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


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.

DOI: 10.1093/hmg/ddw211

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@inproceedings{Lamina2016AGA, title={A genome-wide association meta-analysis on apolipoprotein A-IV concentrations}, author={Claudia Lamina and Salome Friedel and Stefan Coassin and Rico Rueedi and Noha A. Yousri and Ilkka Sepp{\"a}l{\"a} and Christian Gieger and Sebastian Sch{\"{o}nherr and Lukas Forer and Gertraud Erhart and Barbara Kollerits and Pedro Marques-Vidal and Janina Ried and Gerard Waeber and Sven Bergmann and Doreen D{\"a}hnhardt and Andrea St{\"{o}ckl and Stefan Kiechl and Olli T. Raitakari and Mika K{\"a}h{\"{o}nen and Johann Willeit and Ludmilla Kedenko and Bernhard Paulweber and Annette Peters and Thomas Meitinger and Konstantin Strauch and KORA Study Group and Terho Lehtim{\"a}ki and Steven C. Hunt and Peter Vollenweider and Florian Kronenberg}, booktitle={Human molecular genetics}, year={2016} }