In general, the higher the quality of evidence, the stronger the clinical recommendation (15). The strengths and limitations of the body of evidence have been detailed in the previously conducted systematic review (5). The vast majority of genetic variant(s) identified in the systematic review (5) had weak evidence (GRADE evidence quality rating: low or very low) for their impact on plasma lipid/lipoprotein/apolipoprotein responsiveness to omega-3 fatty acids and thus guidelines for practice were not developed for these nutrigenetic associations. At this time, these should not be considered for incorporation into clinical practice given their low scientific validity. The systematic review and evidence GRADE process previously conducted (5), indicated strong evidence for TG responsiveness to EPA and/or DHA based on APOE (rs429358, rs7412) genetic variants in men (GRADE evidence quality rating: moderate) (16–24), and TG responsiveness to EPA+DHA based on a 31-SNP nutri-GRS in men and women with overweight/obesity (GRADE evidence quality rating: high) (25, 26). It should be noted that there is no evidence for the effectiveness for TG responsiveness to alpha-linolenic acid (ALA) for either of these two nutrigenetic associations. Furthermore, there is no evidence to support nutrigenetic associations related to ALA intake and other plasma lipids/lipoproteins/apolipoproteins (5). A more thorough description of the strengths and limitations of the body of evidence has been detailed previously (5).

Trade-offs between desirable and undesirable consequences of alternative TG management strategies (nutrigenetic intervention vs. other population-based strategies for TG management), as well as risks and benefits of omega-3 consumption and nutrigenetic testing were considered herein.

In addition to EPA+DHA consumption, effective lifestyle strategies for maintaining healthy TG levels can also include reducing the intake of refined sugar/carbohydrates, alcohol, trans fatty acids, and/or increasing physical activity (27). These strategies should be considered and recommended to patients on an individualized basis to maintain healthy TG levels, in addition to nutrigenetic-based advice for omega-3s if the HCP and patient decide to complete such genetic testing. Drug therapy may also be warranted in some patients, but this is beyond the scope of these nutrition CPGs. Given the large interindividual variability observed in plasma TG responsiveness to EPA+DHA (18, 28, 29), nutrigenetic testing can help evaluate which patients will benefit the most from EPA+DHA consumption for TG management. Moreover, providing a “one-size fits all” recommendation for all patients to consume EPA+DHA to reduce TG may have undesirable effects and risks for approximately one third of the population, who have been shown to be non-responders, or adverse responders (i.e., exhibit increases in TG) to EPA+DHA intake for TG changes (25, 26). In addition to an increase in TG in adverse responders, an insulin sensitivity lowering was observed following an n-3 supplementation in 23% of the subjects and a GRS built with 8 of the lead SNPs associated with HOMA-IR changes in this sample accurately predicted the occurrence of this adverse effect (30). The harms of a nutrigenetic intervention for omega-3 and TGs were deemed to be negligible, but genetic testing could be a way to prevent adverse effects of an EPA and/or DHA supplementation intervention, even for people taking n-3 for other conditions. Also, important ethical considerations for APOE genetic testing exist and must be considered. Compared to non-carriers, carriers of APOE-E4 have a 15 times greater risk of developing Alzheimer's disease (31). As such, ethical and regulatory considerations with APOE testing may present barriers to implementation. These implications are discussed in depth in CPG recommendation #1, below.

While there are some concerns about omega-3 supplementation potentially leading to mild adverse effects on certain other lipids and non-lipid biochemical markers (27, 32), as well as gastrointestinal discomfort and skin abnormalities in some patients, health organizations generally consider omega-3s to be safe and well-tolerated (32). In addition, cardiovascular guidelines recommend screening for dyslipidemia starting at age 40 or earlier if the patient has risk factors (e.g., high body mass index), so in many adults, plasma lipid, and other biochemical markers should be regularly monitored (33). Moreover, elevated plasma TG is associated with CVD risk and therefore TG reduction (which can be achieved through higher omega-3 intake in certain patients) has several potential health benefits (27, 34). Omega-3 intake has also demonstrated additional health benefits such as improving major depressive disorder in conjunction with other therapies (35–37), potentially improving cognitive function in very mild Alzheimer's disease (37, 38), and improving outcomes of inflammatory diseases (39, 40). To mitigate any potential risks, while consuming enough omega-3s to result in possible health benefits, the United States Food and Drug Administration (FDA) states that EPA+DHA supplementation should not exceed 5.0 g/day (41). However, it should also be noted that dosages of 3.0 g/day EPA+DHA are considered pharmacological dosages by the American Heart Association (42); this was taken into consideration in developing the CPG recommendations. In Canada, EPA+DHA omega-3 supplementation is not listed as a scheduled drug at any dosage level, but icosapent ethyl (a pure EPA) is considered a Schedule I drug according to the National Association of Pharmacy Regulatory Authorities and therefore limits its implementation in practice to HCPs who can provide prescriptions such as medical doctors (43). Therefore, location-specific regulatory requirements should be taken into consideration by the HCP recommending EPA+DHA to their patients. Regulations may differ depending on the type of HCP recommending EPA+DHA to the patient. Given the above considerations, it was determined by the authors of the present CPGs that overall the potential benefits outweighed the risks of taking these omega-3 fatty acids (EPA+DHA) up to this dosage. HCPs should still assess patients for any contraindications of omega-3 consumption such as fish allergy, adverse reactions, or drug-nutrient interactions (e.g., taking omega-3 supplements in combination with anticoagulant medications) (41). In addition, it is possible to achieve omega-3 (EPA+DHA) intake targets through food sources alone such as fish. For example, 150 g of Atlantic salmon contains just over 3 g of EPA+DHA (44), but some patients may still prefer omega-3 supplementation.

Overall, the balance between desirable and undesirable effects of a nutrigenetic intervention vs. standard population-based nutrition care regarding the use of omega-3 fatty acids (EPA+DHA) to reduce TG was deemed to be “important not critical” using the GRADE terminology (13).

The information described in this section was used primarily to determine whether a weak/conditional (level 2) or strong (level 1) recommendation would be made in the present CPGs, as well as the potential caveats of these recommendation(s). Values and preferences of the target population (adult consumers and potential consumers of genetic testing for personalized nutrition) as well as HCPs were assessed through a literature review, which overall indicated that there is substantial interest globally in genetic testing for personalized nutrition (45–49). Consumers express interest in genetically-guided nutrition advice, especially if such advice provides advantageous recommendations that could be implemented into one's daily routine (48, 50); omega-3 supplementation provides an example of this type of advice. There have, however, been some concerns raised by consumers about genetic testing for personalized nutrition (45). Consumers have expressed their concern for the potential for companies to be more interested in financial gain rather than health (50). In addition, consumers have expressed concerns about nutrigenetic results being unclear or inaccurate, and preferred to undergo nutrigenetic testing through a HCP, such as a registered dietitian (45, 50). However, only a subset of registered dietitians (between 24 and 33% depending on their practice sector) perceives they have the knowledge to integrate nutrigenomics in their practice (51). Still, 50% of registered dietitians who recently received their licenses know about nutrigenetic testing compared to 12% of registered dietitians who have practiced for 25 years or more. This demonstrates an increasing interest in nutritional genomics among (certain) HCPs. Coupled with a similar interest among patient populations, these are considered facilitators to providing nutrigenetic-guided recommendations for omega-3s and TG responsiveness.

The panel deemed it important to consider resource use for the present recommendations (in determining strength and direction), although this is considered optional in the GRADE approach (15). Resource use was considered through literature review and discussion among the guideline developers. There are financial costs associated with both omega-3 consumption (supplementation and through food sources) and nutrigenetic testing, which should be considered. The cost of nutrigenetic testing is highly variable and has been documented at between $90 and $450 CDN (52). Given this, evidence-based personalized nutrition advice should only be implemented if the patient is willing and able to cover their costs. Some HCPs are already offering genetic testing for personalized nutrition, and interest for genetic testing among consumers is high (53). However, it should be noted that several HCPs do not feel competent in the field of nutrigenetics and would thus require further training in the field prior to implementing this personalized nutrition approach in their practice (51, 54). In some cases, patients may have already completed a genetic test for the evidence-based SNPs and may bring their genotype results to a HCP for interpretation. If all SNPs have been tested, the 31-SNP nutri-GRS (detailed in Supplementary Table 2) could then be calculated and used by HCPs to interpret raw data from other genetic tests. A similar approach could be used for the two APOE SNPs. In other cases, a patient may be looking to complete genetic testing for these specific SNPs, and the feasibility of this will depend on what is offered by genetic testing laboratories and companies. With CPG development, the hope/goal is for companies to use the CPGs to develop evidence-based tests that can be offered to patients. Other additional resources beyond standard nutrigenetic care would include the initial investment of time required for the HCP to learn and understand the ethical and regulatory implications of APOE testing in their specific setting.

An “Evidence to recommendations framework” (15) is provided in Table 1. Recommendations 1 and 2 are conditional on the HCP offering the genetic testing being adequately trained in nutrigenetics (i.e., being competent in this area of nutrition care); this is considered a facilitator to implementation. These recommendations are further conditional on a patient's willingness to undergo genetic testing, including incurring any associated costs, which may be a barrier for patients. It is important to recognize that, similar to a personalized nutrition approach, the decision to undergo nutrigenetic testing should also be individualized and patient centered. The generalizability of the tests should also be noted (Table 2). Given these caveats, recommendations 1 and 2 were considered conditional (GRADE level 2), while recommendation 3 was considered “strong” (GRADE level 1). The following recommendations intend to allow for more targeted dietary advice specific to the individual in an effort to optimize cardiovascular health through TG management/prevention, in an evidence-based manner.

Recommendation 1: The expert panel conditionally recommends that in male patients (but not females), nutrigenetic testing for TG responsiveness to EPA and/or DHA omega-3s can be based on genetic testing of APOE SNPs (rs429358, rs7412). Adult males with the APOE-E3/E4 or E4/E4 genotype appear to be most likely to experience significant TG reductions in response to 0.7–3.0 g/day EPA and/or DHA; higher dosages may have greater TG lowering effects (18). It should be noted that while research suggests that up to 3.7 g/day can be effective for TG lowering, 3.0 g/day of EPA+DHA are considered pharmacological dosages by the AHA (42) and as such we have revised the upper dosage recommendation accordingly for those with the APOE-E3/E4 or E4/E4 genotype. Maximum EPA+DHA dosage regulations may vary depending on location therefore the HCP must take their location-specific regulations into consideration when deciding on the appropriate dose for the patient.

Given the link between these APOE genetic variations and Alzheimer's Disease (31), Companies/laboratories producing nutrigenetic tests that include APOE (rs429358 and rs7412) as it relates to plasma TG responsiveness to EPA and/or DHA, and HCPs offering such tests to patients must comply with the regulations relevant to their territory of practice, while also considering any ethical and legal implications of this test. Research laboratories testing these SNPs must work with their institutional research ethics board to determine how to proceed with APOE testing. How to best proceed with this test in an industry, clinical or research setting will be context specific. Consent for APOE genotyping should always be obtained from patients prior to completing genotyping, as they would incidentally also be learning about other disease risks, including Alzheimer's disease. Disclosure of results to patients and referral to appropriate HCPs such as genetic counselors and medical doctors for Alzheimer's disease risk counseling may be warranted if it is in accordance with the consent form signed by the patient. Thus, nutrition professionals (or company offering DTC testing) must be aware of available referral sources (e.g., medical doctors and genetic counselors) prior to offering this test. This recommendation is also conditional on any context-specific policies and regulations related to APOE genetic testing, as well as the patient's consent to undergo APOE testing and disclosure of the results related to Alzheimer's disease risk (or not).

Recommendation 2: The expert panel further conditionally recommends that the nutri-GRS developed by Vallée Marcotte et al. (25, 26) can be used to evaluate TG responsiveness to ~3.0 g/day of EPA+DHA. This risk score is generalizable to adults with overweight and obesity and has been studied in samples of men and women (combined) and therefore can be used for both male and female patients. The details of the nutri-GRS are outlined in Supplementary Table 2 and are described in the original studies (25, 26). EPA+DHA could be recommended to patients with a low nutri-GRS for TG reduction, however EPA+DHA should not be recommended to individuals with higher nutri-GRSs to reduce plasma TG levels. While the research conducted to date intervened with a dosage of ~3.0 g/day EPA+DHA, dosage regulations differ by location so the HCP should of course only recommend a dosage level and type that is in accordance with their location-specific regulations. Furthermore, while the precise cut-off value for classifying a low vs. high nutri-GRS has not yet been identified, cut-off values of two or lower and five or higher for low and high scores, respectively, may be used as a starting point; scores in between two and five appear to be less clear in terms of the classification as a responder or adverse responder (25). For these mid-range scores, providing nutrigenetic advice may not be appropriate at this time. In cases where EPA+DHA are recommended to adverse responders (those with high nutri-GRSs) for reasons other than plasma TG management, TG levels should be monitored.

Recommendation 3: Finally, the panel strongly recommends not to provide personalized omega-3 fatty acid recommendations for plasma lipids, lipoproteins and apolipoproteins based on genetic variation of any SNPs, outcomes and types of omega-3 beyond those specified in Recommendation 1 and 2, based on the Vallée Marcotte et al. nutri-GRS (25, 26), or APOE genotype given the evidence currently available. However, the committee anticipates that these current recommendations will be expanded in the future as more high-quality intervention studies are conducted.

Table 2 provides a brief overarching summary of these CPGs.