Genome-Wide Association Studies in Primary Biliary Cirrhosis

Abstract

Genome-wide association studies (GWASs) have been a significant technological advance in our ability to evaluate the genetic architecture of complex diseases such as primary biliary cirrhosis (PBC). To date, six large-scale studies have been performed that have identified 27 risk loci in addition to human leukocyte antigen (HLA) associated with PBC. The identified risk variants emphasize important disease concepts; namely, that disturbances in immunoregulatory pathways are important in the pathogenesis of PBC and that such perturbations are shared among a diverse number of autoimmune diseases-suggesting the risk architecture may confer a generalized propensity to autoimmunity not necessarily specific to PBC. Furthermore, the impact of non-HLA risk variants, particularly in genes involved with interleukin-12 signaling, and ethnic variation in conferring susceptibility to PBC have been highlighted. Although GWASs have been a critical stepping stone in understanding common genetic variation contributing to PBC, limitations pertaining to power, sample availability, and strong linkage disequilibrium across genes have left us with an incomplete understanding of the genetic underpinnings of disease pathogenesis. Future efforts to gain insight into this missing heritability, the genetic variation that contributes to important disease outcomes, and the functional consequences of associated variants will be critical if practical clinical translation is to be realized.

Figure 1

Chain-sharing between IL-12 and other members of the IL-12 cytokine family. Protein units comprising the dimeric cytokines and receptors, as well as the key downstream kinases and transcription factors, are shown for the proinflammatory IL-12 family members IL-23 and IL-12 and the inhibitory IL-12 family member IL-35. IL-12, the key cytokine in T_H1 immune polarization, shares the IL-12 p40 and IL-12 receptor β1 subunits with T_H17 polarizing IL-23 as well as the IL-12 p35 and IL-12 receptor β2 subunits with inhibitory IL-35. GWAS in PBC has identified associations with the genes encoding IL-12 p35 (IL12A) and IL-12 receptor β2 (IL12RB2), as well as with TYK2 and STAT4.