rs10864728 (GALNT2): HDL Cholesterol and Triglycerides
Key takeaways
- rs10864728 in GALNT2 (polypeptide N-acetylgalactosaminyltransferase 2) is linked to HDL cholesterol and triglyceride levels in studies of up to 136,016 participants
- The association has been replicated across European and multi-ethnic cohorts using NMR spectroscopy, clinical serum panels, and electronic health record data
- GTEx data show the alternative allele at rs10864728 is associated with increased GALNT2 expression in subcutaneous fat tissue
- GALNT2 encodes an enzyme that attaches sugar molecules to proteins involved in lipid transport, providing a plausible biological mechanism
- No lifestyle-specific guidance has been established from the studies reviewed for this variant
Key takeaways
- rs10864728 in GALNT2 (polypeptide N-acetylgalactosaminyltransferase 2) is consistently linked to HDL cholesterol and triglyceride levels in studies covering up to 136,016 participants across multiple cohorts and ancestries
- The association has been replicated across European and multi-ethnic cohorts using NMR spectroscopy, clinical serum lipid panels, and longitudinal electronic health record measurements
- GTEx expression data show that the alternative allele at this variant is associated with increased GALNT2 activity in subcutaneous fat tissue
- The gene encodes an enzyme that attaches sugar molecules to proteins involved in lipid transport, suggesting a plausible biological mechanism for its effects on circulating lipid levels
- No lifestyle-specific guidance has been established from the studies reviewed for this variant
What the research says A genome-wide meta-analysis of 233 circulating metabolic traits in up to 136,016 participants from 33 cohorts identified the GALNT2 region among more than 400 independent genomic loci influencing lipoprotein and lipid parameters, with NMR-based subclass profiling characterizing its effects across multiple lipoprotein particle concentrations and compositions PMID 38374256. A multi-ethnic electronic health record-based GWAS in 94,674 Kaiser Permanente members, drawing on 478,866 longitudinal untreated lipid measurements, confirmed this locus at genome-wide significance for HDL cholesterol, with eQTL tissue enrichment implicating liver, adipose tissue, and pancreas PMID 31217584. A 1000 Genomes-imputed screen of 9.6 million variants in up to 62,166 Europeans confirmed the locus among 93 genomic regions reaching genome-wide significance for HDL cholesterol and triglycerides PMID 25961943.
Reported associations
- HDL cholesterol: Identified among more than 400 loci in a 136,016-participant NMR metabolomics GWAS; subclass profiling characterized effects across HDL particle concentrations and lipoprotein compositions PMID 38374256
- HDL cholesterol (multi-ethnic replication): Confirmed at genome-wide significance in a multi-ethnic GWAS of 94,674 individuals; genetic effects on HDL were notably greater in females than in males PMID 31217584
- Triglycerides: Among 93 loci at genome-wide significance in a 62,166-person European GWAS screening 9.6 million imputed variants PMID 25961943
- Total cholesterol: Also identified at genome-wide significance for total cholesterol in the multi-ethnic EHR-based lipid GWAS (n=94,674) PMID 31217584
- Multiple circulating lipoprotein subclasses: NMR-based profiling of 233 metabolic traits found extensive pleiotropy at this locus, with associations spanning lipoprotein particle concentrations, lipid compositions, and fatty acid parameters PMID 38374256
Evidence quality Three independent large-scale GWAS studies reviewed here all detect this locus at genome-wide significance (p less than 5 x 10^-8), with discovery samples ranging from 62,166 to 136,016 participants PMID 25961943 PMID 31217584 PMID 38374256. Replication spans European and multi-ethnic cohorts across NMR spectroscopy, clinical serum panels, and longitudinal EHR-derived measurements. The NMR metabolomics study applied the more stringent threshold of p less than 1.8 x 10^-9 across 233 metabolic traits PMID 38374256, and the 1000 Genomes-imputed analysis showed that denser reference panels identified novel lead SNPs at many established lipid loci compared to earlier HapMap2-based studies PMID 25961943. No conflicting findings were identified among the studies reviewed. The EHR-based study demonstrated that use of multiple longitudinal lipid measurements increased the proportion of variance explained by 33-42% compared to single measurements, supporting the robustness of associations at this locus PMID 31217584.
Tissue-specific expression effects
- GALNT2: The alternative allele is associated with increased expression in subcutaneous adipose tissue (p = 3.9 x 10^-5, FDR less than 0.05) GTEx Portal
Lifestyle considerations No lifestyle considerations on file for this variant.
Frequently asked questions
What does the GALNT2 gene do?
GALNT2 encodes polypeptide N-acetylgalactosaminyltransferase 2, an enzyme that attaches a specific sugar (GalNAc) to proteins in a process called O-glycosylation. This modification affects how certain proteins involved in fat transport function in the bloodstream.
Is rs10864728 linked to HDL cholesterol levels?
Yes. Multiple large genome-wide studies consistently associate the GALNT2 region with HDL cholesterol levels across samples of up to 136,016 participants, and one study using NMR spectroscopy characterized effects at the level of individual HDL particle subclasses.
What tissues does rs10864728 affect gene expression in?
GTEx data show the alternative allele at rs10864728 is linked to increased GALNT2 expression in subcutaneous adipose tissue. A large multi-ethnic lipid GWAS also found that lipid-associated loci as a group show eQTL enrichment in the liver, adipose tissue, and pancreas.
How many independent studies have found an association at rs10864728?
Three independent large-scale genome-wide studies reviewed here all detect this locus at genome-wide significance, covering between 62,166 and 136,016 participants each, spanning European and multi-ethnic cohorts and different measurement platforms.
Is the evidence for rs10864728 and lipid levels reliable?
Yes, by GWAS standards the evidence is strong. The locus is detected at genome-wide significance in three independent studies replicated across ancestries and platforms, and one study applied a more stringent threshold of p less than 1.8 x 10^-9 across 233 metabolic traits.