The complexity and diversity of major histocompatibility complex challenge disease association studies

Abstract

The major histocompatibility complex (MHC; 6p21.3) contains the most polymorphic genes, the most gene dense parts, and the highest diversity of functional gene clusters of the human genome. The clusters form haplotypes, which differ in linkage disequilibrium and show large variations in strength and extent between populations. Haplotype cis- and trans-expression quantitative trait loci have increased the knowledge of regulatory interactions between multiple MHC genes. The detailed haplotype data offer a reference for future studies in immune-mediated diseases and may unravel disease associations in conditions traditionally considered not to be immunologic. This article aims to describe the structural and functional variations of the MHC genes and haplotypes and their role on selected immune-mediated diseases. In immune-/inflammation-mediated complex diseases, hundreds of common variants influence the development of the disease trait, but the individual variants have small effects on the disease phenotypes as seen in genome-wide association studies. The genetic influence may still be significant on the cellular or molecular level. Nonetheless, the HLA alone is not sufficient as a susceptible genetic background to deduce the disease. For a comprehensive insight of the disease mechanisms, both immunological and genome assays methods are required.