Effect of Bcl-2 rs956572 polymorphism on age-related gray matter volume changes

Abstract

The anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) gene is a major regulator of neural plasticity and cellular resilience. Recently, the Bcl-2 rs956572 single nucleotide polymorphism was proposed to be a functional allelic variant that modulates cellular vulnerability to apoptosis. Our cross-sectional study investigated the genetic effect of this Bcl-2 polymorphism on age-related decreases in gray matter (GM) volume across the adult lifespan. Our sample comprised 330 healthy volunteers (191 male, 139 female) with a mean age of 56.2±22.0 years (range: 21-92). Magnetic resonance imaging and genotyping of the Bcl-2 rs956572 were performed for each participant. The differences in regional GM volumes between G homozygotes and A-allele carriers were tested using optimized voxel-based morphometry. The association between the Bcl-2 rs956572 polymorphism and age was a predictor of regional GM volumes in the right cerebellum, bilateral lingual gyrus, right middle temporal gyrus, and right parahippocampal gyrus. We found that the volume of these five regions decreased with increasing age (all P<.001). Moreover, the downward slope was steeper among the Bcl-2 rs956572 A-allele carriers than in the G-homozygous participants. Our data provide convergent evidence for the genetic effect of the Bcl-2 functional allelic variant in brain aging. The rs956572 G-allele, which is associated with significantly higher Bcl-2 protein expression and diminished cellular sensitivity to stress-induced apoptosis, conferred a protective effect against age-related changes in brain GM volume, particularly in the cerebellum.

Figure 1. Interaction of Bcl-2 genotype and age on regional gray matter volume.

Interaction of Bcl-2 genotype and age on (A) right cerebellum, (B) right lingual gyrus (BA17), (C) left lingual gyrus (BA18), (D) right middle temporal gyrus (BA19), and (E) right parahippocampal gyrus (hippocampus). (F) Showing the interaction results of voxel-wised covariate analysis using Bcl-2 genotype as a condition and age as covariates, controlling sex and education level as nuisance variables (uncorrected p<0.001, cluster size larger than 50). Abbreviations: MTG, middle temporal gyrus; BA, Brodmann Area.