Helping you assess risk
Navigenics services are not diagnostic. Instead, our tests establish genetic predispositions to common conditions and pharmacogenomic outcomes, so that prevention, early detection, or personalized medication selections may be possible.
Here are caveats to consider as you assess individuals at elevated risk for the conditions and medication outcomes we cover.
Health Conditions
- Abdominal aneurysm
- Alzheimer's disease
- Atrial fibrillation
- Brain aneurysm
- Breast cancer
- Celiac disease
- Colon cancer
- Crohn's disease
- Deep vein thrombosis
- Diabetes, type 2
Medications
Abdominal aneurysm
An abdominal aneurysm usually results from a mix of genetic and environmental causes. Family and case-control studies indicate that about 72 percent of your patient's potential risk is caused by genetic factors.
Men are four times more likely than women to develop this type of aneurysm, with men who have a history of smoking and those over 65 at the highest risk. For younger individuals, having smoked and having a family history increase risk.
Your patient's genetic risk, in the context of his or her family history and other risk factors, can signal whether your patient would benefit from screening for an aneurysm.
Note that the data from the genome study indicate that the genetic variant leads to increased susceptibility for developing an aneurysm, rather than an increased risk of rapid progression or rupture.
Alzheimer's disease
The Navigenics Health Compass genetic test addresses late-onset disease, not early onset. There are some early and promising things that can be done for Alzheimer's, which we describe to our members on our website. We tell our members that they may be at greater risk than we have reported and should consult a Genetic Counselor if any of their relatives have been diagnosed with Alzheimer's before age 60.
Atrial fibrillation
In view of an increased tendency to atrial fibrillation, it may be worthwhile to readdress with your patient any symptoms not previously categorized: palpitations, syncope, etc. Reviewing avoidance of precipitating factors such as stimulants and decongestants also may be prudent.
Brain aneurysm
In view of an increased tendency to brain aneurysm, it may be worthwhile readdressing with your patient any symptoms not previously categorized, such as severe or recurrent headaches or other neurological symptoms, even if they come and go. Viewing these in light of a possible underlying brain aneurysm may be prudent.
Breast cancer
Our panel does not cover certain important monogenic breast cancers such as Hereditary Breast and Ovarian Syndrome (HBOC), BRCA mutations or Cowden syndrome (PTEN). We tell our members that they may be at greater risk than we have reported and should consult a Genetic Counselor if they answer "yes" to any of these questions:
- Have you or anyone in your family had breast cancer before age 50, cancer in both breasts at any age or ovarian cancer at any age?
- Have two or more close relatives on the same side of your family (maternal or paternal) had breast or ovarian cancer, or has one relative had both?
- Do you have any male relatives with breast cancer?
- Do you have Ashkenazi (Eastern European) Jewish ancestry and at least one family member with breast or ovarian cancer at any age?
- Do you have any relatives with an identified genetic mutation that increases their risk for cancer?
Celiac disease
Symptoms, if any, may be subtle and mimic irritable colon, etc. Perhaps readdress complaints previously passed over. If the individual's diet is low in gluten, confirmatory tests such as gliadin antibody, endomysial antibody and anti tissue transglutaminase may be negative; so if appropriate a gastroenterologist referral might be considered.
Colon cancer
Pending evaluation and a detailed family history, it may be appropriate to consider early colon screening. Also note, our panel does not cover certain important monogenic familial colon cancer syndromes such as HNPCC or FAP. We tell our members that they may be at greater risk than we have reported and should consult a Genetic Counselor if they answer "yes" to any of these questions:
- Have you or anyone in your family had colon cancer before the age of 50, or multiple colon polyps?
- Have two or more close relatives on the same side of your family (maternal or paternal) had colon, uterine or ovarian cancer, or has one relative had more than one of these cancers?
- Do you have Ashkenazi (Eastern European) Jewish ancestry and at least one family member with colon cancer at any age?
- Do you have any relatives with an identified genetic mutation that increases their risk for cancer?
Crohn's disease
Symptoms if any, may be subtle and mimic irritable colon, etc. Perhaps readdress complaints previously passed over.Deep vein thrombosis
We test for four SNPs that relate to deep vein thrombosis (DVT). One is associated with Factor V Leiden, one with the prothrombin G20210A mutation (in Factor II), one with the SERPINC1 gene (which encodes antithrombin) and one located in the CYP4V2 gene. Even if your patient is average or below average on our genetic screen for DVT, it is still possible that he or she could be at increased risk based on personal and family history or other relevant risk factors. For instance, having elevated levels of homocysteine in the blood (which can be acquired or inherited) also raises risk for DVT. The Navigenics test does not replace doing the actual protein assays for suspected thrombophilia (Protein C, Protein S and antithrombin deficiencies), but may assist in determining whether such testing is warranted.
Even with no increased risk of DVT based on the Navigenics panel, if your patient has a personal or family history of DVT, especially in someone under age 50; if the same relative had more than one clot; or if there is a family history of recurrent pregnancy loss (e.g. the same person has had more than three pregnancy losses), there may be an underlying genetic cause. If so, additional testing may be appropriate. And if the Navigenics test is shows increased risk it is still appropriate to get confirmatory Factor V Leiden and prothrombin G20210A mutation assays in another clinical laboratory.
Diabetes, type 2
A baseline Hemoglobin A1c may be appropriate for future reference.Glaucoma
Our panel screens for genetic markers that increase the risk for exfoliation glaucoma. Consider obtaining a baseline eye exam with visual fields.Graves' disease
You might be attuned to -- and make your patient aware of -- unusual presentations such as diarrhea, fatigue, muscle weakness, etc.Heart attack
Consider readdressing borderline lipids.Hemochromatosis
We test for several genetic variants in the HFE gene, each conferring different degrees of risk for developing iron overload. At any given time people at genetic risk for hemochromatosis can still have normal iron levels (transferrin saturation and serum ferritin) due to their age, sex, and environmental factors. Consideration should be given to confirming a positive Navigenics screen for hemochromatosis with a standard HFE gene test in a clinical laboratory.
Lactose intolerance
Lactose intolerance is very common among people of Asian and African descent. However, some Asians and Africans may have two copies of the risk marker that Navigenics tests for, and still be able to tolerate lactose. This is because lactase production may also be regulated at other loci. These loci are not well understood by scientists, and so they are not included in Navigenics’ service. In a patient with symptoms and a positive genetic risk you may want to confirm the diagnosis of lactose intolerance with a lactose tolerance test or hydrogen breath test. Also, remember that other conditions such as celiac disease can result in a secondary form of lactose intolerance.
Lung cancer
The available data indicate that these results apply primarily to current and former smokers. It's difficult to evaluate non-smokers as they are affected so infrequently. In the study our test relies on most heavily, the researchers found no association between the genetic variant and lung cancer in non-smokers, though the number of non-smokers was small. Another study, however, did show a modest association in non-smokers. An even more recent study provided convincing evidence that the gene variant we test for actually predisposes to nicotine addiction, which in turn raises risk for lung cancer.
This genetic variant was not found to predispose to any subtype of lung cancer in particular. One study found the association in populations of non-small cell lung cancer cases only, another in subgroup analyses of small cell, squamous cell, and adenocarcinomas and a third in a combination of various lung cancer subtypes.
Lupus
Your patient may have no symptoms, mild symptoms, or symptoms not initially thought to be significantly related to any specific entity. Consider readdressing any complaints that might be related to lupus in view of a possible increased tendency.Macular degeneration
A baseline eye exam may be appropriate. Also, instructing your patient in the use of the Amsler Grid to detect degeneration early should be considered.Melanoma
When seeing patients who have an increased genetic risk for melanoma, you may want to reexamine their skin or have them see a dermatologist for a skin check. Remember that a melanoma may occur in a dark-complected individual, may be amelanotic and may occur in areas that aren't exposed to the sun.
Also note: Navigenics tests for common markers associated with melanoma. We do not screen for rare mutations in genes such as CDKN2A (also known as p16) or CDK4, which are associated with rare hereditary melanoma syndromes. If you have patients who answer “yes” to any of the questions below, they should be referred to a Genetic Counselor or dermatologist and considered for additional genetic testing.
- Have you or anyone in your family had melanoma (especially two or more cases in the same person)?
- Do you have a personal or family history of melanoma and pancreatic cancer — either both diagnoses occurring in the same family member or in two different relatives?
- Does anyone in your family have a known mutation in a gene associated with hereditary melanoma?
- Have you been diagnosed with multiple atypical or dysplastic nevi?
Multiple sclerosis
Consider neurological referral for even subtle symptoms, because early treatment might make a difference.Obesity
Even if your patient is not obese, and there is no strong family history of such, it may not be unreasonable to remind your patient that caloric needs decrease with age, and the prevalence of obesity increases with age.Osteoarthritis
Your patient may have no symptoms, but it may still be reasonable to encourage appropriate lifestyle changes like weight reduction, being careful about repeated joint trauma, etc.Prostate cancer
For men at increased genetic risk, consider doing a baseline PSA and digital rectal exam earlier than usual, even if family history is not striking.Psoriasis
While classical patches of psoriasis are fairly obvious, consider checking your patient periodically for lesions in less common places, such as the intergluteal region, that may present differently. Also be alert to nail changes and arthritic symptoms that may suggest psoriatic arthritis, which has a better prognosis if treated early.Restless legs syndrome
This syndrome appears to be associated with a number of common genetic variants, each having a small effect on its own but a greater impact in combination.
Rheumatoid arthritis
Consider reassessing even mild joint complaints or questioning your patient about extra-articular rheumatoid symptoms. A baseline sedimentation rate may be helpful in the future.Sarcoidosis
Over 60 percent of the risk for sarcoidosis is genetic, probably with an environmental trigger. As a "great masquerader," sarcoidosis needs to be considered in the differential diagnosis of pulmonary, dermatologic, and arthritic complaints especially with lymphadenopathy. A person’s increased genetic predisposition for sarcoidosis can serve as a clue to understanding varied and vague complaints. Confirmatory tests may be appropriate.
Stomach cancer, diffuse
Navigenics tests for common genetic markers associated with diffuse stomach cancer. Much less common are single-gene mutations that carry a much greater likelihood of diffuse stomach cancer. Navigenics does not test for these rare single-gene mutations. If your patient answers "yes" to any of the questions below, you should have the person consult a Genetic Counselor.
- Have two or more close relatives in your family had diffuse stomach cancer, with at least one person diagnosed before age 50?
- Have three or more close relatives been diagnosed with diffuse stomach cancer at any age?
- Has a close relative been diagnosed with diffuse stomach cancer before age 40?
- Has a close relative been diagnosed with both diffuse stomach cancer and lobular breast cancer?
- Has a close relative been diagnosed with diffuse stomach cancer and a different family member with either lobular breast cancer or signet ring colon cancer?
Although the association between H. pylori and the intestinal form of stomach cancer is better understood, there may also be an association between H. pylori and diffuse stomach cancer. You may want to consider having your patient tested for H. pylori.
Abacavir
The FDA recommends that in order to minimize the risk for abacavir hypersensitivity reaction physicians should avoid prescribing abacavir to HIV patients carrying the HLA-B*5701 variant. Since it is difficult to directly assay HLA-B *5701, Navigenics uses a well-established, reliable genetic proxy for this variation. It is important to know that for some people of Asian ancestry (specifically Han Chinese), this proxy may not be the most accurate way to assess for abacavir side effects. In some cases additional testing, known as HLA sequencing, may be required.
Beta blockers
G protein-coupled receptor kinases (GRKs) regulate and desensitize beta adrenergic receptors. A specific GRK5 gene variant (Gln41Leu), common in African Americans, reduces beta-AR signaling, essentially acting as an endogenous beta blocker. Patients with this GRK5 variant respond less well to beta blocker treatment after heart failure. This may explain why clinical trials of beta blockers in heart failure have generally shown less promising results in African-American populations than in European-Americans.
In some cases, this genetic result may allow you to use genotype, rather than race or ancestry, to optimize hypertension treatment, especially since about 60 percent of African Americans have an unaltered version of the gene and thus may actually benefit from beta blocker treatment.
Carbamazepine
Genetic testing for carbamazepine side effects is important for patients of certain ancestries, but is also complex. According to the U.S. Food and Drug Administration and the drug manufacturer, carbamazepine therapy is contraindicated for patients carrying the HLA-B*1502 risk variant, the variant assessed by the Navigenics service. However, HLA-B*1502 is largely absent in individuals not of Asian origin (e.g., Caucasians, African-Americans, Hispanics, and Native Americans). While HLA-B*1502 is seen among a wide range of Asian populations, the genetic analysis method used in this test is most relevant to people of Han Chinese ancestry. Additional testing such as HLA sequencing may be considered for patients with non-Han Chinese Asian ancestry. The testing method does not accurately represent HLA-B*1502 in individuals with African ancestry, and research has not shown whether or not it is an accurate representation in other groups, including Caucasians and Japanese.
Clopidogrel
Clopidogrel (Plavix), prescribed for a wide range of cardiovascular indications, is a “pro-drug” requiring hepatic bioactivation by the CYP450 system in order to exert its anti-clotting effects. Navigenics tests for two of the most common CYP2C19 variants, CYP2C19*2 (rs4244285) and CYP2C19*3 (rs4986893), known to reduce CYP2C19 protein function. Both of these “loss of function” variants result in a less efficient CYP2C19 protein and have been associated with clopidogrel resistance. Preliminary research shows that other genetic variants may also play a role in decreased clopidogrel effectiveness, but Navigenics does not currently include these in the testing panel.
The FDA has has added a drug warning label stating potential adverse drug interactions between clopidogrel and other drugs metabolized by CYP2C19. The agency also states that CYP2C19 poor metabolizer status is associated with diminished response to clopidogrel, and advises physicians to consider modifying treatment for such patients.
Floxacillin
In countries where floxacillin is prescribed, a small percentage of patients experience drug-induced liver toxicity. Navigenics tests for a single SNP that tags HLA-B*5701 (rs2395029). This SNP is an excellent predictor of floxacillin sensitivity in most people. For a subset of people of Asian ancestry (Han Chinese), however, the Navigenics floxacillin sensitivity test will be less accurate. Since the Navigenics test does not directly assay the HLA-B*5701 haplotype, for some patients, especially those with Asian ancestry, additional genotyping or HLA sequencing may be appropriate to most accurately determine your patient’s risk.
Fluorouracil
Pharmacogenomic testing identifies the most common genetic cause of DPD deficiency, a key enzyme deficiency linked to fluorouracil (5-FU) toxicity. The DPYD*2A variant accounts for roughly 50 percent of the known DPD deficiency-associated variants. Navigenics does not currently include testing for other, less common DPYD variants or variants in other genes including TYMS or MTHFR, which have less common or questionable clinical significance. However, you may want to order follow-up testing – such as additional genotyping or gene sequencing, or DPD enzyme activity - to further clarify your patient's genetic risks.
Irinotecan
The FDA recommends that physicians consider a reduced initial irinotecan dose for patients known to carry two copies of be the UGT1A1*28 genetic variant and suggests that patients with one copy may also be at increased risk for serious side effects with this drug. The test performed by Navigenics is based on more recent papers that indicate a single SNP, rs10929302, is actually a better predictor of irinotecan toxicity. However, this genetic variant alone does not explain all cases of irinotecan side effects.
Of note, irinotecan, given at standard doses is actually likely to be more effective for people with one or two copies of the risk variant. In such cases, physicians and patients need to weight the risk of side effects against potential drug benefits.
Simvastatin
Navigenics tests for a single genetic variant in the SLCO1B1 gene (known as SLCO1B1*5). This genetic variant increases the risk of simvastatin-induced myopathy. It is also important to note that these genetic results apply most directly to simvastatin. While the genetic variant covered by this test has also been linked to varying risks for other types of statins, this link is not yet sufficiently proven by scientific research, and Navigenics is not directly applying this genetic result to statins other than simvastatin at this time.
Statins
The APOE-4 allele has been implicated in patients with higher levels of LDL cholesterol and a higher risk of both cardiovascular disease and Alzheimer’s disease. Several studies have shown that individuals who carry one or more copies of APOE-4 don’t experience as much of a reduction in LDL as would be expected after statin treatment. However, rigorous randomized controlled studies indicate that APOE-4 carriers receiving regular simvastatin or pravastatin treatment who experience myocardial infarction actually have improved outcomes compared to APOE-4 carriers who do not take a statin. This effect appears to be independent of cholesterol lowering, but rather may be due to these statins’ other properties, such as their ability to reduce inflammation and CHD risk factors.
Note on Lipitor: While some evidence suggests that beyond simvastatin and pravastatin, other types of statins, such as atorvastatin (Lipitor) may also share this APOE-4-related pattern, these other types of statins have not yet been sufficiently investigated in rigorous scientific trials that look at overall health outcomes.
Succinylcholine
Variants in a gene called BCHE make its related protein, butyrylcholinesterase (BChE), less effective at breaking down several drugs, including the surgical skeletal muscle relaxant succinylcholine. About 65 percent of prolonged post-succinylcholine apnea is attributed to BChE protein deficiency, the majority of which is due to two variants, known as BCHE A and BCHE K, included in this analysis. Other factors that contribute to succinylcholine sensitivity are rare BCHE variants not included in this test, as well as other factors such as a range of contraindicated medications and your patient’s health status.
Thiopurines
The TPMT gene, located on chromosome 6, is named for the enzyme it produces, thiopurine S-methyltransferase. Variants in the TPMT gene make this enzyme less effective at breaking down thiopurine drugs such as azathioprine (AZA) and 6-Mercaptopurine (6-MP), which are used to treat a variety of conditions, including autoimmune conditions and cancer.
How much TPMT enzyme a person has, and how well that enzyme functions, plays a big part in how likely a person is to experience bone marrow toxicity after AZA or 6-MP therapy. Navigenics tests for three SNPs that allow us to determine the four most common versions of the TPMT gene associated with reduced levels of enzyme activity, which account for 80 to 95 percent of individuals with decreased or absent TPMT enzyme activity.
The FDA recommends that “consideration be given to either genotype or phenotype patients for TPMT” before prescribing AZA or 6-MP. Treatment strategy may be adjusted based on both genotype and phenotype results.
Warfarin
The genetics of warfarin are complex, as are the challenges of personalized warfarin dosing. Navigenics looks at four places contained within three genes in your patient's genetic code – CYP2C9, CYP4F2, and VKORC1. The FDA recommends that VKORC1 and CYP2C9 gene variants, which are included in this test result, be used to optimize warfarin dosing. If your patient requires warfarin treatment, these genetic results, combined with standard warfarin-dosing considerations, can help determine the safest and most effective warfarin dose for him/her. Dosing calculators are available to assist in integrating genetic results.
Navigenics provides warfarin-related genetic results in two formats – one preferred by Navigenics and many other genetic testing providers, and one preferred by www.warfarindosing.org, a dosing calculation tool for clinicians. If you choose to use the warfarindosing.org calculator, please use the warfarindosing.org version of your patient’s results when entering patient data into the calculation tool. These differences in formats reflect only preferences in the way genetic data can be reported, and do not make the results provided by Navigenics any less accurate.