rs1801020

badMag 4.5

This is a 5 prime utr variant variant in the F12 gene.

Key Literature Trait Associations

Plasma Factor XII Level

The rs1801020 variant sits in the 5'-untranslated region of the Factor XII (F12) gene and disrupts the canonical Kozak translation-initiation sequence. It also introduces a competing upstream ATG that stalls ribosomes, collectively reducing FXII protein production. Individuals homozygous for the minor allele have roughly half the circulating Factor XII of those homozygous for the major allele. Factor XII initiates the contact activation pathway of coagulation; lower FXII levels are paradoxically not associated with a clinically significant bleeding tendency, but may modulate thrombosis and inflammatory signaling.

Calafell F et al. “Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels.” Human Molecular Genetics (2010)

Allele G

OR —

p 1.0e-5

N 398

Candidate gene study

multi-ancestry (21 families)

Sabater-Lleal M et al. “Combined cis-regulator elements as important mechanism affecting FXII plasma levels.” Thrombosis Research 125(2):e55-e60 (2010)

Allele G

OR —

p 1.0e-20

Large GWAS

Olson NC et al. “Coagulation factor XII genetic variation, ex vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.” Journal of Thrombosis and Haemostasis : Jth (2015)

Allele G

OR —

β -34.200 ±3.500

p 3.3e-22

N 5,411

Large GWAS

multi-ancestry (European-American and African-American)

Kohler HP et al. “FXII (46C-->T) polymorphism and in vivo generation of FXII activity--gene frequencies and relationship in patients with coronary artery disease.” Thrombosis and Haemostasis (1999)

Allele G

OR —

p 1.0e-4

N 451

Candidate gene study

European

Venous thromboembolism

Homozygosity for the T allele (T/T genotype) of rs1801020 is associated with elevated venous thromboembolism risk in candidate-gene studies, with an adjusted OR of approximately 4.8 in one Spanish cohort, though the mechanistic basis for increased clotting risk despite lower FXII levels remains debated. A HuGE meta-analysis of 16 studies (4,386 cases, 40,089 controls) found only weak overall evidence for VTE association, with no statistically significant effect in most genetic contrasts; a borderline myocardial infarction signal (OR=1.13) was observed only for the combined CT+TT vs. CC comparison. rs1801020 is included in the validated Thrombo inCode (TiC) multilocus risk score, which improved VTE prediction area under the curve from 0.575 to 0.677 over single-gene testing.

Johnson CY et al. “The factor XII -4C>T variant and risk of common thrombotic disorders: A HuGE review and meta-analysis of evidence from observational studies.” American Journal of Epidemiology (2011)

Allele T

OR 1.13

p 5.0e-2

N 44,475

Meta-analysis

multi-ancestry

Soria JM et al. “Multilocus genetic risk scores for venous thromboembolism risk assessment.” Journal of the American Heart Association (2014)

Allele T

OR —

p 1.0e-3

N 1,452

Preliminary work

European

Tirado I et al. “Association after linkage analysis indicates that homozygosity for the 46C-->T polymorphism in the F12 gene is a genetic risk factor for venous thrombosis.” Thrombosis and Haemostasis (2004)

Allele T

OR 4.82

p —

N 500

Preliminary work

European (Spanish)

Serum L-arginine levels

A GWAS identified rs1801020 at the F12 locus as significantly associated with lower serum L-arginine concentrations, mediated through the kallikrein-kinin system. The sentinel variant rs2545801, in strong LD with rs1801020, was associated with a reduction of ~7 µmol/L per allele copy (p=7×10^-12) in a discovery cohort of 901 Europeans and 1,394 Indian Asians. Together with the KLKB1 locus, the F12 region explains approximately 7% of total variance in serum L-arginine, a precursor for nitric oxide synthesis relevant to vascular function and cardiovascular risk.

Zhang W et al. “Genome-wide association reveals that common genetic variation in the kallikrein-kinin system is associated with serum L-arginine levels.” Thrombosis and Haemostasis 116(6):1041-1049 (2016)

Allele T

OR —

β -7.000

p 7.0e-12

N 2,295

Large GWAS

European and Indian Asian

Ischemic stroke

Homozygosity for the T allele of rs1801020 was associated with increased ischemic stroke risk in two small Spanish case-control studies (adjusted OR ~4.1–4.8), but these findings have not been confirmed in larger populations. The Cardiovascular Health Study (n=5,411) found no significant association between rs1801020 and incident ischemic stroke (β=-0.02, p=0.81), and a meta-analysis of F12 polymorphisms in 6,100 stroke cases and 9,249 controls found no significant association. The elevated ORs in the Spanish cohorts may reflect population-specific linkage disequilibrium, small-study bias, or coincidental enrichment for compound thrombophilia.

Allele T

OR —

β -0.020 ±0.080

p 8.1e-1

N 5,411

Preliminary work

multi-ancestry (European-American and African-American)

Wei LK et al. “Meta-Analysis of Factor V, Factor VII, Factor XII, and Factor XIII-A Gene Polymorphisms and Ischemic Stroke.” Medicina (kaunas, Lithuania) (2019)

Allele T

OR —

p —

N 15,349

Meta-analysis

multi-ancestry

Santamaría A et al. “Homozygosity of the T allele of the 46 C->T polymorphism in the F12 gene is a risk factor for ischemic stroke in the Spanish population.” Stroke (2004)

Allele T

OR 4.10

p —

N 436

Candidate gene study

European (Spanish)

Plasma renin levels

The minor T allele of rs1801020 in F12 was associated with reduced levels of active plasma renin in a study of 1,180 subjects, providing evidence that FXII influences renin-angiotensin system activation through kallikrein-mediated cleavage of prorenin. Carriers of the minor allele at both F12 rs1801020 and KLKB1 showed a significant combined association with reduced renin, suggesting the contact activation pathway regulates circulating renin in vivo. This finding links genetically lower FXII activity to potential effects on blood pressure regulation.

Biswas N et al. “Polymorphisms at the F12 and KLKB1 loci have significant trait association with activation of the renin-angiotensin system.” Bmc Medical Genetics (2016)

Allele T

OR —

p —

N 1,180

Preliminary work

multi-ancestry (civilian twins/siblings and U.S. Marines)

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GWAS Catalog Trait Associations (38)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Benign★★★☆

9 submitters5 publications

F12 POLYMORPHISM; Hereditary angioedema type 3; not specified; Factor XII deficiency disease; not provided

rs1801020

Key Literature Trait Associations

Plasma Factor XII Level

Venous thromboembolism

Serum L-arginine levels

Ischemic stroke

Plasma renin levels

GWAS Catalog Trait Associations (38)

ClinVar annotation

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