rs662 — PON1 Q192R

PON1 Q192R — Your HDL's Antioxidant Power

Paraoxonase-1 (PON1) is an enzyme that rides on HDL particles¹¹ HDL particles
High-density lipoprotein, often called "good cholesterol," transports cholesterol from tissues back to the liver in your bloodstream, where it performs two critical jobs: detoxifying organophosphate pesticides²² organophosphate pesticides
Compounds widely used in agriculture that can be neurotoxic; PON1 breaks down their active metabolites and protecting LDL cholesterol from oxidative damage³³ oxidative damage
Oxidized LDL is a key driver of atherosclerosis, the buildup of plaques in artery walls. The Q192R variant creates two functionally different versions of the enzyme with a striking tradeoff: the R variant is better at breaking down pesticides, while the Q variant is superior at preventing LDL oxidation and protecting against cardiovascular disease.

The Mechanism

The Q192R polymorphism results from an A>G nucleotide change that exchanges an arginine (R) for glutamine (Q) at position 192 of the protein . This amino acid substitution alters the enzyme's active site⁴⁴ active site
The region of an enzyme where substrates bind and chemical reactions occur, changing its catalytic efficiency for different substrates.

The Q isoform can reduce copper-mediated LDL oxidation by 58-61%, whereas the R genotype inhibits LDL oxidation by only 36-48% . However, the situation reverses for organophosphate metabolism— purified PON192 alloforms show the R variant has higher catalytic efficiency for hydrolysis of specific oxon substrates , making RR individuals better protected against pesticide poisoning but more vulnerable to cardiovascular disease.

The Evidence

The cardiovascular implications are substantial.

In a Saudi study of 2,456 individuals, the RR genotype was associated with CAD risk with an OR of 2.2 (95% CI 1.4-7.4, p < 0.01), independent of age, gender, smoking, obesity, and diabetes .

In Chinese Han individuals, after adjusting for conventional risk factors, 192R allele carriers had a significantly higher risk of CAD than other allele carriers . The mechanism is clear: the diminished ability of the RR variant genotype of PON1 to blunt LDL oxidation allows oxidized LDL to accumulate in artery walls.

Interestingly, the cardiovascular risk associated with the R allele shows ethnic variation⁵⁵ ethnic variation
Genetic risk can vary across populations due to differences in genetic background and environmental exposures.

In Asian populations, the 192R allele was a susceptible factor for type 2 diabetes, but represented a protective factor in the European population (OR = 0.66, 95% CI = 0.45-0.98) under a heterozygous genetic model . This may reflect different patterns of oxidative stress, diet, or gene-gene interactions across populations.

For organophosphate exposure, the evidence is also compelling.

A meta-analysis of nine studies with 1,042 patients showed that the PON1 192Q polymorphism increases the risk of organophosphate toxicity , with significant associations among Caucasian populations .

In Colombian coffee harvesters, the 192Q genotype was associated with hypertension , potentially reflecting both cardiovascular vulnerability and cumulative pesticide exposure effects.

Practical Implications

Your genotype shapes how your body handles two distinct challenges: protecting your arteries from oxidative damage and clearing environmental toxins. QQ individuals have superior antioxidant protection but are more vulnerable to organophosphate toxicity. RR individuals have the opposite profile—better pesticide clearance but reduced cardiovascular protection. Heterozygotes (QR) fall somewhere in between.

For cardiovascular health, tomato juice consumption reduced LDL oxidation and improved antioxidant status in R-allele carriers, but not in the QQ genotype group , suggesting dietary antioxidants may compensate for the R variant's reduced intrinsic antioxidant capacity. Polyphenol-rich foods (berries, green tea, dark chocolate, olive oil) provide similar oxidized LDL protection.

If you have occupational or recreational exposure to organophosphate pesticides (agricultural work, home gardening with conventional pesticides), your Q192R genotype affects your vulnerability. QQ individuals should be especially cautious about pesticide exposure, using protective equipment and favoring organic produce when practical.

Interactions

The Q192R polymorphism interacts with PON1 L55M (rs854560)⁶⁶ PON1 L55M (rs854560)
Another PON1 variant affecting enzyme expression levels; the M allele is associated with lower PON1 concentrations in the same gene.

The 55M homozygotes have over 50% less activity toward paraoxon compared to the LL and LM genotypes regardless of the 192 genotype, and the 55 polymorphism accounts for 16% of the variation in PON1 activity . The combination of Q192R with unfavorable L55M genotypes compounds cardiovascular risk and pesticide sensitivity.

In rheumatoid arthritis patients, the TLQ haplotype (combining promoter, L55M, and Q192R variants) was associated with low PON1 activity (OR = 2.29) and low PON1 protein levels (OR = 1.65) , demonstrating how multiple PON1 variants can synergistically impair enzyme function.