Single gene contributions: genetic variants of peroxisome proliferator-activated receptor (isoforms α, β/δ and γ) and mechanisms of dyslipidemias

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Purpose of review

Polymorphisms in peroxisome proliferator-activated receptor isoforms may be among the most important single-gene contributors to dyslipidemias, insulin resistance, and maturity-onset diabetes.

Recent findings

Familial partial lipodystrophy is a rare but characteristic phenotype associated with carriers of peroxisome proliferator-activated receptor-γ missense mutations. Mutant receptors are transcriptionally defective, exhibit aberrant affinity for co-regulator molecules, and can exert dominant-negative or haplo-insufficiency effects on normal peroxisome proliferator-activated receptor-γ function. The P12A variant of isoform γ is estimated to reduce diabetes risk by 19% in many populations, and has a large attributable risk because of high prevalence of the normal allele. Variants L162V and V227A of isoform α (common in white and Oriental populations, respectively) are associated with sexually dimorphic perturbations of lipid metabolism and cardiovascular risk. Polymorphisms in isoforms α and β/δ are reported to influence lipid and glucose utilization. Apart from lipodystrophic syndromes, metabolic and cardiovascular risk in peroxisome proliferator-activated receptor variants is apparently modulated by dietary and exercise interventions, and interactions with polymorphisms in other genetic loci.


Polymorphisms in peroxisome proliferator-activated receptors are critical susceptibility risk factors for dyslipidemias and diabetes. They provide attractive targets for gene–environment interventions to reduce the burden of metabolic disease.

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