rs12740374 — SORT1 1p13.3 locus

The 1p13.3 Locus — A Genetic LDL-Cholesterol Thermostat

Your chromosomes contain regulatory switches that control how much cholesterol circulates in your blood. At position 1p13.3 on chromosome 1, a single-letter DNA change creates or destroys a binding site for a protein called C/EBP¹¹ C/EBP
CCAAT/enhancer binding protein, a transcription factor that regulates gene expression, fundamentally altering your liver's cholesterol management system.

This variant, rs12740374, sits in the 3' untranslated region of the CELSR2 gene but controls expression of SORT1, which encodes sortilin²² sortilin
a cellular trafficking receptor that directs proteins to different destinations within cells. When the T allele is present, it creates a functional C/EBP binding site that increases sortilin production in liver cells by more than 12-fold³³ more than 12-fold
compared to the major G allele. This isn't a subtle effect — it's one of the strongest genetic regulators of LDL cholesterol discovered through genome-wide studies.

The Mechanism

Sortilin acts as an intracellular sorting receptor in hepatocytes, binding to apolipoprotein B-100 (apoB) in the Golgi apparatus. When sortilin levels are high (T allele carriers), it captures apoB-containing particles and routes them to lysosomes for degradation⁴⁴ captures apoB-containing particles and routes them to lysosomes for degradation
rather than allowing them to be secreted as VLDL particles, reducing the amount of VLDL that leaves the liver. Since VLDL particles are converted to LDL in circulation, less VLDL secretion means lower plasma LDL cholesterol.

The molecular switch works like this: the T allele creates a perfect C/EBP consensus binding site, while the G allele disrupts it. When C/EBP binds to the T allele sequence, it increases SORT1 transcription. Reporter assays show ~4-fold greater gene activity⁵⁵ ~4-fold greater gene activity
with the T allele compared to G in laboratory experiments.

Importantly, sortilin's effect is context-dependent. It restricts apoB secretion specifically under conditions of lipid loading and endoplasmic reticulum stress⁶⁶ lipid loading and endoplasmic reticulum stress
metabolic conditions common after high-fat meals, but has minimal effect under basal conditions. This suggests the variant may be particularly important during metabolic challenges.

Beyond reducing VLDL secretion, increased hepatic sortilin also enhances LDL catabolism⁷⁷ enhances LDL catabolism
the breakdown and clearance of LDL particles from the blood, working through two complementary mechanisms to lower circulating LDL cholesterol.

The Evidence

The 1p13.3 locus ranks among the most robustly replicated genetic associations in cardiovascular disease. Genome-wide association studies⁸⁸ Genome-wide association studies
meta-analyses combining hundreds of thousands of individuals consistently identify rs12740374 and its tightly linked neighbors (rs646776, rs599839) as major LDL-cholesterol regulators.

Effect sizes are clinically meaningful. Each copy of the T allele (the higher-sortilin, protective allele) lowers LDL cholesterol by approximately 0.18-0.19 mmol/L (7-7.5 mg/dL)⁹⁹ 0.18-0.19 mmol/L (7-7.5 mg/dL)
observed in both European Americans and African Americans in the ARIC Study. Other studies report reductions of 5-11 mg/dL per T allele¹⁰¹⁰ 5-11 mg/dL per T allele
effect size varies by ancestry, with Mexican Americans showing ~11 mg/dL reduction.

The cardiovascular benefit is substantial. Homozygosity for the protective T allele is associated with a 40% reduction in myocardial infarction risk¹¹¹¹ 40% reduction in myocardial infarction risk
compared to GG homozygotes, with odds ratios in the 0.51 range for coronary stenosis. The effect is mediated primarily through LDL-cholesterol lowering, though the variant also reduces protein C levels¹²¹² reduces protein C levels
a coagulation factor, suggesting a novel link between lipoprotein metabolism and hemostasis.

Effect sizes are considerably larger in younger populations¹³¹³ considerably larger in younger populations
2.5-4.1% of LDL-C variation in children and young adults, versus 1% in older subjects, suggesting early-life effects may be particularly important for lifelong cardiovascular risk.

Functional studies in mice confirm the mechanism. Sort1 knockout mice show reduced lipoprotein secretion and protection from hypercholesterolemia¹⁴¹⁴ reduced lipoprotein secretion and protection from hypercholesterolemia
when crossed with LDL receptor-deficient mice, while sortilin overexpression increases plasma LDL levels. RNA interference studies in human hepatocytes demonstrate that silencing SORT1 reduces apoB secretion.

A pharmacogenetic meta-analysis¹⁵¹⁵ pharmacogenetic meta-analysis
of statin response studies found that rs12740374 is associated with an additional 1.5% increase per T allele in LDL-C lowering when treated with statins, suggesting the variant may predict drug response.

Practical Actions

If you carry one or two copies of the protective T allele, you start with a genetic advantage for cholesterol management. Your liver naturally produces more sortilin, routing more apoB to degradation and secreting less VLDL. This doesn't mean you're immune to high cholesterol — diet, exercise, and other genetic factors still matter — but you have a lower baseline risk.

For GG homozygotes, the opposite applies: less sortilin means more efficient VLDL secretion and higher baseline LDL-cholesterol. This genetic predisposition makes lifestyle modifications particularly important¹⁶¹⁶ lifestyle modifications particularly important
dietary interventions that reduce LDL-C are especially valuable when genetic factors work against you.

Dietary fiber and plant sterols work through complementary mechanisms. Soluble fiber¹⁷¹⁷ Soluble fiber
5-10 grams daily from oats, barley, psyllium, beans, and vegetables reduces intestinal cholesterol absorption. Plant sterols/stanols¹⁸¹⁸ Plant sterols/stanols
2 grams daily from fortified foods or supplements compete with cholesterol for absorption, lowering LDL-C by 5-15%. A dietary portfolio combining these approaches can reduce LDL-C by ~30%, rivaling first-line statin therapy.

Since sortilin's effects are amplified under conditions of lipid loading and ER stress¹⁹¹⁹ conditions of lipid loading and ER stress
high-fat meals and metabolic stress, GG carriers may see particular benefit from moderating saturated fat intake. Studies show saturated fatty acids activate ERK signaling and suppress Sort1 expression²⁰²⁰ activate ERK signaling and suppress Sort1 expression
in obese and diabetic mice, potentially worsening the GG genotype's baseline disadvantage.

Interactions

The 1p13.3 locus is part of a broader polygenic architecture of LDL cholesterol. Variants in APOE, LDLR, PCSK9, APOB, and HMGCR²¹²¹ APOE, LDLR, PCSK9, APOB, and HMGCR
other major cholesterol-regulating genes combine additively to determine overall cholesterol levels and cardiovascular risk. Genetic risk scores incorporating these loci predict familial hypercholesterolemia in patients without monogenic mutations.

The nearby variants rs646776 and rs599839 are in near-perfect linkage disequilibrium with rs12740374²²²² near-perfect linkage disequilibrium with rs12740374
r² > 0.98, meaning they're almost always inherited together and represent the same biological signal. Other SNPs in this haplotype block include rs629301, rs1277930, and rs583104.

Gene-diet interactions have been observed. While the locus primarily affects baseline LDL-cholesterol, dietary interventions still work: carriers of the higher-risk G allele respond normally to soluble fiber, plant sterols, and Mediterranean dietary patterns²³²³ respond normally to soluble fiber, plant sterols, and Mediterranean dietary patterns
these interventions lower LDL-C regardless of genotype.

Statin pharmacogenetics show that rs12740374 predicts treatment response, with T allele carriers achieving slightly greater LDL-C reduction²⁴²⁴ slightly greater LDL-C reduction
an additional 1.5% per allele on statin therapy. This suggests that genetic testing could help predict who will achieve guideline LDL-C targets on first-line therapy versus requiring combination treatment.

Gene-Gene Interaction Proposals

SORT1 × APOE (rs12740374 × rs429358/rs7412): APOE genotype determines LDL receptor affinity, while SORT1 controls hepatic VLDL secretion. The combination of SORT1 GG (high VLDL secretion) with APOE ε4/ε4 (impaired LDL clearance) may create a compound risk state requiring aggressive dietary or pharmacologic intervention. Conversely, SORT1 TT × APOE ε2/ε2 might confer exceptional protection. Evidence: both loci are included in polygenic risk scores for hypercholesterolemia²⁵²⁵ polygenic risk scores for hypercholesterolemia
and show additive effects.

SORT1 × PCSK9 (rs12740374 × rs11591147): PCSK9 degrades LDL receptors, while sortilin controls VLDL production and facilitates PCSK9 secretion²⁶²⁶ facilitates PCSK9 secretion
SORT1 enhances PCSK9 secretion from hepatocytes. SORT1 GG (low sortilin) with PCSK9 gain-of-function variants may compound LDL-C elevation through both increased production and reduced clearance. Evidence: PCSK9 and LDLR show documented interaction effects²⁷²⁷ PCSK9 and LDLR show documented interaction effects
on statin response.