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Risk Alleles, Complex Disease, and a New Meaning for Negative

Risk Alleles, Complex Disease, and a New Meaning for Negative

Recent advances in genetics have revealed many newfound genetic loci associated with rheumatic disorders. What insights are being gained from this knowledge now, and what can we anticipate for the future?

In this brief interview, rheumatologist Soumya Raychaudhuri MD describes a recent study that led his team to clarify what many rheumatologists already suspected: That ACPA-negative rheumatoid arthritis actually represeents much more than merely a lack of response to an antibody test.

Dr. Raychaudhuri spoke to Rheumatology Network shortlky before his presentation "Using Genetics to Identify Mechanisms for Complex Immune-Mediated Diseases" at the American College of Rheumatology pediatric rheumatology symposium in Orlando, Flordia. Dr. Raychaudhuri is assistant professor of medicine at Harvard Medical School and a member of the genetics division at Brigham & Women's Hospital and the Program in Medical and Population Genetics at the Broad Institute in Boston.

The questions:

--  You've just recently published a study about the use of genetics to understand what's going on with seronegative RA patients ... Can you tell us what questions you were trying to answer, what you were hoping to find, and what you found?

-- And the implication of this was ... ?

-- You're talking at the conference about the power of genetics in general to tease out mechanisms of complex diseases. What would you say are the most important recent advances in this field?
What would you say is the most promising likelihood for applications of  this understanding in the near future?

-- What is the most difficult question to answer that you might receive after your presentation tomorrow? What are they going to ask you that you're really going to have to think hard to answer?

Key quotes:

"It's very clear from the genetics that seronegative RA is actually a heterogeneous set of conditions."

"Current studies are quickly discovering risk alleles for many rheumatic diseases ... The main focus of my research and of other research programs in genetics now is to start thinking about how we can take the alleles we are discovering and use them to discover something mechanistic about disease."

"As we start to understand what the alleles are actually doing ... if we have a biomarker that tracks the function of that cell type, we might actually be able to pick up on early disease in a way that we're not able to do now."

"Newborn screening could quickly become whole-genome sequencing. There is a possibility that in the very near future, in addition to all of the confusing aspects of making a diagnosis ... we could have whole-genome data. ... It also brings a whole bunch of questions as to how one is going to interpret [and] understand this data."



Han B, Diogo D, Eyre S, et al. Fine Mapping Seronegative and Seropositive Rheumatoid Arthritis to Shared and Distinct HLA Alleles by Adjusting for the Effects of Heterogeneity. American Journal of Human Genetics (2014) 94 1-11 - See more at: http://www.rheumatologynetwork.com/rheumatoid-arthritis/what-absence-acp...

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