rs1800206 — PPARA Leu162Val (L162V)

Missense variant in PPARA that reduces receptor transcriptional activity, elevating LDL and triglycerides — particularly with low dietary PUFA intake — and blunting the lipid-improving response to omega-3 fatty acids and aerobic exercise

See your personal result for PPARA

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

PPARA Leu162Val — When Fat Metabolism Depends on What You Eat

PPARα11 PPARα
Peroxisome Proliferator-Activated Receptor Alpha — a nuclear receptor transcription factor that acts as the master regulator of fatty acid oxidation, lipoprotein metabolism, and energy substrate utilization during fasting and exercise is one of the most important lipid-sensing proteins in the human body. It responds to dietary fats, exercise, and fasting by switching on a gene expression program that burns fat for energy and clears lipids from the bloodstream. The Leu162Val missense variant (rs1800206) substitutes valine for leucine at position 162 of the PPARα protein, subtly altering the receptor's transcriptional behavior — with consequences that depend strongly on what you eat.

The Mechanism

Position 162 sits in the DNA-binding domain22 DNA-binding domain
The DNA-binding domain of PPARα recognizes specific peroxisome proliferator response elements (PPREs) in gene promoters and, once ligand-activated, drives transcription of target genes involved in fatty acid oxidation, lipoprotein lipase production, and apolipoprotein synthesis of the PPARα protein. In vitro experiments show that the Val162 variant (G allele) produces consistently lower transcriptional activation33 consistently lower transcriptional activation
Rudkowska et al. 2009 (PPAR Res) showed V162 cells had significantly lower PPARα and APOA1 expression after EPA and DHA treatment in HepG2 hepatoma cells than L162 wild-type cells than the common Leu162 form when stimulated with omega-3 fatty acids. This blunted responsiveness translates into downstream effects: lower lipoprotein lipase (LPL) activity, reduced clearance of triglyceride-rich lipoproteins, and less efficient production of ApoA-I (a key structural protein in HDL particles).

The paradox of this variant is that despite reduced intrinsic activity, V162 carriers do not uniformly show worse lipid profiles — the consequences depend critically on dietary fat composition. When dietary polyunsaturated fatty acid (PUFA) intake is low, the variant exposes its metabolic vulnerability; when PUFA intake is adequate (≥8% of energy), the phenotype largely normalizes.

The Evidence

The largest genetic epidemiology evidence comes from the Framingham Offspring Study44 Framingham Offspring Study
Tai ES et al. Association between the PPARA L162V polymorphism and plasma lipid levels: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol, 2002, which genotyped 2,373 participants (V162 allele frequency 6.9%) and found significant associations in men: higher LDL cholesterol (P=0.0004), higher total cholesterol (P=0.0012), higher ApoB (P=0.009), and elevated ApoC-III concentrations — all pointing toward impaired clearance of atherogenic lipoproteins.

The gene-diet interaction was characterized elegantly in the Framingham Heart Study dietary analysis55 Framingham Heart Study dietary analysis
Tai ES et al. Polyunsaturated fatty acids interact with the PPARA-L162V polymorphism to affect plasma triglyceride and apolipoprotein C-III concentrations in the Framingham Heart Study. J Nutr, 2005, where V162 carriers on low PUFA diets (<6% of energy) showed approximately 28% higher plasma triglycerides than L162 homozygotes (P<0.01), while V162 carriers on high-PUFA diets (>8% of energy) showed 4% lower triglycerides. The interaction was dose-dependent and highly significant (P=0.031 for triglycerides, P<0.001 for ApoC-III), confirming that dietary fat composition determines whether this variant is harmful or neutral.

In a cohort of 610 young adults, Robitaille et al.66 Robitaille et al.
Robitaille J et al. PPARalpha L162V underlies variation in serum triglycerides and subcutaneous fat volume in young males. BMC Med Genet, 2007 found that V allele males had 78% higher serum triglycerides than LL homozygotes (208 vs 116 mg/dL, P=0.004) and significantly lower HDL cholesterol (34 vs 42 mg/dL, P=0.001). The variant also predicted an unusual response to exercise training: V allele males actually increased subcutaneous fat in the untrained limb during unilateral resistance training, while LL males reduced fat. Women showed no effect — suggesting the variant's lipid impact is sex-specific.

At the molecular level, two complementary studies by Rudkowska and colleagues77 two complementary studies by Rudkowska and colleagues
Rudkowska I et al. Omega-3 fatty acids regulate gene expression levels differently in subjects carrying the PPARalpha L162V polymorphism. Genes Nutr, 2009 confirmed that V162 carriers show significantly blunted PPARα and ApoA-I gene expression in response to DHA supplementation — meaning the mechanism for HDL generation is impaired. A paired in vivo/in vitro study (PMID 19937854)88 (PMID 19937854) further showed that n-3 fatty acid-induced LPL activity increase was roughly halved in V162 carriers (6.6% vs 14.4%), reducing their capacity to clear triglycerides from the blood.

In the STOP-NIDDM trial99 STOP-NIDDM trial
Andrulionyte L et al. PPARA gene polymorphisms influence conversion from impaired glucose tolerance to type 2 diabetes: the STOP-NIDDM trial. Diabetes, 2007, the G (Val162) allele increased the risk of progressing from impaired glucose tolerance to overt type 2 diabetes by 1.9-fold (95% CI 1.05–3.58) in the placebo group among 767 participants, with associated elevations in plasma glucose and insulin — likely reflecting the impaired fatty acid oxidation and lipotoxicity consequences of reduced PPARα activity.

There is also an exercise context: a 12-week aerobic training intervention in 168 women (PMID 31319591)1010 (PMID 31319591) found that CG genotype carriers showed a decrease in HDL cholesterol after the program, in contrast to the expected improvements in CC carriers — consistent with the reduced PPARα-driven APOA1 response documented in molecular studies.

Practical Actions

The core insight for V162 allele carriers is that dietary PUFA intake is the primary modifiable lever. The gene-diet interaction is one of the cleaner pharmacogenomic effects in nutritional genomics: omega-3 fatty acids act as direct PPARα ligands and should theoretically be most helpful, yet the V162 variant blunts exactly this response. At the same time, the evidence from the fibrate pharmacogenomics literature shows paradoxical benefit — V162 carriers showed dramatically better HDL response to gemfibrozil (a fibrate that directly activates PPARα), suggesting that at sufficiently high levels of PPARα stimulation, the reduced-activity receptor can still be mobilized.

The practical implication: V162 carriers should monitor lipids proactively, maintain high-quality PUFA intake (even if the response is attenuated, low PUFA unmistakably worsens the phenotype), and be aware that standard aerobic exercise programs may not improve HDL as expected. If pharmacotherapy for lipids becomes necessary, fibrate drugs may show above-average HDL benefit in V162 carriers.

Interactions

This variant is in the same gene as rs4253778 (PPARA intron 7 G/C). The intron 7 variant alters PPARA expression level and muscle fiber composition; Leu162Val alters PPARA protein function. They address distinct molecular mechanisms and are not in high LD with each other, allowing independent contributions. Combined unfavorable alleles (CC at rs4253778 and CG/GG at rs1800206) may compound adverse lipid responses to exercise training — the existing rs4253778 entry already notes this interaction (C allele at rs4253778 combined with Val162 at rs1800206 has been associated with more pronounced adverse lipid changes during training).

PPARD (rs2016520, rs1053049) works in the same fat-oxidation pathway as PPARA. While both nuclear receptors regulate lipid metabolism, their actions are largely independent at the genotype level; no formal interaction studies between rs1800206 and PPARD variants have been published in exercise cohorts. The PPARGC1A Gly482Ser variant (rs8192678) is a PGC-1alpha coactivator that physically interacts with PPARα; combined analysis with rs1800206 has not been studied but represents a plausible compound effect.

Nutrient Interactions

polyunsaturated fatty acids (PUFA) altered_metabolism
omega-3 fatty acids (EPA/DHA) reduced_absorption

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal L162 Normal

Common Leu162 genotype — normal PPARα lipid response

You carry two copies of the common C allele (Leu162), the ancestral form of the PPARA protein at position 162. About 87% of people of European ancestry share this genotype. Your PPARα receptor shows full transcriptional activity in response to fatty acids and omega-3 supplementation, supporting normal lipoprotein clearance and expected lipid improvements from both aerobic exercise and high-PUFA diets.

CG One Val162 Allele Intermediate

Reduced PPARα function — dietary fat quality matters more for your lipids

The Val162 substitution reduces PPARα's transcriptional response to omega-3 fatty acids (EPA and DHA), blunting activation of downstream genes including lipoprotein lipase (LPL) and apolipoprotein A-I (ApoA-I). LPL is the enzyme that clears triglycerides from the bloodstream; ApoA-I is the structural scaffold of HDL particles. Reduced activity in these pathways explains both the higher triglyceride and lower HDL phenotype documented in male V162 carriers.

The Framingham Offspring Study (n=2,373) found that V162 allele men had significantly higher LDL (P=0.0004) and total cholesterol (P=0.0012) than L162 homozygotes. The dietary interaction study in the same cohort confirmed that the adverse effect is greatest when PUFA intake is low (<6% of energy from PUFA), where V162 carriers showed ~28% higher triglycerides, but disappeared with adequate PUFA intake (>8% of energy).

Regarding fibrate therapy: the gemfibrozil RCT (n=63 men) showed paradoxically greater HDL2-C improvement in V162 carriers (50% vs 5.5% in LL, P=0.03). This suggests that pharmacological PPARα stimulation at therapeutic doses can overcome the reduced basal activity — relevant if lipid management becomes necessary.

GG Two Val162 Alleles Reduced

Full Val162 homozygote — substantially elevated triglycerides and impaired omega-3 response

As a GG homozygote, both copies of your PPARA gene carry the Val162 variant. The in vitro evidence shows that the V162 form produces lower transcriptional activation than L162 when stimulated by EPA, DHA, or EPA:DHA mixtures in hepatocyte cells. With both alleles impaired, the downstream consequences — reduced LPL activity (impaired triglyceride clearance), reduced ApoA-I production (impaired HDL assembly), and elevated atherogenic lipoproteins — are expected to be more pronounced than in CG heterozygotes.

The STOP-NIDDM trial found a 1.9-fold increased risk of progressing from impaired glucose tolerance to type 2 diabetes for the G allele (95% CI 1.05–3.58), with elevated plasma glucose and insulin as associated findings. While the trial examined G-allele carriers broadly (CG + GG), GG individuals carry the highest allele burden.

One practical note: the fibrate study (gemfibrozil RCT, n=63) showed that V162 allele carriers had dramatically better HDL2-C improvement than L162 homozygotes (50% vs 5.5%, P=0.03). If pharmacological lipid management becomes necessary, fibrate drugs that directly activate PPARα may offer above-average benefit for your genotype.