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

作者：Lamina Claudia; Friedel Salome; Coassin Stefan; Rueedi Rico; Yousri Noha A; Seppala Ilkka; Gieger Christian; Schoenherr Sebastian; Forer Lukas; Erhart Gertraud; Kollerits Barbara; Marques Vidal Pedro; Ried Janina; Waeber Gerard; Bergmann Sven; Daehnhardt Doreen; Stoeckl Andrea; Kiechl Stefan; Raitakari Olli T; Kahonen Mika; Willeit Johann; Kedenko Ludmilla; Paulweber Bernhard; Peters Annette; Meitinger Thomas; Strauch Konstantin; Lehtimaki Terho; Hunt Steven C

来源：Human Molecular Genetics, 2016, 25(16): 3635-3646.

DOI：10.1093/hmg/ddw211

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 x 10(-44)), rs5104 in APOA4 (P - 1.79 x 10(-24)) and rs4241819 in KLKB1 (P - 5.6 x 10(-14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 x 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 x 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.

• 出版日期2016-8-15
• 单位河北医科大学