Does the T allele at SORT1 rs12740374 lower LDL cholesterol?

The association between the rs12740374 polymorphism at the 1p13.3 locus and cholesterol levels is one of the most robust findings in lipid genetics, with the SORT1 gene serving as the primary mediator of this effect.

Genetic and clinical evidence

Large-scale genome-wide association studies (GWAS) have consistently identified the T allele at rs12740374 as the protective variant for lipid profiles.

• LDL-C Association: In diverse populations, including American Indian cohorts, the minor T allele shows a highly significant association with lower LDL cholesterol (LDL-C), with p-values reaching 1 × 10⁻²² in some studies.
• Cardiovascular Impact: Carrying the protective T allele is not only associated with lower circulating cholesterol but also translates to a significant reduction in clinical outcomes. Carriers of this allele exhibit an estimated 20% to 40% decreased risk of myocardial infarction compared to those with the GG genotype.
• Genotype Frequency: The GG genotype represents the major allele homozygote in most populations. Individuals with the GG genotype lack the T allele and typically present with higher baseline LDL-C levels relative to T-allele carriers.

Mechanistic insights

The rs12740374 polymorphism is a functional variant that alters the expression of the SORT1 gene in the liver through a specific transcription factor pathway:

• Transcription Factor Binding: The T allele creates a consensus binding site for the transcription factor C/EBPα.
• Upregulation of SORT1: This binding significantly increases the hepatic expression of SORT1 mRNA and its protein product, sortilin, in liver cells.
• Lipoprotein Clearance: Higher levels of hepatic sortilin facilitate the clearance of LDL particles from the bloodstream and may also inhibit the secretion of very-low-density lipoprotein (VLDL) from the liver. By enhancing the liver's ability to remove these particles, the T allele effectively lowers the concentration of circulating LDL-C.

Bottom line

The claim is strongly supported by genomic evidence. The T allele at rs12740374 increases hepatic SORT1 expression, leading to enhanced LDL clearance and lower cholesterol levels. Conversely, the GG genotype indicates the absence of this protective allele, which is associated with higher LDL-C and an increased risk of cardiovascular events.