PMID- 34059071 OWN - NLM STAT- MEDLINE DCOM- 20210630 LR - 20210630 IS - 1479-5876 (Electronic) IS - 1479-5876 (Linking) VI - 19 IP - 1 DP - 2021 May 31 TI - A large-scale investigation into the role of classical HLA loci in multiple types of severe infections, with a focus on overlaps with autoimmune and mental disorders. PG - 230 LID - 10.1186/s12967-021-02888-1 [doi] LID - 230 AB - BACKGROUND: Infections 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. METHODS: We 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. RESULTS: Associations 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. CONCLUSIONS: Our 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. FAU - Nudel, Ron AU - Nudel R AUID- ORCID: 0000-0003-2309-011X AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. AD - CORE - Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. FAU - Allesoe, Rosa Lundbye AU - Allesoe RL AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. AD - CORE - Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. AD - Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Thompson, Wesley K AU - Thompson WK AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. AD - Division of Biostatistics, Herbert Wertheim School of Public Health and Human Longevity Science, University of California, San Diego, CA, USA. FAU - Werge, Thomas AU - Werge T AD - Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark. AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. AD - Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Rasmussen, Simon AU - Rasmussen S AD - Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. FAU - Benros, Michael E AU - Benros ME AUID- ORCID: 0000-0003-4939-9465 AD - iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark. Michael.Eriksen.Benros@regionh.dk. AD - CORE - Copenhagen Research Centre for Mental Health, Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark. Michael.Eriksen.Benros@regionh.dk. AD - Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. Michael.Eriksen.Benros@regionh.dk. LA - eng GR - U01 MH094432/MH/NIMH NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20210531 PL - England TA - J Transl Med JT - Journal of translational medicine JID - 101190741 RN - 0 (HLA-A Antigens) RN - 0 (HLA-DQ beta-Chains) RN - 0 (HLA-DRB1 Chains) SB - IM MH - Alleles MH - Gene Frequency MH - Genetic Predisposition to Disease MH - *HLA-A Antigens/genetics MH - HLA-DQ beta-Chains/genetics MH - HLA-DRB1 Chains/genetics MH - Haplotypes MH - Humans MH - *Mental Disorders/genetics PMC - PMC8165335 OTO - NOTNLM OT - Association study OT - Autoimmune disease OT - HLA OT - Immunogenetics OT - Infections OT - MHC OT - Psychiatric disorder COIS- All researchers had full independence from the funders. The authors report no biomedical financial interests or potential conflicts of interest. TW states that he has acted as a lecturer and scientific counselor to H. Lundbeck A/S. EDAT- 2021/06/02 06:00 MHDA- 2021/07/01 06:00 PMCR- 2021/05/31 CRDT- 2021/06/01 05:41 PHST- 2021/01/21 00:00 [received] PHST- 2021/05/17 00:00 [accepted] PHST- 2021/06/01 05:41 [entrez] PHST- 2021/06/02 06:00 [pubmed] PHST- 2021/07/01 06:00 [medline] PHST- 2021/05/31 00:00 [pmc-release] AID - 10.1186/s12967-021-02888-1 [pii] AID - 2888 [pii] AID - 10.1186/s12967-021-02888-1 [doi] PST - epublish SO - J Transl Med. 2021 May 31;19(1):230. doi: 10.1186/s12967-021-02888-1.