Robert M. Plenge talks with
ScienceWatch.com and answers a few questions about
this month's Fast Breaking Paper in the field of Molecular
Biology & Genetics.
Article Title: Two independent alleles at 6q23
associated with risk of
rheumatoid
arthritis
Authors: Plenge,
RM, et al. Journal: NAT GENET
Volume: 39
Issue: 12
Page: 1477-1482
Year: DEC 2007
* MIT, Broad Inst Harvard, Program Med & Populat Genet,
77 Massachusetts Ave, Cambridge, MA 02142 USA.
(addresses have been truncated)
Why do you think your paper is highly
cited?
There may be four reasons. The first is that our study represents one of
the first genome-wide association study (GWAS) in patients with
rheumatoid arthritis (RA). The
second is that two independent alleles at a single locus (6q23/TNFAIP3)
were identified that contribute to risk of one disease, in this case, RA.
This is an emerging theme in genetic studies. Third, we investigated
technical and genetic biases that may be introduced into GWAS that use a
common set of "shared controls." And fourth, this region is associated with
other autoimmune diseases (notably systemic lupus erythematosus).
Also see: Robert R Graham, et al., "Genetic variants near TNFAIP3
on 6q23 are associated with systemic lupus erythematosus," Nature
Genetics 40(9): 1059-61, September, 2008.
Stacy L. Musone, et al., "Multiple polymorphisms in the TNFAIP3
region are independently associated with systemic lupus erythematosus,"
Nature Genetics 40[9]: 1062-64, September, 2008.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
"We still cannot explain the entire
genetic burden of RA."
One novel RA risk locus was identified as part of this study. In that
sense, it represents a new discovery.
Would you summarize the significance of your paper in
layman's terms?
We do not understand the fundamental mechanisms that cause RA. Genetics
offers one approach to understanding which biological pathways are involved
in disease risk. Our study tested approximately 30% of common genetic
variation in the human genome, and found one locus (two different genetic
variants) that contributes to risk of disease. Both variants are near a
biological candidate gene, TNFAIP3, which is involved in TNF
signaling—and important inflammatory cytokine in RA.
How did you become involved in this research, and were
there any problems along the way?
I had an interest in studying rheumatoid arthritis specifically because, as
a practicing rheumatologist, I see patients with this disease. I quickly
came to learn that, for many patients with RA, the disease can be quite
disabling.
I became involved in this research because of opportunities created by
others—clinical researchers who had collected thousands of RA
patients and controls, and geneticists who established technological and
statistical advances to study 100,000 SNPs (single nucleotide
polymorphisms) across the genome. Without the efforts of many people before
me, our study would not have been possible.
There were challenges encountered while conducting our study. The most
substantial challenge was that we used first-generation genotyping
technology (Affymetrix 100K array) and calling algorithm (DM), which we now
know are fraught with biases. We had to overcome these biases to convince
ourselves that the signal we observed was a true positive association.
Where do you see your research leading in the
future?
There are three important avenues of research:
We still cannot explain the entire genetic burden of RA. More RA
risk genes need to be identified.
We don't understand how these gene variants predispose RA.
Functional biological studies need to be done.
We don't understand how these discoveries will be translated to
patients. Clinical outcome studies for relevant phenotypes (e.g.,
response to treatment) need to be done.
Do you foresee any social or political implications for
your research?
As with all genetic studies, there are social and political implications.
Robert M. Plenge, M.D., Ph.D.
Assistant Professor of Medicine
Harvard-Partners Center for Genetics & Genomics
Harvard Medical School
and Director, Genetics & Genomics
Division of Rheumatology, Immunology and Allergy
Brigham and Women's Hospital
Boston, MA, USA
Keywords: rheumatoid arthritis, genome-wide association study,
two independent alleles at a single locus, autoimmune diseases, systemic
lupus erythematosus, single nucleotide polymorphisms.