The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

Maria C Borges; Philip C Haycock; Jie Zheng; Gibran Hemani; Laurence J M S Howe; Amand Floriaan  Schmidt; James R Staley; R Thomas  Lumbers; Albert  Henry; Rozenn N  Lemaitre; Tom R Gaunt; Michael V Holmes; George Davey Smith; Aroon Hingorani; Debbie A Lawlor

doi:10.1093/hmg/ddac153

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

Maria C Borges^*, Philip C Haycock, Jie Zheng, Gibran Hemani, Laurence J M S Howe, Amand Floriaan Schmidt, James R Staley, R Thomas Lumbers, Albert Henry, Rozenn N Lemaitre, Tom R Gaunt, Michael V Holmes, George Davey Smith, Aroon Hingorani, Debbie A Lawlor

^*Corresponding author for this work

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Abstract

Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European (maximum 123,668 cases) and 212,453 East Asian (maximum 29,319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.

Original language	English
Article number	ddac153
Pages (from-to)	4034-4054
Number of pages	21
Journal	Human Molecular Genetics
Volume	31
Issue number	23
Early online date	7 Jul 2022
DOIs	https://doi.org/10.1093/hmg/ddac153
Publication status	Published - 1 Dec 2022

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© The Author(s) 2022. Published by Oxford University Press.

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Borges, M. C., Haycock, P. C., Zheng, J., Hemani, G., Howe, L. J. M. S., Schmidt, A. F., Staley, J. R., Lumbers, R. T., Henry, A., Lemaitre, R. N., Gaunt, T. R., Holmes, M. V., Davey Smith, G., Hingorani, A., & Lawlor, D. A. (2022). The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study. Human Molecular Genetics, 31(23), 4034-4054. Article ddac153. https://doi.org/10.1093/hmg/ddac153

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title = "The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study",

abstract = "Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European (maximum 123,668 cases) and 212,453 East Asian (maximum 29,319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk. ",

author = "Borges, \{Maria C\} and Haycock, \{Philip C\} and Jie Zheng and Gibran Hemani and Howe, \{Laurence J M S\} and Schmidt, \{Amand Floriaan\} and Staley, \{James R\} and Lumbers, \{R Thomas\} and Albert Henry and Lemaitre, \{Rozenn N\} and Gaunt, \{Tom R\} and Holmes, \{Michael V\} and \{Davey Smith\}, George and Aroon Hingorani and Lawlor, \{Debbie A\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press.",

year = "2022",

month = dec,

day = "1",

doi = "10.1093/hmg/ddac153",

language = "English",

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Borges, MC , Haycock, PC, Zheng, J, Hemani, G, Howe, LJMS, Schmidt, AF, Staley, JR, Lumbers, RT, Henry, A, Lemaitre, RN, Gaunt, TR, Holmes, MV, Davey Smith, G, Hingorani, A & Lawlor, DA 2022, 'The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study', Human Molecular Genetics, vol. 31, no. 23, ddac153, pp. 4034-4054. https://doi.org/10.1093/hmg/ddac153

TY - JOUR

T1 - The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians

T2 - A Mendelian randomization study

AU - Borges, Maria C

AU - Haycock, Philip C

AU - Zheng, Jie

AU - Hemani, Gibran

AU - Howe, Laurence J M S

AU - Schmidt, Amand Floriaan

AU - Staley, James R

AU - Lumbers, R Thomas

AU - Henry, Albert

AU - Lemaitre, Rozenn N

AU - Gaunt, Tom R

AU - Holmes, Michael V

AU - Davey Smith, George

AU - Hingorani, Aroon

AU - Lawlor, Debbie A

PY - 2022/12/1

Y1 - 2022/12/1

N2 - Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European (maximum 123,668 cases) and 212,453 East Asian (maximum 29,319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.

AB - Despite early interest, the evidence linking fatty acids to cardiovascular diseases remains controversial. We used Mendelian randomization to explore the involvement of polyunsaturated (PUFA) and monounsaturated (MUFA) fatty acids biosynthesis in the aetiology of several cardiovascular disease endpoints in up to 1,153,768 European (maximum 123,668 cases) and 212,453 East Asian (maximum 29,319 cases) ancestry individuals. As instruments, we selected single nucleotide polymorphisms (SNP) mapping to genes with well-known roles in PUFA (i.e. FADS1/2 and ELOVL2) and MUFA (i.e. SCD) biosynthesis. Our findings suggest that higher PUFA biosynthesis rate (proxied by rs174576 near FADS1/2) is related to higher odds of multiple cardiovascular diseases, particularly ischemic stroke, peripheral artery disease and venous thromboembolism, whereas higher MUFA biosynthesis rate (proxied by rs603424 near SCD) is related to lower odds of coronary artery disease among Europeans. Results were unclear for East Asians as most effect estimates were imprecise. By triangulating multiple approaches (i.e. uni-/multi-variable Mendelian randomization, a phenome-wide scan, genetic colocalization and within-sibling analyses), our results are compatible with higher low-density lipoprotein (LDL)-cholesterol (and possibly glucose) being a downstream effect of higher PUFA biosynthesis rate. Our findings indicate that PUFA and MUFA biosynthesis are involved in the aetiology of cardiovascular diseases and suggest LDL-cholesterol as a potential mediating trait between PUFA biosynthesis and cardiovascular diseases risk.

U2 - 10.1093/hmg/ddac153

DO - 10.1093/hmg/ddac153

M3 - Article (Academic Journal)

C2 - 35796550

SN - 0964-6906

VL - 31

SP - 4034

EP - 4054

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 23

M1 - ddac153

ER -

The impact of fatty acids biosynthesis on the risk of cardiovascular diseases in Europeans and East Asians: A Mendelian randomization study

Abstract

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