Expressive

rs115594766 (LDLR/SMARCA4): Metabolic Variant

Key takeaways

  • This variant lies near LDLR, the cholesterol receptor gene, and SMARCA4, a gene that helps switch other genes on or off
  • GTEx data from over 950 donors links the alternate allele to increased LDLR activity in the pancreas and reduced SMARCA4 activity in the esophageal lining
  • The alternate allele also associates with increased SLC44A2 expression in skeletal muscle tissue
  • The variant falls within a region studied in a genome-wide analysis of 233 metabolic biomarkers in over 136,000 people
  • Tissue-specific gene expression effects from GTEx are the primary well-characterized data for this variant

Key takeaways

  • This variant lies near two functionally distinct genes: LDLR (Low-Density Lipoprotein Receptor), which helps cells absorb LDL cholesterol from the blood, and SMARCA4, a chromatin remodeling gene that helps switch other genes on or off
  • GTEx data from over 950 donors links the alternate allele to increased LDLR expression in pancreatic tissue and reduced SMARCA4 expression in the esophageal lining
  • The alternate allele also associates with increased SLC44A2 (a choline transporter gene) expression in skeletal muscle
  • A genome-wide study of 233 circulating metabolic traits in over 136,000 participants provides broader research context for this locus
  • Tissue-specific gene expression effects from GTEx are the primary well-characterized data available for this variant

What the research says A genome-wide association study (GWAS) of 233 circulating metabolic traits - including lipid, lipoprotein, fatty acid, and amino acid markers - was conducted across 33 cohorts with up to 136,016 participants using nuclear magnetic resonance (NMR) spectroscopy, identifying more than 400 independent loci and assigning probable causal genes at roughly two-thirds of these through biological candidate curation. GTEx eQTL analysis (953 donors, FDR less than 0.05) shows the alternate allele at rs115594766 links to increased LDLR expression in the pancreas (slope +0.22, p = 3.1e-5), increased SLC44A2 expression in skeletal muscle (slope +0.23, p = 2.5e-6), and reduced SMARCA4 expression in the esophageal mucosa (slope -0.14, p = 1.7e-6) GTEx Portal.

Reported associations

  • Circulating metabolic biomarker research context: The SMARCA4-LDLR locus falls within the scope of a large GWAS of 233 metabolic traits (including lipids, lipoproteins, and fatty acids) in 136,016 participants; the study specifically characterized lipoprotein metabolism at granular detail across identified loci, but specific effect sizes for rs115594766 on named metabolic traits are not detailed in the provided study text
  • LDLR expression in pancreas: The alternate allele associates with increased expression of the low-density lipoprotein receptor gene in pancreatic tissue GTEx Portal
  • SMARCA4 expression in esophageal mucosa: The alternate allele associates with reduced expression of SMARCA4 (a chromatin remodeling gene that controls how DNA is packaged and which genes are accessible for transcription) in the inner lining of the esophagus GTEx Portal
  • SLC44A2 expression in skeletal muscle: The alternate allele associates with increased expression of SLC44A2 (a membrane protein that transports choline into cells) in skeletal muscle tissue GTEx Portal

Evidence quality The circulating metabolic biomarker GWAS providing research context for this locus enrolled up to 136,016 participants from 33 cohorts and profiled 233 traits by NMR spectroscopy; however, specific association statistics for rs115594766 on particular metabolic outcomes are not available in the provided study excerpt, limiting direct evaluation of this variant's metabolic relevance from that dataset. The three GTEx eQTL associations (953 donors) show p-values ranging from 1.7e-6 to 3.1e-5, all passing an FDR threshold of less than 0.05 GTEx Portal. These eQTL findings have not been independently replicated in the provided sources, and the downstream functional or health consequences of the observed expression changes at LDLR, SMARCA4, and SLC44A2 are not established by the available data.

Tissue-specific expression effects

  • LDLR: Increased expression in pancreatic tissue with the alternate allele; LDLR encodes the low-density lipoprotein receptor responsible for clearing LDL cholesterol from the circulation GTEx Portal
  • SMARCA4: Reduced expression in the esophageal mucosa (the inner cellular lining of the esophagus) with the alternate allele; SMARCA4 is a core subunit of the SWI/SNF chromatin remodeling complex, which regulates the transcription of many other genes across diverse tissue types GTEx Portal
  • SLC44A2: Increased expression in skeletal muscle with the alternate allele; SLC44A2 encodes a membrane protein that transports choline, a nutrient involved in cell membrane composition and neurotransmitter synthesis GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.

Frequently asked questions

What is rs115594766?

rs115594766 is a single nucleotide polymorphism (a one-letter DNA difference) located near two genes: LDLR, which encodes the low-density lipoprotein receptor involved in cholesterol clearance, and SMARCA4, a gene that regulates how other genes are expressed. It has been studied in large-scale genome-wide analyses of circulating metabolic biomarkers.

What does the LDLR gene do?

LDLR encodes the low-density lipoprotein receptor, a protein on the surface of cells that captures LDL cholesterol particles from the bloodstream and brings them inside the cell for processing. Variants near LDLR are commonly studied in lipid metabolism and cardiovascular research.

What does SMARCA4 do?

SMARCA4 is a core component of the SWI/SNF chromatin remodeling complex, a molecular machine that adjusts how tightly DNA is packaged, controlling which genes are switched on or off. It plays broad regulatory roles across many tissue types.

Which tissues show expression changes linked to rs115594766?

According to GTEx data from over 950 donors, the alternate allele at rs115594766 associates with increased LDLR expression in the pancreas, reduced SMARCA4 expression in the esophageal mucosa, and increased SLC44A2 expression in skeletal muscle tissue.

Is rs115594766 linked to cholesterol levels or heart disease?

The variant is located near LDLR, a gene central to LDL cholesterol metabolism, and it was examined within a large genome-wide study of 233 circulating metabolic traits. The provided research does not report a specific confirmed association between rs115594766 and cholesterol levels or cardiovascular disease outcomes.