rs10504554 (LY96): Post-Surgical Atrial Fibrillation

Key takeaways

• Carriers of this variant had roughly half the odds of developing dangerous irregular heartbeat after heart bypass surgery
• The genetic signal held up in two independent patient groups, reaching a combined p-value of 4.0×10^-6
• LY96 is part of the body's first-line immune alarm system, a pathway thought to influence post-surgical heart complications
• GTEx data shows this variant also reduces expression of LY96 and several nearby genes across skeletal muscle, fat, and other tissues

What the research says A genome-wide association study (GWAS - a scan of hundreds of thousands of common genetic variants to identify those statistically linked to a trait) identified rs10504554, located in an intron (a non-coding stretch within a gene) of LY96 (lymphocyte antigen 96), as associated with decreased risk of new-onset postoperative atrial fibrillation (AF - a common and potentially dangerous irregular heart rhythm) following coronary artery bypass graft (CABG) surgery. In the discovery cohort (n=877, patients of self-reported European ancestry), carriers showed an odds ratio (OR) of 0.48 (95% CI: 0.34-0.68; p=2.9×10^-5), meaning roughly half the odds of developing postoperative AF; this direction of effect was confirmed in a second independent replication cohort (n=304; OR=0.55; 95% CI: 0.31-0.99; p=0.046), yielding a combined meta-analysis p-value of 4.0×10^-6. Gene enrichment analysis - a method that tests whether genes near associated variants cluster in known biological pathways - highlighted the gene's involvement in innate immune response activation and modulation, including potential interaction with NF-kappa-B (NF-κB) signaling, a central regulator of inflammation.

Reported associations

• New-onset atrial fibrillation after CABG (discovery cohort, n=877): Associated with decreased odds of postoperative AF; OR=0.48, 95% CI: 0.34-0.68, p=2.9×10^-5
• New-onset atrial fibrillation after CABG (replication cohort, n=304): Same protective direction replicated independently; OR=0.55, 95% CI: 0.31-0.99, p=0.046; combined meta-analysis p=4.0×10^-6
• Innate immune and NF-κB inflammatory signaling pathways: Gene enrichment analysis linked the locus to innate immune activation and modulation, including potential interaction with NF-κB, a master regulator of the inflammatory response

Evidence quality Both cohorts consisted of patients of self-reported European ancestry undergoing CABG at a single center (Duke University Medical Center), limiting demographic and geographic generalizability. Sample sizes - 877 in discovery and 304 in replication - are modest relative to contemporary GWAS, which typically enroll tens to hundreds of thousands of participants. Of 19 SNPs that initially met the discovery threshold (p<5×10^-5), only 3 reached nominal significance (p<0.05) in the replication cohort, and rs10504554 alone showed a consistent protective direction across both datasets - a conservative but selective filter. The combined meta-analysis p-value of 4.0×10^-6 is suggestive but falls short of the conventional genome-wide significance threshold of 5×10^-8. The proposed mechanistic link to NF-κB inflammatory signaling is inferred from enrichment analysis rather than direct functional experiments. No large-scale independent replication in external populations is described in the available data, and the evidence should be treated as preliminary.

Tissue-specific expression effects

• TMEM70: Reduced expression in stomach, skeletal muscle, and pancreas; increased expression in EBV-transformed lymphocytes (a laboratory model of immune cells) - the variant shows opposing directional effects on this gene depending on tissue context GTEx Portal
• DSTNP3: Reduced expression in skeletal muscle GTEx Portal
• ENSG00000254288: Reduced expression in both visceral (abdominal cavity) and subcutaneous (beneath the skin) adipose (fat) tissue GTEx Portal
• LY96: Reduced expression in skeletal muscle, consistent with this variant's intronic location within the gene GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.