rs11650680 — ORMDL3 ORMDL3 17q21 asthma susceptibility

Intronic regulatory variant in the ORMDL3 17q21 haploblock; the C allele drives elevated ORMDL3 expression in airway epithelial cells and immune cells, increasing asthma susceptibility and total IgE levels; the T allele is protective

See your personal result for ORMDL3

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

ORMDL3 rs11650680 — A Protective Variant in the Asthma Susceptibility Haploblock

The chromosome 17q21 locus is the most consistently replicated genetic risk region for childhood-onset asthma. The locus spans a dense 130-kb regulatory haploblock containing six genes — IKZF3, ZPBP2, GSDMB, ORMDL3, LRRC3C, and GSDMA — and harbors a cluster of correlated variants that collectively regulate ORMDL3 expression in airway tissue and immune cells. rs11650680 is an intronic regulatory variant within this haploblock that was identified alongside rs7216389 in the original landmark GWAS11 original landmark GWAS
Moffatt et al. Nature 2007, 994 childhood asthma cases vs 1,243 controls; rs11650680 and rs7216389 were among the top index SNPs at 17q21, p<10⁻¹². Unlike rs7216389 (where T is the risk allele), rs11650680 has the C allele as the risk allele and the T allele as the protective variant — a subtle but important distinction established by multiple meta-analyses.

The Mechanism

rs11650680 sits within an intron of the ORMDL3/GSDMB locus and functions as a regulatory eQTL22 regulatory eQTL
expression quantitative trait locus — a variant that alters nearby gene transcript levels without changing the protein sequence; rs11650680 modulates ORMDL3 and GSDMB expression in a C-allele-dose-dependent manner. The C allele is associated with higher ORMDL3 expression in airway epithelial cells and lymphoblastoid cell lines. Elevated ORMDL3 inhibits serine palmitoyltransferase, reducing de novo ceramide and sphingolipid synthesis in the airway epithelium. This sphingolipid deficit lowers T-cell activation thresholds, promotes Th2-skewed immune polarization, and activates the ATF6 branch of the unfolded protein response — collectively amplifying the eosinophilic airway inflammation that characterises asthma.

The T allele, by contrast, is associated with lower ORMDL3 expression33 lower ORMDL3 expression
the T allele at rs11650680 reduces the C-allele-driven regulatory signal, producing less ORMDL3 mRNA in airway tissue and immune cells, and corresponds to the lowest asthma susceptibility at this locus. Carriers of one or two T alleles (CT and TT genotypes) produce less ORMDL3 and show correspondingly lower markers of airway eosinophilic inflammation than CC homozygotes.

The Evidence

The Shi et al. 2015 meta-analysis44 Shi et al. 2015 meta-analysis
13 published case-control studies, 6,462 asthma cases and 7,357 controls; fixed-effects model; rs11650680 T allele significantly protective in dominant model (TT+CT vs. CC) established the asthma-protective role of the T allele across multiple populations. A second meta-analysis pooling 18 studies and 7,904 cases with 10,874 controls55 pooling 18 studies and 7,904 cases with 10,874 controls
Wan et al. Human Immunology 2014, rs11650680 and rs12603332 T alleles both protective, consistent across Caucasian and Asian subgroups replicated the finding.

Population-specific data reveals important variation. A study of 315 Chinese children (315 asthma cases, 192 controls; Leung et al. Allergy 2009)66 (315 asthma cases, 192 controls; Leung et al. Allergy 2009)
rs11650680 significantly associated with asthma diagnosis, atopy, and total plasma IgE levels (p=0.008–0.0002) in Chinese children; the CC risk genotype correlated with higher IgE burden and atopic sensitisation demonstrated that the rs11650680 locus affects not only asthma diagnosis but also atopic sensitisation and IgE production — linking the variant to the broader Th2-driven atopic phenotype beyond asthma alone.

In Japanese women, the CT heterozygous genotype was significantly inversely associated with asthma77 CT heterozygous genotype was significantly inversely associated with asthma
Miyake et al. DNA Cell Biol 2014, 202 asthma cases and 1,290 controls in the KOMCHS cohort; CT vs. CC OR 0.67 (95% CI 0.46–0.96); effect was specific to adult-onset asthma, consistent with the meta-analysis direction. Separately, Acosta-Perez et al. 201288 Acosta-Perez et al. 2012
JACI, Puerto Rican and Mexican children; CC genotype associated with higher eosinophil-associated biomarkers and bronchial hyperresponsiveness, consistent with elevated ORMDL3-driven eosinophilic inflammation extended the finding to Latino populations.

Practical Implications

The CC genotype is the most common globally (~69%) and represents the reference state for this variant — but it also carries elevated asthma susceptibility. For CC individuals with asthma, the clinical picture is one of elevated eosinophilic airway inflammation driven by increased ORMDL3 activity: monitoring FeNO and blood eosinophil counts helps characterize the inflammatory endotype and guide treatment. For TT and CT carriers, the T allele provides partial to complete attenuation of the ORMDL3-driven airway inflammatory signal.

The rs11650680 signal is partially correlated with rs7216389 and rs12936231, and these SNPs likely tag overlapping but not fully redundant regulatory elements within the 17q21 haploblock. Carrying the protective T allele at rs11650680 does not eliminate risk conferred by other 17q21 variants, so the broader haploblock context matters for a complete risk picture.

Interactions

rs11650680 lies in strong LD with rs7216389 and rs12936231 within the same 17q21 haploblock, but the LD is incomplete — some individuals carry discordant genotypes across these three SNPs, suggesting partially independent regulatory signals. The combination of the CC genotype at rs11650680, the TT genotype at rs7216389, and the CC genotype at rs12936231 represents full engagement of the ORMDL3-overexpressing regulatory state; individuals with this haplotype combination have the highest ORMDL3 expression and the greatest airway inflammatory burden. The 17q21 locus also shows a well-documented inverse relationship with autoimmune disease risk99 inverse relationship with autoimmune disease risk
the asthma-risk haplotype (high ORMDL3) is associated with lower risk of type 1 diabetes and Crohn's disease; the autoimmune-risk allele at rs2872507 is protective for asthma — reflecting the Th1/Th17 vs. Th2 immune axis trade-off.

Genotype Interpretations

What each possible genotype means for this variant.

TT Protective Genotype Normal

Protective genotype — lowest ORMDL3 expression and reduced asthma susceptibility at this locus

You carry two copies of the T allele at rs11650680, the genotype associated with the lowest ORMDL3 expression at this locus and the greatest protection from asthma susceptibility. The TT genotype is uncommon globally (~3%), consistent with T being the minor allele. Meta-analyses confirm that carriers of TT genotype have significantly reduced asthma risk compared to CC homozygotes, with the protective effect most clearly demonstrated in childhood-onset and adult-onset asthma studies across multiple ethnic populations. This genotype alone does not eliminate asthma risk, as many other genetic and environmental factors contribute, but the ORMDL3 17q21 locus is not a source of elevated susceptibility for you.

CT Partial Protection Intermediate

One protective T allele — intermediate ORMDL3 expression and modestly reduced asthma risk

The additive inheritance pattern means each T allele incrementally reduces ORMDL3 expression through attenuation of C-allele-driven regulatory signals in the 17q21 haploblock. CT individuals occupy the middle ground: less constitutive airway eosinophilic inflammation than CC, but more than TT. Studies of asthma endotyping in CT individuals show intermediate eosinophil cationic protein (ECP) levels compared to both homozygous genotypes, consistent with the additive dose-response. In the Japanese KOMCHS study, the CT genotype was specifically inversely associated with adult-onset asthma (OR 0.67), suggesting the protective T allele's effect extends through adulthood.

CC Risk Genotype High Risk

Two risk alleles — highest ORMDL3 expression, elevated asthma susceptibility and higher IgE burden

The CC genotype represents full engagement of the C-allele regulatory state in the 17q21 haploblock: both alleles drive higher ORMDL3 transcription, producing the maximum airway and immune cell ORMDL3 protein burden from this specific regulatory element. Elevated ORMDL3 suppresses serine palmitoyltransferase, reducing ceramide and sphingosine-1-phosphate (S1P) production; S1P depletion creates a constitutively primed inflammatory state that reacts more intensely to allergens, viral infections, and environmental irritants.

Studies specifically examining eosinophilic biomarkers show that CC individuals have higher eosinophil cationic protein (ECP) levels than CT or TT carriers in asthmatic populations, confirming that the greater ORMDL3 activity in CC individuals translates to measurably elevated eosinophilic airway inflammation. This eosinophilic endotype predicts both asthma exacerbation risk and the profile of treatments most likely to provide benefit.

Population-specific data confirms the association across ethnicities: the CC genotype is associated with asthma and elevated total IgE in Chinese children, Puerto Rican and Mexican children, and Japanese adults; the effect is consistent in direction across Caucasian, East Asian, and Latino populations.