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Detecting shared pathogenesis from the shared genetics of immune-related diseases

Key Points

  • Genetic factors play an important part in the development of autoimmune and inflammatory disorders, such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, asthma and coeliac disease. An increase in co-morbidity and clustering of different autoimmune diseases in families suggest the existence of an overlap in the genetic background of these diseases.

  • Until recently, only the human leukocyte antigen (HLA) locus and a few candidate genes have consistently been associated with these immune-related diseases. However, with the development of Genome-wide association (GWA) studies, dozens of new susceptibilty genes and loci have been identified in various immune-related diseases.

  • Many of these newly identified loci are shared by two or more immune-related diseases, and the majority of these shared genes belong to just a few immunological pathways: T-cell signalling and differentiation, innate immunity, and tumour necrosis factor (TNF) signalling. Moreover, many of the disease-specific associated genes are involved in the same pathways.

  • Many immune-related diseases are characterized by high numbers of T cells, as well as by an imbalance in T-cell subsets. The association of T-cell differentiation pathway genes with multiple immune-related diseases suggests that the functional roles of the T helper (TH) 1, TH17 and T regulatory (Treg) molecules in these diseases are altered by genetic factors.

  • Association of autoimmune diseases with genes that are involved in innate immunity provides links to bacterial and viral infections as the triggers of disease and might lead to the development of new tools for prevention, such as vaccines.

  • Understanding the shared pathogenesis between immune-related diseases might provide targets for therapeutic intervention. Targeting pathways rather than genes and correlating the genetic profile of a patient to the effectiveness of a specific therapy might open new avenues in clinical trials.

  • So far, the genetic study of immune-related diseases has only revealed the tip of the iceberg, as more genes need to be found and the true causal variants need to be identified.

  • The notion of shared genetic pathways identifies new and powerful approaches for determining the full repertoire of susceptibility genes — instead of focusing on single diseases, genetic resources can be shared.

Abstract

Recent genetic studies have revealed shared immunological mechanisms in several immune-related disorders that further our understanding of the development and concomitance of these diseases. Our Review focuses on these shared aspects, using the novel findings of recently performed genome-wide association studies and non-synonymous SNP scans as a starting point. We discuss how identifying new genes that are associated with more than one autoimmune or chronic inflammatory disorder could explain the genetic basis of the shared pathogenesis of immune-related diseases. This analysis helps to highlight the key molecular pathways that are involved in these disorders and the potential roles of novel genes in immune-related diseases.

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Figure 1: The proportion of disease-associated genes in different pathways or categories.
Figure 2: T-cell differentiation and signalling.

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Acknowledgements

We thank J. Senior and M. Wapenaar for their help preparing this manuscript. Our work is supported by grants from the Celiac Disease Consortium (an innovative cluster approved by the Netherlands Genomics Initiative and partly funded by the Dutch Government, grant BSIK03009 to C.W.) and the Netherlands Organization for Scientific Research (NWO-VICI grant 918.66.620 to C.W.).

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Correspondence to Cisca Wijmenga.

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DATABASES

OMIM

asthma

coeliac disease

Graves' disease

Hashimoto's disease

multiple sclerosis

rheumatoid arthritis

type 1 diabetes

FURTHER INFORMATION

Cisca Wijmenga's homepage

HapMap

Database for Annotation, Visualization and Integrated Discovery (DAVID) Bioinformatics Resources

Web-based Gene Set Analysis Toolkit (Webgestalt)

Gene Ontology

Catalogue of Published Genome-wide Association Studies

SUPPLEMENTARY INFORMATION

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Glossary

Innate immune system

An immediate nonspecific immune response to foreign infectious agents. It includes chemical defence mechanisms (for example, mucus and complement production), as well as cellular functions, such as phagocytosis by macrophages and neutrophils.

Adaptive immune system

A specific immune response initiated by highly specific receptors that are present on B and T cells, which recognize antigens. There is extensive crosstalk between the innate and adaptive immune responses.

Ascertainment bias

A false conclusion that is made as a result of nonrandom sampling.

Heritability

The proportion of the total phenotypic variation for a given characteristic in a population that can be attributed to genetic variance among individuals.

Genetic heterogeneity

(Also called locus heterogeneity). A situation in which variation in different genes might cause identical or similar forms of the disease in different individuals.

Penetrance

The probability of observing a specific phenotype in individuals who carry a particular genotype. If this probability is less than one for all genotypes of a variant, then the variant has incomplete penetrance.

Genome-wide association study

(GWA study). A large-scale genotyping analysis of markers across the human genome, which is designed to identify genetic association with diseases or observable traits.

Genome-wide non-synonymous SNP scan

Genome-wide scan for disease association that includes only non-synonymous SNPs (nsSNPs).

Linkage analysis

The process of mapping genes by typing genetic markers in families to identify chromosome regions that are associated with disease or trait values within pedigrees more often than would be expected by chance. Such linked regions are more likely to contain a causal genetic variant.

Functional candidate gene

A gene that might be involved in a particular disease because of its biological relevance.

Identical by descent

Describes multiple alleles that are identical because they arose from the same allele in an earlier generation.

Population attributable risk

(PAR). Calculated using the following formula, where f is the allele freqency in the population, and RR is the relative risk:

Linkage disequilibrium

(LD). The nonrandom association of genetic marker alleles. Two markers are in LD when some combinations of alleles in a population occur more or less frequently than would be expected if random assortment occurred.

Major histocompatibility complex

(MHC). A 4-Mb region of human chromosome 6 that contains many genes with immunological functions. It is encoded by the human leukocyte antigen (HLA) locus.

Deep sequence

Massive parallel sequencing of the same DNA target with new-generation sequencing platforms, such as the Roche 454 FLX system, the Illumina Genome Analyzer and the Applied Biosystems SOLiD system.

Meta-analysis

An approach that combines the results of several studies that address a set of related research hypotheses to overcome the problem of reduced statistical power in studies with small sample sizes.

Common disease–common variant hypothesis

This states that many genetic variants that underlie complex diseases are common and are therefore susceptible to detection by population association studies. An alternative possibility is that the genetic contributions to complex diseases arise from many variants, all of which are rare.

Genetical genomics

An approach that brings together genetic analysis and gene expression studies by directly characterizing the genetic influence of gene expression.

TH1 cells

A subset of T-helper cells that produce interferon-γ (and other cytokines) and that activate macrophages.

TH17 cells

A subset of CD4+ T-helper cells that produce interleukin 17 (IL-17) and that are thought to be important in inflammatory and autoimmune diseases.

Regulatory T cells

(Treg cells). A subset of CD4+ T-helper cells that suppresses or regulates effector T cells and other immune cells. The absence or presence of dysfunctional Treg cells are associated with severe autoimmunity.

Auto-antibody seropositivity

The presence of antibodies that are directed against one or more of an individual's own proteins.

Autophagy

A cellular process of degradation of cellular components that occurs by transporting the components to lysosomes. This process maintains a balance between the synthesis and degradation of cellular products, and is also involved in the degradation of intracellular pathogens.

LD block

A segment of DNA with markers that are in linkage disequilbrium (LD) with each other.

Prospective epidemiological studies

A research study that, over a period of time, follows groups of individuals who are alike in many ways but differ by certain characteristics, and compares them for a particular outcome.

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Zhernakova, A., van Diemen, C. & Wijmenga, C. Detecting shared pathogenesis from the shared genetics of immune-related diseases. Nat Rev Genet 10, 43–55 (2009). https://doi.org/10.1038/nrg2489

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