Table 2.

GRADE evidence profile: genetic variation, omega-3 and lipids

Nutrigenetic interactions for omega-3 and plasma lipid/lipoprotein outcomes
Patient or Population: adults Intervention/Exposure: dietary or supplemental omega-3 (EPA and/or DHA and/or ALA) Comparison/Control: genetic variation, different omega-3 intakes Outcomes: plasma lipids and lipoproteins
Gene rs number and lipid: number and type of studies (total n)	Limitations	Inconsistency	Indirectness	Imprecision	Publication bias	Dose– response	Biological plausibility*	Quality	Conclusion
CD36 rs1761667 and HDL-c: 1 RCT and 1 single arm trial (n=115)79 80	Serious limitations†	Serious inconsistency‡	Serious indirectness§	Serious imprecision¶	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that possessing the GA or possibly the AA genotype of CD36 rs1761667 could lead to significant increases in HDL-c in response to 0.8–3.0 g/day of omega-3s
CD36 rs1761667 and TG: 1 RCT and 1 single arm trial (n=115)79 80	Serious limitations†	Serious inconsistency‡	Serious indirectness§	Serious imprecision**	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that possessing the GA or possibly the GG genotype of CD36 rs1761667 could lead to significant reductions in TG in response to 0.8–3.0 g/day of omega-3s
CD36 rs1049673 and HDL-c: 1 RCT and 1 single arm trial (n=115)79 80	Serious limitations†	Serious inconsistency‡	Serious indirectness§	No serious imprecision	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that possessing the CG or possibly the CC genotype of CD36 rs1049673 could lead to significant increases in HDL-c in response to 0.8–3.0 g/day of omega-3s
CD36 rs1527483 and TG: 1 RCT and 1 single arm trial (n=250)65 79	Serious limitations††	No serious inconsistency	Serious indirectness‡‡	Very serious imprecision**	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that possessing the GG genotype of CD36 rs1527483 could lead to significant decreases in TG in response to approximately 2.0 g/day of EPA+DHA (but not ALA)
APOE rs429358, rs7412 and TG: 4 RCTs and 5 single arm trials (1 single arm trial consisted of a subset sample of another single arm trial) (n=980)69–73 75–78	No serious limitations	No serious inconsistency	Serious indirectness§§	No serious imprecision	Undetected	Evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊕⊝ (Moderate)	Strong evidence suggests that adult males (but not females) with the APOE-E3/E4 or E4/E4 genotype (rs429358, rs7412) experience significant reductions in TG in response to 0.7–3.7 g/day of EPA and/or DHA. Higher dosages may have greater TG lowering effects
APOE rs429358, rs7412 and Total-c: 4 RCTs, 5 single arm trials (1 single arm trial consisted of a subset sample of another single arm trial), 1 cross-sectional and longitudinal analysis within an RCT (n=2446)54 69–73 75–78	No serious limitations	Serious inconsistency¶¶	Serious indirectness§§	No serious imprecision	Undetected	No evidence of a gradient	Lack of evidence of a mechanism of action	⊕⊕⊕⊝ (Moderate: Males and Females) and ⊕⊕⊝⊝ (Low: Males)	In males and females combined, strong evidence suggests that there is no nutrigenetic interaction between EPA and/or DHA, APOE (rs429358, rs7412) and total-c. There is no evidence of a nutrigenetic interaction between ALA, APOE (rs429358, rs7412) and total-c. In male subgroups, weak evidence suggests that there is no nutrigenetic interaction between ALA or EPA and/or DHA, APOE (rs429358, rs7412) and total-c
31-SNP nutri-GRS and TG: 1 RCT, 1 single arm trial (n=330)63 64	No serious limitations	No serious inconsistency	Serious indirectness***	No serious imprecision	Undetected	Evidence of a gradient†††	Some evidence of a mechanism of action‡‡‡	⊕⊕⊕⊕ (High)	Strong evidence suggests that in adults with overweight/obesity, a 31-SNP genetic risk score can predict TG responsiveness to EPA+DHA supplementation. Individuals with lower genetic risk scores demonstrate greater responsiveness to EPA+DHA for TG lowering
PPARg2 rs1801282 and LDL-c: 4 RCTs, 1 single arm trial (n=670)61 65 81 84 85	No serious limitations	No serious inconsistency	Serious indirectness§§§	Serious imprecision¶¶¶	Undetected	No evidence of a gradient	Lack of evidence of a mechanism of action	⊕⊕⊕⊝ (Moderate)	Strong evidence suggests that genetic variation in PPARg2 (rs1801282) does not influence LDL-c responses to omega-3s (EPA+DHA)
PPARg2 rs1801282 and Total-c: 4 RCTs, 1 single arm trial (n=670)61 65 81 84 85	No serious limitations	Serious inconsistency****	Serious indirectness§§§	Serious imprecision¶¶¶	Undetected	No evidence of a gradient	Lack of evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that possessing the CG or GG genotype of PPARg2 (rs1801282) could lead to significant increases in total-c in response to approximately 3 g/day of omega-3s (EPA+DHA) in individuals with overweight or obesity, but not for individuals without overweight or obesity
PPARg2 rs1801282 and TG: 4 RCTs, 1 single arm trial (n=670)61 65 81 84 85	No serious limitations	Very serious inconsistency††††	Serious indirectness§§§	Serious imprecision¶¶¶	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊕⊝⊝ (Low)	Weak evidence suggests that genetic variation in PPARg2 (rs1801282) does not influence total-c responses to omega-3s (EPA+DHA), but when dietary total fat and saturated fat intake are low, nutrigenetic interactions may exist
FADS (rs174547¶¶¶¶) and total-c: 2 RCTs, 1 single-arm trial, 4 cross-sectional studies (n=9365)43 44 46 47 60 67 69	Very serious risk of bias‡‡‡‡	No serious inconsistency	Very serious indirectness§§§§	Serious imprecision¶¶¶	Undetected	No evidence of a gradient	Evidence of a mechanism of action	⊕⊝⊝⊝ (Very low)	Weak evidence suggests that genetic variation in FADS (rs174547¶¶¶¶) does not influence total-c responses to omega-3

*Direct mechanisms of action were considered.

†Small sample sizes, especially among homozygous groups in the RCT (with a larger heterozygous group, potentially affecting the results).

‡Some variation in results by genotype.

§One study sample consisted of all males while the other sample consisted of both men and women; differences in age and n-3 dosages (with some overlap).

¶Coefficient of variation >1 for all significant values.

**Coefficient of variation substantially >1 for several values.

††Small sample size within genotype groups for minor allele homozygote and heterozygote groups in the RCT.

‡‡One study sample consisted of all men while the other consisted of men and postmenopausal women with type 2 diabetes.

§§Differences in age, omega-3 dosages and types (with some overlap), and dietary interventions even when considering studies with male study samples separate from male+female study samples.

¶¶Serious inconsistency for men subgroup only; men+women samples were consistent.

***EPA and DHA separate on one study and EPA+DHA in the other, sample stratified into two groups in one study (responders and non-responders) and separated into three groups (responders, non-responders and adverse responders).

†††Evidence of a gradient for GRS and TG responsiveness to omega-3 supplementation.

‡‡‡Some evidence of a potential mechanism of action for IQCJ-SCHIP1, NXPH1, PHF17, MYB and NELL1 as discussed by Rudkowska et al,² Vallée Marcotte et al.⁶²

§§§Differences in population (healthy adults, adults with chronic disease or obesity, infants), some variation in length of follow-up.

¶¶¶Downgraded precision as it was not possible to assess precision in most studies due to lack of reporting of means and SD/SEM.

****Some variation in results even when considering differences in body mass index (BMI) and populations among studies.

††††Major variability in results even when considering differences in BMI and populations among studies.

‡‡‡‡Risk of bias detected in every study except one.

§§§§Major differences in populations, types and amounts of omega-3 and follow-up for interventional studies.

¶¶¶¶FADS rs174547 was in strong LD with the following SNPs from other included studies and therefore these SNPs were also included in the selection of studies assessing FADS genetic variation, n-3 intake and LDL-c: rs174546, rs174599, rs174601, rs174583, rs1353, rs174561, rs174556, rs174545, rs174537 and rs174576.

ALA, alpha-linolenic acid; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GRADE, Grading of Recommendations Assessment, Development and Evaluation; GRSs, genetic risk scores; HDL-c, high-density lipoprotein cholesterol; LDL-c, low-density lipoprotein cholesterol; RCT, randomised controlled trial; SNPs, single nucleotide polymorphisms; TG, triglycerides; total-c, total cholesterol.