Peroximase Proliferator-Activated Receptor
PPARγ Pro12Ala C>G
Allele frequency in population:
2-25% depending on ethnicity or 2-18% in healthy people.
Gene and SNP Summary
The PPARG gene encodes for a ligand activated transcription factor, PPARG, that plays a role in the gene expression for adipocyte differentiation, lipid storage, glucose metabolism and insulin sensitivity. It also modulates inflammation and immunity.
The Pro-allele has been strongly associated with insulin resistance and type 2 diabetes mellitus (T2DM)5 especially in the presence of a high fat diet and/or a high level of circulating lipids; there are however some contradicting studies as to whether this mutation leads to increased or decreased adiposity. The conflicting outcomes are thought to be as a result of environmental influences.
Gene expression and the effect on adiposity seems to be highly influenced by lifestyle and dietary factors, particularly the total and type of dietary fat intake. The PPARG is also the molecular target for anti-diabetic drug Thiazolidinedione (TZD).
PPARG Gene Detail
The PPARG gene is located on the short arm of chromosome 3 (3p25) with two main isoforms of the expressed gamma receptor observed namely PPAR-γ1 and PPAR-γ2. The last-mentioned receptor is mainly expressed in adipose tissue. Disorders observed from dysfunctional PPARG function includes type 2 diabetes, atherosclerosis, glomerulitis and pulmonary hypertension.
PPARG Pro12Ala C>G
A Human Genome Epidemiology (HuGE) review and meta-analysis involving 32 849 cases of T2DM and 47 456 controls from 60 association studies found strong evidence that the 12Ala allele was associated with a reduction in type 2 diabetes risk. The Pro12Pro genotype predicts conversion from impaired glucose tolerance to T2DM with a 3-fold increased T2DM risk in the Pro12 homozygotes compared to 12Ala carriers.
The Pro12Ala SNP is the most common occurring polymorphism in the PPARG gene, the change located in codon 12 of exon 2 of the PPAR-γ2 isoform. A substitution of guanine for cytosine (C>G) results in the change of proline (CCA) to alanine (GCA). It has been found that this missense mutation results in a 30-50% reduction in ligand-induced activity, thus lower DNA binding affinity of the receptor and reduced transcriptional activity in target genes. It is reported to particularly influence insulin sensitivity by the reduced stimulation of genes found in adipose tissue that are implicated in insulin sensitivity, lipid storage, fatty acid uptake and glucose uptake.
The structure and function of the PPARG protein is affected by the relevant amino acid change since the 12Ala variant promotes the formation of α-helices whereas the Pro12 variant inhibits it. The reduced transcriptional activity of the 12Ala variant leads to reduced stimulation of the PPARG gene – this results in a predisposition for lower levels of adipose tissue accumulation and thus improved insulin sensitivity with a reduced risk of T2DM. This protective effect against the development of insulin resistance and T2DM seem valid even amidst dyslipidaemia.
Evidence exists that the PPARG supports the “thrifty gene hypothesis” in which the wild-type genotype favoured an increased fat mass accumulation as source of energy for the necessity of survival when food was scarce or inconsistently available. With the obesogenic, sedentary environments present today, this wild-type genotype becomes detrimental by increasing the risk for developing type 2 diabetes. Obese phenotypes seem to exacerbate the detrimental effect of the Pro12 allele on insulin sensitivity.
Dietary Fat Intake
The influence of dietary fat intake on the Pro12Ala SNP seems to be the largest studied and most significant. Free fatty acids have been described as agonists of the PPARG transcription factor due to its function as ligands for PPARG2. Although studies do differ on the exact impact of PPARG on adiposity, there is evidence suggesting a positive relationship between a high total fat intake and BMI as well as waist circumference in 12Ala carriers.
A case control study found that a higher intake of arachidonic acid was associated with a higher risk of obesity in 12Ala carriers. It was also seen in 12Ala carriers that monounsaturated fatty acid (MUFA) intake was inversely associated with BMI, whereas this was not the case in Pro/Pro homozygotes, while a low MUFA intake was associated with higher HOMA values in an obese but otherwise healthy Spanish population.
A recent randomised control trial found that extra virgin olive oil supplementation for 12 weeks had a favourable effect on body composition in severely obese 12Ala carriers versus no significant changes in Pro/Pro homozygotes. A volume of 52ml extra virgin olive oil was provided supplementary to lunch and/or supper daily in two intervention groups, one group following their usual diet and the other receiving supplementation in conjunction with a calorie-controlled, balanced diet plan. A third intervention group received the calorie-controlled, balanced diet plan without any extra virgin olive oil supplementation. The 12Ala carriers, and not the Pro/Pro homozygotes, in both intervention groups with the extra virgin olive oil supplementation experienced a resultant reduction in body fat percentage and increase in fat free and lean mass, even when no weight loss was observed.
A higher polyunsaturated to saturated fat ratio (P:S) in the diet of 12Ala carriers has been associated with a lower BMI than for Pro/Pro homozygotes whereas a P:S ratio of 0.66 or lower seems to have the opposite effect. This suggests that the protective effect from 12Ala diminishes with high intakes of saturated fat. Physically active 12Ala carriers with a high P:S ratio had lower fasting insulin levels, suggesting not only the influence of dietary fat intake but also the importance of physical activity.
Mediterranean Dietary Approach
A Mediterranean dietary approach was seen attenuating the undesirable effect that 12Ala variant had on waist circumference; in a 2-year study a similar change in waist circumference was seen in both 12Ala carriers and Pro/Pro homozygotes when the 12Ala carriers followed a Mediterranean approach.
When the 12Ala carriers simply followed a conservative low fat diet, waist circumference increased significantly more than in Pro/Pro homozygotes with the same diet. The PREDIMED-NAVARRA randomised trial interestingly also found a reduced shortening of telomeres in 12Ala carriers as compared to Pro/Pro homozygotes after following the Mediterranean dietary pattern for 5 years.
Other Factors: Carbohydrates And Alcohol
The effect of carbohydrate and alcohol intake have also been studied. When carbohydrate intake in 12Ala carriers surpassed 49% of total energy, it was associated with an increased obesity risk. In term of the effect of alcohol, the European Project on Genes in Hypertension found that 12Ala carriers with a higher alcohol consumption seemed to have higher serum HDL cholesterol levels.
Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review