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Title: Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies

Author
item SMITH, CAREN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item NGWA, JULIUS - Boston University
item TANAKA, TOSHIKI - National Institutes Of Health (NIH)
item QI, QIBIN - Harvard University
item WOJCZYNSKI, MARY - Washington University
item LEMAITRE, ROZENN - University Of Washington
item ANDERSON, JENNIFER - Wake Forest School Of Medicine
item MANICHAIKUL, ANI - University Of Virginia
item MIKKILA, VERA - University Of Helsinki
item VAN ROOIJ, FRANK - Erasmus Medical Center
item YE, ZHENG - Addenbrooke'S Hospital
item BANDINELLI, STEFANI - Health Agency Of Florence
item FRAZIER-WOOD, ALEXIS - University Of Alabama
item HOUSTON, DENISE - Wake Forest University
item HU, FRANK - Harvard University
item LANGENBERG, CLAUDIA - Addenbrooke'S Hospital
item MCKEOWN, NICOLA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item MOZAFFARIAN, DARIUSH - Harvard University
item NORTH, KARI - University Of North Carolina
item VIIKARI, JORMA - University Of Turku
item ZILLIKENS, M - Erasmus Medical Center
item DJOUSSE, LUC - Brigham & Women'S Hospital
item HOFMAN, ALBERT - Erasmus Medical Center
item KAHONEN, MIKA - Erasmus Medical Center
item KABAGAMBE, EDMOND - University Of Alabama
item LOOS, RUTH - Addenbrooke'S Hospital
item SAYLOR, GEORGIA - Wake Forest University
item FOROUHI, NITA - Addenbrooke'S Hospital
item LIU, YONGMEI - Wake Forest University
item MUKAMAL, KENNETH - Beth Israel Deaconess Medical Center
item CHEN, YII-DER - Cedars-Sinai Medical Center
item TSAI, MICHAEL - University Of Minnesota
item UITTERLINDEN, ANDRE - Erasmus Medical Center
item RAITAKARI, OLLI - University Of Turku
item VAN DUIJN, CORNELIA - Erasmus Medical Center
item ARNETT, DONNA - University Of Alabama
item BORECKI, INGRID - Washington University
item CUPPLES, L. ADRIENNE - Boston University
item FERRUCCI, LUIGI - National Institutes Of Health (NIH)
item KRITCHEVSKY, STEPHEN - Wake Forest University
item LEHTIMAKI, TERHO - Tampere University Hospital
item QI, LU - Harvard University
item ROTTER, JEROME - Cedars-Sinai Medical Center
item SISCOVICK, DAVID - University Of Washington
item WAREHAM, NICHOLAS - Addenbrooke'S Hospital
item WITTEMAN, JACQUELINE - Erasmus Medical Center
item ORDOVAS, JOSE - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item NETTLETON, JENNIFER - University Of Texas

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/28/2012
Publication Date: 1/29/2013
Citation: Smith, C.E., Ngwa, J., Tanaka, T., Qi, Q., Wojczynski, M.K., Lemaitre, R.N., Anderson, J.S., Manichaikul, A., Mikkila, V., Van Rooij, F.J., Ye, Z., Bandinelli, S., Frazier-Wood, A.C., Houston, D.K., Hu, F., Langenberg, C., Mckeown, N.M., Mozaffarian, D., North, K.E., Viikari, J., Zillikens, M.C., Djousse, L., Hofman, A., Kahonen, M., Kabagambe, E.K., Loos, R.J., Saylor, G.B., Forouhi, N.G., Liu, Y., Mukamal, K.J., Chen, Y.I., Tsai, M.Y., Uitterlinden, A.G., Raitakari, O., Van Duijn, C.M., Arnett, D.K., Borecki, I.B., Cupples, L., Ferrucci, L., Kritchevsky, S.B., Lehtimaki, T., Qi, L., Rotter, J.I., Siscovick, D.S., Wareham, N.J., Witteman, J.C., Ordovas, J.M., Nettleton, J.A. 2013. Lipoprotein receptor-related protein 1 variants and dietary fatty acids: meta-analysis of European origin and African American studies. International Journal of Obesity. DOI: 10.1038/ijo.2012.215.

Interpretive Summary: Obesity is a result of a combination of factors that include both genetics and environment. A growing number of genetic variants have been identified as contributors to obesity, and these results are often strengthened through their confirmation in multiple populations. In a relatively small number of cases, investigators have shown that the genetic risk of obesity is greater under particular environmental conditions, such as high intake of saturated fat. We refer to this result as a ‘gene-diet interaction’. For the gene LRP1, which encodes the protein low-density lipoprotein receptor related protein 1 (LRP1), a single study in one population had previously shown that high consumption of saturated fats was associated with greater body size in people who carried a particular variation of the LRP1 gene. In the current study, we aimed to investigate the same gene-diet interaction, but we performed our analysis in a very large pool of subjects composed of 14 groups of European descent, and 4 groups of African American ancestry. The process of combining results from many different populations is referred to as ‘meta-analysis’. In the current meta-analysis, we found an interaction between saturated fat and one variant of LRP1 in the European origin population, but not in the African Americans. A possible next step might include exploring the same questions using a controlled dietary trial, in which the effects of different amounts of saturated fat are compared in people who have the LRP1 genetic variant to those who don’t have the variant. The long-term objective of gene-diet interaction studies is to more effectively prevent obesity through the development of tailored dietary recommendations that are based on the genetic background of the individual.

Technical Abstract: Low-density lipoprotein-related receptor protein 1 (LRP1) is a multi-functional endocytic receptor and signaling molecule that is expressed in adipose and the hypothalamus. Evidence for a role of LRP1 in adiposity is accumulating from animal and in vitro models, but data from human studies are limited. The study objectives were to evaluate (i) relationships between LRP1 genotype and anthropometric traits, and (ii) whether these relationships were modified by dietary fatty acids. We conducted race/ethnic-specific meta-analyses using data from 14 studies of US and European whites and 4 of African Americans to evaluate associations of dietary fatty acids and LRP1 genotypes with body mass index (BMI), waist circumference and hip circumference, as well as interactions between dietary fatty acids and LRP1 genotypes. Seven single-nucleotide polymorphisms (SNPs) of LRP1 were evaluated in whites (N up to 42'000) and twelve SNPs in African Americans (N up to 5800). After adjustment for age, sex and population substructure if relevant, for each one unit greater intake of percentage of energy from saturated fat (SFA), BMI was 0.104'kg'm(-2) greater, waist was 0.305'cm larger and hip was 0.168'cm larger (all P<0.0001). Other fatty acids were not associated with outcomes. The association of SFA with outcomes varied by genotype at rs2306692 (genotyped in four studies of whites), where the magnitude of the association of SFA intake with each outcome was greater per additional copy of the T allele: 0.107'kg'm(-2) greater for BMI (interaction P=0.0001), 0.267'cm for waist (interaction P=0.001) and 0.21'cm for hip (interaction P=0.001). No other significant interactions were observed. Dietary SFA and LRP1 genotype may interactively influence anthropometric traits. Further exploration of this, and other diet x genotype interactions, may improve understanding of interindividual variability in the relationships of dietary factors with anthropometric traits.