rs822391 — ADIPOQ IVS1+407C>T

Intronic variant in the adiponectin gene associated with ischemic stroke risk; the C allele — present in roughly 14% of people globally and 20% of Europeans — is linked to elevated cerebrovascular risk

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ADIPOQ rs822391 — An Intronic Switch

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.

The Mechanism

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)22 Cheong et al. (2011)
10 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).

At the broader locus level, Heid et al. (2010)33 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.

On the intervention side, Sepidarkish et al. (2022)44 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.

Nutrient Interactions

omega-3 fatty acids altered_metabolism

Genotype Interpretations

What each possible genotype means for this variant.

TT Baseline Stroke Risk Normal

Two T alleles — 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.

CT Moderate Stroke Risk Intermediate

One C allele — associated with elevated ischemic stroke risk

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.

CC Higher Stroke Risk High Risk

Two C alleles — associated with elevated ischemic stroke risk

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.