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Rheumatoid Arthritis Risk

Reporter: Larry H Bernstein, MD, FCAP

Liu Y, Aryee MJ, Padyukov L, et al.
Nat Biotechnol. 2013 Jan 20;31(2):142-7.   http://dx.doi.org/10.1038/nbt.2487. Epub 2013 Jan 20.
The concordance rate for identical twins is only 12%-15%, which tells us that
  • other influences are even more important.
  • the “dark matter” of disease risk might be found in epigenetics,
  • defined as heritable changes in the genome without changes in DNA sequences.

Epigenome-wide association data implicate DNA methylation.
http://www.medscape.com//view-article/778573

Genetics of Rheumatic Disease – Medscape: Medical News, Full …Common variants at CD40 and other loci confer risk of rheumatoid arthritis. …
EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al.: … MM, Klei L, Daly MJ …www.medscape.com/viewarticle/717475  
High impact publications – Ongoing research – Karolinska …
Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis
Liu Y, Aryee MJ, Padyukov L, Fallin MD …
http://www.ki.se/ki/jsp/polopoly.jsp?d=7324&a=61979&l=en
Arthritis Research & Therapy
… Seldin MF, Remmers EF, Lee AT, Padyukov L, Alfredsson L, Coblyn J, et al.: … other loci confer risk of rheumatoid arthritis. Nat …
Liu Y, Helms C , Liao W, Zaba LC …   http://www.arthritis-research.com/content/12/3/r116
CHEST Journal
TRAF1-C5 as a risk locus for rheumatoid arthritis—a genomewide ... Liu G; et al . Whole-genome …
Padyukov L; et al. MHC2TA is associated with http://www. journal.publications.chestnet.org/article.aspx?articleid=1086542
Arthritis Research & Therapy 2010, 12:R116 Published: 16 June 2010    http://dx.doi.org/10.1186/ar3053
The electronic version of this article is the complete one and can be found online at: http://arthritis-research.com/content/12/3/R116
JE Hollis-Moffatt, M Chen-Xu, R Topless, N Dalbeth, … and TR Merriman

Only one independent genetic association with rheumatoid arthritis within the KIAA1109-TENR-IL2-IL21 locus in Caucasian sample sets:

Genetic associations implicate aberrant activation and regulation of autoreactive T-cells as central to RA. In addition to the established human leukocyte antigen locus DRB1, other genes more recently confirmed (either through wide replication or combined analysis at a genome-wide level of significance, P ≤ 10-8) as playing a role in the development of RA are the protein

Aside from HLA-DRB1 and PTPN22, the effects are weak (odds ratio (OR) < 1.3). Most of these loci are also implicated as risk factors in other autoimmune phenotypes [12].
There is extensive linkage disequilibrium across the region,

  • hampering fine-mapping efforts [13],
  • there are two independent autoimmune associated regions within the KIAA1109-TENR-IL2-IL21 gene cluster.
We aimed to consolidate all available data on two SNPs independently associated with autoimmunity within the KIAA1109-TENR-IL2-IL21 gene cluster:
  • rs6822844 (minor allele protective) and rs17388568 (minor allele susceptible),
each into a single meta-analysis of association with RA that included previously published data, new genotype data from Australasia, and
publicly-available data from the Wellcome Trust Case Control Consortium (WTCCC).
 The single nucleotide polymorphism (SNP) rs6822844 within the KIAA1109-TENR-IL2-IL21 gene cluster
  • has been associated with rheumatoid arthritis (RA).

Other variants within this cluster, including

  • rs17388568 that is not in linkage disequilibrium (LD) with rs6822844, and
  • rs907715 that is in moderate LD with rs6822844 and rs17388568, have been associated with a number of autoimmune phenotypes,
    • including type 1 diabetes (T1D).

Here we aimed to:

  1. confirm at a genome-wide level of significance association of rs6822844 with RA
  2. evaluate whether or not there were effects independent of rs6822844 on RA at the KIAA1109-TENR-IL2-IL21 locus.

confirmation of association of rs6822844 with rheumatoid arthritis at a genome-wide level of significance

A total of 842 Australasian RA patients and 1,115 controls of European Caucasian ancestry were

  • genotyped for rs6822844, rs17388568 and rs907715.

Meta-analysis of these data with published and publicly-available data was conducted using STATA.
Imputed RA and control genotypes were obtained for

  • rs6822844, rs17388568 and rs907715 from 100% of the WTCCC dataset (1,856 cases, 2,933 controls) using the publicly available WTCCC data
    • using the program IMPUTE [25] and HapMap (NCBI Build 36 (db126b)) CEU data as reference haplotype set.

Of the Australasian case sample set, 99.1% of subjects for rs6822844, 99.1% of subjects for rs17388568 and 98.9% of subjects for rs9077015 were successfully genotyped and, for the 505 member control sample set, 97.4% of subjects for rs6822844, 99.4% of subjects for rs17388568 and 99.4% of subjects for rs9077015 were successfully genotyped. The remaining New Zealand control genotypes (n = 610) were obtained from the genome-wide data, with 100% successfully genotyped for rs17388568 and 99.6% imputed for rs6822844 and rs907715.
Testing for departures from Hardy-Weinberg equilibrium, for the significance of any difference in minor allele frequencies between patients and controls, calculating odds ratios and conditional association testing was done using the PLINK software package. Logistic regression analysis was applied to the Australasian case-control sample set to stratify data according to gender, RF, CCP and SE status using the STATA 8.0 data analysis and statistics software package (StataCorp, College Station, Texas, USA). Meta-analysis was done using the STATA 8.0 metan software package and cumulative P- values reported. The Mantel-Haenszel test was used to estimate the average conditional common odds ratio between these two independent cohorts and to test for heterogeneity between the groups. P- values from the North American Rheumatoid Arthritis Consortium (NARAC) study, which could not be combined using meta-analysis owing to unavailability of allele counts, were combined using Fisher’s method.

No statistically significant evidence for association was observed in the Australasian sample set for rs6822844 (odds ratio (OR) = 0.95 (0.80 to 1.12), P = 0.54), or rs17388568 (OR = 1.03 (0.90 to 1.19), P = 0.65) or rs907715 (OR = 0.98 (0.86 to 1.12), P = 0.69). When combined in a meta-analysis using data from a total of 9,772 cases and 10,909 controls

  • there was a genome-wide level of significance supporting association of rs6822844 with RA (OR = 0.86 (0.82 to 0.91), P = 8.8 × 10-8, P = 2.1 × 10-8 including NARAC data).

Meta-analysis of rs17388568, using a total of 6,585 cases and 7,528 controls, revealed

  • no significant association with RA (OR = 1.03, (0.98 to 1.09); P = 0.22) and
  • meta-analysis of rs907715 using a total of 2,689 cases and 4,045 controls revealed a
  • trend towards association (OR = 0.93 (0.87 to 1.00), P = 0.07).
    • this trend wasnot independent of the association at   rs6822844.

Zhernakova et al. [21] and Coenen et al. [28] both reported association of the KIAA1109-TENR-IL2-IL21 region with RA in overlapping Dutch case-control cohorts. We used data from the former study, as it was the only one to type rs6822844. The meta-analysis provided very strong (genome-wide) support

  • for rs6822844 playing a role in the development of RA (OR = 0.86 (0.82 to 0.91), P = 8.8 × 10-8).

The NARAC GWAS data (OR rs6822844 = 0.84 (0.74-0.96), P = 0.011) [7] were combined with the meta-analysis result, yielding P = 2.1 × 10-8.

The KIAA1109-TENR-IL2-IL21 gene cluster, that encodes aninterleukin (IL-21)that plays an important role in Th17 cell biology, is the

  • 20th locus for which there is a genome-wide (P ≤ 5 ×10-8) level of support for association with RA.

As for most other autoimmune diseases, with the notable exception of T1D, rs6822844 is the dominant association in the locus. The KIAA1109-TENR-IL2-IL21 locus also

    • confers susceptibility to other autoimmune phenotypes with a heterogeneous pattern of association.

 

Genetic “Tags” Linked with RA Risk
Chemical “tags” that attach to DNA and regulate the activity of genes

  • appear to play a role in the development of rheumatoid arthritis.
    1. These results were published in Nature Biotechnology.
Genes play an important role in rheumatoid arthritis (RA) and many other common chronic diseases, but often do not tell the entire story. Factors that regulate the activity of genes are also thought to be important.

    • These factors include chemical tags that bind to DNA.
If the tagging of certain genes is found to contribute to a disease, it could point to news ways to treat the disease. One of the challenges in studying these tags, however, is

  • determining the sequence of events;
  • some tags may occur prior to disease and influence disease development,
  • while other tags may occur as a result of the disease.
To explore genes and their chemical tags in relation to RA,

  • researchers conducted a study among a group of people with RA and a comparison group of people without RA.
  • The researchers were able to identify DNA sites that were tagged differently in people with RA and that appeared to affect the risk of RA.
  • Most of these sites were in an area of the genome that has been linked with autoimmune disease.
In a prepared statement, the senior author of the study summarized the importance of these findings for patients: “Since RA is a disease in which the body’s immune system turns on itself,

    • current treatments often involve suppressing the entire immune system, which can have serious side effects.

The results of this study may allow clinicians to instead directly target the culpable genes and/or their tags.”

Reference: Liu Y, Aryee MJ, Padyukov L et al. Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nature Biotechnology. Early online publication January 20, 2013;
New Risk Gene for Rheumatoid Arthritis and Lupus Opens Door to More Effective Treatments
gene variant on STAT4 on chromosome 2
http://phys.org/news108298062/
Study identifies genetic risk factor for rheumatoid arthritis, lupus Sept 6, 2007
A genetic variation has been identified that increases the risk of two chronic, autoimmune inflammatory diseases: rheumatoid arthritis (RA) and systemic lupus erythematosus (lupus).
These research findings result from a long-time collaboration between the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases and other organizations.
These results appear in the Sept. 6 issue of the New England Journal of Medicine.
“Although both diseases are believed to have a strong genetic component, identifying the relevant genes has been extremely difficult,” says study coauthor Elaine Remmers, Ph.D.  Dr. Remmers and her colleagues
  • tested variants within 13 candidate genes located in a region of chromosome 2,
  • which they had previously linked with RA,
  • for association with disease in large collections of RA and lupus patients and controls.

Among the variants were several disease-associated single nucleotide polymorphisms (SNPs) —

  • small differences in DNA sequence that represent the most common genetic variations between individuals —
  • in a large segment of the STAT4 gene.

The STAT4 gene encodes a protein that plays an important role in the regulation and activation of certain cells of the immune system.

“It may be too early to predict the impact of identifying the STAT4 gene as a susceptibility locus for rheumatoid arthritis — whether the presence of the variant and others will serve as

  • a predictor of disease,
  • disease outcome or
  • response to therapy,”
says coauthor and NARAC principal investigator Peter K. Gregersen, M.D., of The Feinstein Institute for Medical Research,  in Manhasset, N.Y.

  • “It also remains to be found whether the STAT4 pathway plays such a crucial role in RA and lupus that
  • new therapies targeting this pathway would be effective in these and perhaps other autoimmune diseases.”

One variant form of the gene was present at a significantly higher frequency in RA patient samples from the North American Rheumatoid Arthritis Consortium (NARAC) as compared with controls.
The scientists replicated that result in two independent collections of RA cases and controls. The researchers also found that the same variant of the STAT4 gene was

  • even more strongly linked with lupus in three independent collections of patients and controls.

Frequency data on the genetic profiles of the patients and controls suggest that individuals who carry two copies of the disease-risk variant form of the STAT4 gene have a 60 percent increased risk for RA and more than double the risk for lupus compared with people who carry no copies of the variant form. The research also suggests

  • a shared disease pathway for RA and lupus.

“For this complex disease, rheumatoid arthritis, this is the first instance of a genetic linkage study

  1. leading to a chromosomal location, which then,
  2. in a genetic association study, identified a disease susceptibility gene,” says Dr. Gregersen.

The study’s success, according to NIAMS Director Stephen I. Katz, M.D., Ph.D., can be attributed in part to the uncommon and longstanding collaboration between NIAMS intramural researchers and other scientists the Institute supports around the country. “This work required the collection and genotyping of thousands of RA and lupus cases and controls, a task that would have been difficult to accomplish without the strong partnerships we forged,” he says. NARAC was established 10 years ago by Dr. Gregersen, NIAMS Clinical Director and Genetics and Genomics Branch Chief Daniel Kastner, M.D., Ph.D., and investigators at several academic health centers to facilitate the collection and analysis of RA genetic samples. Adds Dr. Remmers,

“Although we do not yet know precisely how the disease-associated variant of the STAT4 gene increases the risk for developing RA or lupus,
  • it is very exciting to know that this gene plays a fundamental role in these important autoimmune diseases.
” Source: National Institute of Arthritis and Musculoskeletal and Skin Diseases
English: A hand affected by rheumatoid arthritis

English: A hand affected by rheumatoid arthritis (Photo credit: Wikipedia)

Rheumatoid arthritis (1)

Rheumatoid arthritis (1) (Photo credit: Wikipedia)

Typisches Röntgenbild einer Rheumatoiden Arthr...

Typisches Röntgenbild einer Rheumatoiden Arthritis. (Photo credit: Wikipedia)

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