rs964184 — ZNF259 ZNF259/BUD13 Triglyceride Variant

ZNF259/APOA5 — The Triglyceride Control Locus

At chromosome 11q23.3 sits a tightly packed cluster of lipid-metabolism genes — APOA5, APOA4, APOC3, and APOA1 — flanked by ZNF259 (also known as ZPR1) and BUD13. The rs964184 variant lies in the 3' untranslated region of ZNF259, but its most important effect is on the neighboring APOA5 gene, which encodes apolipoprotein AV¹¹ apolipoprotein AV
ApoAV is a secreted protein produced mainly in the liver that activates lipoprotein lipase, the enzyme that breaks down triglyceride-rich particles in the bloodstream. G allele carriers produce less ApoAV protein after meals, impairing the clearance of triglyceride-carrying particles from circulation.

The Mechanism

rs964184 is a 3'UTR regulatory variant in ZNF259. Although its precise molecular mechanism is not fully resolved, functional studies have established a direct link between rs964184 genotype and postprandial ApoAV protein levels²² a direct link between rs964184 genotype and postprandial ApoAV protein levels
Weissglas-Volkov et al. Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci. J Med Genet, 2013. The G allele reduces ApoAV availability, which in turn impairs lipoprotein lipase activation — the rate- limiting step in clearing very-low-density lipoprotein (VLDL) triglycerides from the blood. This effect is dose-dependent: heterozygotes (CG) show intermediate triglyceride levels, while G;G homozygotes show the highest elevations.

The Evidence

rs964184 is one of the most replicated triglyceride-associated variants in the human genome, with genome-wide significant associations across European, East Asian, South Asian, African, and Latin American populations.

A large study of 5,547 patients with established vascular disease³³ large study of 5,547 patients with established vascular disease
van de Woestijne et al. Rs964184 is related to elevated plasma triglyceride levels but not to an increased risk for vascular events. PLoS One, 2014 found each G allele adds approximately 0.12 log-units to fasting triglycerides (p=1.1×10⁻¹⁹), a substantial effect for a common variant. The G allele minor allele frequency rose from 10.9% in patients with the lowest triglycerides (<1 mmol/L) to 24.6% in those with the highest (4–10 mmol/L). Metabolic syndrome prevalence was 52% in CC homozygotes vs 62% in GG homozygotes.

A cross-ethnic fine-mapping study⁴⁴ cross-ethnic fine-mapping study
Weissglas-Volkov et al. Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci. J Med Genet, 2013 narrowed the APOA5 locus signal to rs964184 as the single most likely causal variant underlying both European and Mexican GWAS signals, and demonstrated its functional link to postprandial ApoAV protein levels.

In an Iranian case-control study of metabolic syndrome, Mirhafez et al.⁵⁵ Mirhafez et al.
Mirhafez et al. ZNF259 Gene Polymorphism rs964184 is Associated with Serum Triglyceride Levels and Metabolic Syndrome. Int J Mol Cell Med, 2016 found CG+GG genotypes conferred OR 2.52 (95%CI 1.33–4.77, p=0.005) for metabolic syndrome and elevated TG and LDL-C compared to wild-type CC.

A dietary intervention trial⁶⁶ dietary intervention trial
Zhang et al. APOA5 genotype modulates 2-y changes in lipid profile in response to weight-loss diet. Am J Clin Nutr, 2012 found that G allele carriers showed greater reductions in LDL cholesterol on a long-term low-fat diet (20% fat), supporting genotype-specific dietary guidance.

Practical Actions

The key lever for G allele carriers is dietary fat composition and overall caloric pattern. Saturated fat drives VLDL-TG production independently of ApoAV, so reducing saturated fat intake directly lowers the TG burden that the impaired clearance pathway must handle. Fish-derived omega-3s (EPA/DHA) suppress hepatic TG synthesis via PPAR-alpha activation, providing a separate route to lower fasting and postprandial TG. Fasting TG monitoring every 12 months helps track whether dietary changes are taking effect, since fasting TG above 1.7 mmol/L (150 mg/dL) is a metabolic syndrome criterion and predicts cardiovascular risk.

Interactions

rs964184 sits in the same linkage disequilibrium block as several other triglyceride-associated variants at the APOA5 locus, including rs3135506 (APOA5 S19W missense) and rs662799 (APOA5 -1131T>C promoter). Carrying risk alleles at multiple positions in this cluster produces additive triglyceride elevation. The APOC3 variants rs2854116 and rs2854117 (also on chromosome 11) affect the same triglyceride clearance pathway through a different mechanism (ApoC-III-mediated inhibition of lipoprotein lipase) — users carrying risk alleles at both rs964184 and APOC3 variants face compounded impairment of TG clearance.