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Title: Quality of dietary fat and genetic risk of type 2 diabetes: Individual participant data meta-analysis

Author
item MERINO, JORDI - MASSACHUSETTS GENERAL HOSPITAL
item GAUSCH-FERRE, MARTA - HARVARD SCHOOL OF PUBLIC HEALTH
item ELLERVIK, CHRISTINA - BOSTON CHILDREN'S HOSPITAL
item DASHTI, HASSAN - MASSACHUSETTS GENERAL HOSPITAL
item SHARP, STEPHEN - UNIVERSITY OF CAMBRIDGE
item WU, PEITAO - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item OVERVAD, KIM - AARHUS UNIVERSITY
item SARNOWSKI, CHLOE - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item KUOKKANEN, MIKKO - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item LEMAITRE, ROZENN - UNIVERSITY OF WASHINGTON
item JUSTICE, ANNE - UNIVERSITY OF NORTH CAROLINA
item ERICSON, ULRIKA - LUND UNIVERSITY
item BRAUN, KIM - ERASMUS MEDICAL CENTER
item MAHENDRAN, YUVARAJ - UNIVERSITY OF COPENHAGEN
item FRAZIER-WOOD, ALEXIS - CHILDREN'S NUTRITION RESEARCH CENTER (CNRC)
item SUN, DIANJIANYI - TULANE SCHOOL OF PUBLIC HEALTH
item CHU, AUDREY - BRIGHAM & WOMEN'S HOSPITAL
item TANAKA, TOSHIKO - NATIONAL INSTITUTE ON AGING (NIA, NIH)
item LUAN, JIAN'AN - UNIVERSITY OF CAMBRIDGE
item HONG, JAEYOUNG - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item TJONNELAND, ANNE - DANISH CANCER SOCIETY RESEARCH CENTER
item DING, MING - HARVARD SCHOOL OF PUBLIC HEALTH
item LUNDQVIST, ANNAMARI - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item MULAMAL, KENNETH - BETH ISRAEL DEACONESS MEDICAL CENTER
item ROHDE, REBECCA - UNIVERSITY OF NORTH CAROLINA
item SCHULZ, CHRISTINA - LUND UNIVERSITY
item FRANCO, OSCAR - ERASMUS MEDICAL CENTER
item GRARUP, NIELS - UNIVERSITY OF COPENHAGEN
item CHEN, YII - HARBOR-UCLA MEDICAL CENTER
item BAZZANO, LYDIA - TULANE SCHOOL OF PUBLIC HEALTH
item FRANKS, PAUL - HARVARD SCHOOL OF PUBLIC HEALTH
item BURING, JULIE - BRIGHAM & WOMEN'S HOSPITAL
item LANGENBERG, CLAUDIA - UNIVERSITY OF CAMBRIDGE
item LIU, CHING - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item HANSEN, TORBEN - UNIVERSITY OF COPENHAGEN
item JENSEN, MAJKEN - HARVARD SCHOOL OF PUBLIC HEALTH
item SAAKSJARVI, KATRI - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item PSATY, BRUCE - UNIVERSITY OF WASHINGTON
item YOUNG, KRISTIN - UNIVERSITY OF NORTH CAROLINA
item HINDY, GEORGE - MASSACHUSETTS GENERAL HOSPITAL
item SANDHOLT, CAMILLA - UNIVERSITY OF COPENHAGEN
item RIDKER, PAUL - BRIGHAM & WOMEN'S HOSPITAL
item ORDOVAS, JOSE - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item MEIGS, JAMES - MASSACHUSETTS GENERAL HOSPITAL
item PEDERSON, OLUF - UNIVERSITY OF COPENHAGEN
item KRAFT, PETER - HARVARD SCHOOL OF PUBLIC HEALTH
item PEROLA, MARKUS - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item NORTH, KARI - UNIVERSITY OF NORTH CAROLINA
item ORHO-MELANDER, MARJU - LUND UNIVERSITY
item VOORTMAN, TRUDY - ERASMUS MEDICAL CENTER
item TOFT, ULLA - COPENHAGEN UNIVERSITY
item ROTTER, JEROME - HARBOR-UCLA MEDICAL CENTER
item QI, LU - HARVARD SCHOOL OF PUBLIC HEALTH
item FOROUHI, NITA - UNIVERSITY OF CAMBRIDGE
item MOZAFFARIAN, DARIUSH - FRIEDMAN SCHOOL AT TUFTS
item SORENSEN, THORKILD - UNIVERSITY OF COPENHAGEN
item STAMPFER, MEIR - HARVARD SCHOOL OF PUBLIC HEALTH
item MANNISTO, SATU - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item SELVIN, ELIZABETH - JOHNS HOPKINS SCHOOL OF PUBLIC HEALTH
item IMAMURA, FUMIAKI - UNIVERSITY OF CAMBRIDGE
item SALOMAA, VEIKKO - NATIONAL INSTITUTE FOR HEALTH AND WELFARE (HELSINKI)
item HU, FRANK - HARVARD SCHOOL OF PUBLIC HEALTH
item WAREHAM, NICK - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item DUPUIS, JOSEE - BOSTON UNIVERSITY SCHOOL OF PUBLIC HEALTH
item SMITH, CAREN - JEAN MAYER HUMAN NUTRITION RESEARCH CENTER ON AGING AT TUFTS UNIVERSITY
item KILPELAINEN, TUOMAS - UNIVERSITY OF COPENHAGEN
item CHASMAN, DANIEL - BROAD INSTITUTE OF MIT/HARVARD
item FLOREZ, JOSE - MASSACHUSETTS GENERAL HOSPITAL

Submitted to: The BMJ
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/10/2019
Publication Date: 7/25/2019
Citation: Merino, J., Gausch-Ferre, M., Ellervik, C., Dashti, H.S., Sharp, S.J., Wu, P., Overvad, K., Sarnowski, C., Kuokkanen, M., Lemaitre, R.N., Justice, A.E., Ericson, U., Braun, K.V., Mahendran, Y., Frazier-Wood, A.C., Sun, D., Chu, A.Y., Tanaka, T., Luan, J., Hong, J., Tjonneland, A., Ding, M., Lundqvist, A., Mulamal, K., Rohde, R., Schulz, C.A., Franco, O.H., Grarup, N., Chen, Y.D., Bazzano, L., Franks, P.W., Buring, J.E., Langenberg, C., Liu, C.T., Hansen, T., Jensen, M.K., Saaksjarvi, K., Psaty, B.M., Young, K.L., Hindy, G., Sandholt, C.H., Ridker, P.M., Ordovas, J.M., Meigs, J.B., Pederson, O., Kraft, P., Perola, M., North, K.E., Orho-Melander, M., Voortman, T., Toft, U., Rotter, J.I., Qi, L., Forouhi, N.G., Mozaffarian, D., Sorensen, T.1., Stampfer, M.J., Mannisto, S., Selvin, E., Imamura, F., Salomaa, V., Hu, F.B., Wareham, N.J., Dupuis, J., Smith, C.E., Kilpelainen, T.O., Chasman, D.I., Florez, J.C. 2019. Quality of dietary fat and genetic risk of type 2 diabetes: Individual participant data meta-analysis. The BMJ. 366:14292. https://doi.org/10.1136/bmj.l4292.
DOI: https://doi.org/10.1136/bmj.l4292

Interpretive Summary: Too much fat in the diet, especially saturated fat, increases the risk of type 2 diabetes. We know that the extent to which dietary fat increases the risk of type 2 diabetes is different between different people, but we don't know why. This makes it hard to focus our dietary interventions for preventing type 2 diabetes on those most at risk, and hard to tailor our advice for preventing type 2 diabetes to individual needs. To better understand who is most at risk of type 2 diabetes from the fat in their diet, we examined whether having genes that predispose you to developing type 2 diabetes regardless of your dietary intake, also alter your responses to dietary fat intake and so increase your risk. Using data from over 100,000 participants across the world, we found that this was not the case: whether consuming dietary fat increases your risk for type 2 diabetes is not dependent on your background genetic risk for this condition. This information is useful mostly to researchers – either those who are trying to identify why certain genetic risk factors increase your risk of type 2 diabetes, or those who are trying to identify why some people develop type 2 diabetes as a result of a high-fat diet, but others do not.

Technical Abstract: Our objective was to investigate whether the genetic burden of type 2 diabetes modifies the association between the quality of dietary fat and the incidence of type 2 diabetes using individual participant data meta-analysis. Eligible prospective cohort studies were systematically sourced from studies published between January 1970 and February 2017 through electronic searches in major medical databases (Medline, Embase, and Scopus) and discussion with investigators. Data from cohort studies or multicohort consortia with available genome-wide genetic data and information about the quality of dietary fat and the incidence of type 2 diabetes in participants of European descent was sought. Prospective cohorts that had accrued five or more years of follow-up were included. The type 2 diabetes genetic risk profile was characterized by a 68-variant polygenic risk score weighted by published effect sizes. Diet was recorded by using validated cohort-specific dietary assessment tools. Outcome measures were summary adjusted hazard ratios of incident type 2 diabetes for polygenic risk score, isocaloric replacement of carbohydrate (refined starch and sugars) with types of fat, and the interaction of types of fat with polygenic risk score. Of 102,305 participants from 15 prospective cohort studies, 20,015 type 2 diabetes cases were documented after a median follow-up of 12 years (interquartile range 9.4-14.2). The hazard ratio of type 2 diabetes per increment of 10 risk alleles in the polygenic risk score was 1.64 (95% confidence interval 1.54 to 1.75, I**2=7.1%, t**2=0.003). The increase of polyunsaturated fat and total omega 6 polyunsaturated fat intake in place of carbohydrate was associated with a lower risk of type 2 diabetes, with hazard ratios of 0.90 (0.82 to 0.98, I**2=18.0%, t**2=0.006; per 5% of energy) and 0.99 (0.97 to 1.00, I2=58.8%, t**2=0.001; per increment of 1 g/d), respectively. Increasing monounsaturated fat in place of carbohydrate was associated with a higher risk of type 2 diabetes (hazard ratio 1.10, 95% confidence interval 1.01 to 1.19, I**2=25.9%, t**2=0.006; per 5% of energy). Evidence of small study effects was detected for the overall association of polyunsaturated fat with the risk of type 2 diabetes, but not for the omega 6 polyunsaturated fat and monounsaturated fat associations. Significant interactions between dietary fat and polygenic risk score on the risk of type 2 diabetes (P>0.05 for interaction) were not observed. These data indicate that genetic burden and the quality of dietary fat are each associated with the incidence of type 2 diabetes. The findings do not support tailoring recommendations on the quality of dietary fat to individual type 2 diabetes genetic risk profiles for the primary prevention of type 2 diabetes, and suggest that dietary fat is associated with the risk of type 2 diabetes across the spectrum of type 2 diabetes genetic risk.