Inositol Polyphosphate Multikinase (IPMK), a Gene Coding for a Potential Moonlighting Protein, Contributes to Human Female Longevity

Abstract

Biogerontological research highlighted a complex and dynamic connection between aging, health and longevity, partially determined by genetic factors. Multifunctional proteins with moonlighting features, by integrating different cellular activities in the space and time, may explain part of this complexity. Inositol Polyphosphate Multikinase (IPMK) is a potential moonlighting protein performing multiple unrelated functions. Initially identified as a key enzyme for inositol phosphates synthesis, small messengers regulating many aspects of cell physiology, IPMK is now implicated in a number of metabolic pathways affecting the aging process. IPMK regulates basic transcription, telomere homeostasis, nutrient-sensing, metabolism and oxidative stress. Here, we tested the hypothesis that the genetic variability of IPMK may affect human longevity. Single-SNP (single nuclear polymorphism), haplotype-based association tests as well as survival analysis pointed to the relevance of six out of fourteen genotyped SNPs for female longevity. In particular, haplotype analysis refined the association highlighting two SNPs, rs2790234 and rs6481383, as major contributing variants for longevity in women. Our work, the first to investigate the association between variants of IPMK and longevity, supports IPMK as a novel gender-specific genetic determinant of human longevity, playing a role in the complex network of genetic factors involved in human survival.

Keywords: IPMK; SNP; aging; gender-specific association; inositol phosphates; longevity; moonlighting protein; polymorphism; survival.

Figure 1

Schematic representation of (A) selected polymorphisms in the Inositol Polyphosphate Multikinase (IPMK) region; (B) linkage disequilibrium (r² coefficient) among the single nuclear polymorphisms (SNPs).

Figure 2

Survival functions of female carriers of minor allele (black) vs non-carriers (grey) of IPMK variants. (A) rs2790156; (B) rs2790234; (C) rs2590320; (D) rs6481383; (E) rs1832556; (F) rs2251039. Time is expressed in months, where 0 is considered the time of recruitment and each individual is followed up for survival status till death. The Cox regression was adjusted for age. Hazard ratio (HR) value, confidence interval and p-value from Cox regression analysis are reported inside the figure.