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The association of dimethylarginine dimethylaminohydrolase 1 gene polymorphism with type 2 diabetes: a cohort study.

Lu TM, Lin SJ, Lin MW, Hsu CP, Chung MY - Cardiovasc Diabetol (2011)

Bottom Line: The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes.Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes.One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04).

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R,O,C.

ABSTRACT

Background: Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown.

Methods: From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR).

Results: Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04).

Conclusions: Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome.

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Related in: MedlinePlus

Kaplan-Meier survival analyses with all-cause mortality (A, B) and major adverse cardiovascular events (MACE) (C, D) during follow-up according to the genotype of rs1241321 (AA___ vs. GG + AG....) in diabetic and non-diabetic groups. P values by log-rank test were shown.
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Figure 2: Kaplan-Meier survival analyses with all-cause mortality (A, B) and major adverse cardiovascular events (MACE) (C, D) during follow-up according to the genotype of rs1241321 (AA___ vs. GG + AG....) in diabetic and non-diabetic groups. P values by log-rank test were shown.

Mentions: As for the relation between DDAH1 genetic variants and long-term outcome, Figure 2 showed the Kaplan-Meier estimates of all-cause mortality and probability of MACE-free survival of patients stratified by genotype of DDAH1 rs1241321 in diabetic and non-diabetic groups, and the prognosis of diabetic patients carrying the rs1241321 AA genotype appeared to be better than those carrying GG +AG genotype. Multivariate Cox regression analysis showed that while AA genotype in the DDAH1 rs1241321 was not a predictor for long-term outcome in the whole population, it was independently associated with reduced risk for long-term all-cause mortality (AA versus GG + AG: HR = 0.18, 95% CI = 0.04-0.80, p = 0.02) and MACE (AA versus GG + AG: HR = 0.31, 95% CI = 0.11-0.90, p = 0.03) in type 2 diabetic patients but not in the non-diabetic subgroup (interaction p = 0.16 for all-cause mortality, p = 0.05 for MACE, respectively). There were no significant association between the other SNPs and the long-term clinical outcomes.


The association of dimethylarginine dimethylaminohydrolase 1 gene polymorphism with type 2 diabetes: a cohort study.

Lu TM, Lin SJ, Lin MW, Hsu CP, Chung MY - Cardiovasc Diabetol (2011)

Kaplan-Meier survival analyses with all-cause mortality (A, B) and major adverse cardiovascular events (MACE) (C, D) during follow-up according to the genotype of rs1241321 (AA___ vs. GG + AG....) in diabetic and non-diabetic groups. P values by log-rank test were shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3050685&req=5

Figure 2: Kaplan-Meier survival analyses with all-cause mortality (A, B) and major adverse cardiovascular events (MACE) (C, D) during follow-up according to the genotype of rs1241321 (AA___ vs. GG + AG....) in diabetic and non-diabetic groups. P values by log-rank test were shown.
Mentions: As for the relation between DDAH1 genetic variants and long-term outcome, Figure 2 showed the Kaplan-Meier estimates of all-cause mortality and probability of MACE-free survival of patients stratified by genotype of DDAH1 rs1241321 in diabetic and non-diabetic groups, and the prognosis of diabetic patients carrying the rs1241321 AA genotype appeared to be better than those carrying GG +AG genotype. Multivariate Cox regression analysis showed that while AA genotype in the DDAH1 rs1241321 was not a predictor for long-term outcome in the whole population, it was independently associated with reduced risk for long-term all-cause mortality (AA versus GG + AG: HR = 0.18, 95% CI = 0.04-0.80, p = 0.02) and MACE (AA versus GG + AG: HR = 0.31, 95% CI = 0.11-0.90, p = 0.03) in type 2 diabetic patients but not in the non-diabetic subgroup (interaction p = 0.16 for all-cause mortality, p = 0.05 for MACE, respectively). There were no significant association between the other SNPs and the long-term clinical outcomes.

Bottom Line: The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes.Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes.One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04).

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, R,O,C.

ABSTRACT

Background: Elevated plasma levels of asymmetric dimethylarginine (ADMA) has been reported to be associated with insulin resistance and micro/macrovascular diabetic complications, and may predict cardiovascular events in type 2 diabetic patients. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is the major enzyme eliminating ADMA in humans, but the effect of genetic variations in DDAH1 on type 2 diabetes and its long-term outcome are unknown.

Methods: From July 2006 to June 2009, we assessed the association between polymorphisms in DDAH1 and type 2 diabetes in 814 consecutive unrelated subjects, including 309 type 2 diabetic patients and 505 non-diabetic individuals. Six single nucleotide polymorphisms (SNPs) in DDAH1, rs233112, rs1498373, rs1498374, rs587843, rs1403956, and rs1241321 were analyzed. Plasma ADMA levels were determined by high performance liquid chromatography. Insulin sensitivity was assessed by the homeostasis model assessment of insulin resistance (HOMA-IR).

Results: Among the 6 SNPs, only rs1241321 was significantly associated with a decreased risk of type 2 diabetes (AA vs GG+AG, OR = 0.64, 95% CI 0.47-0.86, p = 0.004). The association remained unchanged after adjustment for plasma ADMA level. The fasting plasma glucose and log HOMA-IR tended to be lower in subjects carrying the homozygous AA genotype of rs1241321 compared with the GG+AG genotypes. Over a median follow-up period of 28.2 months, there were 44 all-cause mortality and 50 major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction and stroke). Compared with the GG and AG genotypes, the AA genotype of rs1241321 was associated with reduced risk of MACE (HR = 0.31, 95% CI: 0.11-0.90, p = 0.03) and all-cause mortality (HR = 0.18, 95% CI: 0.04-0.80, p = 0.02) only in subgroup with type 2 diabetes. One common haplotype (GGCAGC) was found to be significantly associated with a decreased risk of type 2 diabetes (OR = 0.67, 95% CI = 0.46-0.98, p = 0.04).

Conclusions: Our results provide the first evidence that SNP rs1241321 in DDAH1 is associated with type 2 diabetes and its long-term outcome.

Show MeSH
Related in: MedlinePlus