Contraceptives + HRT PGx

Indications for genetic testing:

1. A history of first and recurrent venous thromboembolism (VTE),  especially in women with a history of VTE during pregnancy or in association with use of estrogen-containing contraceptives
2. A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
3. Age greater than 50 years with a first unprovoked VTE
4. A family history of recurrent thrombosis
5. Testing at-risk female relatives
6. Genetic counseling

Venous thromboembolism manifests most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism.  DVT is the most frequent VTE, with the legs being the most common site. Thrombosis in unusual locations may also occur, but less commonly.

Inherited genetic factors predisposing tendency to develop VTE are Factor V Leiden mutation in the F5 gene and mutation 20210G>A in the F2 (prothrombin) gene.

F5 Leiden and prothrombin thrombophilia are inherited in an autosomal dominant manner, heterozygosity for the above mentioned variants results in an increased risk for thrombosis; homozygosity for the variants confers a higher risk for thrombosis than heterozygosity.

The clinical expression of thrombophilia is influenced by family history, coexisting genetic abnormalities, acquired thrombophilic disorders, and circumstantial risk factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travelling, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and older age.

F5 Leiden thrombophilia is the most common inherited form of thrombophilia. Heterozygosity for the Leiden variant occurs in 3%-8% of the general US and European populations. F2 20210G>A heterozygosity occurs in 1.7%-3% of the general US and European populations. The prevalence varies by population. The highest heterozygosity rate is found in Europe.

Women heterozygous for F5 Leiden and F2 20210G>A variants and a history of VTE should avoid estrogen-containing contraception and hormone replacement therapy (HRT). Women homozygous for these variants with or without prior VTE should avoid estrogen-containing contraception and HRT.

Asymptomatic women heterozygous for the variants should be counseled on the risks of estrogen-containing contraception and HRT use and should be encouraged to consider alternative forms of contraception and control of menopausal symptoms, those choosing use of:
• Oral contraceptives should avoid third-generation and progestins with a higher thrombotic risk.
• Short-term HRT for severe menopausal symptoms should avoid oral formulations.

References:

Barrett-Connor E et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–37.
Juul K et al. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med. 2004;140:330–7.
Kujovich JL. Factor V Leiden Thrombophilia. GeneReviews® . Seattle (WA): University of Washington, Seattle; 1993–2021. 1999 May 14 [updated 2018 Jan 4].
Kujovich JL. Prothrombin Thrombophilia. GeneReviews®  Initial Posting: July 25, 2006; Last Update: February 4, 2021.
Pabinger I et al. Factor V. Leiden mutation increases the risk for venous thromboembolism in cancer patients – results from the Vienna Cancer And Thrombosis Study (CATS). J Thromb Haemost. 2015 Jan;13(1):17–22.
Renoux C et al. Hormone replacement therapy and the risk of venous thromboembolism: a population-based study. J Thromb Haemost. 2010;8:979–86.
Rosendaal FR, Reitsma PH. Genetics of venous thrombosis. J Thromb Haemost. 2009;7Suppl 1:301–4.
Sweetland S et al. Venous thromboembolism risk in relation to use of different types of postmenopausal hormone therapy in a large prospective study. J Thromb Haemost. 2012;10:2277–86.
Van Vlijmen EF et al. Combined oral contraceptives, thrombophilia and the risk of venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost. 2016;14:1393–403.

Malignant Hyperthermia NGS panel

Indications for genetic testing:

1. Clinical episode of malignant hyperthermia (MH)
2. Positive caffeine/halothane contracture test
3. Relative with a positive contracture test or a known MH-causing variant
4. Unexplained death with signs of MH during or immediately after anesthesia
5. Exercise-related rhabdomyolysis and/or heat stroke

Malignant hyperthermia is an inherited pharmacogenetic disorder of calcium regulation resulting in uncontrolled skeletal muscle hypermetabolism.

Manifestations of MH are triggered by certain volatile anesthetics (i.e. halothane, isoflurane, sevoflurane, desflurane, enflurane), either alone or in conjunction with succinylcholine, a depolarizing muscle relaxant. The triggering substances initiate uncontrolled release of calcium from the sarcoplasmic reticulum and may promote entry of extracellular calcium into the myoplasm, causing contracture of skeletal muscles, glycogenolysis, and increased cellular metabolism, resulting in production of heat and excess lactate.

MH clinical manifestations are hyperthermia, hypercapnia, tachycardia, acidosis, muscle rigidity, compartment syndrome, rhabdomyolysis with subsequent increase in serum creatine kinase concentration, hyperkalemia with a risk for cardiac arrhythmia or even cardiac arrest, and myoglobinuria with a risk for renal failure.

In nearly all cases, the first manifestations of MH occur in the operating room, MH may also occur in the early postoperative period. Recent studies show that some individuals with MH will also develop the disorder with exercise and/or on exposure to hot environments. Without prompt treatment with dantrolene sodium, mortality is extremely high.

MH is an autosomal dominant disorder.

References:

Riazi S, Kraeva N, Hopkins PM. Updated guide for the management of malignant hyperthermia. Can J Anaesth. 2018;65:709–21.
Rosenberg H et al. Malignant Hyperthermia Susceptibility. GeneReviews® Initial Posting: December 19, 2003; Last Update: January 16, 2020.
Rosenberg H, Pollock N, Schiemann A, Bulger T, Stowell K. Malignant hyperthermia: A review. Orphanet J Rare Dis. 2015;10:93.

Antidepressants PGx

Indications for genetic testing:

1. Optimization of drug therapy to ensure maximum efficacy with minimal adverse effects
2. Dose adjustments or an alternative agent selection

The test provides an interpretation of CYP2D6 and CYP2C19 genotyping results and drug metabolism phenotypes. Dosing recommendations for selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) based on Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines are included in the test report.

SSRIs are primary treatment options for major depressive and anxiety disorders. The SSRIs selectively increase serotonergic activity by decreasing presynaptic serotonin reuptake. Therapeutic outcome is dependent on the polymorphisms in CYP2D6 and CYP2C19 genes influencing the metabolism of SSRIs, thereby affecting drug efficacy and safety. Approximately 50% of patients diagnosed with major depressive disorder will fail initial SSRI therapy.

Common adverse effects induced by this drug class include central nervous system effects (e.g., insomnia, headache), gastrointestinal dysfunction, and sexual dysfunction. Serious adverse events such as arrhythmias caused by QT prolongation have been described in individuals who are CYP2C19 poor metabolizers and are prescribed citalopram.

Tricyclic antidepressants (TCAs) are mixed serotonin and norepinephrine reuptake inhibitors used to treat several diseases including depression, obsessive-compulsive disorder, and neuropathic pain in addition to migraine prophylaxis. CYP2D6 and CYP2C19 polymorphisms affect the exposure, efficacy and safety of TCAs. Patients may be predisposed to treatment failure or adverse effects due to genetic variation in CYP2D6 gene altering drug clearance or in CYP2C19 gene altering the ratio of parent drug to metabolites. Common adverse effects include anticholinergic, central nervous system and cardiac effects.

Utilizing pharmacogenetic results to guide depression therapy could improve treatment response and decrease the occurrence of adverse events.

References:

Hicks, J. K., K. Sangkuhl, J. J. Swen, V. L. Ellingrod, D. J. Müller, K. Shimoda, J. R. Bishop, et al. 2017. “Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update.”
Hicks, J. K., J. R. Bishop, K. Sangkuhl, D. J. Muller, Y. Ji, S. G. Leckband, J. S. Leeder, et al. 2015. “Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors.”
Funk, K.A. & Bostwick, J.R. A comparison of the risk of QT prolongation among SSRIs. Ann. Pharmacother. 47, 1330–1341 (2013).

Asper Pharmacogenetics

Asper Pharmacogenetics is a collection of genetic tests targeting drug-gene interactions including metabolic response to medications and predisposition to adverse drug reactions.

Extensive research has been carried out in the past years to determine the relationship between therapeutic drugs and genes. The studies demonstrate the growing importance of genetically guided treatment, especially in the concept of personalized medicine.

Knowledge on genetic aspects determining drug metabolism allows the implementation of genotype-guided prescription and dosing. It can not only improve drug efficacy but also help prevent adverse drug reactions.