- 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 years) recruited using the complete enumeration survey method in the Nakayama study. - deletion polymorphism in the promotor region with four SNPs (rs307894, rs669173, rs997251, and rs13373844) of DDAH1 were investigated. - 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. - ADMA concentrations were significantly elevated in subjects with two CAAA haplotypes compared with subjects without the CAAA haplotype ( p = 0.033).. - The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. - If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. - 1 Department of Neuropsychiatry, Molecules and Function, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 791-0295, Japan Full list of author information is available at the end of the article. - Further- more, we previously found that the CAAA haplotype pre- dicted by these four functional SNPs is strongly associated with loss of function in AGXT2 activity [7].. - In addition, the variants of two enzymes have been shown to be associated with several vascular conditions and diseases (AGXT2: carotid atherosclerosis [7], atrial fibrillation and ischemic stroke [13], and coronary heart disease [14];. - AGXT2 is known to be expressed abundantly in the liver and kidney (RNA-seq data in GeneCards), and four functional SNPs of AGXT2 may affect the liver and kidney functions of AGXT2 enzyme activity. - 65 years) recruited using the complete enumer- ation survey (census) method in the Nakayama study.. - Lastly, we examined whether the AGXT2 and DDAH1 geno- types were associated with clinical demographical and biological data such as BP and blood sugar using mul- tiple regression analysis.. - Subjects in the urinary excretion of R-3-AIB and plasma ADMA concentration studies. - The cohort consisted of volun- teer hospital workers, students, and citizens living in the same prefecture who did not have any urinary disorders as judged by blood examination. - In addition to these 85 participants, 78 subjects were randomly selected from the Nakayama study to investigate whether ADMA con- centrations were associated with four functional SNPs and the CAAA haplotype of AGXT2.. - ADMA concentrations. - The estimations of the Hardy–. - 90.0% across AGXT2 and DDAH1 SNPs, and none of the p values for the HWE reached statistical significance (Supplemental Table 1).. - In terms of LD, each pair of the four SNPs in AGXT2 was not in linkage equilibrium when considering D′. - Therefore, only rs997251 and rs13373844 within DDAH1 SNPs were used in the multiple regression analysis. - As a result of the predicted haplotype of AGXT2 SNPs (rs37370, rs37369, rs180749, rs16899974), the highest rate was found in the CAAA haplotype (0.2429. - None of the 85 subjects had two CAAC haplotypes.. - Plasma ADMA concentrations were significantly ele- vated in the AA genotype of rs187049 compared with the GG genotype (p = 0.001. - The details of each parameter used in the multiple re- gression analysis are explained in Supplemental Table 4.. - Systolic blood pressure (SBP) and diastolic blood pressure (DBP). - The number of CAAA haplotypes in AGXT2 was signifi- cantly associated with both SBP (p = 0.031) and DBP (p = 0.028), as shown in Tables 3 and 4. - In addition, rs16899974 was significantly associated with DBP (p = 0.040). - Other than the AGXT2 and DDAH1 genotypes, the following parameters were significantly associated with SBP (sex [p <. - The individual SNPs of DDAH1 was not significantly associated with SBP and DBP (Sup- plemental Table 5a and 5b). - The rs16899974 genotype was significantly associated with AST (p = 0.026) and ALT (p = 0.039), as shown in Tables 5 and 6. - Furthermore, the number of CAAA hap- lotypes was significantly associated with AST (p = 0.011), but not with ALT (p = 0.083). - Other than the AGXT2 and DDAH1 genotypes, the following parameters were significantly associated with AST (hypertension [p = 0.029]) and ALT (age [p <. - The individual SNPs of DDAH1 was not significantly associated with AST and ALT (Supplemental Table 7a and 7b). - The rs37370 genotype was significantly associated with BUN (p = 0.020) and creatinine (p = 0.023), as shown in Tables 7 and 8. - Other than the AGXT2 and DDAH1 genotypes, the following parameters were significantly associated with BUN (age [p <. - The individual SNPs of DDAH1 was not signifi- cantly associated with BUN and creatinine (Supplemental Table 8a and 8b). - The average BUN value was not significantly changed in the rs37370 genotype (p = 0.675) and the rs180749 genotype (p = 0.158).. - The rs16899974 genotype was significantly associated with CBS (p = 0.028), as shown in Table 9. - Other than the AGXT2 and DDAH1 genotypes, BMI was significantly associated with CBS (p = 0.013). - associated with CBS (Supplemental Table 9). - CAAA was predicted by each allele of the four SNPs as follows: rs37370 (c), rs37369 (a), rs180749 (a), and rs16899974 (a). - Table 3 Multiple regression analysis for systolic blood pressure within AGXT2 SNPs and haplotype. - CAAA haplotype . - Table 4 Multiple regression analysis for diastolic blood pressure within AGXT2 SNPs and haplotype. - Table 5 Multiple regression analysis for AST within AGXT2 SNPs and haplotype. - Table 6 Multiple regression analysis for ALT within AGXT2 SNPs and haplotype. - 65 years), which aimed to measure all members of the. - The advan- tage of the census method is its accuracy in terms of recruiting a pure population as compared with a sam- pling method using each unit of the population because the effect of community background is theoretically ex- cluded. - We recruited a total of 927 subjects (61.3% of the whole population aged >. - In terms of DDAH1 SNPs and 4 N ins/del, the allele frequencies of these genotypes were also simi- lar to those in the dbSNP database (https://www.ncbi.. - However, we have to consider that ADMA concentrations were significantly higher in the GG genotype (gain of func- tion) than in the AA genotype (loss of function) of rs180749. - Because rs180749 is one of the functional SNPs that regulates AGXT2 activity, it is hard to reach a definite conclusion without considering other functional SNPs. - and haplotype. - Table 8 Multiple regression analysis for creatinine within AGXT2 SNPs and haplotype. - Table 9 Multiple regression analysis for casual blood sugar within AGXT2 SNPs and haplotype. - As only three subjects in the present study had the ins/ins genotype, more subjects are needed to clarify this point. - Our previ- ous study showed that the CAAA haplotype is associated with a loss of function, which was revealed by measuring urine R-3-AIB [7]. - Because the CAAC haplotype changed from the A allele to the C allele on rs16899974, it still plays a role in the loss of function, and the effect of the CAAA haplotype on AGXT2 activity is more ef- fective than that on rs16899974. - Indeed, decreased plasma NO was found in Agxt2 KO mice, which also showed elevated plasma ADMA concentrations and mean arterial pres- sure as measured in the carotid artery [17]. - Doğan et al.. - Collectively, we hypothesize that the loss of AGXT2 function induces elevated SBP and DBP through the dysregulation of the NOS/ADMA pathway, which means that we can estimate the risk of cardiovascular diseases by detecting AGXT2 SNPs.. - The loss of AGXT2 function predicted by the CAAA haplotype contributes to a decrease in AST. - AGXT2 is mainly present in the mitochondria of hepatocytes [21]. - These lines of evi- dence suggest that metabolism from ADMA to DMVG occurs even in the liver. - However, the functions of AGXT2 and. - ADMA in the liver are still unknown under both the normal condition and disease state.. - Higher BUN values were found in the CC genotype of rs37370 (loss of function) and GG genotype of rs180749 (gain of function), which are discrepant results in terms of the predicted AGXT2 function. - Within kidney tissues, AGXT2 is strongly expressed in the renal proximal tubular epithelium [21]. - It has been shown that HNF4α, a nuclear transcription factor that can work by binding on promoter regions of AGXT2, is co-localized in the renal proximal tubular epithelium [21]. - Surprisingly, the loss of function of AGXT2 activity predicted by rs16899974 (AA genotype) was associated with elevated CBS. - Given that subjects who have the AA genotype show higher ADMA concentrations [32], the elevated CBS in the AA genotype of AGXT2 is caused by changes in ADMA levels. - Second, several discrepant results were found in the results of the biochemical tests on liver and kidney functions. - In addition, AGXT2 functions in the liver and kidney are still unknown, even though these expressions were con- firmed [21]. - In conclusion, we revealed that the loss of AGXT2 func- tion predicted by the CAAA haplotype induces elevated ADMA concentrations. - Despite the fact that additional re- search is needed in terms of AGXT2 function in the kid- ney and liver, the four functional SNPs of AGXT2 and their haplotypes are useful tools for predicting hyperten- sion, DM, and their related complications. - BP: Blood pressure. - CAAC, was predicted by each al- lele of the four SNPs as follows: rs37370 (C), rs37369 (A), rs180749 (A), rs16899974 (C).. - Main characteristics of the select tagging SNPs in AGXT2 and DDAH1. - Explanation of each parameters used in the demographic data and multiple regression analysis. - Multiple regression analysis for systolic blood pressure in non-HT subjects within AGXT2 SNPs and haplotype. - Multiple regression analysis for diastolic blood pressure in non-HT subjects within AGXT2 SNPs and haplotype. - Multiple regression analysis for casual blood sugar within AGXT2 SNPs and haplotype.. - A genome- wide association study of the human metabolome in a community-based cohort. - Yoshino Y, Abe M, Numata S, Ochi S, Mori Y, Ishimaru T, et al. - Missense variants of the alanine:glyoxylate aminotransferase 2 gene are not associated with Japanese schizophrenia patients. - Yoshino Y, Kohara K, Abe M, Ochi S, Mori Y, Yamashita K, et al. - Missense variants of the alanine: glyoxylate aminotransferase 2 gene correlated with carotid atherosclerosis in the Japanese population. - Tang WH, Tong W, Shrestha K, Wang Z, Levison BS, Delfraino B, et al.. - Association of the AGXT2 V140I polymorphism with risk for coronary heart disease in a Chinese population. - Wang Z, Chen S, Zhang L, Lu G, Zhou C, Wang DW, et al. - Association between variation in the genes DDAH1 and DDAH2 and hypertension among Uygur, Kazakh and Han ethnic groups in China. - DDAH1 promoter − 396 4N insertion variant is associated with increased risk of type 2 diabetes in a gender- dependent manner. - Caplin B, Wang Z, Slaviero A, Tomlinson J, Dowsett L, Delahaye M, et al.. - Endothelial nitric oxide synthase gene is associated with diabetic macular edema in type 2 diabetes. - A novel loss-of-function DDAH1 promoter polymorphism is associated with increased susceptibility to thrombosis stroke and coronary heart disease. - Mookerjee RP, Malaki M, Davies NA, Hodges SJ, Dalton RN, Turner C, et al.. - Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis. - Mookerjee RP, Dalton RN, Davies NA, Hodges SJ, Turner C, Williams R, et al.. - Inflammation is an important determinant of levels of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) in acute liver failure. - Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations
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