The effect of histo-blood group ABO system transferase (BGAT) on pregnancy related outcomes：A Mendelian randomization study.

Protein level of Histo-Blood Group ABO System Transferase (BGAT) has been reported to be associated with cardiometabolic diseases. But its effect on pregnancy related outcomes still remains unclear. Here we conducted a two-sample Mendelian randomization (MR) study to ascertain the putative causal roles of protein levels of BGAT in pregnancy related outcomes. Cis-acting protein quantitative trait loci (pQTLs) robustly associated with protein level of BGAT (P < 5 ×10-8) were used as instruments to proxy the BGAT protein level (N = 35,559, data from deCODE), with two additional pQTL datasets from Fenland (N = 10,708) and INTERVAL (N = 3301) used as validation exposures. Ten pregnancy related diseases and complications were selected as outcomes. We observed that a higher protein level of BGAT showed a putative causal effect on venous complications and haemorrhoids in pregnancy (VH) (odds ratio [OR]=1.19, 95% confidence interval [95% CI]=1.12-1.27, colocalization probability=91%), which was validated by using pQTLs from Fenland and INTERVAL. The Mendelian randomization results further showed effects of the BGAT protein on gestational hypertension (GH) (OR=0.97, 95% CI=0.96-0.99), despite little colocalization evidence to support it. Sensitivity analyses, including proteome-wide Mendelian randomization of the cis-acting BGAT pQTLs, showed little evidence of horizontal pleiotropy. Correctively, our study prioritised BGAT as a putative causal protein for venous complications and haemorrhoids in pregnancy. Future epidemiology and clinical studies are needed to investigate whether BGAT can be considered as a drug target to prevent adverse pregnancy outcomes.