rs822391 — ADIPOQ IVS1+407C>T

Intronic variant in the adiponectin gene associated with circulating adiponectin levels, ischemic stroke risk, and metabolic cardiovascular traits; the C allele — present in roughly 14% of people globally and 20% of Europeans — is linked to lower adiponectin output and elevated cerebrovascular risk

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ADIPOQ rs822391 — An Intronic Switch That Dims Your Adiponectin Signal

Adiponectin is one of the body's most protective metabolic hormones — secreted exclusively by fat cells, it simultaneously suppresses hepatic glucose output, activates AMPK in skeletal muscle, and shields artery walls from inflammation. People with high circulating adiponectin have meaningfully lower rates of type 2 diabetes, coronary artery disease, and ischemic stroke. rs822391 is an intronic C-to-T substitution in the first intron of ADIPOQ11 ADIPOQ
The gene encoding adiponectin (also called APM1 or Acrp30), located at chromosome 3q27 — a locus strongly and repeatedly confirmed as the primary genetic determinant of circulating adiponectin levels in population studies, sitting 407 nucleotides into intron 1 at GRCh38 position chr3:186,846,014. The C allele (the minor allele, at roughly 20% frequency in Europeans and only 4% in Africans) has been associated with ischemic stroke risk and is implicated in modulation of adiponectin output at the 3q27 locus.

The Mechanism

Intronic variants in ADIPOQ influence adiponectin levels through several possible mechanisms: disruption of intronic enhancer elements22 intronic enhancer elements
Regulatory sequences within introns that recruit transcription factors to boost gene expression from a distance; intron 1 of ADIPOQ contains multiple such elements active in adipocytes, alterations in pre-mRNA splicing33 pre-mRNA splicing
The process removing introns from precursor RNA; variants within the first few hundred nucleotides of an intron can affect splice site recognition and exon inclusion rates even without changing the consensus AG/GT dinucleotides, or tagging of nearby functional variants through linkage disequilibrium44 linkage disequilibrium
The tendency for nearby genetic variants to be inherited together as a haplotype; rs822391 sits in the same ADIPOQ locus LD block as known functional variants including rs2241766 (T45G) and rs1501299 (+276G>T). The rs822391 C allele is the minor allele globally, with strong population stratification: frequency of roughly 20% in Europeans and South Asians, 10% in East Asians, and as low as 4% in African populations — a pattern consistent with population-specific selection acting on the ADIPOQ locus. The GTEx database identifies this variant as an eQTL for ADIPOQ-AS1 in testis tissue (NES −0.23, p=1.6×10⁻⁹), and the T allele shows positive regulatory effects in arterial tissue (NES +0.21, p=4.2×10⁻⁵), suggesting allele-specific effects on ADIPOQ-neighborhood gene regulation.

The Evidence

The most direct clinical evidence for rs822391 comes from a Korean case-control study by Cheong et al. (2011)55 Cheong et al. (2011)
Six ADIPOQ polymorphisms were genotyped in a stroke vs. control cohort; rs822391 was among those showing significant association in both dominant and additive logistic regression models after adjustment for age and sex, which reported that the C allele (described in that paper as the T>C substitution, confirming C as the risk direction on the plus strand) was significantly associated with ischemic stroke risk (p<0.05). This is biologically coherent: adiponectin is an established anti-atherosclerotic and anti-thrombotic hormone, and variants that reduce its circulating levels — including rs822391 C allele carriers — face downstream consequences in cerebrovascular protection.

At the broader locus level, Heid et al. (2010)66 Heid et al. (2010)
Genome-wide association analyses of 4,659 Europeans followed by replication in 13,795 additional subjects, n=18,454 total, identifying ADIPOQ as the dominant genetic determinant of plasma adiponectin established that the ADIPOQ 3q27 region explains approximately 6.7% of variance in circulating adiponectin levels in Europeans — the single largest genetic contributor to this phenotype. rs822391 lies within this locus, and the Jackson Heart Study (n>5,000 African Americans) included it among a panel of ADIPOQ variants examined for adiponectin associations with gender-specific effects, finding locus-wide signals concentrated in several correlated variants including rs16861205, a close neighbor at chr3:186,843,845.

On the intervention side, Sepidarkish et al. (2022)77 Sepidarkish et al. (2022)
Systematic review and meta-analysis of 43 randomized controlled trials, n=3,434 participants across diverse populations demonstrated that omega-3 fatty acid supplementation raises circulating adiponectin with a pooled effect size of SMD 0.21 (95% CI 0.04–0.37, p=0.01), with the strongest effects at doses exceeding 2,000 mg EPA/DHA per day for more than 10 weeks. This intervention-level evidence directly informs the management of C allele carriers whose baseline adiponectin is already genetically suppressed.

Practical Actions

Carriers of the C allele cannot override the intronic regulatory change, but circulating adiponectin is modifiable through targeted nutrition. Long-chain omega-3 fatty acids (EPA and DHA) are the best-supported dietary upregulators of adiponectin, acting through PPAR-alpha activation in adipocytes to increase ADIPOQ transcription — a mechanism that partially compensates for genetically lower baseline secretion. Saturated fatty acids specifically suppress ADIPOQ promoter activity through competitive PPAR-gamma antagonism, so replacing saturated fat with mono- and polyunsaturated sources measurably raises adiponectin independent of total caloric intake.

Given the documented association with stroke risk, C allele carriers — particularly CT and CC individuals — benefit from monitoring the biomarkers that reflect the downstream consequences of lower adiponectin: fasting serum adiponectin, fasting insulin, and blood pressure. Early detection of hypoadiponectinemia (below 5 µg/mL) or elevated fasting insulin (above 8 µIU/mL) allows targeted intervention before vascular consequences develop.

Interactions

rs822391 lies within the same ADIPOQ intron 1 locus block as rs16861194 (−11426A>G upstream promoter), rs16861205 (intron 1 A>G), and nearby rs1501299 (+276G>T, intron 2). Individuals carrying risk alleles at multiple ADIPOQ locus variants — which tend to cluster in the same low-adiponectin haplotype — show substantially greater reductions in circulating adiponectin than any single variant predicts. The compounding of rs822391 C allele with rs2241767 G or rs1501299 T creates a high-priority metabolic target where direct adiponectin measurement is especially warranted. See related SNPs for individual variant profiles.

Nutrient Interactions

omega-3 fatty acids altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

TT Normal Adiponectin Output Normal

Two T alleles — standard ADIPOQ intron 1 regulation, no elevated risk from this variant

You carry two copies of the T allele at rs822391 — the common genotype, present in roughly 72% of people globally and about 64% of those of European ancestry. Your ADIPOQ intron 1 regulatory elements at this position are unaffected by the C allele variant, meaning your adiponectin mRNA production from this locus is not impaired at this position. This does not guarantee high circulating adiponectin — other ADIPOQ locus variants and lifestyle factors still modulate your total adiponectin levels — but this specific intronic variant does not impose an additional deficit.

CT Reduced Adiponectin Output Intermediate

One C allele — modestly lower adiponectin and elevated stroke and cardiovascular risk under metabolic stress

The heterozygous CT state means one of your two ADIPOQ copies carries the intron 1 variant that reduces adiponectin mRNA production, while the other copy functions normally. The net adiponectin output reflects this partial impairment — measurably lower than TT on population averages but not as severely depressed as CC. Because the ADIPOQ 3q27 locus operates in a codominant fashion, the heterozygous state represents a genuine intermediate phenotype.

The stroke association from the Korean cohort (PMID 21155030) applied under both dominant (CT+CC vs. TT) and additive models, meaning CT carriers carry a real but smaller excess risk compared to CC. The clinical significance depends on coexisting risk factors: CT individuals who also carry risk alleles at other ADIPOQ locus variants (rs16861194, rs2241767, rs1501299) compound their adiponectin deficit substantially.

Omega-3 supplementation is particularly well-positioned for CT carriers: the modest adiponectin deficit is within the range that 12–16 weeks of omega-3 supplementation can meaningfully correct, as demonstrated in the Sepidarkish et al. meta-analysis (SMD 0.21 at doses >2 g EPA/DHA/day).

CC Low Adiponectin Output High Risk

Two C alleles — genetically impaired adiponectin secretion with elevated cardiovascular and stroke risk

The CC genotype means both copies of your ADIPOQ intron 1 carry the variant that diminishes the intronic enhancer or splicing signals regulating adiponectin mRNA production. The net result is a chronically lower adiponectin output from adipose tissue — and because adiponectin suppresses hepatic glucose production, activates skeletal muscle AMPK, and reduces vascular inflammation, that reduction creates a compounding risk across metabolic and cardiovascular domains.

The ischemic stroke association — reported in a Korean cohort (Cheong et al. 2011) across multiple logistic regression models — reflects the biological reality that low adiponectin creates a more pro-thrombotic and pro-atherogenic vascular environment. Adiponectin normally inhibits platelet aggregation, reduces endothelial expression of adhesion molecules, and promotes nitric oxide production; CC carriers lose a significant fraction of this protection.

Importantly, the CC genotype is rare enough (2% globally) that it is often underrepresented in individual studies, and most published effect estimates apply to the CT+CC combined dominant model rather than CC alone. The true effect size at CC may be larger than the combined estimates suggest.