Table 1.
A summary of human PPARγ genetic variants and their main characteristics.
| Variant | Main characteristics and phenotypic effects | References |
|---|---|---|
| Common polymorphisms | ||
| Pro12Ala | Specific to PPARγ2 isoform; ethnicity-dependent frequency ≤20%. Ala variant less active, protects from T2DM and weight gain in lean subjects, but with opposite effect in obese subjects. Effects on longevity, cognition, atherosclerosis, HT, birth weight, MI and cancer. Phenotypic effects modulated by environmental and genetic factors. |
[30,31,33-36,53] [41-48] [37-40,49] |
| His477His | Silent, single nucleotide polymorphism; frequency ∼14-20%. Associated with leptin levels, BMI, bone density, MI, and atherotic lipid changes. |
[64-68] |
| Dominant-negative, loss-of-function mutations | ||
| Pro467Leu Val290Met Cys114Arg Cys131Tyr Cys162Trp 315Stop Arg357X |
Mutant proteins that inhibit also the wild type protein. Either lack DNA or cofactor binding capacity. Severe insulin resistance or full diabetes, fatty liver, partial lipodystrophy, dyslipidemia, and often also HT. |
[54-59] |
| Haploinsufficient mutations | ||
| Arg425Cys Phe388Leu Tyr355X 185Stop |
Result in non-functional or missing protein without effect on the wild type variant. Severe insulin resistance or full diabetes, fatty liver, partial lipodystrophy, dyslipidemia, and often also HT, i.e. the same as for dominant-negative variants. |
[54,56,61,62] |
| Gain-of-function mutations | ||
| Pro115Gln | Constitutively active. Carriers extremely obese, but paradoxically with normal insulin sensitivity. |
[60] |
| Promoter variants | ||
| P2 C-689T | Associates with increased body weight and LDL levels; mechanism unknown. | [71] |
| P2 C-2821T | Associates with whole-body and hepatic insulin action; affects MyoD binding (?) | [69] |
| P3 C-681G | Associates with large body size and LDL levels; affects STAT5B binding. | [70] |
| P4 A-14G | Partial lipodystrophy, metabolic syndrome, no HT; reduced promoter activity. | [63] |
Notes: Frequencies are given only for the common polymorphisms as the rest are typically very rare, each found only in a hand-full of subjects. Reference list for the Pro12Ala variant is far from complete, e.g. several studies on the other variants also include this variant. T2DM, type 2 diabetes mellitus; HT, hypertension; MI, myocardial infarction; BMI, body mass index; MyoD, myogenin differentiation 1; STAT5B, signal transducer and activator of transcription 5B.