Associations of ABO and Rhesus D Blood Groups with Phenome-Wide Disease Incidence: A 41-year Retrospective Cohort Study of 482,914 Patients

Abstract

Background The natural selection responsible for the observed blood group frequency differences between populations remains debatable. The ABO system has been associated with several diseases and recently also with susceptibility to COVID-19 infection. Associative studies of the RhD system and diseases are sparser. A large disease-wide risk analysis may further elucidate the relationship between the ABO/RhD blood groups and disease incidence.

Methods We performed a systematic log-linear quasi-Poisson regression analysis of the ABO/RhD blood groups across 1,312 phecode diagnoses. Unlike prior studies, we determined the uniqueness of each individual ABO blood group as opposed to using blood group O as the reference. Moreover, we used up to 41-years of nationwide Danish follow-up data, and a disease categorization scheme specifically developed for diagnosis-wide analysis. Further, we determined associations between the ABO/RhD blood groups and the age at the first diagnosis. Estimates were adjusted for multiple testing.

Results The retrospective cohort included 482,914 Danish patients (60.4% females). The incidence rate ratios (IRRs) of 101 phecodes were found statistically significant between the ABO blood groups, while the IRRs of 28 phecodes were found statistically significant for the RhD blood group. The associations included cancers and musculoskeletal-, genitourinary-, endocrinal-, infectious-, cardiovascular-, and gastrointestinal diseases.

Conclusions We found associations of disease-wide susceptibility differences between the blood groups of the ABO and RhD systems, including cancer of the tongue, monocytic leukemia, cervical cancer, osteoarthrosis, asthma, and HIV- and hepatitis B infection. This may indicate that the ABO/RhD blood groups are the results of a selective pressure driven partly by robustness to disease. We found marginal evidence of associations between the blood groups and disease onset.

Funding Novo Nordisk Foundation and the Innovation Fund Denmark

Competing Interest Statement

P. Bruun-Rasmussen, M.H. Dziegiel, and K. Banasik declare that they have no conflicts of interest. P.I. Johansson reports ownership of stocks in Trial-Lab AB, Endothel Pharma ApS, TissueLink ApS, and MoxieLab ApS. S. Brunak reports ownerships in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S, ALK Abello, and managing board memberships in Proscion A/S and Intomics A/S outside the submitted work. P.I. Johansson and S. Brunak declare that the financial interests listed have no impact on the submitted work.

Funding Statement

The study was supported by the Novo Nordisk Foundation (grants NNF14CC0001 and NNF17OC0027594) and the Innovation Fund Denmark (grant 5153-00002B). The funders played no role in the conduct of the study.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Danish Patient Safety Authority, the Danish Data Protection Agency, and the Danish Health Data Authority

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.

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Data Availability

This is a register-based study and informed consent for such studies is waived by the Danish Data Protection Agency. Data access was approved by the Danish Patient Safety Authority (3-3013-1731), the Danish Data Protection Agency (DT SUND 2016-50 and 2017-57) and the Danish Health Data Authority (FSEID 00003092 and FSEID 00003724). The study was conducted using anonymized patient data not publicly accessible. Data access may be granted by contacting the Danish Patient Safety Authority, the Danish Data Protection Agency, and the Danish Health Data Authority.

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