KLOTHO G-395A Research Articles

Klotho G-395A Gene Polymorphism: Impact on Progression of End-Stage Renal Disease and Development of Cardiovascular Complications in Children on Dialysis

Klotho G-395A Gene Polymorphism: Impact on Progression of End-Stage Renal Disease and Development of Cardiovascular Complications in Children on Dialysis

Klotho G395A variants are associated with T2DM and diabetic nephropathy and influence on the levels of biochemical parameters

AimsThe current study aimed to investigate the association between klotho G395A (rs1207568) polymorphism with the risk of type 2 diabetes mellitus (T2DM) and its complication of nephropathy in relation to biochemical and hematological parameters in the Kurdish population of Iraq. MethodsIn a case-control study, 310 individuals aged 45–65 years, (157 males and 153 females), were recruited from AL-Sulaymaniyah, Kurdistan, Iraq. Patients with T2DM were categorized into three groups of microalbuminuria, macroalbuminuria, and normoalbuminuria. Also, 105 healthy individuals as controls were studied. In another category, individuals were considered as two groups of with and without nephropathy. Biochemical parameters were analyzed by colorimetric enzymatic assay. The polymerase chain reaction (PCR)-with confronting two-pair primers (CTTP) method was used to detect the klotho G395A polymorphism. ResultsVitamin D level was significantly lower in all T2DM patients (with and without nephropathy) compared to the controls. The klotho GA genotype increased the risk of T2DM by 2.2 times (95%CI 1.3–4.0; P = 0.007) and the klotho AA genotype increased the risk of diabetic nephropathy by 2.72-fold (95%CI 1.18–6.25, P = 0.019) and enhanced the risk of macroalbuminuria by 3.74-fold (95 % 1.43–9.7, p = 0.007). ConclusionThe present study found significantly lower levels of vitamin D in T2DM compared to the controls. We detected an association between increased risk of T2DM and diabetic nephropathy with the klotho G395A polymorphism and the influence of this polymorphism on the levels of some biochemical parameters in women.

The Role of Klotho G395A Gene Polymorphism in Atherosclerotic Cardiovascular Disease and Mortality Risk Scores in Non-dialysis Chronic Kidney Disease

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Klotho expression was reduced in patients with CKD, leading to vascular calcification, endothelial dysfunction, and atherosclerosis. We investigated the role of the klotho G395A gene polymorphism and plasma klotho level in the ten-year risk of atherosclerotic cardiovascular disease (ASCVD) and CVD mortality in CKD patients.METHODS: We used the PCR-CTPP assay method to genotype klotho G395A single nucleotide polymorphism (SNP) in 72 non-dialysis CKD patients. The klotho level was determined using the enzyme-linked immunoassay (ELISA) method. Path analysis was used to determine the relationship between the klotho G395A SNP, plasma klotho level, ASCVD risk score, and CVD mortality risk score.RESULTS: Our results showed that the GA genotype had lower plasma klotho levels than the GG genotype (path coefficient=-0.185, p=0.000). There was a significant negative correlation between plasma klotho level and the ASCVD risk score (r=-0.243, p=0.040), but no significant correlation was found between plasma klotho level and the CVD mortality risk score (r=-0.145, p=0.225). Path analysis showed that plasma klotho level had a significant negative direct effect on ASCVD risk score (path coefficient=-0.272, p=0.000) and an indirect effect on CVD mortality risk score (path coefficient=0.187, p=0.005).CONCLUSION: Klotho G395A SNP might reduce lower plasma klotho levels, which increased ASCVD and CVD mortality risk scores in non-dialysis CKD patients. However, other risk factors such as age, CKD stages, hypertension, and smoking should be taken into consideration. Therefore, large-scale genetic association studies with adjusted variables could be conducted in various ethnic groups for a more robust result.KEYWORDS: klotho, single nucleotide polymorphism, cardiovascular disease, chronic kidney disease

Investigation of Klotho G395A and C1818T Polymorphisms and Their Association with Serum Glucose Level and Risk of Type 2 Diabetes Mellitus.

Objective: The objective was to study the association of Klotho gene G395A and C1818T single nucleotide polymorphisms with glycemia, serum, glycosylated hemoglobin (HbA1c) level and the risk of type 2 diabetes mellitus (T2DM) in the Pashtun population of Pakistan. Methods: In this study, 195 normal individuals and 217 T2DM patients were enrolled. All subjects were divided into three groups, namely overall subjects (control + T2DM patients), control individuals and T2DM patients, and their fasting glucose, HbA1c level, lipid profile and C1818T and G395A polymorphisms were determined. Results: The allele frequencies of G395A in overall subjects were 0.568 for A and 0.432 for G. Similarly, allele frequencies for G395A in overall subjects were 0.597 and 0.403 for C and T alleles, respectively. The AA genotype of G395A was observed to be a risk factor for T2DM. In normal individuals, no significant (p > 0.05) association was observed between klotho C1818T and G395A polymorphisms and hyperglycemia. In overall subjects, the C1818T polymorphism was associated (p < 0.05) with high fasting glucose and HbA1c levels in female subjects only. In T2DM patients, both C1818T and G395A polymorphisms were found to be significantly (p < 0.05) associated with high fasting glucose and HbA1c levels both in males and females. Conclusion: The G395A polymorphism was observed to increase the risk of T2DM. Both C1818T and G395 were associated with high fasting glucose and HbA1c levels in T2DM patients.

Nitride oxide synthase 3 and klotho gene polymorphisms in the pathogenesis of chronic kidney disease and age-related cognitive impairment: a systematic review and meta-analysis.

Background: While it has been known that the development of chronic kidney disease (CKD) and age-related cognitive impairment involves several mediators, the evidence in clinical practice only reveals nitride oxide synthase (NOS) and klotho. However, the evidence for this topic is conflicted. The aim of this study was to assess the role of NOS and klotho single nucleotide polymorphisms (SNPs) in the pathogenesis of CKD and age-related cognitive impairment. Methods: We performed a meta-analysis during October to December 2019. Paper collection was performed in major scientific websites, and we extracted information of interest from each paper. Data were analyzed using a Z-test with either random or fixed effect model. Results: Our initial assessment identified NOS3 G894T, NOS3 T786C, NOS3 4b/4a, klotho ( KL) G395A, and KL C1818T as the gene candidate for our meta-analysis. Our pooled calculation revealed that NOS3 G894T was associated with the risk of both age-related cognitive impairment and CKD. Increased susceptibility to age-related cognitive impairment was observed in the GG genotype, and increased risk of CKD was found in patients with a single T allele and TT genotype for NOS3 nucleotide 894. For NOS3 4b/4a, increased risk of CKD was only found in 4a4a genotype. For NOS3 T786C, we failed to show the association with both CKD and age-related cognitive impairment. Subsequently, for KL G395A, A allele and GA genotype were found to correlate with increased susceptibility to CKD, while its correlation to age-related cognitive impairment was failed to clarify. For KL C1818T, our analysis failed to find the correlation with the risk of CKD. Conclusions: Our results reveal that the NOS3 G894T gene polymorphism has a crucial role in the pathogenesis of both CKD and age-related cognitive impairment.

Polymorphism of the Klotho G-395a Gene Promoter with the Incidence of Preeclampsia

A B S T R A C TIntroduction. Preeclampsia is one of the leading causes of maternal and perinatalmorbidity and mortality and is still a disease of theory. Klotho is a new gene, inseveral biological processes in the pathophysiology of preeclampsia that play a rolein regulating endothelial nitric oxide production, angiogenesis, production ofantioxidant enzymes and protection against endothelial dysfunction. The Klotho G-395A genotype AA promoter polymorphism is the cause of hypertension. This studyaims to determine the relationship of the Klotho G-395A promoter polymorphism tothe incidence of preeclampsia. Methods. This study is an analytical study with acase-control design. The research was conducted at Pembina community healthcentre of Palembang and the public hospital of Prabumulih in February - July 2020and involving 50 case group and 50 control group. To determine the genotype andallotype of the Klotho G-395A gene promoter polymorphism, using polymerase chainreaction examination. Result. The results showed that the risk factors for maternalage and maternal gestational age had a significant relationship with the incidence ofpreeclampsia (p-value 0.015; p-value 0.000). There was a significant relationshipbetween the Klotho G-395A genotype GA + AA promoter polymorphism and theincidence of preeclampsia (p-value 0.024; OR = 2.571; 95% CI = 1.122-5.895), whileallotypes in the study sample also had a significant relationship with the incidenceof preeclampsia. preeclampsia (p-value 0.025; OR = 1.978; 95% CI = 1.087-3.599).Conclusion: There is a significant relationship between the Klotho G-395A genepromoter polymorphism and the incidence of preeclampsia.

Klotho gene G395A and C1818T polymorphisms in acromegaly: Association with clinical presentation and comorbidities.

Klotho is a new identified anti-ageing gene with tumour suppressor activities. Current data suggest that there is a tight relationship between Klotho protein and growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. This study aimed to investigate the possible association of Klotho gene polymorphisms with acromegaly and to assess whether these polymorphisms contribute to clinical characteristics, comorbidities and biochemical variables in these patients. The study included 52 patients with acromegaly and 52 unrelated healthy subjects. The Klotho G395A and C1818T polymorphisms were assessed by Sanger sequencing. Serum levels of sKlotho were determined by ELISA method. Subjects carrying GA genotype of Klotho G395A polymorphism had 3.27 times higher risk of developing acromegaly [odds ratio (OR), 3.27; 95% confidence interval (CI): 1.37-7.81; p=.023]. The A allele of G395A was significantly associated with acromegaly risk (OR, 2.27; 95% CI: 1.1-4.72; p=.022). No association was observed between the studied polymorphisms and disease characteristics including age at acromegaly diagnosis, size of adenoma, baseline GH and IGF-1 concentrations, and final outcome. G395A polymorphism was associated with the presence of malignancy (OR, 2.24, 95% CI: 1.63-3.08; p=.019) and colorectal polyps (OR, 1.99; 95% CI: 1.02-3.88; p=.047) in patients with acromegaly. Serum sKlotho levels were significantly higher and correlated with GH and IGF-1 levels among acromegaly patients. There was no association between the studied polymorphisms and sKlotho levels. Klotho G395A polymorphism is associated with acromegaly susceptibility and increased risk of malignancy and colorectal polyps in these patients.

Nitride oxide synthase 3 and klotho gene polymorphisms in the pathogenesis of chronic kidney disease and age-related cognitive impairment: a systematic review and meta-analysis.

Background: While it has been known that the development of chronic kidney disease (CKD) and age-related cognitive impairment involves several mediators, the evidence in clinical practice only reveals nitride oxide synthase (NOS) and klotho. However, the evidence for this topic is conflicted. The aim of this study was to assess the role of NOS and klotho single nucleotide polymorphisms (SNPs) in the pathogenesis of CKD and age-related cognitive impairment. Methods: We performed a meta-analysis during October to December 2019. Paper collection was performed in major scientific websites, and we extracted information of interest from each paper. Data were analyzed using a Z-test with either random or fixed effect model. Results: Our initial assessment identified NOS3 G894T, NOS3 T786C, NOS3 4b/4a, klotho ( KL) G395A, and KL C1818T as the gene candidate for our meta-analysis. Our pooled calculation revealed that NOS3 G894T was associated with the risk of both age-related cognitive impairment and CKD. Increased susceptibility to age-related cognitive impairment was observed in the GG genotype, and increased risk of CKD was found in patients with a single T allele and TT genotype for NOS3 nucleotide 894. For NOS3 4b/4a, increased risk of CKD was only found in 4a4a genotype. For NOS3 T786C, we failed to show the association with both CKD and age-related cognitive impairment. Subsequently, for KL G395A, A allele and GA genotype were found to correlate with increased susceptibility to CKD, while its correlation to age-related cognitive impairment was failed to clarify. For KL C1818T, our analysis failed to find the correlation with the risk of CKD. Conclusions: Our results reveal that the NOS3 G894T gene polymorphism has a crucial role in the pathogenesis of both CKD and age-related cognitive impairment.

G-395A polymorphism in the promoter region of the KLOTHO gene associates with frailty among the oldest-old

Frailty is characterized by a decline in physiological reserve and increased vulnerability. Previous studies have shown that KLOTHO (KL) plays a protective role in several age-related diseases. We hypothesize a probable protective effect of KL on frailty in the elderly population and included a cohort of Chinese nonagenarians and centenarians for our study. This study is part of a cross-sectional study and secondary analysis of the Project of Longevity and Aging in Dujiangyan (PLAD) study, which was conducted in Southwest China. Community-dwelling Chinese residents aged 90 years or older were included in this study. Frailty was determined using the FRAIL scale as proposed by the International Association of Nutrition and Aging. On the FRAIL scale, frailty was defined by a score of ≥3. G-395A (rs1207568) genotyping of the promoter region of the KL gene was performed using TaqMan allelic discrimination assay. A total of 632 participants (68.4% females; mean age: 93.5 ± 3.2 years) were included. KL G-395A polymorphism genotype frequencies were 1.7% AA, 25.6% GA, and 72.7% GG in our sample. GG genotype frequencies for the frailty and control groups were 83.6% and 71.2%, respectively. Frailty prevalence was significantly lower in the GA+AA group when compared to the GG genotype group (6.9% vs. 13.3%, P = 0.026). In addition, subjects with a GA+AA genotype had a significantly lower risk of frailty (odds ratio (OR): 0.47, 95% confidence interval (CI) 0.23 to 0.97, P = 0.040) compared to the GG genotype after adjusting for age, gender, education level, smoking, alcohol consumption, exercise, body mass index (BMI), cognitive impairment, and other potential factors. KL-395A allele carrying genotypes (GA and AA) is associated with a lower risk of frailty relative to GG genotypes in a sample of Chinese nonagenarians and centenarians.

Klotho G-395A gene polymorphism: impact on progression of end-stage renal disease and development of cardiovascular complications in children on dialysis.

Klotho G-395-A gene polymorphism may impact children with end-stage renal disease (ESRD). We investigated the relevance of Klotho G-395-A on ESRD development and progression, and its relationship with evolution of cardiovascular complications in pediatric dialysis patients. Fifty-five children with chronic kidney disease (CKD) and seventy healthy children were genotyped for Klotho G-395A. Incidence of GA/AA genotypes and A allele were higher in ESRD patients compared with controls (54.5 vs. 7.1%, P < 0.001; 30.9 vs. 13.6%, P = 0.001, respectively). Also, children with GA/AA genotypes were 15.6 times more likely to develop ESRD than with GG genotype (95% CI 5.4-44.7, P < 0.001). A allele carriers have 2.8 times higher risk of developing ESRD than those with G allele (95% CI 1.5-5.35, P = 0.001). Also, the A allele could be considered a predictor of cardiovascular disease (CVD), as carriers have 161 times higher risk of cardiovascular complications than non-carriers (95% CI 21-1233, P < 0.001). All ESRD patients with CVD presented with left ventricular hypertrophy (LVH) and the frequency of A allele was significantly higher among ESRD children with LVH, whereas G allele frequency was significantly higher among ESRD children without LVH. The A allele of the G-395A Klotho gene polymorphism shows a significantly higher frequency among children with CKD and those with CVD and LVH. This mutant allele could be used as a risk marker for the development of ESRD as well as a predictor of CVD in these children.

The Klotho gene G-395A polymorphism and metabolic syndrome in very elderly people.

BackgroundTo investigate the possible association of the Klotho G-395A polymorphism and metabolic syndrome (MetS) among a population of Chinese nonagenarians and centenarians.MethodsSubjects were from the Project of Longevity and Aging in Dujiangyan (PLAD). The genotyping of G-395A (rs1207568) in the promoter region of the Klotho gene was performed using the TaqMan allelic discrimination assay. MetS was diagnosed according to the International Diabetes Federation criteria.ResultsWe included 695 subjects aged 93.5 ± 3.2 years. G and A allele frequencies were 0.852 and 0.148, respectively. In the whole population, the frequency of MetS was 10.8 % and 5.9 % in the GG and GA + AA genotype group, respectively (p = 0.004). The -395A allele carriers had significantly lower risk of MetS in the whole population (odd ratio [OR] 0.50, 95 % confidential interval [CI] 0.25 to 0.98) and in women (OR 0.51, 95 % CI 0.24 to 0.97), but not in men (OR 0.42, 95 % CI 0.05 to 3.85). In the whole population and women, the relationship between the Klotho G-395A SNP and MetS might due to its influence on high blood pressure (OR 0.48, 95 % CI 0.34 to 0.67; OR 0.47, 95 % CI 0.31 to 0.71, respectively) and hypertriglyceridemia (OR 0.66, 95 % CI 0.39 to 0.95; OR 0.54, 95 % CI 0.31 to 0.98, respectively). In men, this relationship might due to its influence on high blood pressure (OR 0.47, 95 % CI 0.25 to 0.90) and low HDL-C (OR 0.69, 95 % CI 0.27 to 0.93).ConclusionsThe -395A allele carriers of the Klotho gene were correlated with lower risk of MetS among Chinese nonagenarians and centenarians, especially in women.Electronic supplementary materialThe online version of this article (doi:10.1186/s12877-016-0221-6) contains supplementary material, which is available to authorized users.

G-395A polymorphism in the promoter region of the KLOTHO gene associates with reduced cognitive impairment among the oldest old.

This study aimed to examine the possible association between G-395A polymorphism in the promoter region of the KLOTHO gene and cognitive impairment among Chinese nonagenarians and centenarians. This study is a secondary analysis of the Project of Longevity and Aging in Dujiangyan (PLAD) study. Community-dwelling Chinese people aged 90years or older were included. G-395A (rs1207568) genotyping in the promoter region of the KLOTHO gene was performed using the TaqMan allelic discrimination assay. Cognitive function was assessed with the mini-mental status examination (MMSE). A total of 706 participants (68.0% female; mean age 93.5 ± 3.6years) were included. The KLOTHO G-395A polymorphism genotype frequencies for the whole sample were 2.0% AA, 30.3% GA, and 67.7% GG. The GG genotype frequencies for the cognitive impairment and control groups were 70.2 and 62.7%, respectively. Cognitive impairment prevalence was significantly lower in the GA+AA group than in the GG genotype group (61.4 vs. 69.0%, p = 0.044). GA+AA genotype subjects had a significantly lower risk of cognitive impairment (odds ratio 0.66; 95% confidence interval 0.44 to 0.98) than GG genotype individuals after adjusting for age, gender, and other relevant risk factors. KLOTHO G-395A polymorphism associates with reduced cognitive impairment in a sample of Chinese nonagenarians and centenarians.

G-395A polymorphism in the promoter region of the KLOTHO gene and hypertension among elderly (90 years and older) Chinese individuals.

The aim of this study was to examine the possible associations between the KLOTHO G-395A gene polymorphism and hypertension in Chinese nonagenarians and centenarians. The G-395A (rs1207568) in the promoter region of the KLOTHO gene was genotyped using a standard TaqMan allelic discrimination assay. We included 710 participants aged 93.5 ± 3.2 years in the analyses. The expression of the A allele of the KLOTHO G-395A polymorphism was significantly downregulated in the hypertension group compared to the control group (0.137 vs 0.200, P < 0.001). The genotype distribution of the G-395A polymorphism between the hypertension and control groups was significantly different in women and smokers, and not in men or non-smokers. The mean systolic blood pressure, percentage of hypertension, and percentage of isolated systolic hypertension was significantly higher in the group with the GG genotype than in the group with the GA+AA genotype. Subjects expressing the GA+AA genotype demonstrated a significantly lower risk of hypertension even after adjusting for age, gender, and other relevant risk factors compared to the population expressing the GG genotype (odds ratio, 0.68; 95% confidence interval: 0.49 to 0.95).The -395A allele of the KLOTHO gene may be a protective genetic factor for hypertension in the Chinese population.

Klotho G395A Polymorphism in Egyptian Patients with Diabetic Nephropathy and Hemodialysis

Klotho G395A Polymorphism in Egyptian Patients with Diabetic Nephropathy and Hemodialysis

KLOTHO Gene Polymorphisms G-395A and C1818T Are Associated with Low-Density Lipoprotein Cholesterol and Uric Acid in Japanese Hemodialysis Patients

Background/Aims: This study aimed to investigate the association of the KLOTHO gene single nucleotide polymorphisms (SNPs), G-395A and C1818T, with various laboratory data in 219 Japanese hemodialysis (HD) patients. Methods: The genotyping of G-395A in the promoter region and C1818T in exon 4 was performed using polymerase chain reaction with confronting two-pair primers (PCR-CTPP) assay. Results: In HD patients, the allele frequencies of G-395A were 0.847 for the G allele and 0.153 for the A allele and those of the C1818T were 0.829 for the C allele and 0.171 for the T allele. There were no significant differences in allele frequencies of G-395A and those of the C1818T between HD patients and healthy subjects. Multivariate analysis adjusted for age and duration on HD demonstrated that uric acid was significantly high in A allele carriers of G-395A compared with GG genotype in all and female patients. Low-density lipoprotein cholesterol was significantly low in T allele carriers of C1818T compared with CC genotype in all and male patients. Conclusion:KLOTHO gene SNPs G-395A and C1818T are associated with low-density lipoprotein cholesterol and uric acid in HD patients.

KLOTHO Gene Polymorphism Is Associated With Coronary Artery Stenosis but Not With Coronary Calcification in a Korean Population

Experimental studies have demonstrated KLOTHO gene polymorphism might be associated with vascular atherosclerosis and calcification. However, the impact of this genetic variant on human coronary arteries still remains to be elucidated. We investigated the effect of a KLOTHO gene variant on coronary artery stenosis and calcification. Four hundred and thirty-four patients referred for chest pain were enrolled. All the patients underwent coronary angiography and were investigated for polymorphism of the KLOTHO G395A gene. Coronary artery disease (CAD) was defined as > or = 50% diameter stenosis in at least one coronary artery. The other patients were considered to be controls. Homozygotes or heterozygotes for G395A were significantly more common in the CAD patients than in the controls (30.2% versus 21.5%, P = 0.039). In the subgroup aged < 60 years, the G395A mutant was more frequent in CAD than in control (35.3% versus 18.8%, P = 0.016), but in patients > or = 60 years, there was no difference (28.0% versus 24.1%, P = 0.473). Using multivariate analysis, we identified the KLOTHO gene G395A mutant as an independent risk factor of CAD (OR 1.712, 95% CI [1.066-2.749], P = 0.026). The frequency of the KLOTHO gene G395A mutant was not different between the calcified and noncalcified coronary artery groups (25.7%, 26.4%, respectively, P = 0.861) and an A allele carrier state was not an independent risk factor of coronary artery calcification. In conclusion, the KLOTHO gene G395A allele carrier state may be associated with CAD but not with coronary artery calcification in this Korean population.

Polymorphism in the promoter region of the klotho gene (G-395A) is associated with early dysfunction in vascular access in hemodialysis patients.

Background/AimsVascular access dysfunction is an important cause of morbidity and mortality in hemodialysis (HD) patients. Recent studies have shown that a klotho gene mutation is related to endothelial dysfunction, thrombosis, and arteriosclerosis, which are regarded as causes of vascular access dysfunction. We investigated the relationship between the klotho G-395A polymorphism and early dysfunction in vascular access in HD patients.MethodsPatients who underwent vascular access operations between 1999 and 2002 were enrolled (n=126). Genotyping was performed by allelic discrimination using a 5'-nuclease polymerase chain reaction assay. Clinical data that could be relevant to access dysfunction were obtained from medical records. Early dysfunction of vascular access was defined as the need for any angioplastic or surgical intervention to correct or replace a poorly or nonfunctioning vascular access within 1 year and at least 8 weeks after initial access placement.ResultsOf the 126 patients, the genotype frequency of G-395A was 72.2% for GG (n=91), 24.6% for GA (n=31), and 3.2% for AA (n=4), and the frequency of minor allele was 0.155. Clinical data were similar between the two groups, divided according to the status of the A allele. Early dysfunction occurred in 34 (27.0%) of patients, but it occurred at a significantly higher rate in A allele carriers (45.7%, 16/35) than in noncarriers (19.8%, 18/91; p=0.003).ConclusionsOur results suggest that the klotho G-395A polymorphism could be a risk factor for early dysfunction of vascular access in HD patients.

The differential effects of age on the association of KLOTHO gene polymorphisms with coronary artery disease

The Klotho knockout mouse is thought to be a good animal model for human aging. Recent studies have reported on the association of KLOTHO gene mutation with cardiovascular disease in humans. We observed the frequencies of single nucleotide polymorphisms, that is, G-395A in the promoter region, C1818T in exon 4, and a functional variant, KL-VS, of KLOTHO gene in Koreans, and we investigated their relationships with the presence of coronary artery disease (CAD) in patients who had undergone coronary angiograms. A total of 274 subjects who underwent coronary angiograms because of chest pain were enrolled, and their blood pressure, body mass index, fasting blood glucose level, and lipid profiles were measured. Genotypings were performed on samples of their blood with real-time polymerase chain reaction. Two single nucleotide polymorphisms, G-395A and C1818T, complied with Hardy-Weinberg equilibrium. For the KL-VS genotype, 1 homozygote subject for the adverse allele was detected among the entire population (GG for F352V and CC for C370S). When the subjects were classified into 4 groups according to the number of stenotic vessels, there were no differences among the mean values of the cardiovascular risk factors, except for age and the fasting blood glucose levels, which showed a significant difference between that of the normal and the diseased vessel groups. There were no differences in the prevalence of CAD according to the genotypes of the G-395A polymorphism; however, for the C1818T polymorphism, those subjects with the T allele showed a lower prevalence of CAD than those with the CC genotype. When the subjects were divided into 2 groups according to age, in the group younger than 60 years, T allele carriers of the C1818T polymorphism showed a lower prevalence of CAD than did the noncarriers. In the group older than 60 years, A allele carriers of the G-395A polymorphism showed a lower prevalence of CAD than did the noncarriers. On the haplotype analysis, the GG-CC haplotype showed an increased risk for CAD with an odds ratio of 2.594 (95% confidence interval, 1.385-4.858; P = 0.003). Differential effects of age were observed in the association of KLOTHO G-395A and C1818T polymorphisms with CAD in Koreans. The KL-VS variant seems to be rarely found in the Korean population. These results infer the possibility of the KLOTHO gene being a candidate gene of atherosclerosis in humans, and further research on this topic needs to be done.

Relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women

Recently, klotho has been proposed as a link between cardiovascular diseases and premature aging, but the relationship between KLOTHO genes and cardiovascular risk factors, especially glucose metabolism, in humans is unclear. We investigate the relationship between polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene with glucose metabolism and cardiovascular risk factors in Korean women. In 251 women (mean age 51.3+/-6.9 yr), body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, insulin and lipid profiles were measured. The genotyping of polymorphisms G395A in promoter and C1818T in exon 4 of the KLOTHO gene was performed by allelic discrimination using a 5' nuclease polymerase chain reaction assay. Allele frequencies of G395A polymorphism was 0.829 for the G allele and 0.171 for the A allele and allele frequencies of C1818T polymorphism were 0.804 for the C allele and 0.196 for the T allele, both of which were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in linkage disequilibrium (D'=0.43, p<0.01). Mean systolic blood pressure was significantly higher in A allele carriers of G395A polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Mean fasting plasma glucose was significantly higher in T allele carriers of C1818T polymorphism compared with non-carriers, and the significance was persistent even after adjustment for age and BMI. Subjects without any minor allele from either single nucleotide polymorphisms (SNP) had significantly lower mean values for systolic, diastolic blood pressure and fasting plasma glucose levels compared with subjects with both minor allele from either SNP. We observed that KLOTHO G395A polymorphism was associated with blood pressure and KLOTHO C1818T polymorphism was associated with glucose metabolism in Korean women. Further studies are needed to clarify this relationship.