rs693 — APOB XbaI (C/T)

APOB XbaI — The Silent Variant That Speaks Volumes for Heart Health

The rs693 variant, known historically as the XbaI polymorphism, sits in exon 26 of the APOB gene¹¹ APOB gene
apolipoprotein B, the structural protein of LDL particles. Despite being a "silent" or synonymous mutation—the DNA change from C to T doesn't alter the amino acid (both code for threonine)—this variant has surprisingly robust effects on blood lipid levels and cardiovascular risk. It's a reminder that not all functional variants change protein sequence²² It's a reminder that not all functional variants change protein sequence
some affect mRNA stability, splicing efficiency, or are in linkage disequilibrium with truly causal variants.

The Mechanism

The rs693 SNP changes position 7673 in the APOB gene from cytosine (C) to thymine (T), creating a restriction site for the XbaI enzyme—hence its historical name. This transition occurs at codon 2488, changing ACC to ACT, but both encode threonine. Despite the synonymous nature, the T allele is consistently associated with elevated apolipoprotein B levels³³ Despite the synonymous nature, the T allele is consistently associated with elevated apolipoprotein B levels
the key structural protein in LDL, VLDL, and other atherogenic particles.

The mechanism likely involves effects on mRNA stability or translation efficiency rather than direct protein structure changes. ApoB is the main protein component of LDL particles⁴⁴ LDL particles
each LDL particle contains exactly one ApoB-100 molecule, making ApoB count a direct measure of atherogenic particle number. More ApoB means more LDL particles capable of infiltrating arterial walls and initiating atherosclerosis.

The Evidence

The evidence for rs693's cardiovascular impact is substantial. A 2017 meta-analysis of 61 studies including 50,018 subjects⁵⁵ 2017 meta-analysis of 61 studies including 50,018 subjects
showed T allele carriers had significantly higher ApoB levels (SMD 0.26), LDL-C (SMD 0.22), total cholesterol (SMD 0.24), and triglycerides (SMD 0.12). They also had slightly lower HDL-C (SMD -0.06).

In a Brazilian elderly cohort of 644 individuals⁶⁶ Brazilian elderly cohort of 644 individuals
TT homozygotes had mean LDL and total cholesterol levels about 10 mg/dL higher than CC or CT genotypes, with Cohen's d effect sizes of 0.35 for LDL. While 10 mg/dL may seem modest, population studies show that a 27 mg/dL increase in total cholesterol translates to 25-30% higher coronary disease incidence.

A meta-analysis specific to Han Chinese populations⁷⁷ meta-analysis specific to Han Chinese populations
analyzed 1,195 CHD patients and 1,178 controls, confirming the XbaI T allele confers significant CHD risk. The 2008 Malmö Diet and Cancer Study⁸⁸ 2008 Malmö Diet and Cancer Study
created a 9-SNP genotype score including rs693 that independently predicted 10-year cardiovascular events (MI, stroke, CHD death).

The T allele frequency varies dramatically by ancestry: 49-50% in Europeans, 38% in Africans and Latinos, 45% in South Asians, but only 2-10% in East Asians. This makes the variant particularly relevant for European-ancestry individuals, where roughly half the population carries at least one copy.

Practical Implications

If you're a T carrier (CT or TT genotype), your baseline lipid profile is likely shifted toward higher atherogenic particle counts. This doesn't guarantee cardiovascular disease— many factors contribute to risk—but it does mean your LDL particle number may be higher than LDL-C alone would suggest. ApoB directly measures particle number⁹⁹ ApoB directly measures particle number
and is increasingly recognized as superior to LDL-C for risk assessment when discordant.

Dietary response may differ by genotype. Saturated fat intake tends to raise LDL-C more in those genetically predisposed to higher ApoB production. Some evidence suggests T carriers benefit more from dietary modifications targeting particle number reduction: prioritizing monounsaturated fats, increasing soluble fiber, and limiting refined carbohydrates that drive VLDL and small dense LDL production.

Statin response can vary by APOB genotype, though rs693 itself has shown mixed results in pharmacogenetic studies. More important is ensuring treatment targets account for ApoB or non-HDL-C, not just LDL-C, if you're a T carrier—your particle number may be higher than cholesterol-based calculations suggest.

Interactions

The APOB rs693 variant interacts with other lipid-related SNPs to influence cardiovascular risk. The Kathiresan 9-SNP score¹⁰¹⁰ Kathiresan 9-SNP score
includes rs693 along with variants in APOE, LDLR, PCSK9, CETP, and other lipid genes, showing additive effects on LDL elevation and CVD risk. Those with multiple unfavorable alleles across these genes show progressively higher LDL and ApoB levels.

The related rs17240441 variant (a 9-bp insertion/deletion in APOB exon 1) also affects ApoB and lipid levels, with combined effects possible when both variants are present. Additionally, variants in MTHFR (like rs1801133) can interact with lipid metabolism through homocysteine pathways, potentially compounding cardiovascular risk in those with elevated ApoB.

Dietary gene-nutrient interactions are relevant: the effect of rs693 on lipid levels may be modified by saturated fat intake, omega-3 consumption, and overall dietary pattern. Some studies suggest Mediterranean-style diets may attenuate the lipid-raising effects of the T allele more effectively than high-saturated-fat Western diets.