PharmGKB variant annotations provide information about variant-drug pairs or variant-disease pairs based on
individual PubMed publications. Each annotation represents information from a single paper and the goal is to
report the information that the author states, not an interpretation of the paper. The PMID for supporting
PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the
publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators
may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of
participants used for the calculation of the association statistics, so the number may vary slightly
from what is reported in the abstract of the paper. OMB Race Category information is derived from the
paper and mapped to standardized categories. Category definitions may be found by clicking on the
"OMB Race Category" link.
List of all variant annotations for this variant.
The T allele at rs2108622, which has been designated as *3 by the CYP Allele Nomenclature Database http://www.cypalleles.ki.se, replaces a valine residue with a methionine residue at position 433. Although this polymorphism does not affect mRNA transcription, or enzymatic activity of the protein, it does result in decreased protein levels. This could be due to a decreased rate of protein translation or an increased rate of protein degradation [Article:19297519]. Functional in vitro assays show that the T allele decreases 20-HETE synthesis by 50-60% in human liver microsomes [Article:17341693].
Warfarin is the most commonly prescribed oral anticoagulant in the world to prevent the occurrence of thromboembolic events, but achieving therapeutic dose of warfarin is difficult. There is high inter-individual variability of therapeutic dose between patients and warfarin has a narrow therapeutic index. Too high of a dose increases a patient's risk of hemorrhage, but too low of a dose increases a patient's risk of thromboembolisms. A common cause of emergency room visits is attributed to error in warfarin dosing [Articles:21900891, 19228618]. Multiple blood-clotting factors (II, VII, VIIII, X, and proteins C, S, and Z) require post-translational carboxylation of their glutamate residues in order to become biologically active. Carboxylation of these glutamate residues is catalyzed by the enzyme γ-glutamyl carboxylase (GGCX), which requires vitamin K as a co-factor. An enzyme complex called vitamin K epoxide reductase (VKORC) ensures vitamin K bioavailability. By inhibiting a subunit of VKORC (VKORC1) warfarin inhibits the ability of GGCX to activate clotting factors. CYP4F2 metabolizes vitamin K and counteracts the effects of VKORC. CYP4F2 metabolizes vitamin K and limits vitamin K availability.
A 2008 study in three separate Caucasian populations was the first to report that the T allele at rs2108622 in CYP4F2 was associated with an increase in warfarin dose. The study calculated that each T allele at rs2108622 is associated with a 4-12% increase in warfarin dose, such that a patient with the TT genotype could require an approximate 1mg/day higher dose of warfarin compared to a patient with the CC genotype [Article:18250228]. An independent study in Han Chinese confirmed an association between T allele at rs2108622 and increased warfarin dose,. The study also reported that the T allele was responsible for approximately 4% of the inter-individual variation in dose within Han Chinese. Table 2 summarizes the results of several studies investigating the T allele at rs2108622 and its association with warfarin dose. A systematic review and meta-analysis stratified for common genetic variants in CYP2C9 (*2 and *3) and VKORC1 (-1639 G>A) and reported that patients carrying a T allele at rs2108622 required an 8.3% higher mean daily dose of warfarin than patients with the CC genotype [Article:23132553]. The majority of the studies investigating associations between the T allele at rs2108622 and warfarin dose are of patients in the induction phase, but Roth et al. investigated whether CYP2C9, VKORC1, or CYP4F2 genotypes were significantly associated with risk of bleeding events in long-term users of warfarin (the average duration of use was 3.4 and 3.7 years for cases and controls, respectively). In these patients the T allele at rs2108622 was significantly associated with an approximately 40% lower risk of bleeding events [Article:24503627].
The T allele at rs2108622 in CYP4F2 is found at a much lower frequency in populations of African descent when compared to populations of White or Asian descent, and studies investigating the effects of rs2108622 in non-White and non-Asian populations repeatedly report no association between the T allele and dose of warfarin [Articles:21228733, 22855348, 22417713, 20072124, 20182420]. The low frequency of the T allele at rs2108662 in some populations, combined with its small effect size may explain why so many studies in more ethnically diverse populations report no association between warfarin dose and presence of the T allele at rs2108622 (see Table 1 for allele frequencies of the T allele at rs2108622 in various ethnic groups) [Articles:20555338, 20504253]. For example, a study in a multiethnic population investigated whether the inclusion of additional SNPs, including the T allele at rs2108622, enhanced the predictive power of existing warfarin dosing algorithms. The study compared the weekly doses of warfarin that were predicted by those algorithms to the actual weekly doses in patients that had reached a target international normalized ratio (INR) of between 2 and 3. The study concluded that inclusion of the rs2108622 genotype did not enhance the predictive power of any of the algorithms tested [Article:20128861]. A recent study investigated whether copy number variants (CNV) of CYP4F2, CYP2C9, or VKORC1 might affect warfarin dose, but CNVs were so rare that they were deemed unlikely to contribute to variability in warfarin dose [Article:22188360].
Although warfarin is by far the most commonly prescribed oral anti-coagulant in the world acenocoumarol is commonly prescribed in Europe. Like warfarin, acenocoumarol is a vitamin K antagonist and it is administered as a racemate. Unlike warfarin, however, the half-life of acenocoumarol is significantly shorter (T 1/2 acenocoumarol is 2-8 hours and T 1/2 warfarin is 32-43 hours) and it is the R-enantiomer of acenocoumarol that is the most biologically active, unlike the S-enantiomer of warfarin [Article:19132230]. There are far fewer studies investigating how polymorphisms in vitamin K pathway genes affect acenocoumarol dose but the findings are similar to what is known about warfarin. In addition to various polymorphisms in CYP2C9 and VKORC1, the T allele at rs2108622 also affects acenocoumarol dose. Two studies reported that patients that were carriers of the T allele had small but significant increases in acenocoumarol dose when compared to patients that were homozygous for the C allele. One of the two studies also reported that the T allele was protective against acenocoumarol overdosing in patients 3 months after starting therapy [Articles:25042728, 24956252].
Two randomized clinical studies, one in adults and one in pediatric patients, concluded that supplements of the α-tocopherol form of vitamin E may improve liver histology in patients with non-alcoholic fatty liver disease (NAFLD) [Articles:18804555, 21521847]. Data from those studies, including rs2108622 genotype information, were also analyzed in a separate study to investigate whether the T allele was associated with improvement in patient prognosis or with baseline α-tocopherol levels before and after administration of α-tocopherol supplements. The study reported that the T allele was associated with increased baseline α-tocopherol levels in pediatric patients, but not in adult patients. The study also reported that, in patients given α-tocopherol, the T allele was associated with a significant increase in α-tocopherol levels when compared to patients with the C allele at 48 weeks, but the difference dissipated by 96 weeks. Overall, the T allele was not associated with improvement of hepatic steatosis in patients with NAFLD administered vitamin E [Articles:14638353, 24759732]. Finally, a genome-wide association study reported that the T allele at rs2108622 was associated with increased plasma α-tocopherol, but not γ-tocopherol levels [Article:21729881].
Table 1. Frequencies of the T allele at rs2108622 in different populations
Centre Etude Polyphormisme Humain/Human Genome Diversity Project (CEPH/HGDP), Molecular Anthropology Laboratory, Canadian volunteers for University of Toronto at Mississauga (UT Mississauga),Patients from Instituto Nacional de Cardiologia de Laranjeiras, Rio de Janeiro, Brazil (INCL), Patients Volunteers from the New York Blood Center (NYBC), Exome Variant Server, NHLBI GO Exome Sequencing Project (ESP), Seattle, WA (URL: http://evs.gs.washington.edu/EVS/) July, 2014
|Population Reported||OMB||Sample Size||T allele frequency||Source||PMID|
|E. Asian||Asian||100||0.233||UT Mississauga||20555338|
|Central/S. Asian||Asian||95||0.484||UT Mississauga||20555338|
|African||Black or African-American||108||0.070||CEPH/HGDP||20555338|
|Brazilian Black||Black or African-American||74||0.15||INCL||20182420|
|African-American||Black or African-American||600||0.302||NYBC||20504253|
|African-American||Black or African-American||2203||0.0971||ESP||N/A|
|Oceanian||Native Hawaiian or Other Pacific Islander||31||0.613||CEPH/HGDP||20555338|
|Hispanic||Hispanic or Latino||600||0.355||NYBC||20504253|
Table 2. A chronology of association studies of rs2108622 and coumarin drug dose
|Year||Title||Summary of Findings||PMID|
|2008||CYP4F2 genetic variant alters required warfarin dose||The T allele at rs2108622 is associated with increased warfarin dose in two of three independent Caucasian populations.||18250228|
|2009||CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M||Functional studies that demonstrate that CYP4F2 oxidizes, and inactivates vitamin K1; the T allele at rs2108622 is associated with a reduced capacity to oxidize vitamin K||19297519|
|2009||A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose||The T allele at rs2108622 is significantly associated with a higher mean warfarin dose in Swedish patients.||19300499|
|2010||CYP4F2 rs2108622: a minor significant genetic factor for warfarin dose in Han Chinese patients with mechanical heart valve replacement||The T allele at rs2108622 is significantly associated with a higher mean warfarin dose in Han Chinese patients. The genotype at rs2108622 contributes 4% to interindividual variability in dosage within the Han Chinese population, but does not explain the difference in mean warfarin dose between Han Chinese and Caucasians.||20653676|
|2010||Impact of CYP4F2 rs2108622 on the Stable Warfarin Dose in an Admixed Population||The T allele at rs2108622 is not associated with warfarin dose in a Brazilian population, which includes people with European and African ancestry.||20182420|
|2010||Genetic and Clinical Predictors of Warfarin Dose Requirements in African Americans||The T allele at rs2108622 is not associated with warfarin dose in African-American patients. The study also confirms the low allele frequency in African-Americans as compared to Caucasians.||20072124|
|2011||Genetic and nongenetic factors associated with warfarin dose requirements in Egyptian patients||rs2108622 is not significantly associated with warfarin dose in an Egyptian population.||21228733|
|2011||Influence of CYP4F2 rs2108622 (V433M) on warfarin dose requirement in Asian patients||The frequency of the T allele at rs2108622 is higher in Indian and Caucasian populations compared to Chinese, Malay, and African-American populations. The T allele in CYP4F2 is significantly associated with a higher daily mean warfarin dose in patients of Asian descent.||21084764|
|2013||Responsiveness to low-dose warfarin associated with genetic variants of VKORC1, CYP2C9, CYP2C19, and CYP4F2 in an Indonesian population||rs218622 is not significantly associated with warfarin dose in an Indonesian population.||22855348|
|2014||Genetic Risk Factors for Major Bleeding in Patients Treated with Warfarin in a Community Setting||rs2108622 is significantly associated with a decreased risk of major bleeding events in long-term users of warfarin (the average duration was ~3 years).||24503627|