title: Exploring biologically relevant pathways in frailty.
abstract: BACKGROUND
  Frailty is a late-life syndrome of vulnerability to adverse health outcomes characterized by a phenotype that includes muscle weakness, fatigue, and inflammatory pathway activation. The identification of biologically relevant pathways that influence frailty is challenged by its biological complexity and the necessity in separating disease states from the syndrome of frailty. As with longevity research, genetic analyses may help to provide insights into biologically relevant pathways that contribute to frailty.
  
  
  METHODS
  Based on current understanding of the physiological basis of frailty, we hypothesize that variation in genes related to inflammation and muscle maintenance would associate with frailty. One thousand three hundred and fifty-four single-nucleotide polymorphisms were genotyped across 134 candidate genes using the Illumina Genotyping platform, and the rank order by strength of association between frailty and genotype was determined in a cross-sectional study.
  
  
  RESULTS
  Although no single-nucleotide polymorphism reached study-wide significance after controlling family-wise false-discovery rate at 0.05, single-nucleotide polymorphisms within the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), Caspase 8 (CASP8), CREB-binding protein (CREBBP), lysine acetyltransferase 2B (KAT2B), and beta-transducin repeat containing (BTRC) loci were among those strongly associated with frailty.
  
  
  CONCLUSIONS
  The apoptosis- and transcription regulation-related pathways highlighted by this preliminary analysis were consistent with prior gene expression studies in a frail mouse model and provide useful etiological insights for future biological studies of frailty.
authors: Division of Geriatric Medicine and Gerontology, Johns Hopkins University School of Medicine, 5505 Bayview Circle, Baltimore, MD 21224, USA. jwalston@jhmi.edu
authors: Yen-Yi
authors: YY
authors: Ho
authors: Amy M
authors: AM
authors: Matteini
authors: Brock
authors: B
authors: Beamer
authors: Linda
authors: L
authors: Fried
authors: Qian-li
authors: QL
authors: Xue
authors: Dan E
authors: DE
authors: Arking
authors: Aravinda
authors: A
authors: Chakravarti
authors: M Daniele
authors: MD
authors: Fallin
authors: Jeremy
authors: J
authors: Walston
mesh_terms: D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003430:Cross-Sectional Studies; D005260:Female; D016330:Frail Elderly; D005838:Genotype; D006801:Humans; D051379:Mice; D020641:Polymorphism, Single Nucleotide