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Genetic Analysis of 16 NMR-Lipoprotein Fractions in Humans, the GOLDN Study

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Lipids

Abstract

Sixteen nuclear magnetic resonance (NMR) spectroscopy lipoprotein measurements of more than 1,000 subjects of GOLDN study, at fasting and at 3.5 and 6 h after a postprandial fat (PPL) challenge at visits 2 and 4, before and after a 3 weeks Fenofibrate (FF) treatment, were included in 6 time-independent multivariate factor analyses. Their top 1,541 unique SNPs were assessed for association with GOLDN NMR-particles and classical lipids. Several SNPs with −log10 p > 7.3 and MAF ≥ 0.10, mostly intergenic associated with NMR-single traits near genes FAM84B (8q24.21), CRIPT (2p21), ACOXL (2q13), BCL2L11 (2q13), PCDH10 (4q28.3), NXPH1 (7p22), and SLC24A4 (14q32.12) in association with NMR-LDLs; HOMER1 (5q14.2), KIT (4q11–q12), VSNL1 (2p24.3), QPRT (16p11.2), SYNPR (3p14.2), NXPH1 (7p22), NELL1 (11p15.1), and RUNX3 (1p36) with NMR-HDLs; and DOK5-CBLN4-MC3R (20q13), NELL1 (11p15.1), STXBP6 (14q12), APOB (2p24-p23), GPR133 (12q24.33), FAM84B (8q24.21) and NR5A2 (1q32.1) in association with NMR-VLDLs particles. NMR single traits associations produced 75 % of 114 significant candidates, 7 % belonged to classical lipids and 18 % overlapped, and 16 % matched for time of discovery between NMR- and classical traits. Five proxy genes, (ACOXL, FAM84B, NXPH1, STK40 and VAPA) showed pleiotropic effects. While tagged for significant associations in our study and with some extra evidence from the literature, candidates as CBNL4, FAM84B, NXPH1, SLC24A4 remain unclear for their functional relation to lipid metabolism. Although GOLDN study is one of the largest in studying PPL and FF treatment effects, the relatively small samples (over 700–1,000 subjects) in association tests appeals for a replication of such a study. Thus, further investigation is needed.

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Abbreviations

CHYL:

Chylomicrons

dbGaP:

The database of Genotypes and Phenotypes

FF:

Fenofibrate

GOLDN:

Genetics of Lipid Lowering Drugs and Diet Network study

HDL:

High density lipoprotein

IDL:

Intermediate density lipoproteins

LDL:

Low density lipoprotein

MAF:

Minor allele frequency

NMR:

Nuclear magnetic resonance spectroscopy lipoprotein measurements

NCBI:

The National Center for Biotechnology Information

PPL:

Oral fat challenge

SNPs:

Single nucleotide polymorphisms

TC:

Total cholesterol

TAG:

Triglycerides

VLDL:

Very low density lipoprotein

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Acknowledgments

The authors are thankful to Jim Otvos of Liposciences Inc. for providing comments on a preliminary draft of the manuscript. This work was supported in part by the GOLDN NIH grant R01 HL09135701.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Division of Statistical Genomics, Washington University School of Medicine, 4444 Forest Park Ave, Campus Box 8506, St. Louis, MO, 63108, USA

    Aldi T. Kraja, Ingrid B. Borecki & Michael A. Province

  2. Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA

    Michael Y. Tsai

  3. Nutrition and Genomics Laboratory, Tufts University, Boston, MA, USA

    Jose M. Ordovas & Chao-Qiang Lai

  4. Cardiovascular Genetics Research, University of Utah, Salt Lake City, UT, USA

    Paul N. Hopkins

  5. Centro Nacional Investigaciones Cardiovasculares (CNIC), Madrid, Spain

    Jose M. Ordovas

  6. Instituto Madrileno de Estudios Avanzados (IMIDEA) Alimentacion, Madrid, Spain

    Jose M. Ordovas

  7. Department of Epidemiology, University of Alabama, Birmingham, AL, USA

    Alexis C. Frazier-Wood & Donna K. Arnett

  8. Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Robert J. Straka

  9. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, TX, USA

    James E. Hixson

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  1. Aldi T. Kraja
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Corresponding author

Correspondence to Aldi T. Kraja.

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Kraja, A.T., Borecki, I.B., Tsai, M.Y. et al. Genetic Analysis of 16 NMR-Lipoprotein Fractions in Humans, the GOLDN Study. Lipids 48, 155–165 (2013). https://doi.org/10.1007/s11745-012-3740-8

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  • DOI: https://doi.org/10.1007/s11745-012-3740-8

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