Effects of AGXT2 variants on blood pressure and blood sugar among 750 older Japanese subjects recruited by the complete enumeration survey method

Abstract

Background Alanine:glyoxylate aminotransferase 2 (AGXT2; EC 2.6.1.44) is the only enzyme that degrades the R-form of 3-aminoisobutyrate, an intermediate metabolite of thymine. AGXT2, as well as diaminoarginine dimethylaminohydrolase 1 (DDAH1; EC 3.5.3.18), works as an enzyme that degrades asymmetric dimethylarginine (ADMA), which competitively inhibits the nitric oxide synthase family. Thus, these two enzyme activities may change vascular vulnerability for a lifetime via the nitric oxide (NO) system. We investigated the association between vascular conditions and diseases such as hypertension and diabetes mellitus and polymorphisms of these two genes in 750 older Japanese subjects (mean age ± standard deviation, 77.0 ± 7.6 years) recruited using the complete enumeration survey method in the Nakayama study. Demographic and biochemical data, such as blood pressure (BP) and casual blood sugar (CBS), were obtained. Four functional single nucleotide polymorphisms (SNPs; rs37370, rs37369, rs180749, and rs16899974) of AGXT2 and one functional insertion/deletion polymorphism in the promotor region with four SNPs (rs307894, rs669173, rs997251, and rs13373844) of DDAH1 were investigated. Plasma ADMA was also analyzed in 163 subjects. Results The results of multiple regression analysis showed that a loss of the functional haplotype of AGXT2, CAAA, was significantly positively correlated with BP (systolic BP, p = 0.034; diastolic BP, p = 0.025) and CBS (p = 0.021). No correlation was observed between DDAH1 and either BP or CBS. ADMA concentrations were significantly elevated in subjects with two CAAA haplotypes compared with subjects without the CAAA haplotype (p = 0.033). Conclusions Missense variants of AGXT2, but not DDAH1, may be related to vulnerability to vascular diseases such as hypertension and DM via the NO system.

An individualized Bayesian method for estimating genomic variants of hypertension

“…In Table 2, the missense variant of rs37369 [30] has been shown to be one of the 4 functional SNPs of AGXT2, which has been reported to have strong associations with several cardiorenal traits, such as coronary heart disease [31]. Its significant association with hypertension was very recently reported via multiple regression analysis involving only several targeted SNPs [32]. The missense variant rs11575542 was very recently identified as a functional variant of the DOPA Decarboxylase ( DDC ) gene during the systematic polymorphism screening across the 15-Exon DCC locus [33].…”

Functional AGXT2 SNP rs37369 Variant Is a Risk Factor for Diabetes Mellitus: Baseline Data From the Aidai Cohort Study in Japan

“…SNP rs37370, but not rs37369 or rs180749, and the aforementioned CAAA haplotype were significantly related to carotid atherosclerosis in a study of 1,426 Japanese individuals (10). Another study of 750 older Japanese adults showed that SNP rs16899974 and the CAAA haplotype, but not rs37370, rs37369 or rs180749, were significantly associated with diastolic blood pressure, and that rs16899974, but not rs37370, rs37369, rs180749 or the CAAA haplotype, was significantly associated with casual blood sugar (13). In another Chinese caseecontrol study of 942 patients with coronary heart disease and 1,103 controls, rs37369 was not independently related to coronary heart disease (17).…”

“…In a German study, plasma concentrations of SDMA, but not ADMA, were higher in those heterozygous or homozygous for the minor allele of rs37369, whereas no such positive relationship was found between rs16899974 and plasma concentrations of ADMA or SDMA (8). AGXT2 SNPs have also been shown to be related to the following vascular conditions and diseases and related biological data: coronary artery disease (7); heart rate variability (9); carotid atherosclerosis (10); atrial fibrillation (11); chronic heart failure (12); and blood pressure, blood sugar and blood creatinine (13).…”

“…AGXT2 activity is abolished among 30% to 40% of Japanese people, whereas <10% of individuals with European ancestry show a lack of AGXT2 activity (14). AGXT2 SNPs rs37370 (S102N), rs37369, rs180749 (T212I) and rs16899974, and the CAAA haplotype decided by these SNPs, are associated with loss of function in AGXT2 activity (13,15).…”

Association of Variability in the DDAH1, DDAH2, AGXT2 and PRMT1 Genes with Circulating ADMA Concentration in Human Whole Blood

“…As AGXT2 degrades both ADMA and SDMA, whilst DDAH is inactive towards SDMA, this pattern of metabolite changes in plasma would be consistent with downregulation of DDAH in hypoxia, as has been shown experimentally, and compensatory upregulation of AGXT2. In a recent study in 750 elderly Japanese individuals, a loss-of-function haplotype comprising four SNPs in AGXT2 was positively associated with blood pressure and serum glucose levels; individuals homozygous for this haplotype had significantly elevated ADMA levels [35]. Thus, the physiological and pathophysiological roles of AGXT2 in dimethylarginine metabolism in humans require further study.…”