_Kicker
Joined: Oct 2008
Posts: 758
Originally Posted By DavidP
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.


Hi David

That's cool, thanks for interpreting that. Good to know that my ERAP1 trimming shouldn't be too wayward. I like how they are looking at the combination of different SNPs and how they affect immunological processes. Seems like that approach would yield much more useful information compared to just looking at the odds ratios for individual SNPs, as it's likely to be a combination of different genes and SNPs that lead to particular pathologies.

Cheers

Joined: Sep 2007
Posts: 608
D
Master_Sergeant_AS_Kicker
Offline
Master_Sergeant_AS_Kicker
D
Joined: Sep 2007
Posts: 608
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.”


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


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
Joined: Oct 2008
Posts: 758
Magical_AS_Kicker
Offline
Magical_AS_Kicker
Joined: Oct 2008
Posts: 758
Wow, that's complex stuff!

Are you up with the play on the latest HLA-B27 research with regards to arthritogenic peptide vs unfolded protein response vs cell surface homodimers? I haven't kept up to date with the research from the last couple of years, but back when I was reading all the papers it seemed to be a 3 horse race, and figuring out ERAP1's involvement looked like it was going to be the key to figuring the pathogenic mechanism of B27. From the look of this abstract it doesn't look like there have been any major breakthroughs - http://www.annualreviews.org/doi/abs/10.1146/annurev-immunol-032414-112110

Joined: Sep 2007
Posts: 608
D
Master_Sergeant_AS_Kicker
Offline
Master_Sergeant_AS_Kicker
D
Joined: Sep 2007
Posts: 608
Hi jroc,

Sorry to have been a bit slow off the mark in replying to your question.

The classic role of HLA-B27 is (in combination with beta2-microglobulin) to present short peptides from intracellular pathogens for recognition by the T cell receptor of CD8 T-cells. B27 can also be expressed as cell surface beta2-microglobluin free homodimers. In addition to binding to the TCR, MHC class I molecules can also bind to immunoglobulin-like receptors (KIR). Natural Killer (NK) cells and some T-cells expressing the immune receptor KIR3DL2 can bind to B27 homodimers and are known to be expanded in B27+ AS patients.

The paper quoted put the hypothesis that ERAP1 allotypes form three functional groups; “normal”, “hypo-” or “hyper-” trimmers of peptides and that the prevalence of different ERAP1 allotype combinations has been shown to be different between AS cases and controls. This idea that low or high ERAP1 trimming activity might lead to the restricted supply of optimal peptides has the effect of unifying the mechanisms of homodimer formation and activation of innate and/or Th17 cells through the engagement KIR3DL2 receptors.

It is postulated that sub-optimal peptides (B27-ligands) generated by aberrant ERAP1 activity are able to bind with B27 sufficiently to pass intracellular quality control but that they may dissociate rapidly at the cell surface leading to increased levels of aberrant forms of B27. The authors were not able to rule out the possibility that different ERAP1 variants could generate specific arthritogenic peptides - so long story short - the question of unfolded protein response in the ER Vs cell surface B27 homodimers Vs arthritogenic peptide - remains unresolved.

Regards David.


Dx Oct 2006 B27+ undifferentiated spondlyarthropathy (uSpA) with mild sebhorrhoeic dermatitis and mild Inflammatory Bowel Disease (IBD) controlled by NSD since 2007.
Joined: Nov 2001
Posts: 18,141
Likes: 5
Very_Addicted_to_AS_Kickin
Offline
Very_Addicted_to_AS_Kickin
Joined: Nov 2001
Posts: 18,141
Likes: 5
Hi,

Please will you re-explain all of that in lay language? My brain shuts down trying to read these sometimes.

Thanks.

Warm hugs,


Kat

A life lived in fear is a life half lived.
"Strictly Ballroom"

Joined: Apr 2013
Posts: 372
Fifth_Degree_AS_Kicker
OP Offline
Fifth_Degree_AS_Kicker
Joined: Apr 2013
Posts: 372
Sadly I have to agree with Kat. Unless from a Scientific background, it all runs together....help David....

Signed,

Me Too! eek2

Page 8 of 8 1 2 3 4 5 6 7 8

Link Copied to Clipboard
Who's Online Now
0 members (), 43 guests, and 50 robots.
Key: Admin, Global Mod, Mod
Recent Posts
Uveitis again and I miss you guys!
by Magician - 01/20/22 05:14 AM
Popular Topics(Views)
3,180,889 hmmm
1,239,753 OMG!!!!
644,793 PARTY TIME!
Powered by UBB.threads™ PHP Forum Software 7.7.5
(Release build 20201027)
Responsive Width:

PHP: 5.5.38 Page Time: 0.026s Queries: 34 (0.009s) Memory: 3.2765 MB (Peak: 3.5322 MB) Data Comp: Zlib Server Time: 2022-06-30 06:24:02 UTC
Valid HTML 5 and Valid CSS