Background: Creatine is a central regulator of cellular energy homeostasis and one of the most extensively studied dietary supplements in human nutrition. Although creatine supplementation consistently increases tissue creatine availability and supports performance and health across diverse populations, substantial interindividual variability in responsiveness persists. Approximately one-quarter of individuals demonstrate minimal increases in tissue creatine or functional benefit following supplementation. While non-genetic factors such as baseline creatine status, diet, age, sex, and training load contribute to this heterogeneity, the role of common genetic variation remains insufficiently explored. Importantly, creatine bioavailability and functional responsiveness are related but distinct outcomes, and both may be modified by genetic background. Objective: This paper aims to reframe creatine responsiveness as a quantitative, polygenic trait shaped by common low-impact genetic variants rather than a binary responder-non-responder phenomenon driven by rare pathogenic mutations. The review synthesizes evidence on genetic variation affecting creatine transport, endogenous synthesis, and downstream energy metabolism, with an emphasis on population-relevant mechanisms. Methods: A narrative, mechanism-oriented review was conducted integrating data from human genetics databases, biochemical pathways, and physiological studies. The analysis focused on (i) common low-impact variants in genes directly regulating creatine transport (SLC6A8) and biosynthesis (GATM, GAMT), and (ii) modifier genes involved in mitochondrial function, phosphagen buffering, and muscle or neural energetic phenotype. Variant classification frameworks from expert curation initiatives were used to distinguish pathogenic from low-impact population variants. Results: Low-impact variants in the creatine transporter gene SLC6A8 are highly prevalent and likely contribute to a continuum of creatine transport efficiency, with sex-dependent effects due to X-linked inheritance. Similarly, common polymorphisms in creatine biosynthetic enzymes (GATM and GAMT) may subtly alter synthetic efficiency or methyl-group demand, increasing dietary creatine dependence while not causing overt deficiency. Beyond creatine-specific pathways, genetic variation in mitochondrial regulators, electron transport chain components, creatine kinase isoforms, and muscle fiber-type determinants can act as effect modifiers, amplifying or dampening the functional benefits of creatine despite comparable tissue uptake. Collectively, small additive effects across transport, synthesis, and utilization pathways may prevent supplementation from exceeding the threshold required for measurable benefit in certain individuals. Conclusions: Creatine non-responsiveness in the general population is more plausibly explained by the cumulative influence of common low-impact genetic variants than by rare monogenic defects. Viewing creatine responsiveness as a graded, polygenic trait provides a coherent framework to interpret heterogeneous findings in supplementation trials. Incorporating genetic context into study design, through stratified analyses or pathway-based approaches, may improve sensitivity to detect true effects and support the development of precision-guided creatine supplementation strategies in both clinical and public health settings.
Ostojic et al. (Fri,) studied this question.