Associations of ABO and rhesus d blood groups with phenome-wide disease incidence: a 41-year retrospective cohort study of 482,914 patients

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Abstract

Background: Whether natural selection may have attributed to 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 incidence rate ratio foreach individual ABO blood group relative to all other ABO blood groups 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.. We found marginal evidence of associations between the blood groups and the age at first diagnosis.

Funding:; Novo Nordisk Foundation and the Innovation Fund Denmark.

Data availability

Anonymized patient data was used in this study. Due to national and EU regulations, the data cannot be shared with the wider research community. However, data can be accessed upon relevant application to the Danish authorities. The Danish Patient Safety Authority and the Danish Health Data Authority have permitted the use of the data in this study; whilst currently, the appropriate authority for journal data use in research is the regional committee ("Regionsråd"). The statistical summary data used to create the tables and graphs are available as Supplementary Data 1 and Supplementary Data 2. The analysis code is publicly available through www.github.com/peterbruun/blood_type_study.

Article and author information

Author details

Peter Bruun-Rasmussen

Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0002-3595-1311
Morten Hanefeld Dziegiel

Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-8034-1523
Karina Banasik

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark

Competing interests
No competing interests declared.
Pär Ingemar Johansson

Department of Clinical Immunology, Copenhagen University Hospital, Copenhagen, Denmark

Competing interests
Pär Ingemar Johansson, has received grants from the AP Møller Foundation, Innovation Fund Denmark and Novo Nordisk Foundation. The author has been issued the following patents: Publication no: 20110201553, 20110268732, 20130040898, 20130261177, 20150057325, 20160113891, 9381166, 9381243, 20160250164, 9433589, 20160303040 and US20090053193A1. P.I. Johansson reports ownership of stocks in Trial-Lab AB, Endothel Pharma ApS, TissueLink ApS, and MoxieLab ApS. P.I. Johansson declares that the financial interests listed have no impact on the submitted work. The author has no other competing interests to declare. The author declares that the financial interests listed have no impact on the submitted work..
Søren Brunak

Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen N, Denmark

For correspondence
soren.brunak@cpr.ku.dk

Competing interests
Søren Brunak, participates on the Danish National Genome Center advisory board and is the Chairman for the data infrastructure board. The author has stock in Intomics A/S, Hoba Therapeutics Aps, Novo Nordisk A/S, Lundbeck A/S and ALK Abello. The author participates on the board of directors for both Proscion A/S and Intomics A/S. The author has no other competing interests to declare. Søren Brunak declares that the financial interests listed have no impact on the submitted work..

"This ORCID iD identifies the author of this article:" 0000-0003-0316-5866

Funding

Novo Nordisk Fonden (NNF14CC0001)

Søren Brunak

Novo Nordisk Fonden (NNF17OC0027594)

Søren Brunak

Innovation Fund (5153-00002B)

Søren Brunak

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: 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).

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.