Genome-wide association study on dimethylarginines reveals novel AGXT2 variants associated with heart rate variability but not with overall mortality

The purpose of this study was to identify novel genetic variants influencing circulating asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels and to evaluate whether they have a prognostic value on cardiovascular mortality. We conducted a genome-wide association study on the methylarginine traits and investigated the predictive value of the new discovered variants on mortality. Our meta-analyses replicated the previously known locus for ADMA levels in DDAH1 (rs997251; P = 1.4 × 10−40), identified two non-synomyous polymorphisms for SDMA levels in AGXT2 (rs37369; P = 1.4 × 10−40 and rs16899974; P = 1.5 × 10−38) and one in SLC25A45 (rs34400381; P = 2.5 × 10−10). We also fine-mapped the AGXT2 locus for further independent association signals. The two non-synonymous AGXT2 variants independently associated with SDMA levels were also significantly related with short-term heart rate variability (HRV) indices in young adults. The major allele (C) of the novel non-synonymous rs16899974 (V498L) variant associated with decreased SDMA levels and an increase in the ratio between the low- and high-frequency spectral components of HRV (P = 0.00047). Furthermore, the SDMA decreasing allele (G) of the non-synomyous SLC25A45 (R285C) variant was associated with a lower resting mean heart rate during the HRV measurements (P = 0.0046), but not with the HRV indices. None of the studied genome-wide significant variants had any major effect on cardiovascular or total mortality in patients referred for coronary angiography. AGXT2 has an important role in SDMA metabolism in humans. AGXT2 may additionally have an unanticipated role in the autonomic nervous system regulation of cardiac function.