# X chromosome dosage drives statin-induced dysglycemia and mitochondrial dysfunction

## TL;DR

Women are more likely to experience statin side effects like diabetes and muscle weakness due to X chromosome dosage and low DHA levels, which can be mitigated with fish oil.

## Contribution

The study identifies X chromosome dosage and Kdm5c gene as genetic risk factors for statin-induced dysglycemia and mitochondrial dysfunction in females.

## Key findings

- Statin-treated female mice show reduced DHA levels, impaired redox tone, and reduced mitochondrial respiration.
- Administering fish oil or reducing X chromosome dosage prevents statin adverse effects in female mice.
- Women experience greater DHA reduction after statin treatment than men, and DHA levels are inversely correlated with glucose levels.

## Abstract

Statin drugs lower blood cholesterol levels for cardiovascular disease prevention. Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes (NOD) and muscle weakness. Here we find that impaired glucose homeostasis and muscle weakness in statin-treated female mice are associated with reduced levels of the omega-3 fatty acid, docosahexaenoic acid (DHA), impaired redox tone, and reduced mitochondrial respiration. Statin adverse effects are prevented in females by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene, which escapes X chromosome inactivation and is normally expressed at higher levels in females than males. As seen in female mice, we find that women experience more severe reductions than men in DHA levels after statin administration, and that DHA levels are inversely correlated with glucose levels. Furthermore, induced pluripotent stem cells from women who developed NOD exhibit impaired mitochondrial function when treated with statin, whereas cells from men do not. These studies identify X chromosome dosage as a genetic risk factor for statin adverse effects and suggest DHA supplementation as a preventive co-therapy.

Women are more likely than men to experience adverse statin effects, particularly new-onset diabetes and muscle weakness. Here the authors show that statin-treated female mice show reduced levels of docosahexaenoic acid (DHA) and that the adverse effects are prevented by administering fish oil as a source of DHA, by reducing dosage of the X chromosome or the Kdm5c gene.