AGTR1
Type-1 angiotensin II receptor (AT1AR) (AT1BR) (Angiotensin II type-1 receptor) (AT1) [AGTR1A] [AGTR1B] [AT2R1] [AT2R1B]
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Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead. We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events. We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study. Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50-3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063). Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data.
MeSH Terms
- Aged
- Aging
- Bone and Bones
- Coronary Disease
- Environmental Exposure
- Female
- Genetic Predisposition to Disease
- Humans
- Lead
- Male
- Middle Aged
- Polymorphism, Genetic
Genetic factors confer risk for neuropsychiatric phenotypes, but the polygenic etiology of these phenotypes makes identification of genetic culprits challenging. An approach to this challenge is to examine the effects of genetic variation on relevant endophenotypes, such as hippocampal volume loss. A smaller hippocampus is associated with gene variants of the renin-angiotensin system (RAS), a system implicated in vascular disease. However, no studies to date have investigated longitudinally the effects of genetic variation of RAS on the hippocampus. The authors examined the effects of polymorphisms of AGTR1, the gene encoding angiotensin-II type 1 receptor of RAS, on longitudinal hippocampal volumes of older adults. In all, 138 older adults (age ≥60 years) were followed for an average of about 4 years. The participants underwent repeated structural MRI and comprehensive neurocognitive testing, and they were genotyped for four AGTR1 single-nucleotide polymorphisms (SNPs) with low pairwise linkage disequilibrium values and apolipoprotein E (APOE) genotype. Genetic variants at three AGTR1 SNPs (rs2638363, rs1492103, and rs2675511) were independently associated with accelerated hippocampal volume loss over the 4-year follow-up period in the right but not left hemisphere. Intriguingly, these AGTR1 risk alleles also predicted worse episodic memory performance but were not related to other cognitive measures. Two risk variants (rs2638363 and rs12721331) interacted with the APOE4 allele to accelerate right hippocampal volume loss. Risk genetic variants of the RAS may accelerate memory decline in older adults, an effect that may be conferred by accelerated hippocampal volume loss. Molecules involved in this system may hold promise as early therapeutic targets for late-life neuropsychiatric disorders.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Apolipoprotein E4
- Cognition Disorders
- Endophenotypes
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Genetic Variation
- Hippocampus
- Humans
- Linkage Disequilibrium
- Male
- Memory, Episodic
- Middle Aged
- Organ Size
- Polymorphism, Single Nucleotide
- Receptor, Angiotensin, Type 1
- Renin-Angiotensin System
Vascular aging consists of complex and multifaceted processes that may be influenced by genetic polymorphisms of the renin-angiotensin system. A polymorphism in the angiotensin II type 1 receptor gene (AGTR1/rs5186) has been associated with an increased risk for arterial stiffness, hypertension, and ischemic stroke. Despite these identified relationships, the impact of AGTR1 A1166C on white matter integrity and cognition is less clear in a healthy aging population. The present study utilized indices of neuroimaging and neuropsychological assessment to examine the impact of the A1166C polymorphism on subcortical hyperintensities (SH) and cognition in 49 healthy adults between ages 51-85. Using a dominant statistical model (CC CA (risk) vs. AA), results revealed significantly larger SH volume for individuals with the C1166 variant (p < 0.05, partial eta(2) = 0.117) compared with those with the AA genotype. Post hoc analyses indicated that increased SH volume in C allele carriers could not be explained by vascular factors such as pulse pressure or body mass index. In addition, cognitive performance did not differ significantly between groups and was not significantly associated with SH in this cohort. Results suggest that presence of the C1166 variant may serve as a biomarker of risk for suboptimal brain integrity in otherwise healthy older adults prior to changes in cognition.
MeSH Terms
- Aging
- Cognition
- Female
- Follow-Up Studies
- Genotype
- Humans
- Intracranial Hypertension
- Male
- Middle Aged
- Polymorphism, Genetic
- Receptor, Angiotensin, Type 1
- Reference Values
- Risk Factors
- Vascular Stiffness
We examined the influence of the AGTR1 A1166C genotype on the 16-year evolution of pulse wave velocity (PWV) in a middle-aged population. In a cross-sectional study, we reported that the presence of the AGTR1 1166C allele was associated with higher aortic stiffness compared with the AGTR1 1166AA genotype. The study was conducted in 259 subjects who underwent 3 health check-ups over 16 years at the Centre IPC-Paris: an initial visit in 1992-1993, an intermediate visit in 1998-1999, and a final visit in 2007-2008. Aortic stiffness was assessed during the 3 visits by measuring carotid-femoral PWV. AGTR1 A1166C polymorphism was assayed by allele-specific oligonucleotide hybridization. AGTR1 1166C allele carriers (AC CC genotypes) had a 35% more pronounced increase in PWV over this 16-year period when compared with the AGTR1 1166AA subjects (3.01 ± 0.32 vs. 1.92 ± 0.23 m/s; P < 0.001). This increase remained significant after adjustment for age, sex, initial PWV values, and changes in blood pressure ( 37%; P < 0.05). The genotype-related differences in PWV were only observed at the last visit (i.e., later in life, after the age of 55 years). The effects of this genotype on PWV were not related to the presence of antihypertensive treatment. This is the first long-term longitudinal study indicating that AT1 1166C carriers are at increased risk of pronounced arterial stiffening during aging especially after the age of 55.
MeSH Terms
- Adult
- Aged
- Alleles
- Biomarkers
- Cohort Studies
- Cross-Sectional Studies
- Disease Progression
- Female
- Genotype
- Heterozygote
- Humans
- Hypertension
- Longitudinal Studies
- Male
- Middle Aged
- Polymorphism, Genetic
- Predictive Value of Tests
- Receptor, Angiotensin, Type 1
- Sensitivity and Specificity
- Vascular Stiffness
Keywords
- aging
- angiotensin receptors
- arterial stiffness
- blood pressure
- genetic polymorphism
- hypertension.
The aim of this study was to evaluate the role of polymorphisms of renin-angiotensin system (RAS) genes in modulating outdoor temperature-related blood pressure (BP) responses. Data for RAS gene polymorphisms, BP and outdoor temperature were collected from 4903 subjects from February 2003 to August 2004. Generalized additive and linear models were used to determine whether genetic variants of RAS affected the interplay between outdoor temperature and BP. Outdoor temperature (°C) was inversely associated with systolic BP and diastolic BP. These inverse relationships were stronger in subjects with ACE DD, AGT TT and AGTR1 AA genotypes. In contrast, significant positive temperature-dependent BP responses were found at temperatures above 21.4 °C in subjects with the AGTR1 C allele, but not at temperatures below 21.4 °C. Our findings suggest that subjects with ACE DD, AGT TT or AGTR1 AA genotypes are susceptible to cold temperature-induced BP increase, whereas subjects with AGTR1 C allele have a high risk of BP elevation when exposed to hot temperatures.
MeSH Terms
- Aging
- Angiotensinogen
- Blood Pressure
- DNA
- Female
- Genotype
- Humans
- Male
- Middle Aged
- Peptidyl-Dipeptidase A
- Polymorphism, Genetic
- Receptor, Angiotensin, Type 1
- Renin-Angiotensin System
- Sex Characteristics
- Sex Factors
- Temperature
Longevity phenotype in humans results from the influence of environmental and genetic factors. Few gene polymorphisms have been identified so far with a modest effect on lifespan leaving room for the search of other players in the longevity game. It has been recently demonstrated that targeted disruption of the mouse homolog of the human angiotensin II type 1 receptor (AT1R) gene (AGTR1) translates into marked prolongation of animal lifespan (Benigni et al., J Clin Invest 119(3):524-530, 2009). Based on the above study in mice, here we sought to search for AGTR1 variations associated to reduced AT1 receptor protein levels and to prolonged lifespan in humans. AGTR1 was sequenced in 173 Italian centenarians and 376 younger controls. A novel non-synonymous mutation was detected in a centenarian. Two polymorphisms in AGTR1 promoter, rs422858 and rs275653, in complete linkage disequilibrium, were significantly associated with the ability to attain extreme old age. We then replicated the study of rs275653 in a large independent cohort of Japanese origin (598 centenarians and semi-supercentenarians, 422 younger controls) and indeed confirmed its association with exceptional old age. In combined analyses, rs275653 was associated to extreme longevity either at recessive model (P = 0.007, odds ratio (OR) 3.57) or at genotype level (P = 0.015). Significance was maintained after correcting for confounding factors. Fluorescence activated cell sorting analysis revealed that subjects homozygous for the minor allele of rs275653 had less AT1R-positive peripheral blood polymorphonuclear cells. Moreover, rs275653 was associated to lower blood pressure in centenarians. These findings highlight the role of AGTR1 as a possible candidate among longevity-enabling genes.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Alleles
- DNA
- Female
- Gene Frequency
- Genotype
- Humans
- Italy
- Linkage Disequilibrium
- Longevity
- Male
- Middle Aged
- Phenotype
- Polymorphism, Genetic
- Receptor, Angiotensin, Type 1
- Retrospective Studies
Incidental white matter lesions (WML) are a common neuroradiological finding in elderly people and have been linked to dementia and depression. Various mechanisms including hypoxia and increased production of reactive oxygen species (ROS) are implicated in the etiology of WML. The hemochromatosis (HFE) gene p.H63D and p.C282Y polymorphisms have been linked to dysregulation of iron metabolism and increased levels of ROS, whereas Angiotensin II receptor 1 (AGTR1) c.1166A → C polymorphism is known as a vascular risk factor. These genetic polymorphisms were characterized in brains donated to the UK MRC Cognitive Function and Ageing Study (CFAS) to assess their potential role in the risk for development of age-related WML. The study cohort comprised 258 brain donated to CFAS. WML severity was assessed in the postmortem brain donations using magnetic resonance imaging (MRI) scans and scored using the Scheltens' scale. Polymerase chain reaction (PCR) amplification of extracted DNA followed by restriction enzyme digestion was used to genotype the samples. Genotypes were validated using direct sequencing in a smaller sample. The results show that HFE p.H63D polymorphism is not associated with WML severity in the whole cohort. However, there is a significant association of the D allele with severity of WML in noncarriers of the APOE ε4 allele. No association is demonstrated between the HFE p.C282Y nor the AGTR1 c.1166A → C polymorphisms and WML severity. The HFE gene appears to be a genetic risk factor for severe aging WML independently of the APOE ε4 genotype. This would support the role of iron-related oxidative stress, in addition to previously studied factors, e.g., hypoxia as potential risk factors for developing prominent aging WML.
MeSH Terms
- Aged
- Aged, 80 and over
- Aging
- Amino Acids
- Brain
- Female
- Gene Frequency
- Genetic Predisposition to Disease
- Genotype
- Hemochromatosis Protein
- Histocompatibility Antigens Class I
- Humans
- Leukoencephalopathies
- Magnetic Resonance Imaging
- Male
- Membrane Proteins
- Middle Aged
- Polymorphism, Single Nucleotide
- Receptor, Angiotensin, Type 1
- Risk Factors