Caren E Smith1, Jack L Follis2, Hassan S Dashti3,4, Toshiko Tanaka5, Mariaelisa Graff6, Amanda M Fretts7, Tuomas O Kilpeläinen8, Mary K Wojczynski9, Kris Richardson10, Mike A Nalls11,12, Christina-Alexandra Schulz13, Yongmei Liu14, Alexis C Frazier-Wood15, Esther van Eekelen16, Carol Wang17, Paul S de Vries18,19, Vera Mikkilä20,21, Rebecca Rohde6, Bruce M Psaty22,23, Torben Hansen8, Mary F Feitosa9, Chao-Qiang Lai24, Denise K Houston25, Luigi Ferruci5, Ulrika Ericson13, Zhe Wang26, Renée de Mutsert16, Wendy H Oddy27, Ester A L de Jonge19,28, Ilkka Seppälä29, Anne E Justice6, Rozenn N Lemaitre30, Thorkild I A Sørensen8,31,32, Michael A Province9, Laurence D Parnell24, Melissa E Garcia33, Stefania Bandinelli34, Marju Orho-Melander13, Stephen S Rich35, Frits R Rosendaal16, Craig E Pennell17, Jessica C Kiefte-de Jong19, Mika Kähönen36, Kristin L Young6, Oluf Pedersen8, Stella Aslibekyan37, Jerome I Rotter38, Dennis O Mook-Kanamori16,39, M Carola Zillikens28, Olli T Raitakari21,40, Kari E North6,41, Kim Overvad42,43, Donna K Arnett44, Albert Hofman19,45, Terho Lehtimäki29, Anne Tjønneland46, André G Uitterlinden28, Fernando Rivadeneira28,47, Oscar H Franco19, J Bruce German48, David S Siscovick49, L Adrienne Cupples50, José M Ordovás1,51,52. 1. Nutrition and Genomics Laboratory, Jean Mayer-US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA. 2. University of St Thomas, Houston, TX, USA. 3. Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA, USA. 4. Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA. 5. Translational Gerontology Branch, National Institute on Aging, Baltimore, MD, USA. 6. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA. 7. Department of Epidemiology, University of Washington, Seattle, WA, USA. 8. Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, 2100, Denmark. 9. Department of Genetics, Washington University School of Medicine, St. Louis, MO, USA. 10. Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. 11. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD, USA. 12. Contractor/consultant with Kelly Services, Rockville, MD, USA. 13. LUDC, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden. 14. Department of Epidemiology & Prevention, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, USA. 15. USDA / ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas, USA. 16. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 17. School of Women's and Infants' Health, University of Western Australia, Perth, Australia. 18. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX, USA. 19. Department of Epidemiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. 20. Division of Nutrition, Department of Food and Environmental Sciences, University of Helsinki, Helsinki. 21. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. 22. Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA. 23. Group Health Research Institute, Group Health Cooperative, Seattle, WA, USA. 24. USDA ARS, Nutrition and Genomics Laboratory, Jean Mayer-USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA. 25. Department of Internal Medicine, Wake Forest School of Medicine, Wake Forest University, Winston-Salem, NC, USA. 26. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA. 27. Menzies Institute for Medical Research, University of Tasmania, Australia. 28. Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands. 29. Department of Clinical Chemistry, Fimlab Laboratories, Tampere University School of Medicine, Tampere, Finland. 30. Department of Medicine, University of Washington, Seattle, WA, USA. 31. Department of Clinical Epidemiology (formerly Institute of Preventive Medicine), Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, 2000, Denmark. 32. MRC Integrative Epidemiology Unit & School of Social and community Medicine, University of Bristol, Bristol, BS82BN, UK. 33. National Institute of Aging, Bethesda, MD, USA. 34. Geriatric Unit, Azienda Sanitaria Firenze (ASF), Florence, Italy. 35. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA. 36. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland. 37. Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA. 38. Institute for Translational Genomics and Population Sciences Los Angeles BioMedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA. 39. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, The Netherlands. 40. Department of Clinical Physiology and Nuclear Medicine, University of Turku, Turku, Finland. 41. Carolina Center for Genome Sciences, University of North Carolina, Chapel Hill, NC, 27514, USA. 42. Department of Public Health, Section for Epidemiology, Aarhus University, DK-8000, Aarhus C, Denmark. 43. Aalborg University Hospital, DK-9000, Aalborg, Denmark. 44. College of Public Health, University of Kentucky, Lexington, KY, USA. 45. Department of Nutrition, Harvard School of Public Health, Boston, USA. 46. Danish Cancer Society Research Center, Copenhagen, 2100, Denmark. 47. Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden, the Netherlands. 48. Department of Food Science and Technology, University of California, Davis, CA, USA. 49. New York Academy of Medicine, New York, NY, USA. 50. Department of Biostatistics, Boston University School of Public Health, Boston, USA. 51. The Department of Epidemiology and Population Genetics, Centro Nacional Investigación Cardiovasculares (CNIC) Madrid, Spain. 52. IMDEA Food, Madrid, Spain.
Abstract
SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
SCOPE: Body weight responds variably to the intake of dairy foods. Genetic variation may contribute to inter-individual variability in associations between body weight and dairy consumption. METHODS AND RESULTS: A genome-wide interaction study to discover genetic variants that account for variation in BMI in the context of low-fat, high-fat and total dairy intake in cross-sectional analysis was conducted. Data from nine discovery studies (up to 25 513 European descent individuals) were meta-analyzed. Twenty-six genetic variants reached the selected significance threshold (p-interaction <10-7) , and six independent variants (LINC01512-rs7751666, PALM2/AKAP2-rs914359, ACTA2-rs1388, PPP1R12A-rs7961195, LINC00333-rs9635058, AC098847.1-rs1791355) were evaluated meta-analytically for replication of interaction in up to 17 675 individuals. Variant rs9635058 (128 kb 3' of LINC00333) was replicated (p-interaction = 0.004). In the discovery cohorts, rs9635058 interacted with dairy (p-interaction = 7.36 × 10-8) such that each serving of low-fat dairy was associated with 0.225 kg m-2 lower BMI per each additional copy of the effect allele (A). A second genetic variant (ACTA2-rs1388) approached interaction replication significance for low-fat dairy exposure. CONCLUSION: Body weight responses to dairy intake may be modified by genotype, in that greater dairy intake may protect a genetic subgroup from higher body weight.
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