Genome-wide association study of the plasma triglyceride response to an n-3 polyunsaturated fatty acid supplementation

Studies have shown a large interindividual variability in plasma TG response to long-chain n-3 PUFA supplementation, which may likely be attributable to genetic variability within the populations studied. The objective is to compare the frequency of SNPs in a genome-wide association study between responders (reduction in plasma TG levels ≥0.01 mM) and nonresponders (increase in plasma TG of ≥0 mM) to supplementation. Genomic DNA from 141 subjects who completed a 2-week run-in period followed by 6-week supplementation with 5 g of fish oil daily (1.9–2.2 g EPA and 1.1 g DHA daily) were genotyped on Illumina HumanOmni-5-QuadBeadChip. Thirteen loci had frequency differences between responders and nonresponders (P < 1 × 10−5), including SNPs in or near IQCJ-SCHIP1, MYB, NELL1, NXPH1, PHF17, and SLIT2 genes. A genetic risk score (GRS) was constructed by summing the number of risk alleles. This GRS explained 21.53% of the variation in TG response to n-3 PUFA supplementation when adjusted for age, sex, and BMI (P = 0.0002). Using Fish Oil Intervention and Genotype as a replication cohort, the GRS was able to explain 2% of variation in TG response when adjusted. In conclusion, subjects who decrease their plasma TG levels following n-3 PUFA supplementation may have a different genetic profile than individuals who do not respond. Studies have shown a large interindividual variability in plasma TG response to long-chain n-3 PUFA supplementation, which may likely be attributable to genetic variability within the populations studied. The objective is to compare the frequency of SNPs in a genome-wide association study between responders (reduction in plasma TG levels ≥0.01 mM) and nonresponders (increase in plasma TG of ≥0 mM) to supplementation. Genomic DNA from 141 subjects who completed a 2-week run-in period followed by 6-week supplementation with 5 g of fish oil daily (1.9–2.2 g EPA and 1.1 g DHA daily) were genotyped on Illumina HumanOmni-5-QuadBeadChip. Thirteen loci had frequency differences between responders and nonresponders (P < 1 × 10−5), including SNPs in or near IQCJ-SCHIP1, MYB, NELL1, NXPH1, PHF17, and SLIT2 genes. A genetic risk score (GRS) was constructed by summing the number of risk alleles. This GRS explained 21.53% of the variation in TG response to n-3 PUFA supplementation when adjusted for age, sex, and BMI (P = 0.0002). Using Fish Oil Intervention and Genotype as a replication cohort, the GRS was able to explain 2% of variation in TG response when adjusted. In conclusion, subjects who decrease their plasma TG levels following n-3 PUFA supplementation may have a different genetic profile than individuals who do not respond. Numerous meta-analyses have demonstrated that the long-chain n-3 PUFAs (LC n-3 PUFAs; EPA and DHA) significantly reduce plasma TG levels in a dose-dependent manner, with the TG lowering being proportional to baseline levels (1Harris W.S. n-3 fatty acids and serum lipoproteins: human studies.Am. J. Clin. Nutr. 1997; 65: 1645S-1654SCrossref PubMed Scopus (972) Google Scholar, 2Hartweg J. Perera R. Montori V. Dinneen S. Neil H.A. Farmer A. Omega-3 polyunsaturated fatty acids (PUFA) for type 2 diabetes mellitus.Cochrane Database Syst. Rev. 2008; : CD003205PubMed Google Scholar). In trials of subjects with high TG levels, n-3 PUFAs in dosages of 3.4–4.0 g/day decreased TG levels by 16% to 45% (1Harris W.S. n-3 fatty acids and serum lipoproteins: human studies.Am. J. Clin. Nutr. 1997; 65: 1645S-1654SCrossref PubMed Scopus (972) Google Scholar). However, there is well-recognized heterogeneity in the plasma TG response to LC n-3 PUFA supplementation (3Madden J. Williams C.M. Calder P.C. Lietz G. Miles E.A. Cordell H. Mathers J.C. Minihane A.M. The impact of common gene variants on the response of biomarkers of cardiovascular disease (CVD) risk to increased fish oil fatty acids intakes.Annu. Rev. Nutr. 2011; 31: 203-234Crossref PubMed Scopus (53) Google Scholar): for example, 31% of all volunteers from the Fish Oil Intervention and Genotype (FINGEN) Study showed no reduction in TG after 1.8 g EPA and DHA per day for 8 weeks (4Caslake M.J. Miles E.A. Kofler B.M. Lietz G. Curtis P. Armah C.K. Kimber A.C. Grew J.P. Farrell L. Stannard J. et al.Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.Am. J. Clin. Nutr. 2008; 88: 618-629Crossref PubMed Scopus (133) Google Scholar). Similarly, our research group has reported that 29% of all subjects showed no reduction in plasma TG after a 6-week supplementation with 5 g of fish oil daily (1.9–2.2 g EPA and 1.1 g DHA daily) (5Cormier H. Rudkowska I. Paradis A.M. Thifault E. Garneau V. Lemieux S. Couture P. Vohl M.C. Association between polymorphisms in the fatty acid desaturase gene cluster and the plasma triacylglycerol response to an n-3 PUFA supplementation.Nutrients. 2012; 4: 1026-1041Crossref PubMed Scopus (46) Google Scholar, 6Rudkowska I. Paradis A.M. Thifault E. Julien P. Barbier O. Couture P. Lemieux S. Vohl M.C. Differences in metabolomic and transcriptomic profiles between responders and non-responders to an n-3 polyunsaturated fatty acids (PUFAs) supplementation.Genes Nutr. 2013; 8: 411-423Crossref PubMed Scopus (32) Google Scholar). This large heterogeneity in the TG response is likely to be partly attributable to genetic variability within the study populations. Studies have examined whether the APOE genotype contributes to the lipid response to n-3 PUFAs; these studies have yielded inconsistent results (4Caslake M.J. Miles E.A. Kofler B.M. Lietz G. Curtis P. Armah C.K. Kimber A.C. Grew J.P. Farrell L. Stannard J. et al.Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.Am. J. Clin. Nutr. 2008; 88: 618-629Crossref PubMed Scopus (133) Google Scholar, 7Minihane A.M. Khan S. Leigh-Firbank E.C. Talmud P. Wright J.W. Murphy M.C. Griffin B.A. Williams C.M. ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 1990-1997Crossref PubMed Scopus (197) Google Scholar, 8Olano-Martin E. Anil E. Caslake M.J. Packard C.J. Bedford D. Stewart G. Peiris D. Williams C.M. Minihane A.M. Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil.Atherosclerosis. 2010; 209: 104-110Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 9Thifault E. Cormier H. Bouchard-Mercier A. Rudkowska I. Paradis A.M. Garneau V. Ouellette C. Lemieux S. Couture P. Vohl M.C. Effects of age, sex, body mass index and APOE genotype on cardiovascular biomarker response to an n-3 polyunsaturated fatty acid supplementation.J. Nutrigenet. Nutrigenomics. 2013; 6: 73-82Crossref PubMed Scopus (37) Google Scholar). Further, research has demonstrated that the effect of the PPAR α L162V polymorphism (rs1800206) on plasma TG and apoC-III concentrations depends on dietary PUFAs, with a high intake triggering lower TG in carriers of the V162 allele (10Tai E.S. Corella D. Demissie S. Cupples L.A. Coltell O. Schaefer E.J. Tucker K.L. Ordovas J.M. Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and apolipoprotein C–III concentrations in the Framingham Heart Study.J. Nutr. 2005; 135: 397-403Crossref PubMed Scopus (127) Google Scholar). Likewise, Lindi et al. (11Lindi V. Schwab U. Louheranta A. Laakso M. Vessby B. Hermansen K. Storlien L. Riccardi G. Rivellese A. Impact of the Pro12Ala polymorphism of the PPAR-gamma2 gene on serum triacylglycerol response to n-3 fatty acid supplementation.Mol. Genet. Metab. 2003; 79: 52-60Crossref PubMed Scopus (75) Google Scholar), investigated the influence of the Pro12Ala (rs1801282) polymorphism of the PPAR γ gene: carriers of the Ala12 allele presented a greater decrease in plasma TG concentrations in response to LC n-3 PUFA supplementation than did homozygotes for Pro12 when the total dietary fat or saturated fat intake was low (11Lindi V. Schwab U. Louheranta A. Laakso M. Vessby B. Hermansen K. Storlien L. Riccardi G. Rivellese A. Impact of the Pro12Ala polymorphism of the PPAR-gamma2 gene on serum triacylglycerol response to n-3 fatty acid supplementation.Mol. Genet. Metab. 2003; 79: 52-60Crossref PubMed Scopus (75) Google Scholar). Recently, studies have also supported the notion that the fatty acid desaturase 1 and 2 (FADS1 and 2) gene cluster is a major determinant of plasma TG levels (5Cormier H. Rudkowska I. Paradis A.M. Thifault E. Garneau V. Lemieux S. Couture P. Vohl M.C. Association between polymorphisms in the fatty acid desaturase gene cluster and the plasma triacylglycerol response to an n-3 PUFA supplementation.Nutrients. 2012; 4: 1026-1041Crossref PubMed Scopus (46) Google Scholar). Thus, these genetic variations may influence the response to LC n-3 PUFA supplementation; however, other unknown genetic variations may also exist. Genome-wide association studies (GWASs) provide a more comprehensive approach unconstrained by existing knowledge to test common genetic variants across the genome. Therefore, a GWAS approach is ideal to identify SNPs that have not been discovered previously. The objective of this study was to compare the frequency of alleles in individuals with and without a decrease in plasma TG levels after LC n-3 PUFA supplementation, in order to determine whether an association exists between the responsiveness to LC n-3 PUFA supplementation and specific SNPs. In addition, a genetic risk model was developed with the specific SNPs identified to be able to predict the response to LC n-3 PUFA supplementation. To validate the results, we genotyped the DNA of participants in the FINGEN Study (3Madden J. Williams C.M. Calder P.C. Lietz G. Miles E.A. Cordell H. Mathers J.C. Minihane A.M. The impact of common gene variants on the response of biomarkers of cardiovascular disease (CVD) risk to increased fish oil fatty acids intakes.Annu. Rev. Nutr. 2011; 31: 203-234Crossref PubMed Scopus (53) Google Scholar, 4Caslake M.J. Miles E.A. Kofler B.M. Lietz G. Curtis P. Armah C.K. Kimber A.C. Grew J.P. Farrell L. Stannard J. et al.Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.Am. J. Clin. Nutr. 2008; 88: 618-629Crossref PubMed Scopus (133) Google Scholar) to demonstrate whether the genetic risk score (GRS) may explain, at least partly, the variability of the TG-lowering effect of LC n-3 PUFA supplementation. A total of 254 subjects from the greater Quebec City metropolitan area were recruited to participate in the study. In total, 210 subjects completed the intervention protocol. Further, subjects who completed the study were separated into subgroups: responders and nonresponders. Responders are as reduction in plasma TG in plasma TG levels ≥0.01 TG with n-3 PUFAs TG with n-3 and nonresponders are by no reduction in plasma TG concentrations after the LC n-3 PUFA supplementation in plasma TG of ≥0 TG with n-3 PUFAs TG with n-3 this a total of 141 subjects with the response to LC n-3 PUFA supplementation were including responders and nonresponders. had a BMI between and and were not were from the study had LC n-3 PUFA for at least or had been with or other as or The was by the of and This was at as subjects followed a run-in period of 2 dietary were by a to the from were to these dietary and a body the study were LC n-3 PUFA dietary not to fish or per fish of fatty fish were and to LC n-3 PUFA dietary as and were also to their the per g of per were In addition, subjects were not to n-3 PUFA as or fish or the study after the run-in a the fish oil to be in the following were to 1 g of fish oil per day a total of g of LC n-3 PUFAs g EPA and 1.1 g DHA) per To we the fish oil was from the of were to from the to their and fish and to subjects and on their were from an into after a and were to identify and individuals with participants had to and after the LC n-3 PUFA supplementation was separated by g for at and were and for total and TG concentrations were M. J. a of the to the serum and PubMed Scopus Google Scholar). The was after of and in the with D. P. P. L. C. A. K. S. et of for in PubMed Scopus Google Scholar). was with the of the of lipoprotein in without of the PubMed Scopus Google Scholar). concentrations were by with B. of to and in Clin. Metab. PubMed Scopus Google Scholar). concentrations were R. H. of plasma by Google Scholar). concentrations were in plasma by the of of by in PubMed Scopus Google Scholar), as was by a as M. J. B. J.P. B. and of as of the risk for disease with high plasma levels in PubMed Scopus Google Scholar). were with by to a E. of in levels A of the PubMed Scopus Google Scholar). plasma were separated by a of and and of were was to The for plasma has been E. R. J. Julien P. E. P. D. Omega-3 fatty acids and risk of the Study of and J. Clin. Nutr. PubMed Scopus Google Scholar). of concentrations are as of total in plasma The was to DNA from and of DNA an = were for This was at the and Illumina to the was by and the 141 no subjects were to low across all no were to lower than in with subjects of Therefore, all 141 subjects for of allele and of for were The for the SNPs were the allele frequency and × A total of SNPs were SNPs for of these we investigated whether the allele frequency was significantly different between nonresponders and The the between which in the of GWAS is the of individuals in the nonresponders group a specific allele and the of individuals in the responders group the a for the of the was a and of the for was < × with is that all are However, SNPs in are not and the to for when in of type for test in large polymorphism studies Genet. 2005; 6: PubMed Scopus Google Scholar). Thus, a was as < P. an adjusted to the type 1 in association 2008; PubMed Scopus Google Scholar) and was in order to was to test for the of of the SNPs on when adjusted for age, sex, and A of SNPs was into the of whether these SNPs were with and their and of to the of by The FINGEN Study is a that was at the of and in the between and The study was a study of intervention of 8 weeks and separated by the intervention participants the g or 1.8 g in The study subjects and are in (3Madden J. Williams C.M. Calder P.C. Lietz G. Miles E.A. Cordell H. Mathers J.C. Minihane A.M. The impact of common gene variants on the response of biomarkers of cardiovascular disease (CVD) risk to increased fish oil fatty acids intakes.Annu. Rev. Nutr. 2011; 31: 203-234Crossref PubMed Scopus (53) Google Scholar, 4Caslake M.J. Miles E.A. Kofler B.M. Lietz G. Curtis P. Armah C.K. Kimber A.C. Grew J.P. Farrell L. Stannard J. et al.Effect of sex and genotype on cardiovascular biomarker response to fish oils: the FINGEN Study.Am. J. Clin. Nutr. 2008; 88: 618-629Crossref PubMed Scopus (133) Google Scholar). In the of the we the TG results from subjects who completed the 1.8 g intervention to individuals as responders and nonresponders. In the as the responders are as a reduction in plasma TG in plasma TG levels ≥0.01 TG with n-3 PUFAs TG with n-3 and nonresponders are by no reduction in plasma TG concentrations after the LC n-3 PUFA supplementation in plasma TG of ≥0 TG with n-3 PUFAs TG with n-3 The SNPs by the GWAS were on the A total of DNA were to of and 2 of were in a and the the The results were in are presented as not were by to their were a to determine between and for of the subgroups: responders and nonresponders. was to differences between between the A genetic risk model was for from the of risk alleles. GRS was with SNPs that are and in to the effect of LC n-3 PUFAs on plasma TG in an on this genetic risk subjects were with the and of the genetic risk model to individuals into and were The model was to the effect of the GRS on TG response to LC n-3 PUFAs into the of age, sex, and were with and as with were to determine whether SNPs were of different frequency between the responders and and nonresponders and 1 the of the responders and nonresponders The was and the subjects were with a BMI of The of and are to reported I. Paradis A.M. Thifault E. Julien P. Barbier O. Couture P. Lemieux S. Vohl M.C. Differences in metabolomic and transcriptomic profiles between responders and non-responders to an n-3 polyunsaturated fatty acids (PUFAs) supplementation.Genes Nutr. 2013; 8: 411-423Crossref PubMed Scopus (32) Google Scholar). The of nonresponders were to of that plasma TG (P < (P = (P = and (P = with lower levels (P = were in 2 the response of group to LC n-3 PUFA supplementation. the plasma TG decreased in responders (P < and increased in nonresponders (P < Further, responders showed decreased plasma (P = and increased plasma levels (P < as as decreased (P < after LC n-3 PUFA supplementation. In nonresponders showed increased (P = and levels (P = levels to in the responders (P = and nonresponders (P = levels decreased in responders (P = and increased in nonresponders (P = = = and and from from from from from are shown as from in a of responders and nonresponders and with n-3 = = n-3 n-3 to to n-3 n-3 to to from from from from from are shown as from in a are shown as are shown as were no differences in of plasma between the responders and the nonresponders with n-3 the weeks of LC n-3 PUFA supplementation increased the of total n-3 PUFAs and decreased total PUFAs in in In the LC n-3 PUFA supplementation was with a in total n-3 PUFAs in from to of total for responders and from to of total for nonresponders. were also for of EPA and DHA and the of total for the responders and profiles of responders and nonresponders and with n-3 = = of n-3 n-3 n-3 n-3 between Responders and n-3 total are shown as supplementation is the effect of n-3 PUFA supplementation on in a are shown as supplementation is the effect of n-3 PUFA supplementation on 1 the GWAS the association of the TG response to LC n-3 PUFA supplementation. Thirteen loci showed than the (P < 1 × as in in SNPs SNPs of the 2 of the variants of 1 of of 1 and of showed that of the SNPs were with the in TG levels as as with other when adjusted for age, sex, and BMI differences in frequency of alleles of SNPs in individuals with and without a decrease in TG levels following LC n-3 PUFA of between Responders and between Responders and within the gene an between these SNPs × within the gene an between these SNPs × × × within the gene an between these SNPs of × within the gene an between these SNPs of × within the gene an between these SNPs of × within the gene an between these SNPs of × of × within the gene an between these SNPs of × × × × The within the gene an between these SNPs in a A GRS was of the SNPs SNPs were in on this genetic risk subjects were into genetic risk the lower genetic risk from to and genetic risk from to The and of the GRS to identify nonresponders and responders were as to and to In the the GRS was significantly with TG response when adjusted for age, sex, and BMI (P = The GRS explained 21.53% of variation in TG the LC n-3 PUFA supplementation when adjusted for age, sex, and BMI (P = and of GRS in study to to in a Using the with the SNPs were PPAR and not subjects were identified as responders and and nonresponders and the of the responders and nonresponders. the plasma TG decreased in responders from to of < and increased in nonresponders from to of < after the daily intake of 1.8 g in FINGEN replication = = and and in a allele frequency and GRS were in the FINGEN the discovered SNPs differences in allele were between the populations not Further, the subjects were into genetic risk the score of the genetic risk model lower genetic risk from to and genetic risk from to The and of the GRS to identify nonresponders and responders were as to and to not the GRS explained 2% of variation in TG response to LC n-3 PUFA supplementation in the replication from the when adjusted for age, sex, and BMI (P = not and of GRS in FINGEN replication to to in a This study the frequency of alleles of SNPs in individuals with and without a decrease in plasma TG levels following LC n-3 PUFA supplementation. TG levels were significantly different between responders and nonresponders with n-3 PUFAs, the interindividual variability in response to LC n-3 PUFA supplementation. However, no (P < × was identified by the likely of the of the However, a association be to identify SNPs for in that SNPs had different between responders and nonresponders to LC n-3 PUFA supplementation, including SNPs in or near IQCJ-SCHIP1, MYB, NELL1, NXPH1, PHF17, and Further, a GRS on these identified SNPs with risk subjects who may or may not to LC n-3 PUFAs for TG In the the in the of the gene was more in nonresponders with The gene a that is in and a in the of and A study has that is also a K. E. Genome-wide association response to in J. PubMed Scopus Google Scholar). a GWAS examined the of an that is to be with and that SNPs and at the gene genome-wide for association with in plasma TG levels in allele was with a in the in TG K. E. Genome-wide association response to in J. PubMed Scopus Google Scholar). The that NELL1, to of plasma TG in subjects K. E. Genome-wide association response to in J. PubMed Scopus Google Scholar). a the of and study cohort, investigated which genetic variants may explain the heterogeneity in response to with Ordovas J.M. A.C. et of in the 2013; PubMed Scopus Google Scholar). The results demonstrate that showed on lipoprotein including the gene on and Ordovas J.M. A.C. et of in the 2013; PubMed Scopus Google Scholar). In the SNPs near the gene were also with Ordovas J.M. A.C. et of in the 2013; PubMed Scopus Google Scholar). In the SNPs of the of were more in the nonresponders with the is in the that is by TG in and studies that the TG-lowering effect of LC n-3 PUFAs is with the decreased K. C. J. H. H. Omega-3 fatty acid decrease plasma triglyceride concentrations in by triglyceride and the of Nutr. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar, Omega-3 fatty acid supplementation lipoprotein triacylglycerol in 2013; PubMed Scopus Google Scholar). Thus, the impact of these genetic variations on plasma lipid and LC n-3 PUFA response be demonstrate that SNPs in and were of different frequency between responders and nonresponders. have been to of in the of the gene had frequency of allele in nonresponders than in This gene a that an in the of and Recently, a study showed that in was with and with BMI were and not after for E. J.M. J. of genetic between and in Clin. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). Further, the of the SLIT2 which is to had a lower frequency in nonresponders with have shown that SLIT2 was in from with S. E. C. of from increased of 2005; PubMed Scopus Google Scholar). is that subjects have atherogenic including and as as decreased The of these specific and their SNPs in and the plasma lipid response to LC n-3 PUFA supplementation to be Further, identified have been been with and However, studies have been to the of the by these genes. of these is to determine whether the from these SNPs are to or are to a impact of these genes. that these SNPs are to the following PPAR and as LC n-3 PUFAs, which the to lipid levels I. M. Barbier O. Vohl M.C. Differences in by the variants of after fatty acids PubMed Scopus Google Scholar). are the of and that participate in the of and of are a of that to and as an The of of the lipid Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). have been shown to be in subjects with type 2 diabetes and with the of J.M. R. J.P. are in subjects with type 2 diabetes and with the of PubMed Scopus Google Scholar). these are to the SNPs to lipid and in on SNPs from GWAS results, we a GRS that subjects with high or low genetic risk who may or may not to LC n-3 PUFA supplementation. The replication study that subjects with a low GRS are more likely to be responders to LC n-3 studies have that a GRS from variants explained of variation in BMI J. L. et genetic and body mass in PubMed Scopus Google Scholar, C.J. K.L. G. C.M. J. R. et of individuals loci with body mass Genet. 2010; PubMed Scopus Google Scholar). Thus, in the our GRS from SNPs to LC n-3 PUFA supplementation explained 2% of TG response in the replication this effect did not Differences may be attributable other differences in the study including the of the supplementation the of LC n-3 PUFAs, and of the or The of other genetic variations and risk the of this risk may also have an or effect with this GRS to TG variation after LC n-3 PUFA supplementation. In the of a GRS to risk be an of for LC n-3 PUFA To our this is the GWAS to TG response to LC n-3 PUFA supplementation. In the of were identified that explain interindividual variability in lipid studies are to these that may explain variability in the plasma lipid response to LC n-3 PUFA supplementation. studies to this GRS with other SNPs or risk in other and this study that subjects who decrease their plasma TG levels following LC n-3 PUFA supplementation have a different genetic profile than individuals who do not to the LC n-3 PUFA supplementation. 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