Single Nucleotide Polymorphisms in the Arginase 1 and 2 Genes Are Differentially Associated with Circulating L-Arginine Concentration in Unsupplemented and L-Arginine-Supplemented Adults

Background: Genetic variation in arginase may underlie variability in whole blood L-arginine concentrations in unsupplemented and L-arginine-supplemented adults. Objectives: We aimed to study whether single nucleotide polymorphisms (SNPs) in the arginase 1 (ARG1) and arginase 2 (ARG2) genes are associated with blood L-arginine concentrations in unsupplemented and L-arginine-supplemented individuals. Methods: In 374 adults (mean +/- SD age: 59.6 +/- 14.6 y; 180 males), we analyzed SNPs in the ARG1 (rs2246012 and rs2781667) and ARG2 genes (rs3742879 and rs2759757) and their associations with blood L-arginine concentrations. We analyzed associations of haplotypes for the ARG1 gene and for the ARG1 and ARG2 genes combined with blood L-arginine concentrations in supplement users and unsupplemented participants. Results: Of study participants, 120 had low (<42 mu mol/L), 133 had medium (42-114 mu mol/L), and 121 had high blood L-arginine concentrations (>114 mu mol/L); 58 individuals were current L-arginine supplement users. We found a significantly higher prevalence of the minor allele of ARG1 rs2246012 in supplement users with higher blood L-arginine concentrations (P = 0.03). Mean +/- SEM L-arginine concentration was 263 +/- 9.76 mu mol/L in supplement users homozygous for the minor allele of ARG1 rs2246012 IP = 0.004); it was 70.4 +/- 25.6 mu mol/L in unsupplemented participants homozygous for the minor allele of ARG2 rs3759757 (P = 0.03). The ARG1 haplotype was significantly associated with blood L-arginine concentrations in supplement users (P= 0.046), whereas the combined ARG1/ARG2 haplotype was significantly associated with blood L-arginine concentrations in the cohort as a whole (P = 0.012). Conclusions: Genetic variability in the ARG1 and ARG2 genes is associated with blood L-arginine concentrations in humans: ARG1 is associated with blood L-arginine concentrations in L-arginine supplement users, whereas ARG2 is associated with blood L-arginine concentrations in unsupplemented participants. Our study is the first to describe a possible functional relation between ARG1 and ARG2 SNPs and blood L-arginine concentrations; genetic variability in ARG1 may explain variation in blood L-arginine concentrations during supplement use and discrepant study results.