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.

Figure 1.

Heat map of ranked association p values for single-nucleotide polymorphisms (SNPs) in Table 1. First column: frailty association p values; second column: combined p values of frailty component variables; subsequent columns: individual phenotypic components of frailty. Each row represents one SNP with darker shades indicating increased strength of association compared with lighter shades.

Figure 2.

Scatter plot of −log₁₀ p value of individual single-nucleotide polymorphism association with frailty and combined p value.