rs11071559 — RORA

RORA rs11071559 — A Circadian Clock Gene's Role in Airway Immunity

RORA (RAR-related Orphan Receptor Alpha) occupies a dual role in human biology: it is a core activator of the circadian clock¹¹ circadian clock
RORA binds ROR-response elements in the BMAL1 promoter, driving its transcription and sustaining the ~24-hour oscillation in the suprachiasmatic nucleus and a key regulator of immune tolerance in the airways. The rs11071559 variant sits in the first intron of the RORA-1 transcript on chromosome 15q22.2 — a regulatory region, not a coding sequence — which means it likely influences how much RORA protein is produced rather than altering the protein itself. The best-replicated association for this specific variant is with asthma susceptibility: the common C allele carries slightly elevated risk, while the rarer T allele is protective.

The Mechanism

As an intronic variant with no known amino acid change, rs11071559 is thought to act as a regulatory tag SNP²² regulatory tag SNP
A tag SNP marks a block of correlated variants; rs11071559 may be in linkage disequilibrium with a causal variant that alters a transcription factor binding site or splicing regulatory element in RORA intron 1. RORA itself regulates the promoter activity of NPSR1 (neuropeptide S receptor 1), a gene independently associated with asthma and panic disorder. When RORA expression is altered, NPSR1 promoter activity changes reciprocally³³ NPSR1 promoter activity changes reciprocally
Overexpression of RORA in cell models decreased NPSR1 promoter activity, suggesting a negative regulatory loop. NPSR1 signaling in turn activates a pathway that includes circadian clock genes, creating a feedback loop linking the circadian system to airway inflammation. This may partly explain why asthma symptoms — particularly nocturnal asthma — follow a circadian pattern⁴⁴ circadian pattern
Airway inflammation and bronchoconstriction peak between 2–4 AM in susceptible individuals, mirroring diurnal rhythms in cortisol, melatonin, and mast cell activity.

The Evidence

The asthma association for rs11071559 is among the better-replicated findings in the RORA locus. The APCAT consortium meta-analysis⁵⁵ APCAT consortium meta-analysis
Ramasamy et al. PLOS One 2012 brought this variant to genome-wide significance (p = 2.4 × 10⁻⁹) across six European population-based cohorts totaling approximately 5,751 asthmatics and 28,139 controls. Within the BAMSE and PARSIFAL cohorts, Acevedo et al. 2013⁶⁶ Acevedo et al. 2013
PLOS One found the T allele protective against physician-diagnosed childhood asthma with an odds ratio of 0.71 (95% CI: 0.55–0.92, p = 0.007) in the combined dataset, a modest but replicable effect. Importantly, the RORA association was primarily with asthma diagnosis rather than atopic traits (IgE levels, eczema), suggesting RORA's role in airway inflammation specifically rather than general atopic tendency.

A note on sleep and hormonal phenotypes: RORA is a validated circadian clock gene and BMAL1 activator, and other RORA variants (notably rs75981965) have been associated with sleep duration in a Taiwanese biobank study⁷⁷ Taiwanese biobank study
10,112 subjects, p = 9.93 × 10⁻⁵ after Bonferroni correction. However, rs11071559 itself has not been associated with sleep duration, chronotype, or hormonal traits in any published GWAS. The association for this specific SNP is asthma only. The batch placed this variant in the hormones-sleep category because RORA is a circadian gene, but the actionable evidence for rs11071559 is in airway immunity. Users with the CC genotype should focus on the respiratory health implications described below.

Practical Actions

For the common C-allele carriers (CC or CT), the slightly elevated asthma risk from the RORA locus is modest and modifiable. The circadian-immune link means that circadian disruption amplifies airway inflammation⁸⁸ circadian disruption amplifies airway inflammation
Shift workers and those with social jet lag have higher rates of asthma exacerbation and more severe symptom patterns. Maintaining consistent sleep-wake timing is therefore a genotype-relevant action — not as a generic sleep hygiene recommendation, but because circadian misalignment specifically impairs RORA function in airway epithelial and immune cells, which is the pathway through which this variant acts. Avoiding known asthma triggers and monitoring for nocturnal symptoms are warranted.

Interactions

RORA interacts genetically and biologically with NPSR1 (neuropeptide S receptor 1 gene, chromosome 7p15). The interaction is strongest for nocturnal asthma: rs7164773 in RORA and NPSR1 variants jointly predict asthma phenotype better than either alone. If you have both RORA and NPSR1 risk genotypes and experience primarily night-time or early-morning asthma symptoms, the RORA-NPSR1 interaction may be the relevant mechanism.

The circadian clock gene REV-ERBα (NR1D1) is RORA's functional antagonist at the BMAL1 promoter — both bind the same response element, with opposing effects. Variants in NR1D1 that reduce its repressive activity can partially compensate for reduced RORA activity, and vice versa. Pathway-level interactions between RORA, NR1D1, and RORB on sleep and circadian phenotypes have been reported but not yet linked to this specific rsid.