Investigators have made key advances in rheumatoid arthritis (RA) genetics in 
the past 10 years. Although genetic studies have had limited influence on 
clinical practice and drug discovery, they are currently generating testable 
hypotheses to explain disease pathogenesis. Firstly, we review here the major 
advances in identifying RA genetic susceptibility markers both within and 
outside of the MHC. Understanding how genetic variants translate into pathogenic 
mechanisms and ultimately into phenotypes remains a mystery for most of the 
polymorphisms that confer susceptibility to RA, but functional data are 
emerging. Interplay between environmental and genetic factors is poorly 
understood and in need of further investigation. Secondly, we review current 
knowledge of the role of epigenetics in RA susceptibility. Differences in the 
epigenome could represent one of the ways in which environmental exposures 
translate into phenotypic outcomes. The best understood epigenetic phenomena 
include post-translational histone modifications and DNA methylation events, 
both of which have critical roles in gene regulation. Epigenetic studies in RA 
represent a new area of research with the potential to answer unsolved 
questions.