Population-specific ABO haplotypes reveal distinct venous thromboembolism risk in East Asians: insights from a...

The ABO blood group locus is a well-established genetic determinant of venous thromboembolism (VTE) risk in both individuals of European and East Asian ancestry. Recent studies have identified key ABO haplotypes tagged by four common SNPs-rs2519093 (A1), rs1053878 (A2), rs8176743 (B), and rs8176719/rs41302905 (O1/O2)-that influence both incident and recurrent VTE risk in Europeans. However, marked differences in ABO allele frequencies and haplotype structures across ancestries may render European findings inapplicable to East Asians, highlighting a critical gap in understanding the genetic basis of VTE in this population.

We conducted a haplotype-based association study using ABO-tagging SNPs (including rs512770 that distinguishes between O1.1 and O1.2) in 1576 VTE cases from China Pulmonary Thromboembolism Registry Study (CURES) and 17,535 ancestry-matched controls, adjusted for age, sex, and genetic principal components to evaluate the effects of ABO haplotypes on VTE risk and recurrence.

Our analyses revealed key population-specific differences: in East Asians, the rs1053878-A allele is consistently co-inherited with the rs2519093-T allele, precluding its use as a specific marker for the A2 blood group, unlike in Europeans. Furthermore, all non-O1 haplotypes were homogeneously associated with a ∼1.4-fold increased risk of VTE (p = 5.2 × 10^-20) and a ∼1.7-fold increased risk of recurrence (p = 0.023), compared to the O1.1 group. Notably, the O1.2 blood group was also associated with a 1.7-fold increased risk of recurrence (p = 0.039).

These findings highlight fundamental differences in ABO haplotype structure and disease associations between East Asians and Europeans. Our study provides a population-specific SNP panel-rs8176719, rs2519093, rs1053878, rs8176743, and rs512770-for accurate genetic risk assessment of VTE in East Asians, underscoring the importance of ancestry-tailored approaches to thrombotic disease prediction.

This study is funded by the Chinese Academy of Medical Science Innovation Fund for Medical Sciences (No. 2024-I2M-TS-035, No. 2021-I2M-1-061), National Key Research and Development Program of China (No. 2024YFE0101900, No. 2023YFC2507200), National Natural Science Foundation of China (No. 82470046, No. 82241029) and Noncommunicable Chronic Diseases-National Science and Technology Major Project (No. 2024ZD0528700).