Additive association of blood group A allele with 15 cardiometabolic diseases: a UK Biobank life-course study

Ran Zhao; Wenyan Xian; Yihao Ma; Valerio Napolioni; Patrick W.C. Lau; Xiao Li Tian; Yann Le Guen; Andre Franke; Jie Huang

doi:10.1186/s12933-025-02669-w

Additive association of blood group A allele with 15 cardiometabolic diseases: a UK Biobank life-course study

Ran Zhao
, Wenyan Xian
, Yihao Ma
, Valerio Napolioni
, Patrick W.C. Lau
, Xiao Li Tian
, Yann Le Guen
, Andre Franke
, Jie Huang^*

^*Corresponding author for this work

Academy of Wellness and Human Development

Research output: Contribution to journal › Journal article › peer-review

6 Citations (Scopus)

Abstract

Background: Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators. Methods: This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD. Results: The additive model demonstrates a dose–response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10⁻⁹⁶). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms. Conclusions: Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.

Original language	English
Article number	113
Number of pages	13
Journal	Cardiovascular Diabetology
Volume	24
Issue number	1
DOIs	https://doi.org/10.1186/s12933-025-02669-w
Publication status	Published - 10 Mar 2025

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

User-Defined Keywords

ABO A allele
Additive association
Blood group
Cardiometabolic disease
Mediation analysis

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10.1186/s12933-025-02669-w

Cite this

@article{051a01589dc144f7912a8ab247ec92a8,

title = "Additive association of blood group A allele with 15 cardiometabolic diseases: a UK Biobank life-course study",

abstract = "Background: Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators. Methods: This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD. Results: The additive model demonstrates a dose–response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10−96). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms. Conclusions: Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.",

keywords = "ABO A allele, Additive association, Blood group, Cardiometabolic disease, Mediation analysis",

author = "Ran Zhao and Wenyan Xian and Yihao Ma and Valerio Napolioni and Lau, \{Patrick W.C.\} and Tian, \{Xiao Li\} and \{Le Guen\}, Yann and Andre Franke and Jie Huang",

note = "This work was supported by National Key Research and Development Program of China [2022YFC3600800]. Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = mar,

day = "10",

doi = "10.1186/s12933-025-02669-w",

language = "English",

volume = "24",

journal = "Cardiovascular Diabetology",

issn = "1475-2840",

publisher = "BioMed Central Ltd.",

number = "1",

}

TY - JOUR

T1 - Additive association of blood group A allele with 15 cardiometabolic diseases

T2 - a UK Biobank life-course study

AU - Zhao, Ran

AU - Xian, Wenyan

AU - Ma, Yihao

AU - Napolioni, Valerio

AU - Lau, Patrick W.C.

AU - Tian, Xiao Li

AU - Le Guen, Yann

AU - Franke, Andre

AU - Huang, Jie

PY - 2025/3/10

Y1 - 2025/3/10

N2 - Background: Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators. Methods: This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD. Results: The additive model demonstrates a dose–response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10−96). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms. Conclusions: Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.

AB - Background: Although existing studies have reported associations between blood group A and cardiometabolic diseases (CMD), most have focused on dominant inheritance models. However, genome-wide association studies have mostly been based on additive genotypes. This study aims to investigate the association between the blood group A allele and 15 CMD using recessive, dominant, and additive models and identify potential mediators. Methods: This study leveraged data from over 320,000 participants with O and A blood groups in the UK Biobank to investigate the association between blood group A allele and 15 major CMD under recessive, dominant, and gene dosage (additive) models. Protein data from nearly 30,000 participants were used to analyze the association between ABO protein levels and CMD. Mediation analysis further explored whether blood cell count traits and blood biochemistry mediate the association between the number of A allele and CMD. Results: The additive model demonstrates a dose–response association of the blood group A allele with venous thromboembolism (VTE), myocardial infarction (MI), ischemic stroke (IS), type 2 diabetes mellitus (T2DM), and heart failure (HF), among others. Each additional A allele increased disease risk, particularly for VTE (HR = 1.273, P[FDR] = 4.43 × 10−96). ABO protein levels also correlated with five CMD outcomes, particularly VTE and coronary artery disease (CAD). Mediation analyses revealed that blood cell traits (e.g., hemoglobin, hematocrit) and biochemistries (e.g., aspartate aminotransferase to alanine aminotransferase ratio, apolipoprotein B) significantly mediated the associations for specific CMD, suggesting shared biological mechanisms. Conclusions: Our findings reveal that blood group A allele is associated with an increased risk of multiple CMD, particularly under the additive model. Some blood cell count traits and blood biochemistries play significant mediating roles.

KW - ABO A allele

KW - Additive association

KW - Blood group

KW - Cardiometabolic disease

KW - Mediation analysis

UR - https://www.scopus.com/pages/publications/105000067176

U2 - 10.1186/s12933-025-02669-w

DO - 10.1186/s12933-025-02669-w

M3 - Journal article

C2 - 40065387

AN - SCOPUS:105000067176

SN - 1475-2840

VL - 24

JO - Cardiovascular Diabetology

JF - Cardiovascular Diabetology

IS - 1

M1 - 113

ER -

Additive association of blood group A allele with 15 cardiometabolic diseases: a UK Biobank life-course study

Abstract

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