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

C. E. Smith, J. Ngwa, T. Tanaka, Q. Qi, M. K. Wojczynski, R. N. Lemaitre, J. S. Anderson, A. Manichaikul, V. Mikkilä, F. J.A. Van Rooij, Z. Ye, S. Bandinelli, A. C. Frazier-Wood, D. K. Houston, F. Hu, C. Langenberg, N. M. McKeown, D. Mozaffarian, K. E. North, J. ViikariM. C. Zillikens, L. Djoussé, A. Hofman, M. Kähönen, E. K. Kabagambe, R. J.F. Loos, G. B. Saylor, N. G. Forouhi, Y. Liu, K. J. Mukamal, Y. Di Chen, M. Y. Tsai, A. G. Uitterlinden, O. Raitakari, C. M. Van Duijn, D. K. Arnett, I. B. Borecki, L. A. Cupples, L. Ferrucci, S. B. Kritchevsky, T. Lehtimäki, Lu Qi, J. I. Rotter, D. S. Siscovick, N. J. Wareham, J. C.M. Witteman, J. M. Ordovás, J. A. Nettleton

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


Objective: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.Design and methods: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).Results: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.Conclusion: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.

Original languageEnglish
Pages (from-to)1211-1220
Number of pages10
JournalInternational Journal of Obesity
Issue number9
StatePublished - Sep 2013

Bibliographical note

Funding Information:
The Atherosclerosis Risk In Communities (ARIC) Study is carried out as a collaborative study supported by National Heart, Lung and Blood Institute contracts (HHSN268 201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C and HHSN268 201100012C), R01HL087641, R01HL59367 and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. We the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. Dr Nettleton is supported by a K01 from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (5K01DK 082729-04). Cardiovascular Health Study (CHS) research was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, R01-HL085251 HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-023629, AG-15928, AG-20098 and AG-027058 from the NIA. See also pi.htm. DNA handling and genotyping was supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. European Prospective Investigation of Cancer Norfolk (EPIC Norfolk): EPIC-Norfolk is supported by grant funding from the Medical Research Council and Cancer Research United Kingdom with additional support from the Stroke Association, British Heart Foundation, Research Into Ageing and the Academy of Medical Science. The Family Heart Study (FamHS) work was supported by NIH grants R01 HL087700, R01 HL088215 (Michael A. Province) from NHLBI; and R01 DK075681 and R01 DK8925601 from NIDDK (Ingrid B. Borecki). The investigators thank the staff and participants of the FamHS for their important contributions. The Fenland Study is funded by the Wellcome Trust and the Medical Research Council. We are grateful to all the volunteers for their time and help and to the General Practitioners and practice staff for help with recruitment. We thank the Fenland Study co-ordination team, the Field Epidemiology team and the Fenland Study investigators. Biochemical assays were performed by the National Institute for Health Research, Cambridge Biomedical Research Centre, Core Biochemistry Assay Laboratory and the Cambridge University Hospitals NHS Foundation Trust. The Framingham Offspring Study and Framingham Third Generation Study (FHS) were conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute’s Framingham Heart Study (Contract No. N01-HC-25195) and its contract with Affymetrix, Inc., for genotyping services (Contract No. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. Dr Cupples and Mr Ngwa are partially supported by NIH/ NIDDK grant R01 DK089256-01. Dr Nicola McKeown is supported by the USDA agreement No. 58-1950-7-707. The GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study was funded by the National Heart, Lung and Blood Institute Grant No. U01-HL072524, Genetic and Environmental Determinants of Triglycerides. Dr Smith and Dr Ordovás are partially supported by P50 HL105185-01 and contracts 53-K06-5-10 and 58–1950-9–001 from the US Department of Agriculture Research Service. The Health, Aging and Body Composition (Health ABC) study was supported in part by the Intramural Research Program of the NIH, National Institute on Aging contracts N01AG62101, N01AG62103 and N01AG62106. The genome-wide association study was funded by NIA grant R01 AG032098 to Wake Forest University Health Sciences and genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C. Health Professionals Follow-up Study (HPFS): The HPFS was supported by grants HL71981 and CA055075 from the National Institutes of Health. Dr Lu Qi is a recipient of the American Heart Association Scientist Development Award (0730094N). We thank the participants of the HPFS for their continued cooperation. Invecchiare in Chianti (aging in the Chianti area, InCHIANTI) study investigators thank the Intramural Research Program of the NIH, National Institute on Aging who are responsible for the InCHIANTI samples. Investigators also thank the InCHIANTI participants. The InCHIANTI study baseline (1998–2000) was supported as a ‘targeted project’ (ICS110.1/RF97.71) by the Italian Ministry of Health and in part by the US National Institute on Aging (Contracts: 263 MD 9164 and 263 MD 821336). MESA and the MESA SHARe project are conducted and supported by contracts N01-HC-95159 through N01-HC-95169 and RR-024156 from the National Heart, Lung and Blood Institute (NHLBI). Funding for MESA SHARe genotyping was provided by NHLBI Contract N02-HL-6-4278. MESA Family is conducted and supported in collaboration with MESA investigators; support is provided by grants and contracts R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL 071258, R01HL071259. We thank the participants of the MESA study, the Coordinating Center, MESA investigators, and study staff for their valuable contributions. A full list of participating MESA investigators and institutions can be found at Nurses Health Study (NHS): The NHS was supported by grants HL71981, CA87969 and CA49449 from the National Institutes of Health. Dr Lu Qi is a recipient of the American Heart Association Scientist Development Award (0730094N). We thank the participants of the NHS for their continued cooperation. Rotterdam Study: The generation and management of GWAS genotype data for the Rotterdam Study is supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters for their help in creating the GWAS database, and Karol Estrada and Maksim V. Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII) and the Municipality of Rotterdam. We are grateful to the study participants, the staff from the Rotterdam Study and the participating general practitioners and pharmacists. Young Finns Study: The Young Finns Study has been financially supported by the Academy of Finland: grants 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi) and 41071 (Skidi), the Social Insurance Institution of Finland, Kuopio, Tampere and Turku University Hospital Medical Funds (grant 9M048 and 9N035 for TeLeht), Juho Vainio Foundation, Paavo Nurmi Foundation, Finnish Foundation of Cardiovascular Research and Finnish Cultural Foundation, Tampere Tuberculosis Foundation and Emil Aaltonen Foundation (T.L). The authors gratefully acknowledge the statistical analyses provided by Ville Aalto.


  • Low-density lipoprotein receptor-related protein 1
  • SNPs
  • gene-diet interactions
  • saturated fatty acids

ASJC Scopus subject areas

  • Nutrition and Dietetics
  • Medicine (miscellaneous)
  • Endocrinology, Diabetes and Metabolism


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