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United States Department of Agriculture

Agricultural Research Service

Research Project: NUTRITION, OBESITY, CARDIOVASCULAR HEALTH AND GENOMICS

Location: Human Nutrition Research Center on Aging

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

Authors
item Smith, Caren -
item Ngwa, Julius -
item Tanaka, Toshiki -
item Qi, Qibin -
item Wojczynski, Mary -
item Lemaitre, Rozenn -
item Anderson, Jennifer -
item Manichaikul, Ani -
item Mikkila, Vera -
item Van Rooij, Frank -
item Ye, Zheng -
item Bandinelli, Stefani -
item Frazier-Wood, Alexis -
item Houston, Denise -
item Hu, Frank -
item Langenberg, Claudia -
item Mckeown, Nicola -
item Mozaffarian, Dariush -
item North, Kari -
item Viikari, Jorma -
item Zillikens, M -
item Djousse, Luc -
item Hofman, Albert -
item Kahonen, Mika -
item Kabagambe, Edmond -
item Loos, Ruth -
item Saylor, Georgia -
item Forouhi, Nita -
item Liu, Yongmei -
item Mukamal, Kenneth -
item Chen, Yii-Der -
item Tsai, Michael -
item Uitterlinden, Andre -
item Raitakari, Olli -
item Van Duijn, Cornelia -
item Arnett, Donna -
item Borecki, Ingrid -
item Cupples, L. Adrienne -
item Ferrucci, Luigi -
item Kritchevsky, Stephen -
item Lehtimaki, Terho -
item Qi, Lu -
item Rotter, Jerome -
item Siscovick, David -
item Wareham, Nicholas -
item Witteman, Jacqueline -
item Ordovas, Jose -
item Nettleton, Jennifer -

Submitted to: International Journal of Obesity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 28, 2012
Publication Date: January 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.

Last Modified: 7/25/2014
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