. 2024 Jan 23;149(4):305-316.

doi: 10.1161/CIRCULATIONAHA.123.065530. Epub 2023 Dec 4.

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies

Federica Laguzzi¹, Agneta Åkesson¹, Matti Marklund^{2

3}, Frank Qian^{4

5}, Bruna Gigante⁶, Traci M Bartz^{7

8}, Julie K Bassett⁹, Anna Birukov^{10

11}, Hannia Campos¹², Yoichiro Hirakawa¹³, Fumiaki Imamura¹⁴, Susanne Jäger¹⁰, Maria Lankinen¹⁵, Rachel A Murphy^{16

17}, Mackenzie Senn^{18

19}, Toshiko Tanaka²⁰, Nathan Tintle^{21

22}, Jyrki K Virtanen¹⁵, Kazumasa Yamagishi^{23

24}, Matthew Allison²⁵, Ingeborg A Brouwer^{26

27}, Ulf De Faire¹, Gudny Eiriksdottir²⁸, Luigi Ferrucci²⁰, Nita G Forouhi¹⁴, Johanna M Geleijnse²⁹, Allison M Hodge^{9

30}, Hitomi Kimura^{23

24}, Markku Laakso^{31

32}, Ulf Risérus³³, Anniek C van Westing^{18

29}, Stefania Bandinelli³⁴, Ana Baylin³⁵, Graham G Giles^{9

30

36}, Vilmundur Gudnason^{28

37}, Hiroyasu Iso^{38

39}, Rozenn N Lemaitre⁸, Toshiharu Ninomiya¹³, Wendy S Post^{2

40}, Bruce M Psaty^{8

41

42}, Jukka T Salonen^{43

44}, Matthias B Schulze^{10

11}, Michael Y Tsai⁴⁵, Matti Uusitupa¹⁵, Nicholas J Wareham¹⁴, Seung-Won Oh⁴⁶, Alexis C Wood¹⁸, William S Harris^{21

47}, David Siscovick⁴⁸, Dariush Mozaffarian⁴⁹, Karin Leander¹; Fatty Acids and Outcomes Research Consortium (FORCE)

Affiliations

¹ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine (F.L., A.A., U.D.F., K.L.), Karolinska Institutet, Stockholm, Sweden.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (M.M., W.S.P).
³ The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia (M.M.).
⁴ Section of Cardiovascular Medicine, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, MA (F.Q.).
⁵ Department of Nutrition (F.Q.), Boston, MA.
⁶ Cardiovascular Medicine Unit, Department of Medicine Solna (B.G.), Karolinska Institutet, Stockholm, Sweden.
⁷ Cardiovascular Health Research Unit, Departments of Biostatistics (T.M.B.), University of Washington, Seattle.
⁸ Medicine (T.M.B., R.N.L., B.M.P.), University of Washington, Seattle.
⁹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia (J.K.B., A.M.H., G.G.G.).
¹⁰ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal (A.K.B., S.J., M.B.S.).
¹¹ German Center for Diabetes Research, Neuherberg (A.K.B., S.J., M.B.S.).
¹² Harvard T.H. Chan School of Public Health (H.C.), Boston, MA.
¹³ Departments of Epidemiology and Public Health and Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Y.H., T.N.).
¹⁴ Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, UK (F.I., N.G.F., N.J.W.).
¹⁵ Institutes of Public Health and Clinical Nutrition (M. Lankinen, J.K.V., M.U.), University of Eastern Finland, Kuopio.
¹⁶ Cancer Control Research, BC Cancer Agency, Vancouver, Canada (R.A.M.).
¹⁷ School of Population and Public Health, University of British Columbia, Vancouver, Canada (R.A.M.).
¹⁸ United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (M.S., A.C.W.).
¹⁹ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany (M.B.S.).
²⁰ Longitudinal Study Section, National Institute on Aging, Baltimore, MD (T.T., L.F.).
²¹ Fatty Acid Research Institute, Sioux Falls, SD (N.T., W.S.H.).
²² Department of Population Health Nursing Science, University of Illinois - Chicago (N.T.).
²³ Department of Public Health Medicine, Institute of Medicine (K.Y., H.K.), University of Tsukuba, Japan.
²⁴ Health Services Research and Development Center (K.Y., H.K.), University of Tsukuba, Japan.
²⁵ Department of Family Medicine, University of California, San Diego, La Jolla (M.A.).
²⁶ Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, The Netherlands (I.A.B.).
²⁷ Amsterdam Public Health Research Institute, The Netherlands (I.A.B.).
²⁸ Icelandic Heart Association, Kopavogur (G.E., V.G.).
²⁹ Division of Human Nutrition and Health, Wageningen University and Research, The Netherlands (J.M.G., A.C.v.W.).
³⁰ Centre for Epidemiology and Biostatistics, University of Melbourne, Victoria, Australia (A.M.H., G.G.G.).
³¹ Clinical Medicine, Internal Medicine (M. Laakso), University of Eastern Finland, Kuopio.
³² Kuopio University Hospital (M. Laakso), University of Eastern Finland, Kuopio.
³³ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Sweden (M.M., U.R).
³⁴ Geriatric Unit, Azienda Unità Sanitaria Locale Toscana Centro, Florence, Italy (S.B.).
³⁵ University of Michigan School of Public Health, Ann Arbor (A. Baylin).
³⁶ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia (G.G.G.).
³⁷ Faculty of Medicine, University of Iceland, Reykjavik (V.G.).
³⁸ Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Suita, Japan (H.I.).
³⁹ Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo, Japan (H.I.).
⁴⁰ Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P.).
⁴¹ Epidemiology (B.M.P.), University of Washington, Seattle.
⁴² Health Systems and Population Health (B.M.P.), University of Washington, Seattle.
⁴³ Metabolic Analytical Services Oy, Helsinki, Finland (J.T.S.).
⁴⁴ University of Helsinki, the Faculty of Medicine, Department of Public Health, Finland (J.T.S.).
⁴⁵ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (M.Y.T.).
⁴⁶ Department of Family Medicine, Seoul National University College of Medicine, and Healthcare System Gangnam Center, Seoul National University Hospital, Republic of Korea (S.W.O.).
⁴⁷ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls (W.S.H.).
⁴⁸ The New York Academy of Medicine, New York (D.S.).
⁴⁹ Food Is Medicine Institute, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (D.M.).

PMID: 38047387
PMCID: PMC10798593
DOI: 10.1161/CIRCULATIONAHA.123.065530

Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies

Federica Laguzzi et al. Circulation. 2024.

. 2024 Jan 23;149(4):305-316.

doi: 10.1161/CIRCULATIONAHA.123.065530. Epub 2023 Dec 4.

Authors

Affiliations

¹ Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine (F.L., A.A., U.D.F., K.L.), Karolinska Institutet, Stockholm, Sweden.
² Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD (M.M., W.S.P).
³ The George Institute for Global Health, Faculty of Medicine, University of New South Wales, Sydney, Australia (M.M.).
⁴ Section of Cardiovascular Medicine, Boston Medical Center and Boston University Chobanian and Avedisian School of Medicine, MA (F.Q.).
⁵ Department of Nutrition (F.Q.), Boston, MA.
⁶ Cardiovascular Medicine Unit, Department of Medicine Solna (B.G.), Karolinska Institutet, Stockholm, Sweden.
⁷ Cardiovascular Health Research Unit, Departments of Biostatistics (T.M.B.), University of Washington, Seattle.
⁸ Medicine (T.M.B., R.N.L., B.M.P.), University of Washington, Seattle.
⁹ Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Australia (J.K.B., A.M.H., G.G.G.).
¹⁰ Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal (A.K.B., S.J., M.B.S.).
¹¹ German Center for Diabetes Research, Neuherberg (A.K.B., S.J., M.B.S.).
¹² Harvard T.H. Chan School of Public Health (H.C.), Boston, MA.
¹³ Departments of Epidemiology and Public Health and Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan (Y.H., T.N.).
¹⁴ Medical Research Council Epidemiology Unit, University of Cambridge School of Clinical Medicine, UK (F.I., N.G.F., N.J.W.).
¹⁵ Institutes of Public Health and Clinical Nutrition (M. Lankinen, J.K.V., M.U.), University of Eastern Finland, Kuopio.
¹⁶ Cancer Control Research, BC Cancer Agency, Vancouver, Canada (R.A.M.).
¹⁷ School of Population and Public Health, University of British Columbia, Vancouver, Canada (R.A.M.).
¹⁸ United States Department of Agriculture/Agricultural Research Service Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX (M.S., A.C.W.).
¹⁹ Institute of Nutritional Science, University of Potsdam, Nuthetal, Germany (M.B.S.).
²⁰ Longitudinal Study Section, National Institute on Aging, Baltimore, MD (T.T., L.F.).
²¹ Fatty Acid Research Institute, Sioux Falls, SD (N.T., W.S.H.).
²² Department of Population Health Nursing Science, University of Illinois - Chicago (N.T.).
²³ Department of Public Health Medicine, Institute of Medicine (K.Y., H.K.), University of Tsukuba, Japan.
²⁴ Health Services Research and Development Center (K.Y., H.K.), University of Tsukuba, Japan.
²⁵ Department of Family Medicine, University of California, San Diego, La Jolla (M.A.).
²⁶ Department of Health Sciences, Faculty of Science, Vrije Universiteit Amsterdam, The Netherlands (I.A.B.).
²⁷ Amsterdam Public Health Research Institute, The Netherlands (I.A.B.).
²⁸ Icelandic Heart Association, Kopavogur (G.E., V.G.).
²⁹ Division of Human Nutrition and Health, Wageningen University and Research, The Netherlands (J.M.G., A.C.v.W.).
³⁰ Centre for Epidemiology and Biostatistics, University of Melbourne, Victoria, Australia (A.M.H., G.G.G.).
³¹ Clinical Medicine, Internal Medicine (M. Laakso), University of Eastern Finland, Kuopio.
³² Kuopio University Hospital (M. Laakso), University of Eastern Finland, Kuopio.
³³ Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism, Uppsala University, Sweden (M.M., U.R).
³⁴ Geriatric Unit, Azienda Unità Sanitaria Locale Toscana Centro, Florence, Italy (S.B.).
³⁵ University of Michigan School of Public Health, Ann Arbor (A. Baylin).
³⁶ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Victoria, Australia (G.G.G.).
³⁷ Faculty of Medicine, University of Iceland, Reykjavik (V.G.).
³⁸ Public Health, Department of Social Medicine, Osaka University Graduate School of Medicine, Suita, Japan (H.I.).
³⁹ Institute for Global Health Policy Research, Bureau of International Health Cooperation, National Center for Global Health and Medicine, Tokyo, Japan (H.I.).
⁴⁰ Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD (W.S.P.).
⁴¹ Epidemiology (B.M.P.), University of Washington, Seattle.
⁴² Health Systems and Population Health (B.M.P.), University of Washington, Seattle.
⁴³ Metabolic Analytical Services Oy, Helsinki, Finland (J.T.S.).
⁴⁴ University of Helsinki, the Faculty of Medicine, Department of Public Health, Finland (J.T.S.).
⁴⁵ Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis (M.Y.T.).
⁴⁶ Department of Family Medicine, Seoul National University College of Medicine, and Healthcare System Gangnam Center, Seoul National University Hospital, Republic of Korea (S.W.O.).
⁴⁷ Department of Internal Medicine, Sanford School of Medicine, University of South Dakota, Sioux Falls (W.S.H.).
⁴⁸ The New York Academy of Medicine, New York (D.S.).
⁴⁹ Food Is Medicine Institute, Friedman School of Nutrition Science and Policy, Tufts University, Boston, MA (D.M.).

PMID: 38047387
PMCID: PMC10798593
DOI: 10.1161/CIRCULATIONAHA.123.065530

Abstract

Background: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

Methods: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

Results: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; P=0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

Conclusions: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

Keywords: biomarkers; cardiovascular diseases; family medical history; polyunsaturated fatty acids; precision medicine.

PubMed Disclaimer

Conflict of interest statement

Disclosures Dr Murphy reports having worked as a consultant for Pharmavite (until 2021). The remaining authors have reported no relationships relevant to the contents of this article. Dr Psaty serves on the steering committee of the Yale Open Data Access Project, funded by Johnson and Johnson.

Figures

**Figure 1.**
**EPA/DHA cut-off for family history A.** Study-specific and pooled risk estimates for cardiovascular disease in relation to low EPA/DHA (≤25th percentile cut-off) and family history of cardiovascular disease (ie, family history A). A, Presence of low EPA/DHA in absence of family history definition A. B, Presence of family history A in absence of low EPA/DHA. C, Presence of low EPA/DHA, and family history A. A through C, Reference category consists of individuals with neither low EPA/DHA nor family history A. For pooled analyses, 15 408 individuals formed the reference category; 3408 were cases of cardiovascular disease. 60YO indicates Stockholm Cohort of 60-Year-Olds; AGES-R, Age, Gene/Environment Susceptibility–Reykjavik study; CHS, Cardiovascular Health Study; CIRCS, Circulatory Risk in Communities Study; CRHS, Costa Rica Heart Study; EPIC-Norfolk, European Prospective Investigation into Cancer and Nutrition–Norfolk study; EPIC-Potsdam, European Prospective Investigation into Cancer and Nutrition–Potsdam study; FHS, Framingham Heart Study–Offspring Cohort; Hisayama, Hisayama Study; InCHIANTI, Invecchiare in Chianti; KIHD, Kuopio Ischaemic Heart Disease Risk Factor study; MCCS, Melbourne Collaborative Cohort Study; MESA, Multi-Ethnic Study of Atherosclerosis; METSIM, Metabolic Syndrome in Men; and WHIMS, Women’s Health Initiative Memory Study.

**Figure 2.**
**LA cut-off for family history A.** Study-specific and pooled risk estimates for cardiovascular disease in relation to low LA (≤25th percentile cut-off) and family history of cardiovascular disease (ie, family history A). A, Presence of low LA in absence of family history A. B, Presence of family history A in absence of low LA. C, Presence of low LA and family history A. A through C, Reference category consists of individuals with neither low LA nor family history A. For pooled analyses, 17 060 individuals formed the reference category; 3665 were cases of cardiovascular disease. 60YO indicates Stockholm Cohort of 60-Year-Olds; AGES-R, Age, Gene/Environment Susceptibility–Reykjavik study; CHS, Cardiovascular Health Study; CIRCS, Circulatory Risk in Communities Study; CRHS, Costa Rica Heart Study; EPIC-Norfolk, European Prospective Investigation into Cancer and Nutrition–Norfolk study; EPIC-Potsdam, European Prospective Investigation into Cancer and Nutrition–Potsdam study; FHS, Framingham Heart Study–Offspring Cohort; Hisayama, Hisayama Study; InCHIANTI, Invecchiare in Chianti; KIHD, Kuopio Ischaemic Heart Disease Risk Factor study; LA, linoleic acid; MCCS, Melbourne Collaborative Cohort Study; MESA, Multi-Ethnic Study of Atherosclerosis; METSIM, Metabolic Syndrome in Men; and WHIMS, Women’s Health Initiative Memory Study.

**Figure 3.**
**ALA cut-off for family history A.** Study-specific and pooled risk estimates for cardiovascular disease in relation to low ALA (≤25th percentile cut-off) and family history of cardiovascular disease (ie, family history A). A, Presence of low ALA in absence of family history A. B, Presence of family history A in absence of low ALA. C, Presence of low ALA and family history A. A through C, Reference category consists of individuals with neither low ALA nor family history A. For pooled analyses, 17 210 individuals formed the reference category; 3715 were cases of cardiovascular disease. 60YO indicates Stockholm Cohort of 60-Year-Olds; AGES-R, Age, Gene/Environment Susceptibility–Reykjavik study; ALA, alpha linolenic acid; CHS, Cardiovascular Health Study; CIRCS, Circulatory Risk in Communities Study; CRHS, Costa Rica Heart Study; EPIC-Norfolk, European Prospective Investigation into Cancer and Nutrition–Norfolk study; EPIC-Potsdam, European Prospective Investigation into Cancer and Nutrition–Potsdam study; FHS, Framingham Heart Study–Offspring Cohort; Hisayama, Hisayama Study; InCHIANTI, Invecchiare in Chianti; KIHD, Kuopio Ischaemic Heart Disease Risk Factor study; MCCS, Melbourne Collaborative Cohort Study; MESA, Multi-Ethnic Study of Atherosclerosis; METSIM, Metabolic Syndrome in Men; and WHIMS, Women’s Health Initiative Memory Study.

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Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies

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Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies

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Conflict of interest statement

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