ADARB1
Double-stranded RNA-specific editase 1 (EC 3.5.4.37) (RNA-editing deaminase 1) (RNA-editing enzyme 1) (dsRNA adenosine deaminase) [ADAR2] [DRADA2] [RED1]
PublicationsПравить
Single nucleotide polymorphisms (SNPs) of the adenosine deaminase, RNA-specific (ADAR) gene were reported to be associated with human longevity. There are possibilities that ADAR is associated with major risk factors of atherosclerotic cardiovascular diseases (CVD), such as hypertension, diabetes, dyslipidemia, and obesity. To investigate the association between SNPs of the ADAR gene and clinical data associated with major risk factors of atherosclerotic CVD. A total of 1504 general population residents (586 males and 918 females) of two towns, Tanno-cho and Sobestu-cho, in Hokkaido, Japan. Clinical data associated with risk factors of atherosclerotic CVD were collected from these study subjects. DNA from peripheral blood and written informed consent were obtained. Three single nucleotide polymorphisms of ADARB1 and ADARB2, which were previously reported to be associated with longevity, were genotyped employing the TaqMan PCR method. The associations between SNPs in ADARB1 and ADARB2 and clinical parameters related to risk factors of atherosclerosis were analyzed. On uni- and multivariate analyses, rs2805533 in ADARB2 was significantly associated with the abdominal circumference, body mass index, serum triglyceride level, and serum adiponectin level. The subjects with the AA genotype of rs2805533 had a greater abdominal circumference, higher body mass index, higher triglyceride level, and lower adiponectin level than those with AG and GG genotypes. The SNP in ADARB2 related to longevity is associated with metabolic disorders. This finding suggests that genetic factors modulate human longevity via the regulation of metabolic factors such as abdominal obesity and lipid profiles.
MeSH Terms
- Adenosine Deaminase
- Adiponectin
- Aged
- Analysis of Variance
- Asian Continental Ancestry Group
- Biomarkers
- Female
- Humans
- Intra-Abdominal Fat
- Japan
- Longevity
- Male
- Middle Aged
- Polymorphism, Single Nucleotide
- RNA Editing
- RNA-Binding Proteins
- Risk Factors
- Triglycerides
- Waist Circumference
The strong familiality of living to extreme ages suggests that human longevity is genetically regulated. The majority of genes found thus far to be associated with longevity primarily function in lipoprotein metabolism and insulin/IGF-1 signaling. There are likely many more genetic modifiers of human longevity that remain to be discovered. Here, we first show that 18 single nucleotide polymorphisms (SNPs) in the RNA editing genes ADARB1 and ADARB2 are associated with extreme old age in a U.S. based study of centenarians, the New England Centenarian Study. We describe replications of these findings in three independently conducted centenarian studies with different genetic backgrounds (Italian, Ashkenazi Jewish and Japanese) that collectively support an association of ADARB1 and ADARB2 with longevity. Some SNPs in ADARB2 replicate consistently in the four populations and suggest a strong effect that is independent of the different genetic backgrounds and environments. To evaluate the functional association of these genes with lifespan, we demonstrate that inactivation of their orthologues adr-1 and adr-2 in C. elegans reduces median survival by 50%. We further demonstrate that inactivation of the argonaute gene, rde-1, a critical regulator of RNA interference, completely restores lifespan to normal levels in the context of adr-1 and adr-2 loss of function. Our results suggest that RNA editors may be an important regulator of aging in humans and that, when evaluated in C. elegans, this pathway may interact with the RNA interference machinery to regulate lifespan.
MeSH Terms
- Adenosine Deaminase
- Adolescent
- Adult
- Aged
- Aged, 80 and over
- Algorithms
- Animals
- Caenorhabditis elegans
- Chromosomes, Human, Pair 10
- Female
- Gene Frequency
- Genes, Helminth
- Genotype
- Humans
- Linkage Disequilibrium
- Longevity
- Male
- Middle Aged
- Odds Ratio
- Polymorphism, Single Nucleotide
- RNA Editing
- RNA-Binding Proteins
- Reproducibility of Results
- Young Adult