Abstract
GDF15 (growth-differentiation factor 15) is a novel antihypertrophic factor which is induced in the heart in response to pressure overload and plays an important regulatory role in the process of hypertrophy. In the present study, we have investigated the relationship between GDF15 gene variants and left ventricular hypertrophy in human essential hypertension. A community-based hypertensive population sample of 1527 individuals (506 men and 1021 women) was genotyped for three GDF15 genetic variants, including one tag variant -3148C>G (rs4808793) and two exonic variants +157A>T (rs1059369) and +2438C>G (rs1058587). The effects of those variants on gene expression were studied by use of luciferase reporter assays and the determination of plasma GDF15 levels. Only the tag variant -3148G was significantly associated with a lower risk of left ventricular hypertrophy [odds ratio=0.75 (95% confidence interval, 0.63-0.89); P=0.0009]. Multiple regression analyses confirmed that -3148G predicted the decrease in left ventricular end-diastolic diameter (beta=-0.10, P=0.0001), end-systolic diameter (beta=-0.09, P=0.0007), mass (beta=-0.11, P<0.0001) and indexed mass (beta=-0.12, P<0.0001). These effects were independent of conventional factors, including gender, age, body surface area, blood pressure, diabetes, cigarette smoking and alcohol consumption. The transcription activity of the -3148G-containing construct was increased 1.45-fold (P=0.015) at baseline and 1.73-fold (P=0.008) after stimulation with phenylephrine when compared with the -3148C construct. The -3148G allele was also associated with a significant increase in the plasma GDF15 level in hypertensive subjects (P=0.04). In conclusion, the results show that a promoter haplotype containing the -3148G variant increases GDF15 transcription activity and is associated with favourable left ventricular remodelling in human essential hypertension.
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