Association between protein arginine -methyltransferase 1 polymorphism and overt diabetic nephropathy: Role of asymmetric dimethylarginine in vascular tone.

BACKGROUND

ω-,-asymmetric dimethylarginine (ADMA) regulates vascular tone and may participate in the pathogenesis of diabetic nephropathy (DN).

OBJECTIVE

To investigate whether single-nucleotide polymorphisms (SNPs) around the protein arginine -methyltransferase 1 gene () influence ADMA dynamics and DN incidence and severity.

METHODS

This study utilized a hospital-based database containing 310 Japanese patients with type 2 diabetes mellitus (T2DM). The association of -related tagged SNPs with DN stage distribution was examined using a dominant model of minor alleles. mRNA, serum ADMA, reactive hyperemia-peripheral arterial tonometry index (RHI), and brachial-ankle pulse wave velocity (baPWV) were compared between the genotype-based subgroups of causal SNP, and correlations between these variables were evaluated.

RESULTS

The composition of DN stages significantly differed between the GG and GA + AA subgroups of rs892151 ( = 0.026). In a propensity-matching cohort of rs892151, the GA + AA subgroup had an increased incidence of overt DN (odds ratio 2.92, 95 % confidence interval 1.12-7.62,  = 0.028), along with higher mRNA, serum ADMA levels, and baPWV than the GG subgroup ( < 0.001,  = 0.023 and 0.047, respectively). There were correlations between mRNA and serum ADMA levels, between serum ADMA levels and RHI, and between baPWV and urinary albumin excretion ( = 0.335,  < 0.001,  = -0.221,  = 0.029, and  = 0.254,  = 0.004, respectively).

CONCLUSIONS

T2DM patients carrying the -related variant rs892151 were susceptible to overt DN. ADMA-mediated endothelial dysfunction and arterial stiffness may be involved in the variant-related pathogenesis of overt DN.