APOA5 variants and metabolic syndrome in Caucasians

Harald Grallert,Eva-Maria Sedlmeier,Cornelia Huth,Melanie Kolz,Iris M Heid,Christa Meisinger,Christian Herder,Klaus Strassburger,Anke Gehringer,Markus Haak,Guido Giani,Florian Kronenberg,H-Erich Wichmann,Jerzy Adamski,Bernhard Paulweber,Thomas Illig,Wolfgang Rathmann

doi:10.1194/jlr.m700011-jlr200

Abstract

Apolipoprotein A5 (APOA5) gene variants were reported to be associated with two components of metabolic syndrome (MetS): higher TG levels and lower HDL levels. Moreover, a recent Japanese case-control study found variant -1131T>C associated with MetS itself. Thus, our study systematically analyzed the APOA5 gene for association with lipid parameters, any other features of MetS, including waist circumference, glucose-related parameters, blood pressure, uric acid, and MetS itself in Caucasians. Ten polymorphisms were analyzed in a large fasting sample of the population-based Cooperative Health Research in the Region of Augsburg (KORA) survey S4 (n = 1,354; southern Germany) and in a second fasting sample, the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1,770; Austria). Minor alleles of variants -1131T>C, -3A>G, c.56C>G, 476G>A, and 1259T>C were significantly associated with higher TG levels in single polymorphism (P < 0.001) and haplotype (P <or= 6.6 x 10(-6)) analysis. Besides associations with lower HDL levels in SAPHIR (P <or= 0.001), there were no significant findings with any other features of MetS. Variant c.56C>G was associated with higher risk for MetS [odds ratio (95% confidence interval) = 1.43 (1.04, 1.99), P = 0.03 for KORA and 1.48 (1.10, 1.99), P = 0.009 for SAPHIR). Our study confirms the association of the APOA5 locus with TG and HDL levels in humans. Furthermore, the data suggest a different mechanism of APOA5 impact on MetS in Caucasians, as variant c.56C>G (not analyzed in the Japanese study) and not -1131T>C, as in the Japanese subjects, was associated with MetS.

Highlights

Apolipoprotein A5 (APOA5) gene variants were reported to be associated with two components of metabolic syndrome (MetS): higher TG levels and lower HDL levels
Apolipoprotein A5 (APOA5) is considered as important modifying gene for familial combined hyperlipidemia (FCHL), a disorder characterized by higher plasma triglyceride (TG) levels and lower HDL levels [1, 2]
Two major haplotypes associated with higher TG levels are tagged by the rare genotypes of variant 21131T.C and coding variant c.56C.G, which results in the substitution of tryptophan for serine at residue 19 within the predicted signal peptide responsible for APOA5 secretion [20]

Summary

Introduction

Apolipoprotein A5 (APOA5) gene variants were reported to be associated with two components of metabolic syndrome (MetS): higher TG levels and lower HDL levels. Apolipoprotein A5 (APOA5) is considered as important modifying gene for familial combined hyperlipidemia (FCHL), a disorder characterized by higher plasma triglyceride (TG) levels and lower HDL levels [1, 2] As these parameters are two components of the metabolic syndrome (MetS) [3], APOA5 may have a role in this complex disorder. The association of common APOA5 variants with higher TG levels was confirmed in several studies [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19]. C.56C.G is the only common variant with known influence on APOA5 expression [23]

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Conclusion