Abstract
BackgroundInfections are a major disease burden worldwide. While they are caused by external pathogens, host genetics also plays a part in susceptibility to infections. Past studies have reported diverse associations between human leukocyte antigen (HLA) alleles and infections, but many were limited by small sample sizes and/or focused on only one infection.MethodsWe performed an immunogenetic association study examining 13 categories of severe infection (bacterial, viral, central nervous system, gastrointestinal, genital, hepatitis, otitis, pregnancy-related, respiratory, sepsis, skin infection, urological and other infections), as well as a phenotype for having any infection, and seven classical HLA loci (HLA-A, B, C, DPB1, DQA1, DQB1 and DRB1). Additionally, we examined associations between infections and specific alleles highlighted in our previous studies of psychiatric disorders and autoimmune disease, as these conditions are known to be linked to infections.ResultsAssociations between HLA loci and infections were generally not strong. Highlighted associations included associations between DQB1*0302 and DQB1*0604 and viral infections (P = 0.002835 and P = 0.014332, respectively), DQB1*0503 and sepsis (P = 0.006053), and DQA1*0301 with “other” infections (a category which includes infections not included in our main categories e.g. protozoan infections) (P = 0.000369). Some HLA alleles implicated in autoimmune diseases showed association with susceptibility to infections, but the latter associations were generally weaker, or with opposite trends (in the case of HLA-C alleles, but not with alleles of HLA class II genes). HLA alleles associated with psychiatric disorders did not show association with susceptibility to infections.ConclusionsOur results suggest that classical HLA alleles do not play a large role in the etiology of severe infections. The discordant association trends with autoimmune disease for some alleles could contribute to mechanistic theories of disease etiology.
Highlights
Infections are a major disease burden worldwide
False discovery rate (FDR) analysis using all p-values obtained a minimum q-value of 27% for the associations with the four lowest p-values, namely HLADQB1 with sepsis infection, human leukocyte antigen (HLA)-DQA1 with other infections, HLA-DPB1 with central nervous system (CNS) infection and HLADQB1 and viral infection
Comparison with associations of HLA alleles with autoimmune disease and mental illness Twenty-two alleles were highlighted in our previous studies: 20 alleles for autoimmune disease and 2 alleles for mental illness. As both infection and autoimmune disease are correlated with mental illness, and as the immune system is intrinsically linked to both infection and autoimmune disease, we examined potential associations between the 22 alleles highlighted in our previous studies and all infection categories
Summary
Infections are a major disease burden worldwide. While they are caused by external pathogens, host genetics plays a part in susceptibility to infections. Some HLA genes are extremely polymorophic [7] These two aspects of HLA genes made them popular candidates for investigations into susceptibility to infections of various kinds and in various populations, resulting in many reported associations [8, 9]. In parallel with investigations of HLA genes in the context of infections, HLA genes have been studied in the contexts of autoimmune diseases [10] and psychiatric disorders such as schizophrenia [11]. Both susceptibility to infection and autoimmune disorders have been linked to psychiatric disorders, both genetically and from an epidemiological perspective [12,13,14]. Our own previous studies have examined associations between classical HLA alleles and psychiatric disorders [15], as well as overall autoimmune disease [13]
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