Editors' ChoiceGenetics

Genetic Tug of War in the Immune System

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Science Translational Medicine  23 Mar 2011:
Vol. 3, Issue 75, pp. 75ec40
DOI: 10.1126/scitranslmed.3002406

Our immune system is in a constant “arms race” against the microbial world. As different world populations faced various microbial challenges throughout history, the immune system adapted and diversified. Although these adaptations have helped us to survive, a balance must be struck between defending against infection and limiting the immune response to prevent damage to normal tissues. This ongoing battle over the genetic architecture of our immune system comes to the forefront in a recent genome-wide association study (GWAS) of immunoglobulin A (IgA) nephropathy by Gharavi et al. In IgA nephropathy, IgA antibodies (immune system proteins) deposit abnormally in the kidneys, resulting in inflammation and potentially kidney failure.

Gharavi and colleagues performed an initial GWAS in 1228 subjects with IgA nephropathy and 966 unaffected control subjects of Chinese Han ancestry. The results of this study were validated in two independent cohorts that included individuals of both Chinese and European ancestry, for a total of 3144 IgA nephropathy cases and 2822 controls. Five different genetic variants showed significant effects on the risk of developing IgA nephropathy: three within the HLA (human leukocyte antigen) locus on chromosome 6p21 and two non-HLA variants. The human HLA locus is a portion of chromosome 6 that contains hundreds of genes involved in regulation of the immune system. Strikingly, the strongest association detected in this study was protective against IgA nephropathy and is classically associated with risk of developing the autoimmune disease systemic lupus erythematosus. Another one of the three HLA variants—which was also protective against IgA nephropathy—has been associated previously with risk of chronic hepatitis B infection.

These data suggest that HLA has been central to an intense “tug of war” in recent human history, balancing the risk of various immune-mediated diseases against that of endemic infections. Further understanding of the molecular basis for these genetic associations will elucidate certain features of the human immune system that initiate IgA nephropathy as well as some autoimmune and infectious conditions, which could eventually allow for targeted interventions. Unraveling HLA associations will not be simple, but this study clearly underscores the immunoregulatory potential of this locus in human disease.

A. G. Gharavi et al., Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat. Genet. 13 March 2011 (10.1038/ng.787). [Abstract]

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