rs1800790 — FGB -455G>A

The Fibrinogen Dial — How the -455G>A Promoter Variant Sets Your Coagulation Baseline

Fibrinogen is the body's master clotting scaffold. When thrombin cleaves it during an injury response, it polymerizes into fibrin — the structural backbone of every blood clot. But fibrinogen is not merely a clotting protein: it also rises sharply during inflammation as an acute-phase reactant¹¹ acute-phase reactant
Proteins synthesized in the liver whose plasma concentrations increase or decrease by ≥25% in response to infection or inflammation, and chronically elevated levels accelerate atherosclerosis, increase blood viscosity, and predispose to thrombotic events. The rs1800790 (-455G>A) variant, located 455 base pairs upstream of the FGB transcription start site, is the most extensively studied of all FGB promoter polymorphisms — a single letter change that quietly turns up the fibrinogen dial for the roughly 20% of European and East Asian individuals who carry the A allele.

The Mechanism

The FGB gene on chromosome 4q31 encodes the beta chain of fibrinogen, one of three polypeptide chains (Aα, Bβ, γ) that assemble into the hexameric fibrinogen molecule. The promoter region containing the -455 position harbors binding sites for transcription factors that respond to interleukin-6 (IL-6)²² interleukin-6 (IL-6)
The primary cytokine signal driving the acute-phase response; released by macrophages and adipose tissue during inflammation and metabolic stress, the cytokine that signals the liver to ramp up acute-phase protein synthesis.

The G-to-A substitution at -455 alters the transcription factor binding landscape at this locus, leading to constitutively higher FGB expression. A carriers maintain a higher fibrinogen set point at baseline and mount a larger acute-phase surge during inflammatory triggers such as infection, surgery, or metabolic stress. Quantitatively, the 2025 Ken-Dror Mendelian randomization meta-analysis confirmed that AG heterozygotes carry 0.14 g/L higher fibrinogen than GG homozygotes, and AA homozygotes carry 0.18 g/L higher fibrinogen — clinically meaningful increases given that the normal reference range is 2.0-4.0 g/L.

The -455G>A variant is in strong linkage disequilibrium with rs1800787 (-148C>T) in European populations, meaning the two variants are often inherited together as a haplotype. When both risk alleles co-occur, the combined upward pressure on fibrinogen production is likely additive or larger.

The Evidence

The causal relationship between fibrinogen and ischemic stroke was established with Mendelian randomization methodology by Ken-Dror et al. 2025³³ Ken-Dror et al. 2025
Ken-Dror G et al. Mendelian randomization assessing causal relationship between fibrinogen levels and ischemic stroke. J Stroke Cerebrovasc Dis. 2025;34(2):108199. Analyzing 24 studies (20,902 cases, 76,510 controls), they found rs1800790 to be one of the strongest fibrinogen-raising instruments; each 1 g/L increase in fibrinogen was causally associated with stroke risk (OR=2.28, p<0.001). Participants in the above-median fibrinogen group faced 22% higher stroke risk (OR=1.22, p=0.029) compared to those below the median.

The clot biology consequences of the A allele were demonstrated in Klajmon et al. 2022⁴⁴ Klajmon et al. 2022
Klajmon A et al. Fibrinogen β chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism. Eur J Clin Invest. 2022;52(4):e13725. Among 126 acute pulmonary embolism patients, A allele carriers showed reduced clot permeability, extended clot lysis time, and elevated endogenous thrombin potential compared to GG homozygotes. These effects persisted after adjusting for fibrinogen concentration (all p<0.01), suggesting the variant influences not just fibrinogen quantity but also the structural and functional properties of the fibrin clot it forms.

Population-level work by Albert et al. 2009⁵⁵ Albert et al. 2009
Albert MA et al. Candidate genetic variants in the fibrinogen, MTHFR, and ICAM-1 genes among various race/ethnic groups: Women's Genome Health Study. Am Heart J. 2009;157(4):777-83 found the A allele frequency at 17-22% in white, Hispanic, and Asian women versus 6.6% in Black women, with the fibrinogen-raising effect concentrated in white and Asian participants — consistent with the variant's higher prevalence and stronger LD with functional haplotypes in those populations.

A striking pharmacogenetic angle was revealed by Lynch et al. 2009⁶⁶ Lynch et al. 2009
Lynch AI et al. Antihypertensive pharmacogenetic effect of fibrinogen-beta variant -455G>A on cardiovascular disease, end-stage renal disease, and mortality: the GenHAT study. Pharmacogenet Genomics. 2009;19(6):415-21 in the 30,076-patient ALLHAT trial: GG homozygotes assigned to lisinopril (ACE inhibitor) had substantially higher stroke (HR=1.38) and mortality (HR=1.12) risk compared to those receiving amlodipine, while A allele carriers showed the opposite pattern — better outcomes on ACE inhibitor therapy. The mechanism is not yet fully characterized, but this interaction may be relevant to antihypertensive selection in carriers.

Practical Actions

The A allele does not cause disease directly but shifts the fibrinogen set point upward by 0.14-0.18 g/L — enough to be clinically relevant, particularly when combined with other cardiovascular risk factors. The large Fibrinogen Studies Collaboration meta-analysis (154,211 participants) showed that each 1 g/L increase in fibrinogen carries a hazard ratio of ~2.42 for coronary heart disease, making any sustained elevation worth monitoring.

For A allele carriers, plasma fibrinogen measurement belongs in routine cardiovascular risk profiling alongside LDL, CRP, and blood pressure. Elevated levels (>4 g/L) warrant active management of the inflammatory drivers that amplify acute-phase fibrinogen production. The most evidence-backed intervention for genetically elevated fibrinogen is therapeutic-dose omega-3 supplementation, which achieves 0.2-0.5 g/L reductions in controlled trials.

The GenHAT pharmacogenetic finding warrants mention to prescribers when antihypertensive therapy is being selected: GG homozygotes may fare better on calcium-channel blockers than ACE inhibitors for stroke prevention, while A carriers may benefit from ACE inhibitor-based regimens.

Interactions

The -455G>A variant sits in a well-characterized haplotype block with rs1800787 (-148C>T), rs1800789, and rs1800788. These FGB promoter variants are frequently co-inherited in European populations; the combined haplotype effect on fibrinogen production is larger than either single SNP alone. Individuals carrying A alleles at both -455 (rs1800790) and T alleles at -148 (rs1800787) likely have the highest constitutive fibrinogen levels from this locus. See rs1800787 for the -148C>T variant profile.