Genetics of autoimmune diseases: insights from population genetics

Abstract

Human genetic diversity is the result of population genetic forces. This genetic variation influences disease risk and contributes to health disparities. Autoimmune diseases (ADs) are a family of complex heterogeneous disorders with similar underlying mechanisms characterized by immune responses against self. Collectively, ADs are common, exhibit gender and ethnic disparities, and increasing incidence. As natural selection is an important influence on human genetic variation, and immune function genes are enriched for signals of positive selection, it is thought that the prevalence of AD risk alleles seen in different population is partially the result of differing selective pressures (for example, due to pathogens). With the advent of high-throughput technologies, new analytical methodologies and large-scale projects, evidence for the role of natural selection in contributing to the heritable component of ADs keeps growing. This review summarizes the genetic regions associated with susceptibility to different ADs and concomitant evidence for selection, including known agents of selection exerting selective pressure in these regions. Examples of specific adaptive variants with phenotypic effects are included as an evidence of natural selection increasing AD susceptibility. Many of the complexities of gene effects in different ADs can be explained by population genetics phenomena. Integrating AD susceptibility studies with population genetics to investigate how natural selection has contributed to genetic variation that influences disease risk will help to identify functional variants and elucidate biological mechanisms. As such, the study of population genetics in human population holds untapped potential for elucidating the genetic causes of human disease and more rapidly focusing to personalized medicine.

Autoimmune diseases — connecting risk alleles with molecular traits of the immune system

“…Thus, some risk alleles for autoimmune diseases may have increased in frequency in the population because they have been favourable for fighting infectious disease 44 . For example, IL23R , which is associated with six autoimmune diseases, and TYK2 , which is associated with seven autoimmune diseases, are part of the IL-23R response pathway and present evidence for selection implicating Protozoan pathogens 42,43,45 .…”

“…Intriguingly, in some of these pathways there is evidence of natural selection. An examination of 40 autoimmune disease risk loci suggested selective pressure driven by pathogens (such as Plasmodium falciparum , which causes malaria) 43 . Thus, some risk alleles for autoimmune diseases may have increased in frequency in the population because they have been favourable for fighting infectious disease 44 .…”

Altered B cell signalling in autoimmunity

“…It will be important to design studies that specifically define B cell-intrinsic and alternative lineage-intrinsic effects. Moreover, multiple autoimmunity-associated polymorphisms show evidence of selection during human evolution, which may reflect a trade-off between an enhanced immune response to infection and an increased risk of autoimmunity 167,168 . For example, the PTPN22 R620W polymorphism may provide increased protection against tuberculosis 169 , and SLE-associated polymorphisms in FCGR2B (which encodes FcγRIIB) protect against severe Plasmodium falciparum infection 170 .…”

Population Genetics and Natural Selection in Rheumatic Disease

“…There is also growing evidence that autoimmune and inflammatory disease-associated variants are under selection. 17-21 This review expands on our previous work 22 and summarizes the evidence for rheumatic disease-associated loci under selection and the candidate selective pressures. Given that genomic variation can have clinically important consequences, 23 elucidating the patterns of variation and the functional role of the selective pressure might contribute to a better understanding of disease etiology and the development of new therapies for improved disease management.…”