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Hum Mol Genet. 2016 Aug 15;25(16):3635-3646. doi: 10.1093/hmg/ddw211. Epub 2016 Jul 12.

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

Author information

1
Division of Genetic Epidemiology, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
2
Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
3
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
4
Department of Physiology and Biophysics, Weill Cornell Medical College - Qatar, Doha, Qatar.
5
Department of Computer and Systems Engineering, Alexandria University, Alexandria, Egypt.
6
Department of Clinical Chemistry, Fimlab Laboratories and University of Tampere School of Medicine, Tampere, Finland.
7
Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health.
8
Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health.
9
Research Unit of Molecular Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.
10
Department of Medicine, Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.
11
Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
12
Department of Clinical Physiology, Turku University Hospital, Turku, Finland.
13
Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
14
Department of Clinical Physiology, Tampere University Hospital and University of Tampere, Tampere, Finland.
15
First Department of Internal Medicine, Paracelsus Private Medical University, Salzburg, Austria.
16
DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
17
German Center for Diabetes Research (DZD e.V.), Neuherberg, Germany.
18
Institute of Human Genetics, Technische Universität München, München, Germany.
19
Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
20
Munich Cluster for Systems Neurology (SyNergy).
21
Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.
22
Cardiovascular Genetics Division, University of Utah School of Medicine, Salt Lake City, UT, USA.
23
Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar.

Abstract

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 -44), rs5104 in APOA4 (P = 1.79 × 10-24) and rs4241819 in KLKB1 (P = 5.6 × 10-14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 -07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10-05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.

PMID:
27412012
PMCID:
PMC5179953
DOI:
10.1093/hmg/ddw211
[Indexed for MEDLINE]
Free PMC Article

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