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1. The association between genetically elevated polyunsaturated fatty acids and risk of cancer

Author

Tintle, Nathan, Rice, Terri, Cheng, Iona, Jenkins, Mark, Gallinger, Steve, Cornish, Alex J., Sud, Amit, Vijayakrishnan, Jayaram, Wrensch, Margaret, Johansson, Mattias, Norman, Aaron D., Klein, Alison, Clay-Gilmour, Alyssa, Franke, Andre, Ardisson Korat, Andres V., Wheeler, Bill, Nilsson, Björn, Smith, Caren, Heng, Chew-Kiat, Song, Ci, Riadi, David, Claus, Elizabeth B., Ellinghaus, Eva, Ostroumova, Evgenia, Hosnijeh, de Vathaire, Florent, Cugliari, Giovanni, Matullo, Giuseppe, Oi-Lin Ng, Irene, Passow, Jeanette E., Foo, Jia Nee, Han, Jiali, Liu, Jianjun, Barnholtz-Sloan, Jill, Schildkraut, Joellen M., Maris, John, Wiemels, Joseph L., Hemminki, Kari, Yang, Keming, Kiemeney, Lambertus A., Wu, Lang, Amundadottir, Laufey, Stern, Marc-Henri, Boutron, Marie-Christine, Iles, Mark Martin, Purdue, Mark P., Stanulla, Martin, Bondy, Melissa, Gaudet, Mia, Mobuchon, Lenha, Camp, Nicola J., Sham, Pak Chung, Guénel, Pascal, Brennan, Paul, Taylor, Philip R., Ostrom, Quinn, Stolzenberg-Solomon, Rachael, Dorajoo, Rajkumar, Houlston, Richard, Jenkins, Robert B., Diskin, Sharon, Berndt, Sonja I., Tsavachidis, Spiridon, Channock, Stephen J., Harrison, Tabitha, Galesloot, Tessel, Gyllensten, Ulf, Joseph, Vijai, Shi, Y., Yang, Wenjian, Lin, Yi, Van Den Eeden, Stephen K., Haycock, Philip C., Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N., Burgess, Stephen, Khankari, Nikhil K., Tsilidis, Konstantinos K., Gaunt, Tom R., Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M., OMara, Tracy, Spurdle, Amanda B., Iles, Mark M., Law, Matthew H., Slager, Susan L., Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R., Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C., Block, Robert C., Amos, Christopher I., Hung, Rayjean J., Zheng, Wei, Gunter, Marc J., Smith, George Davey, Relton, Caroline, and Martin, Richard M.

Published
2023
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2. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author

Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, Martin, Richard M, Haycock, Philip C, Borges, Maria Carolina, Burrows, Kimberley, Lemaitre, Rozenn N, Burgess, Stephen, Khankari, Nikhil K, Tsilidis, Konstantinos K, Gaunt, Tom R, Hemani, Gibran, Zheng, Jie, Truong, Therese, Birmann, Brenda M, OMara, Tracy, Spurdle, Amanda B, Iles, Mark M, Law, Matthew H, Slager, Susan L, Saberi Hosnijeh, Fatemeh, Mariosa, Daniela, Cotterchio, Michelle, Cerhan, James R, Peters, Ulrike, Enroth, Stefan, Gharahkhani, Puya, Le Marchand, Loic, Williams, Ann C, Block, Robert C, Amos, Christopher I, Hung, Rayjean J, Zheng, Wei, Gunter, Marc J, Smith, George Davey, Relton, Caroline, and Martin, Richard M

Abstract

BACKGROUND: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. METHODS: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. FINDINGS: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; Pheterogeneity = 0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity = 0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity = 0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activi

Published
2023
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3. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

University of Helsinki, Clinicum, Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W., Ingles, Sue A., Kittles, Rick A., Strom, Sara S., Rybicki, Benjamin A., Nemesure, Barbara, Isaacs, William B., Zheng, Wei, Pettaway, Curtis A., Yeboah, Edward D., Tettey, Yao, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P., John, Esther M., Murphy, Adam B., Signorello, Lisa B., Carpten, John, Leske, M. Cristina, Wu, Suh-Yuh, Hennis, Anslem J. M., Neslund-Dudas, Christine, Hsing, Ann W., Chu, Lisa, Goodman, Phyllis J., Klein, Eric A., Witte, John S., Casey, Graham, Kaggwa, Sam, Cook, Michael B., Stram, Daniel O., Blot, William J., Eeles, Rosalind A., Easton, Douglas, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel M., Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L. J., Nordestgaard, Borge G., Key, Tim J., Travis, Ruth C., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K., Arndt, Volker, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A., Teixeira, Manuel R., Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, Conti, David V., Albanes, Demetrius, Berg, Christine, Berndt, Sonja I., Campa, Daniele, Crawford, E. David, Diver, W. Ryan, Gapstur, Susan M., Gaziano, J. Michael, Giovannucci, Edward, Hoover, Robert, Hunter, David J., Johansson, Mattias, Kraft, Peter, Le Marchand, Loic, Lindstrom, Sara, Navarro, Carmen, Overvad, Kim, Riboli, Elio, Siddiq, Afshan, Stevens, Victoria L., Trichopoulos, Dimitrios, Vineis, Paolo, Yeager, Meredith, Trynka, Gosia, Raychaudhuri, Soumya, Schumacher, Frederick R., Price, Alkes L., Freedman, Matthew L., Haiman, Christopher A., Pasaniuc, Bogdan, Cook, Margaret, Guy, Michelle, Govindasami, Koveela, Leongamornlert, Daniel, Sawyer, Emma J., Wilkinson, Rosemary, Saunders, Edward J., Tymrakiewicz, Malgorzata, Dadaev, Tokhir, Morgan, Angela, Fisher, Cyril, Hazel, Steve, Livni, Naomi, Lophatananon, Artitaya, Pedersen, John, Hopper, John L., Adolfson, Jan, Stattin, Paer, Johansson, Jan-Erik, Cavalli-Bjoerkman, Carin, Karlsson, Ami, Broms, Michael, Auvinen, Anssi, Kujala, Paula, Maattanen, Liisa, Murtola, Teemu, Taari, Kimmo, Weischer, Maren, Nielsen, Sune F., Klarskov, Peter, Roder, Andreas, Iversen, Peter, Wallinder, Hans, Gustafsson, Sven, Cox, Angela, Brown, Paul, George, Anne, Marsden, Gemma, Lane, Athene, Davis, Michael, Tillmans, Lori, Riska, Shaun, Wang, Liang, Rinckleb, Antje, Lubiski, Jan, Stegmaier, Christa, Pow-Sang, Julio, Park, Hyun, Radlein, Selina, Rincon, Maria, Haley, James, Zachariah, Babu, Kachakova, Darina, Popov, Elenko, Mitkova, Atanaska, Vlahova, Aleksandrina, Dikov, Tihomir, Christova, Svetlana, Heathcote, Peter, Wood, Glenn, Malone, Greg, Saunders, Pamela, Eckert, Allison, Yeadon, Trina, Kerr, Kris, Collins, Angus, Turner, Megan, Srinivasan, Srilakshmi, Kedda, Mary-Anne, Alexander, Kimberly, Omara, Tracy, Wu, Huihai, Henrique, Rui, Pinto, Pedro, Santos, Joana, Barros-Silva, Joao, PRACTICAL Consortium, University of Helsinki, Clinicum, Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W., Ingles, Sue A., Kittles, Rick A., Strom, Sara S., Rybicki, Benjamin A., Nemesure, Barbara, Isaacs, William B., Zheng, Wei, Pettaway, Curtis A., Yeboah, Edward D., Tettey, Yao, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P., John, Esther M., Murphy, Adam B., Signorello, Lisa B., Carpten, John, Leske, M. Cristina, Wu, Suh-Yuh, Hennis, Anslem J. M., Neslund-Dudas, Christine, Hsing, Ann W., Chu, Lisa, Goodman, Phyllis J., Klein, Eric A., Witte, John S., Casey, Graham, Kaggwa, Sam, Cook, Michael B., Stram, Daniel O., Blot, William J., Eeles, Rosalind A., Easton, Douglas, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel M., Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L. J., Nordestgaard, Borge G., Key, Tim J., Travis, Ruth C., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K., Arndt, Volker, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A., Teixeira, Manuel R., Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, Conti, David V., Albanes, Demetrius, Berg, Christine, Berndt, Sonja I., Campa, Daniele, Crawford, E. David, Diver, W. Ryan, Gapstur, Susan M., Gaziano, J. Michael, Giovannucci, Edward, Hoover, Robert, Hunter, David J., Johansson, Mattias, Kraft, Peter, Le Marchand, Loic, Lindstrom, Sara, Navarro, Carmen, Overvad, Kim, Riboli, Elio, Siddiq, Afshan, Stevens, Victoria L., Trichopoulos, Dimitrios, Vineis, Paolo, Yeager, Meredith, Trynka, Gosia, Raychaudhuri, Soumya, Schumacher, Frederick R., Price, Alkes L., Freedman, Matthew L., Haiman, Christopher A., Pasaniuc, Bogdan, Cook, Margaret, Guy, Michelle, Govindasami, Koveela, Leongamornlert, Daniel, Sawyer, Emma J., Wilkinson, Rosemary, Saunders, Edward J., Tymrakiewicz, Malgorzata, Dadaev, Tokhir, Morgan, Angela, Fisher, Cyril, Hazel, Steve, Livni, Naomi, Lophatananon, Artitaya, Pedersen, John, Hopper, John L., Adolfson, Jan, Stattin, Paer, Johansson, Jan-Erik, Cavalli-Bjoerkman, Carin, Karlsson, Ami, Broms, Michael, Auvinen, Anssi, Kujala, Paula, Maattanen, Liisa, Murtola, Teemu, Taari, Kimmo, Weischer, Maren, Nielsen, Sune F., Klarskov, Peter, Roder, Andreas, Iversen, Peter, Wallinder, Hans, Gustafsson, Sven, Cox, Angela, Brown, Paul, George, Anne, Marsden, Gemma, Lane, Athene, Davis, Michael, Tillmans, Lori, Riska, Shaun, Wang, Liang, Rinckleb, Antje, Lubiski, Jan, Stegmaier, Christa, Pow-Sang, Julio, Park, Hyun, Radlein, Selina, Rincon, Maria, Haley, James, Zachariah, Babu, Kachakova, Darina, Popov, Elenko, Mitkova, Atanaska, Vlahova, Aleksandrina, Dikov, Tihomir, Christova, Svetlana, Heathcote, Peter, Wood, Glenn, Malone, Greg, Saunders, Pamela, Eckert, Allison, Yeadon, Trina, Kerr, Kris, Collins, Angus, Turner, Megan, Srinivasan, Srilakshmi, Kedda, Mary-Anne, Alexander, Kimberly, Omara, Tracy, Wu, Huihai, Henrique, Rui, Pinto, Pedro, Santos, Joana, Barros-Silva, Joao, and PRACTICAL Consortium

Abstract

Although genome-wide association studies have identified over 100 risk loci that explain similar to 33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016

4. Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation

Author

Gusev, Alexander, Shi, Huwenbo, Kichaev, Gleb, Pomerantz, Mark, Li, Fugen, Long, Henry W., Ingles, Sue A., Kittles, Rick A., Strom, Sara S., Rybicki, Benjamin A., Nemesure, Barbara, Isaacs, William B., Zheng, Wei, Pettaway, Curtis A., Yeboah, Edward D., Tettey, Yao, Biritwum, Richard B., Adjei, Andrew A., Tay, Evelyn, Truelove, Ann, Niwa, Shelley, Chokkalingam, Anand P., John, Esther M., Murphy, Adam B., Signorello, Lisa B., Carpten, John, Leske, M. Cristina, Wu, Suh-Yuh, Hennis, Anslem J. M., Neslund-Dudas, Christine, Hsing, Ann W., Chu, Lisa, Goodman, Phyllis J., Klein, Eric A., Witte, John S., Casey, Graham, Kaggwa, Sam, Cook, Michael B., Stram, Daniel O., Blot, William J., Eeles, Rosalind A., Easton, Douglas, Kote-Jarai, ZSofia, Al Olama, Ali Amin, Benlloch, Sara, Muir, Kenneth, Giles, Graham G., Southey, Melissa C., Fitzgerald, Liesel M., Gronberg, Henrik, Wiklund, Fredrik, Aly, Markus, Henderson, Brian E., Schleutker, Johanna, Wahlfors, Tiina, Tammela, Teuvo L. J., Nordestgaard, Børge G., Key, Tim J., Travis, Ruth C., Neal, David E., Donovan, Jenny L., Hamdy, Freddie C., Pharoah, Paul, Pashayan, Nora, Khaw, Kay-Tee, Stanford, Janet L., Thibodeau, Stephen N., McDonnell, Shannon K., Schaid, Daniel J., Maier, Christiane, Vogel, Walther, Luedeke, Manuel, Herkommer, Kathleen, Kibel, Adam S., Cybulski, Cezary, Wokolorczyk, Dominika, Kluzniak, Wojciech, Cannon-Albright, Lisa, Teerlink, Craig, Brenner, Hermann, Dieffenbach, Aida K., Arndt, Volker, Park, Jong Y., Sellers, Thomas A., Lin, Hui-Yi, Slavov, Chavdar, Kaneva, Radka, Mitev, Vanio, Batra, Jyotsna, Spurdle, Amanda, Clements, Judith A., Teixeira, Manuel R., Pandha, Hardev, Michael, Agnieszka, Paulo, Paula, Maia, Sofia, Kierzek, Andrzej, Cook, Margaret, Guy, Michelle, Govindasami, Koveela, Leongamornlert, Daniel, Sawyer, Emma J., Wilkinson, Rosemary, Saunders, Edward J., Tymrakiewicz, Malgorzata, Dadaev, Tokhir, Morgan, Angela, Fisher, Cyril, Hazel, Steve, Livni, Naomi, Lophatananon, Artitaya, Pedersen, John, Hopper, John L., Adolfson, Jan, Stattin, Paer, Johansson, Jan-Erik, Cavalli-Bjoerkman, Carin, Karlsson, Ami, Broms, Michael, Auvinen, Anssi, Kujala, Paula, Maeaettaenen, Liisa, Murtola, Teemu, Taari, Kimmo, Weischer, Maren, Nielsen, Sune F., Klarskov, Peter, Roder, Andreas, Iversen, Peter, Wallinder, Hans, Gustafsson, Sven, Cox, Angela, Brown, Paul, George, Anne, Marsden, Gemma, Lane, Athene, Davis, Michael, Tillmans, Lori, Riska, Shaun, Wang, Liang, Rinckleb, Antje, Lubiski, Jan, Stegmaier, Christa, Pow-Sang, Julio, Park, Hyun, Radlein, Selina, Rincon, Maria, Haley, James, Zachariah, Babu, Kachakova, Darina, Popov, Elenko, Mitkova, Atanaska, Vlahova, Aleksandrina, Dikov, Tihomir, Christova, Svetlana, Heathcote, Peter, Wood, Glenn, Malone, Greg, Saunders, Pamela, Eckert, Allison, Yeadon, Trina, Kerr, Kris, Collins, Angus, Turner, Megan, Srinivasan, Srilakshmi, Kedda, Mary-Anne, Alexander, Kimberly, Omara, Tracy, Wu, Huihai, Henrique, Rui, Pinto, Pedro, Santos, Joana, Barros-Silva, Joao, Conti, David V., Albanes, Demetrius, Berg, Christine, Berndt, Sonja I., Campa, Daniele, Crawford, E. David, Diver, W. Ryan, Gapstur, Susan M., Gaziano, J. Michael, Giovannucci, Edward, Hoover, Robert, Hunter, David J., Johansson, Mattias, Kraft, Peter, Le Marchand, Loic, Lindström, Sara, Navarro, Carmen, Overvad, Kim, Riboli, Elio, Siddiq, Afshan, Stevens, Victoria L., Trichopoulos, Dimitrios, Vineis, Paolo, Yeager, Meredith, Trynka, Gosia, Raychaudhuri, Soumya, Schumacher, Frederick R., Price, Alkes L., Freedman, Matthew L., Haiman, Christopher A., and Pasaniuc, Bogdan

Abstract

Although genome-wide association studies have identified over 100 risk loci that explain ∼33% of familial risk for prostate cancer (PrCa), their functional effects on risk remain largely unknown. Here we use genotype data from 59,089 men of European and African American ancestries combined with cell-type-specific epigenetic data to build a genomic atlas of single-nucleotide polymorphism (SNP) heritability in PrCa. We find significant differences in heritability between variants in prostate-relevant epigenetic marks defined in normal versus tumour tissue as well as between tissue and cell lines. The majority of SNP heritability lies in regions marked by H3k27 acetylation in prostate adenoc7arcinoma cell line (LNCaP) or by DNaseI hypersensitive sites in cancer cell lines. We find a high degree of similarity between European and African American ancestries suggesting a similar genetic architecture from common variation underlying PrCa risk. Our findings showcase the power of integrating functional annotation with genetic data to understand the genetic basis of PrCa.

Published
2016
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5. The association between genetically elevated polyunsaturated fatty acids and risk of cancer.

Author

Haycock PC, Borges MC, Burrows K, Lemaitre RN, Burgess S, Khankari NK, Tsilidis KK, Gaunt TR, Hemani G, Zheng J, Truong T, Birmann BM, OMara T, Spurdle AB, Iles MM, Law MH, Slager SL, Saberi Hosnijeh F, Mariosa D, Cotterchio M, Cerhan JR, Peters U, Enroth S, Gharahkhani P, Le Marchand L, Williams AC, Block RC, Amos CI, Hung RJ, Zheng W, Gunter MJ, Smith GD, Relton C, and Martin RM

Subjects
Humans, Fatty Acid Desaturases genetics, Fatty Acid Desaturases metabolism, Fatty Acids, Unsaturated metabolism, Polymorphism, Single Nucleotide, Esophageal Squamous Cell Carcinoma, Esophageal Neoplasms, Fatty Acids, Omega-3, Inflammatory Bowel Diseases, Colorectal Neoplasms
Abstract

Background: The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain., Methods: Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures., Findings: Genetically elevated PUFA desaturase activity was associated (P < 0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR = 1.00 [95% CI: 0.99-1.01]; P heterogeneity  = 0.25), urinary system cancers (1.03 [0.99-1.06], P heterogeneity  = 0.51), nervous system cancers (0.99 [0.95-1.03], P heterogeneity  = 0.92) or blood cancers (1.01 [0.98-1.04], P heterogeneity  = 0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P < 0.0006) with increased risk of inflammatory bowel disease but not bleeding., Interpretation: The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease., Funding: Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC&#95;UU&#95;00011/1, MC&#95;UU&#95;00011/3, MC&#95;UU&#95;00011/6, and MC&#95;UU&#95;00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973)., Competing Interests: Declaration of interests TRG has received funding from the Medical Research Council, Cancer Research UK and Biogen. BMB has received funding from the US National Institutes of Health/National Cancer Institute, American Institute of Cancer Research and Harvard Chan-NIEHS Center. JRC has received funding from the National Cancer Institute. GDS has received funding from the Medical Research Council. PG has received funding from the National Health and Medical Research Council. RM and PCH have received funding from Cancer Research UK. SB has received funding from the Wellcome Trust and the Medical Research Council. GDS reports Scientific Advisory Board Membership for Relation Therapeutics and Insitro., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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