The genetic makeup of an individual is responsible for their unique characteristics and traits, such as eye color or height. Mutations or alterations within a person’s genome can have significant health consequences and can also impact the way a person responds to prescription medications.
GenMark offers multiplex molecular panels that address a wide variety of clinical needs in the area of genetics. The following information is provided as an educational resource only.
WHAT IS CYSTIC FIBROSIS (CF)?
Cystic fibrosis is a genetic disorder caused by mutations, or alterations, of the CF gene. This results in abnormally thick mucus that causes difficulty breathing, recurrent lung infections, and digestive disorders.
HOW PREVALENT IS CF?
CF is a life threatening illness and is one of the most common inherited diseases. About 30,000 children and adults in the United States (70,000 worldwide) are living with CF and an additional 10 million people are carriers of CF gene mutations.1
WHAT IS INHERITED THROMBOPHILIA?
Thrombophilia is a condition that involves an increased risk of blood clot formation or thrombosis. Inherited thrombosis is associated with congenital predisposing risk factors such as Factor II (Prothrombin, FII) and Factor V (Leiden, FV) proteins involved in the blood coagulation enzyme activity cascade and Methylenetetrahydrofolate Reductase (MTHFR) that converts homocysteine to methionine, an amino acid used to build proteins.2-4 Inherited thrombosis is characterized by increased risk of deep vein thrombosis, ectopic pregnancy, pulmonary embolism, myocardial infarction, cardiovascular disease, and other complications related to abnormal blood coagulation.
HOW PREVALENT IS INHERITED THROMBOPHILIA?
Thrombophilia is one of the most common types of blood coagulation disorders, affecting 1 in 1000 individuals with a fatality rate of 1-2%. The FII and FV mutations are present in approximately 2% and 5% of individuals with Northern European ancestry respectively, but at much lower levels in other populations.5,6 The MTHFR C677T and A1298C mutations are present in approximately 40-50% of Northern European ancestry, but the frequency varies considerably in other ethnic groups.6 Individuals with both Factor V and Factor II mutations have a 20-fold more likely chance of venous thrombosis than individuals without either mutation.7
WHAT IS WARFARIN?
Warfarin is one of the most commonly prescribed anti-coagulants. The dose of warfarin required to achieve a stable therapeutic effect varies widely among individuals. The consequences of incorrect dosage are severe and, in some cases, life-threatening. While variation in drug response is caused by many factors such as diet, age, and medications, a patient’s genotype accounts for one-third (32%) of the variation.8
HOW PREVALENT IS WARFARIN SENSITIVITY?
The prevalence of genotype variants differs by race; 10% and 6% of Caucasians carry the *2 and *3 variants of CYP2C9, respectively, but both variants are rare, less than 2%, in those of African or Asian descent.9 The distribution of the -1639G>A VKORC1 allele is also population-dependent, and is found in about 40% of Caucasians, and as high as 90% in Asians.10,11
1. Cystic Fibrosis Foundation, http://www.cff.org/AboutCF/Faqs/
2. Poort, S.R. et al. (1996). A Common Genetic Variation in the 3'-Untranslated Region of the Prothrombin Gene is Associated with Elevated Plasma Prothrombin Levels and an Increase in Venous Thrombosis. Blood, 88(10), 3698-3703.
3. Bertina, R.M. et al. (1994). Mutation in Blood Coagulation Factor V Associated with Resistance to Activated Protein C. Nature, 369(6475), 64–67.
4. Botto, L.D. and Yang, Q. (2000). 5, 10-Methylenetetrahydrofolate Reductase (MTHFR) Gene Variants and Congenital Anomalies: A HuGE Review. American Journal of Epidemiology, 151(9), 862-877.
5. Franco, R.F. et al (1998). Prevalence of the G20210A Polymorphism in the 3'-Untranslated Region of the Prothrombin Gene in Different Human Populations. Acta Haematologica, 100(1), 9-12.
6. Gregg, J.P. et al. (1997). Prevalence of the Factor V-Leiden Mutation in Four Distinct American Ethnic Populations. American Journal of Medical Genetics, 73(3), 334–336.
7. Tosetto, A. et al. (1998). Additional Genetic Risk Factors for Venous Thromboembolism in Carriers of the Factor V Leiden Mutation. British Journal of Haematology, 103(3), 871-876.
8. Gage, B.F. et al. (2008). Use of Pharmacogenetic and Clinical Factors to Predict the Therapeutic Dose of Warfarin. Clinical Pharmacology and Therapeutics, 84(3),326-331.
9. Au, N., and Rettie, A.E. (2008). Pharmacogenomics of 4-Hydroxycoumarin Anticoagulants. Drug Metabolism Reviews, 40(2), 355-375.
10. Rieder, M.J. et al. (2005). Effect of VKORC1 Haplotypes on Transcriptional Regulation and Warfarin Dose. New England Journal of Medicine, 352(22), 2285-2293.
11. Yuan, H.Y. et al. (2005). A Novel Functional VKORC1 Promoter Polymorphism is Associated with Inter-Individual and Inter-Ethnic Differences in Warfarin Sensitivity. Human Molecular Genetics, 14(13), 1745-1751.