Klotho locus, metabolic traits, and serum hemoglobin in hospitalized older patients: a genetic association analysis

Abstract

Klotho (KL) gene has been involved in severe alterations of physiological biochemical parameters leading to premature aging-like phenotypes and strikingly shortening lifespan. KL participates to the regulation of a number of intracellular biochemical pathways, including lipid profile and glucose metabolism. Aim of this study was to investigate the possible association between KL locus and biological parameters commonly accepted as indicators of the clinical status in hospitalized older patients. We genotyped the single-nucleotide polymorphisms (SNPs) rs9536314, rs1207568, and rs564481 at the KL locus in 594 hospitalized older patients (65-99 years), consecutively attending a geriatric ward, and tested the association of these KL variants with biological quantitative traits using analyses of covariance and genetic risk score models. Significant associations of rs9536314 with serum levels of hemoglobin, albumin, and high-density lipoprotein cholesterol (HDL-C) as well as significant associations of rs564481 with serum levels of hemoglobin, fasting insulin, and fasting glucose were observed. Gender-segregated analyses confirmed these associations, and suggested that the associations of KL genotypes with HDL-C, fasting glucose and fasting insulin levels may be driven by the female gender, while the association with serum levels of hemoglobin may be driven by the male gender. The association of KL genotypes with creatinine levels was found only in females, while the association with insulin-like growth factor-1 (IGF-1) and lymphocytes count (LC) was found only in males. The genetic risk score (GRS) models further confirmed significant associations among KL SNPs and hemoglobin, total cholesterol, and HDL-C. Gender-segregated analyses with the GRS-tagged approach confirmed the associations with HDL-C, fasting glucose, and fasting insulin levels in females, and with hemoglobin and LC in males. Our findings suggested that KL locus AGE (2012) may influence quantitative traits such as serum levels of lipid, fasting glucose, albumin and hemoglobin in hospitalized older patients, with some gender differences suggested for creatinine, IGF-1 levels, and LC, thus being one of the genetic factors possibly contributing to age-related diseases and longevity.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

“…KL was first identified as a gene related to suppression of aging: its reduced expression was associated with reduced lifespan, as well as hypoglycemia 11 . Despite further animal studies supporting a role for KL in glucose metabolism 12 and insulin sensitivity 13 , human studies have generally been small and inconclusive 14 , 15 .…”

“…rs576674 lies ~36 kb upstream of KL . Variation in KL has been associated with insulin regulation, insulin resistance phenotypes and cardiovascular disease in some studies 14 , 15 , 58 , 59 but KL variants were not associated with diabetes risk 60 . The various SNPs in these studies are all in weak LD with rs576674 ( r 2 < 0.125).…”

The role of Klotho in energy metabolism

“…An association between KL genotypes, determined by single nucleotide polymorphism analysis, and fasting levels of either high glucose or low insulin was reported in hospitalized elderly (age >65 years, mean age 79.04 ± 7.14) female patients. 113 …”

Determination of the Relationship Between DNA Methylation Status of KLOTHO and ARNTL Genes With Hypertension

“…The F352V (rs9536314 T> G) polymorphism of the KL gene was correlated with salt-sensitive hypertension in an Italian study [ 14 ]. The KL rs9536314 and rs564481 polymorphisms were associated with increasing levels of HDL-C in females [ 42 ]. High HDL-C levels were suggested to be protective against KL dysfunction [ 40 ].…”