Mendelian randomization assessing causal relationship between fibrinogen levels and ischemic stroke.

Abstract

Objective: High fibrinogen levels are associated with an increased risk of ischaemic stroke (IS). We used mendelian randomisation (MR) to explore a potential causal relationship.

Materials and methods: Data for assessing the relationship between gene variant, disease and biological levels needed for a MR approach was collected using a meta-analytical approach. Inverse-variance weighted (IVW) approach was used for the main analyses and alternative approach for sensitivity analyses. The relationship between fibrinogen levels and IS was assessed using Odds Ratio (OR), while mean difference (g/L) was used for the relationship between SNP (rs1800790) and fibrinogen levels.

Results: The variant FGB rs1800790 SNP was interrogated as an instrumental variable of fibrinogen levels. A meta-analysis with 24 studies (12 case-control and 12 cohort studies, totalling 20,902 cases and 76,510 controls was conducted. Homozygotes (AG) of rs1800790 have 0.14g/L (95%CI: 0.08-0.19, P<0.001) and minor allele (AA) have 0.18g/L (95%CI: 0.01-0.35, P=0.037) higher levels of plasma fibrinogen concentration compared with homozygous for the major allele (GG). The risk of IS was significantly increased in 1-g/L (OR=1.83, 95%CI: 0.92-3.62, P=0.084), or 1-SD of fibrinogen levels (OR=1.39, 95%CI: 1.03-1.87, P=0.030), or above median levels (OR=1.22, 95%CI: 1.02-1.46, P=0.029) or categorical levels tertiles (OR=1.50, 95%CI: 1.26-1.79, P<0.001). Each 1-g/L increase in fibrinogen levels was causally associated with a higher risk of ischemic stroke (OR=2.28, 95%CI: 1.53-3.03, P<0.001) in the Mendelian randomisation analysis.

Conclusions: Elevated fibrinogen levels are a causative risk factor for ischaemic stroke with each 1g/L increase doubling its risk.