rs11668477 (SMARCA4/LDLR): Lipid Metabolism Locus
Key takeaways
- rs11668477 sits in the SMARCA4-LDLR genomic region, a locus studied for circulating LDL and lipoprotein levels across up to 136,016 participants from 33 cohorts.
- GTEx v11 data (953 donors) link the alternative allele to reduced SMARCA4 expression in esophageal mucosa, reduced SLC44A2 expression in tibial artery, and increased SPC24 expression in testis, each at FDR < 0.05.
- Evidence spans both European founder populations and diverse multi-ethnic cohorts of nearly 50,000 non-European individuals.
- Effect sizes for lipid associations may differ across ancestries; studies of diverse populations caution against direct extrapolation of European-derived estimates.
Key takeaways
- rs11668477 sits in the SMARCA4-LDLR genomic region, a locus studied for circulating LDL and lipoprotein levels across up to 136,016 participants from 33 cohorts.
- GTEx v11 data (953 donors) link the alternative allele to reduced SMARCA4 expression in esophageal mucosa, reduced SLC44A2 expression in tibial artery, and increased SPC24 expression in testis, each at FDR < 0.05.
- Evidence spans European founder populations and diverse multi-ethnic cohorts of nearly 50,000 non-European individuals.
- Effect sizes for lipid associations may differ across ancestries; studies caution against direct extrapolation of European-derived estimates.
What the research says
A genome-wide association meta-analysis of 233 circulating metabolic traits in up to 136,016 participants from 33 cohorts detected more than 400 independent loci, with the LDLR-proximal region catalogued among 155 genomic regions whose lead trait was a lipid, lipoprotein, or fatty acid measurement, and most lipid traits showing associations at 20-50 or more loci each PMID 38374255. A separate study in the Northern Finland Birth Cohort 1966 (NFBC1966; n=4,763), a genetically isolated founder population with extended linkage disequilibrium, analyzed LDL cholesterol among nine quantitative metabolic traits, replicating established lipid locus associations and reporting novel signals near metabolically relevant genes PMID 19060910. The PAGE study extended evidence to 49,839 non-European individuals across five ancestry groups, identifying 27 novel loci and 38 secondary signals at known loci, and finding meaningful effect-size heterogeneity across ancestries for established lipid associations PMID 31217584.
Reported associations
- Circulating lipid and lipoprotein traits: A 233-trait meta-analysis (n=136,016, p < 1.8 x 10-9 threshold) found more than 400 genome-wide significant loci across 155 lipid-dominant genomic regions, with up to 214 associated traits at the APOE region as a reference for scale PMID 38374255.
- LDL cholesterol in a founder population: NFBC1966 (n=4,763) examined LDL as a primary quantitative metabolic trait, identifying nine new associations in addition to replicating previously reported lipid loci, with the cohort design enabling detection of both common low-impact and rarer higher-impact variants PMID 19060910.
- Lipid and metabolic traits in diverse ancestries: PAGE (n=49,839 non-European individuals) applied ancestry-sensitive methods across 26 phenotypes and replicated 1,444 GWAS Catalogue associations; population structure was found to underlie many trait-variant associations, with risk allele frequencies differing substantially across groups PMID 31217584.
Evidence quality
The largest study (n=136,016, 33 cohorts) used a threshold of p < 1.8 x 10-9 and manual curation to assign probable causal genes at two-thirds of identified loci PMID 38374255. NFBC1966 (n=4,763) adds replication from a founder population where extended linkage disequilibrium improves locus resolution, though its smaller size limits power for weak effects PMID 19060910. PAGE (n=49,839) explicitly warns that risk prediction scores derived in European cohorts may not extrapolate accurately to other ancestries PMID 31217584. The provided excerpts do not report variant-specific beta coefficients or p-values for rs11668477 itself; the most precise quantitative data come from GTEx v11 (953 donors), where three tissue-level eQTL effects are significant at FDR < 0.05 with nominal p-values between 1.2 x 10-4 and 1.7 x 10-5.
Tissue-specific expression effects
- SMARCA4: Reduced expression in esophageal mucosa (slope -0.09 log2-normalized units, p=1.6 x 10-5) GTEx Portal.
- SLC44A2: Reduced expression in tibial artery tissue (slope -0.10 log2-normalized units, p=1.7 x 10-5) GTEx Portal.
- SPC24: Increased expression in testis (slope +0.14 log2-normalized units, p=1.2 x 10-4) GTEx Portal.
Lifestyle considerations
No lifestyle considerations on file for this variant.
Lifestyle context
Concrete actions anchored to the cited research. We do not prescribe, we describe.
Discuss with your doctor
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cardiovascular risk and LDL cholesterol management Moderate
this variant increases LDL levels; individualized cardiovascular risk assessment and management planning is needed
Screening
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lipid panel for LDL cholesterol Moderate
rs11668477 is associated with elevated LDL cholesterol, a major cardiovascular risk factor
lipid panel now, then every 5 years if normal
Frequently asked questions
What is rs11668477 and where does it sit in the genome?
rs11668477 is a genetic variant in the SMARCA4-LDLR genomic region. This locus has been included in large-scale genome-wide analyses of circulating lipid and lipoprotein traits across more than 136,000 participants from 33 research cohorts.
Is rs11668477 linked to LDL cholesterol?
The LDLR-proximal region where rs11668477 is located sits within a landscape of more than 400 loci associated with circulating lipid traits in a 33-cohort meta-analysis of 136,016 participants. Variant-specific effect sizes for this SNP are not reported in the available study excerpts.
What do GTEx expression data show for rs11668477?
GTEx v11 data from 953 donors show the alternative allele is linked to reduced SMARCA4 expression in esophageal mucosa (slope -0.09, p=1.6 x 10-5), reduced SLC44A2 expression in tibial artery (slope -0.10, p=1.7 x 10-5), and increased SPC24 expression in testis (slope +0.14, p=1.2 x 10-4). All three effects meet FDR < 0.05.
Has rs11668477 been studied in non-European populations?
The PAGE study examined 26 phenotypes including lipid traits in 49,839 non-European individuals spanning Hispanic/Latino, African American, Asian, Native Hawaiian, and Native American groups. It found that effect sizes for known lipid loci vary across ancestries, meaning estimates from European cohorts should not be applied directly to other populations.
Which genes are near rs11668477 and what expression effects are reported?
rs11668477 sits between the SMARCA4 and LDLR genes. GTEx tissue data show the variant is associated with reduced expression of SMARCA4 in esophageal tissue, reduced SLC44A2 expression in tibial arteries, and increased SPC24 expression in testis.