rs16928751 — ADIPOR2 ADIPOR2 CVD co-association variant

Synonymous coding variant in ADIPOR2 (Q265Q) that was co-associated with cardiovascular disease risk in the Finnish Diabetes Prevention Study alongside three other ADIPOR2 intronic variants in people with impaired glucose tolerance

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ADIPOR2 rs16928751: A Haplotype Tag for Cardiovascular Risk in Adiponectin Signaling

Adiponectin is one of the body's most important metabolic hormones, produced by fat tissue and acting primarily through two receptors: ADIPOR1 in skeletal muscle and ADIPOR2 in the liver. In a paradox central to metabolic disease, adiponectin levels fall precisely as body fat rises — removing the hormone's protection at the moment it is needed most. rs16928751 sits in exon 7 of the ADIPOR2 gene and produces a synonymous codon change (CAG to CAA, both encoding glutamine at position 265). No amino acid is altered, yet the A allele was co-identified alongside three other ADIPOR2 variants as associated with cardiovascular disease risk in the Finnish Diabetes Prevention Study (DPS)11 Finnish Diabetes Prevention Study (DPS)
A randomized lifestyle intervention trial enrolling 484 participants with impaired glucose tolerance, followed for a median of 10.2 years for cardiovascular events and 7 years for diabetes progression.

The Mechanism

A synonymous variant changes a codon without altering the encoded amino acid. For most such variants, there is no biological consequence. However, synonymous changes in coding sequence can influence mRNA stability, translational speed, or splicing efficiency, particularly when the altered codon is used at different frequencies across tissues. In ADIPOR2's case, the A allele at rs16928751 sits near the AMPK and PPARα signaling domain22 AMPK and PPARα signaling domain
AMP-activated protein kinase and peroxisome proliferator-activated receptor alpha — two central metabolic regulators activated when adiponectin binds ADIPOR2 in liver cells, suppressing fat synthesis and enhancing fatty acid oxidation. Whether the synonymous change affects ADIPOR2 mRNA levels or translation efficiency has not been directly tested.

The Evidence

The Finnish DPS genotyped eight ADIPOR2 variants in 484 individuals with impaired glucose tolerance. Four showed nominal association with cardiovascular events, including rs16928751. In the joint multi-SNP model, however, only rs11061937 (p = 0.016) and rs1058322 (p = 0.023) retained independent significance — rs16928751 and rs10848554 were attenuated. The study did not report individual hazard ratios for rs16928751 in the abstract and the variant did not survive multi-variant correction, placing its independent effect in the emerging category33 emerging category
Single candidate study, moderate sample size; association was attenuated in the multi-SNP model.

The broader ADIPOR2 biology is well-established. Receptor knockout experiments confirm that ADIPOR2 loss selectively impairs hepatic fatty acid oxidation and insulin sensitivity. A synthetic ADIPOR agonist, AdipoRon, activates both ADIPOR1 and ADIPOR2 and extends lifespan and insulin sensitivity in obese diabetic mice44 synthetic ADIPOR agonist, AdipoRon, activates both ADIPOR1 and ADIPOR2 and extends lifespan and insulin sensitivity in obese diabetic mice
Okada-Iwabu et al. A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature, 2013, confirming the pathway as a genuine therapeutic target. ADIPOR2 is also selectively downregulated in visceral obesity55 selectively downregulated in visceral obesity
AdipoR2 expression falls in obesity while AdipoR1 is preserved; reduced AdipoR2 contributes to insulin resistance through impaired APPL1 signaling.

Interactions

rs16928751 was co-analyzed with rs11061937, rs1058322, and rs10848554 in the Finnish DPS. The four SNPs collectively define a CVD-risk region of the ADIPOR2 locus; their independent effects diminish substantially in the multi-SNP model.

Nutrient Interactions

dietary fat altered_metabolism
omega-3 fatty acids increased_need

Genotype Interpretations

What each possible genotype means for this variant.

GG Reference Haplotype Normal

Common ADIPOR2 reference allele — no elevated cardiovascular risk from this variant

You carry two copies of the G reference allele at rs16928751. In the Finnish Diabetes Prevention Study, this genotype served as the lower-risk reference group. About 78% of people globally carry this genotype, making it by far the most common. This variant alone does not indicate elevated cardiovascular risk, and ADIPOR2 receptor expression is expected to be at the typical population level.

AG Heterozygous A Carrier Intermediate

One copy of the A allele — potential partial contribution to ADIPOR2 risk haplotype

rs16928751 is a synonymous variant in ADIPOR2 exon 7 (Q265Q, CAG>CAA): no amino acid changes. Whether the synonymous change itself affects mRNA stability or translation speed has not been directly demonstrated.

AA Homozygous A Carrier High Risk

Two copies of the A allele — both ADIPOR2 chromosomes carry the CVD risk haplotype marker

The synonymous Q265Q change at rs16928751 does not alter ADIPOR2 protein sequence. Given the rarity of this genotype, all clinical evidence is from the heterozygous-carrier-dominant analyses; individual estimates for AA homozygotes are imprecise.