Association of ABO haplotypes with the risk of venous thrombosis: impact on disease risks estimation

Louisa Goumidi (1) , Florian Thibord (2, 3, 4) , Kerri Wiggins (5) , Ruifang Li-Gao (6) , Michael Brown (7) , Astrid van Hylckama Vlieg (6) , Juan Carlos Souto (8, 9) , Jose Manuel Soria (9) , Manal Ibrahim-Kosta (1, 10) , Noémie Saut (1, 10) , Delphine Daian-Bacq (11) , Robert Olaso (11) , Philippe Amouyel (12, 13, 14) , Stephanie Debette (2, 15) , Anne Boland (11) , Pascal Bailly (16, 17) , Alanna Morrison (7) , Dennis Mook-Kanamori (6) , Jean-François Deleuze (11, 18) , Andrew Johnson (3, 4) , Paul de Vries (7) , Maria Sabater-Lleal (9, 19) , Jacques Chiaroni (16, 17) , Nicholas Smith (5, 20, 21) , Frits Rosendaal (6) , Daniel Chasman (22, 23) , David-Alexandre Tregouet (2) , Pierre-Emmanuel Morange (1, 10)

1 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
2 BPH - Bordeaux population health
3 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
4 Framingham Heart Study
5 University of Washington [Seattle]
6 LUMC - Leiden University Medical Center
7 UTHealth - The University of Texas Health Science Center at Houston
8 Institut Investigacions Biomèdiques (IBB) Sant Pau [Barcelona, Spain]
9 Hospital de la Santa Creu i Sant Pau
10 TIMONE - Hôpital de la Timone [CHU - APHM]
11 CNRGH - Centre National de Recherche en Génomique Humaine
12 RID-AGE - Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167
13 Excellence Laboratory LabEx DISTALZ
14 CHRU Lille - Centre Hospitalier Régional Universitaire [CHU Lille]
15 CHU Bordeaux
16 ADES - Anthropologie bio-culturelle, Droit, Ethique et Santé
17 EFS - Etablissement Français du Sang Provence-Alpes Côte-d'Azur et Corse
18 Fondation Jean Dausset CEPH
19 Karolinska Institutet [Stockholm]
20 KPWHRI - Kaiser Permanente Washington Health Research Institute [Seattle]
21 Seattle Epidemiologic Research and Information Center [Seattle]
22 Brigham and Women's Hospital [Boston]
23 HMS - Harvard Medical School [Boston]

Genetic risk score (GRS) analysis is an increasingly popular approach to derive individual risk prediction models for complex diseases. In the context of venous thrombosis (VT), any GRS shall integrate information at the ABO blood group locus, the latter being one of the major susceptibility locus for this disease. However, there is yet no consensus about which single nucleotide polymorphisms (SNPs) must be investigated when one is interested in properly assessing the association of ABO locus with VT risk. Using comprehensive haplotype analyses of ABO blood group tagging SNPs in up to 5,425 cases and 8,445 controls from 6 studies, we demonstrated that using only rs8176719 (tagging O1) to correctly assess the impact of ABO locus on VT risk is suboptimal as 5% of rs8176719-delG carriers are not exposed at higher VT risk. Instead, we recommend to use 4 SNPs, rs2519093 (tagging A1), rs1053878 (A2), rs8176743 (B) and rs41302905 (O2) in any analysis aimed at assessing the impact of ABO locus on VT risk to avoid any risk misestimation. Compared to O1 haplotype that can be inferred from these 4 SNPs, the A2 haplotype is associated with a modest increase in VT risk (odds ratio ~1.2), A1 and B haplotypes are associated with a ~1.8 fold increased risk while O2 tend to be slightly protective (odds ratio ~0.80). In addition, our analyses clearly showed that while the A1 an B blood group are associated with increased vWF and FVIII plasma levels only the A1 blood group is associated wih ICAM plasma levels but in an opposite direction, leaving additional avenues to be explored in order to fully understand the whole spectrum of biological effect of ABO locus on cardiovascular traits.

Domaines: Sciences du Vivant [q-bio]

Louisa Goumidi, Florian Thibord, Kerri Wiggins, Ruifang Li-Gao, Michael Brown, et al.. Association of ABO haplotypes with the risk of venous thrombosis: impact on disease risks estimation. Blood, 2021, 137 (17), pp.2394-2402. ⟨10.1182/blood.2020008997⟩. ⟨hal-03135635⟩