rs5082

mixedMag 4.5

This is a upstream gene variant variant in the APOA2 gene.

Key Literature Trait Associations

Saturated Fat Response / Obesity Risk

APOA2 is a major HDL cholesterol component influencing fat metabolism and satiety. The rs5082 variant (−265T>C) shows a robust gene-diet interaction: CC homozygotes eating high saturated fat (≥22 g/day) have ~6.2% higher BMI and an obesity OR of 1.84 (95% CI 1.38–2.47) compared to other genotypes eating similarly. Under low saturated fat intake, the difference disappears. Replicated in multiple US, Mediterranean, and Asian populations — one of the most robustly validated nutrigenomics findings. CC individuals may benefit from limiting saturated fat.

Corella D et al. “APOA2, dietary fat, and body mass index: replication of a gene-diet interaction in 3 independent populations.” Archives of Internal Medicine 169(20):1897 (2009)

Allele C

OR 1.84

p 1.0e-2

Candidate gene study

Corella D et al. “Association between the APOA2 promoter polymorphism and body weight in Mediterranean and Asian populations: replication of a gene-saturated fat interaction.” International Journal of Obesity (2005) (2011)

Allele C

OR —

p 1.8e-2

N 4,602

Preliminary work

Mediterranean and Asian

Smith CE et al. “Apolipoprotein A2 polymorphism interacts with intakes of dairy foods to influence body weight in 2 U.S. populations.” The Journal of Nutrition (2013)

Allele C

OR —

p 1.0e-3

N 2,071

Preliminary work

European and Hispanic

Lai CQ et al. “Epigenomics and metabolomics reveal the mechanism of the APOA2-saturated fat intake interaction affecting obesity.” The American Journal of Clinical Nutrition (2018)

Allele C

OR —

p —

N 702

Preliminary work

European and Hispanic

Lai CQ et al. “Differential weight-loss responses of APOA2 genotype carriers to low-carbohydrate and low-fat diets: the DIETFITS trial.” Obesity (silver Spring, Md.) (2025)

Allele C

OR —

p —

N 609

Preliminary work

European

HDL cholesterol

Large-scale GWAS analyses identify the G allele of rs5082 as a genome-wide significant locus for increased HDL cholesterol levels, consistent with APOA2's established role in stabilizing HDL particles and modulating reverse cholesterol transport. The association reaches p-values of 2×10⁻²⁸ to 1×10⁻³⁵ across multiple large analyses with betas in the range of 0.04–0.05 SD units per allele. In contrast, one smaller candidate-gene study in an Iranian population (n=142) found no contribution of rs5082 to extreme HDL phenotypes, likely reflecting limited power. The overall evidence from GWAS strongly supports rs5082-G as an HDL-raising variant.

Karjalainen MK et al. “Genome-wide characterization of circulating metabolic biomarkers.” Nature 628(8006):130-138 (2024)

Allele G

OR —

β 0.049

p 1.0e-33

N 136,016

Large GWAS

multi-ancestry

Bandarian F et al. “Identification of Sequence Variation in the Apolipoprotein A2 Gene and Their Relationship with Serum High-Density Lipoprotein Cholesterol Levels.” Iranian Biomedical Journal (2016)

Allele G

OR —

p —

N 142

Candidate gene study

Iranian

Postprandial triglyceride response

TT homozygotes at rs5082 show a significantly greater postprandial triglyceride surge following a high saturated fat meal compared to C allele carriers (CC/TC genotypes). In 88 normolipidemic young men, TT carriers exhibited ~21% greater total plasma triglyceride increase (P=0.014) and ~25% greater large TRL-triglyceride response (P=0.017). This suggests the C allele confers relative protection against postprandial hypertriglyceridemia, a recognized cardiovascular risk factor. However, this finding derives from a single small candidate-gene study and requires replication in larger populations.

Delgado-Lista J et al. “An apolipoprotein A-II polymorphism (-265T/C, rs5082) regulates postprandial response to a saturated fat overload in healthy men.” The Journal of Nutrition (2007)

Allele T

OR —

p 1.4e-2

N 88

Candidate gene study

European

Lipid response to dietary intervention

In type 2 diabetic patients, the C allele at rs5082 interacts with dietary quality markers to influence lipid profiles. CC and C allele carriers showed higher triglycerides and altered cholesterol ratios in the context of high dietary acid load (n=737), and significant interactions with dietary antioxidant capacity affecting total cholesterol and TC/HDL ratio were observed (n=778). Separately, CC genotype carriers in a cohort of 697 T2D patients consuming high saturated fat showed lower total cholesterol, triglycerides, and non-HDL cholesterol than T allele carriers. These findings suggest that the metabolic consequences of rs5082 on lipids depend strongly on overall diet quality, but all studies are small and limited to diabetic populations.

Abaj F et al. “Dietary acid load modifies the effects of ApoA2-265 T > C polymorphism on lipid profile and serum leptin and ghrelin levels among type 2 diabetic patients.” Bmc Endocrine Disorders (2022)

Allele C

OR —

p —

N 737

Preliminary work

Iranian

Jafari Azad B et al. “Interaction between Apo A-II -265T>C polymorphism and dietary total antioxidant capacity on some anthropometric indices and serum lipid profile in patients with type 2 diabetes mellitus.” Journal of Nutritional Science (2021)

Allele C

OR —

p —

N 778

Preliminary work

Iranian

Noorshahi N et al. “APOA II genotypes frequency and their interaction with saturated fatty acids consumption on lipid profile of patients with type 2 diabetes.” Clinical Nutrition (edinburgh, Scotland) (2016)

Allele C

OR —

p —

N 697

Preliminary work

Iranian

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GWAS Catalog Trait Associations (25)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

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ClinVar annotation

Pathogenic★☆☆☆

2 submitters2 publications

Apolipoprotein A-II amyloidosis; Hypercholesterolemia, familial, 1

View on ClinVar →

Gene information from NCBI Gene. Variant classifications from ClinVar.

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