rs35705950

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This is a upstream gene variant variant in the MUC5B gene.

Key Literature Trait Associations

Idiopathic Pulmonary Fibrosis

The MUC5B rs35705950-T allele is the strongest known common genetic risk factor for IPF. The discovery GWAS (Seibold et al., 2011; n=897) found ORs of 9.0 (heterozygous) and 21.8 (homozygous) for IPF versus controls (p=2.5×10⁻³⁷). Multiple subsequent meta-analyses have confirmed this association: a 2021 meta-analysis of 24 studies (6,749 cases, 13,898 controls) reported an allelic OR of 4.12 (95% CI 3.64–4.67), with the TT genotype conferring OR=10.12. The effect is stronger in Caucasians (OR ~4.50) than Asians (OR ~2.39). The T allele elevates MUC5B expression ~37-fold in lung tissue, impairing mucociliary clearance and promoting fibrosis.

Wu X et al. “The minor T allele of the MUC5B promoter rs35705950 associated with susceptibility to idiopathic pulmonary fibrosis: a meta-analysis.” Scientific Reports (2021)

Allele T

OR 4.12

p 1.0e-50

N 20,647

Meta-analysisLarge GWAS

multi-ancestry

Min-Gu Lee et al. “A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis” Inflammation Research (2015)

Allele T

OR 3.77

p 1.0e-8

N 9,760

Meta-analysis

multi-ancestry

Fingerlin TE et al. “Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis.” Nature Genetics 45(6):613-20 (2013)

Allele T

OR —

p 1.1e-19

N 9,065

Large GWAS

European

Seibold MA et al. “A common MUC5B promoter polymorphism and pulmonary fibrosis.” The New England Journal of Medicine (2011)

Allele T

OR 9.00

p 2.5e-37

N 897

Small GWAS

European

Familial interstitial pneumonia

The MUC5B rs35705950-T allele confers markedly elevated risk for familial interstitial pneumonia (FIP), a heritable form of progressive lung fibrosis. The original Seibold et al. discovery study found T allele frequency of 34% in FIP patients versus 9% in controls, with heterozygous OR=6.8 and homozygous OR=20.8 (p=1.2×10⁻¹⁵). A subsequent meta-analysis (Lou et al., 2020; 28 studies) confirmed extremely high risk for the TT genotype (OR=17.08 vs GG) and significant T allele risk (OR=1.64). FIP carriers of the variant may present with subclinical interstitial lung changes years before clinical diagnosis.

Seibold MA et al. “A common MUC5B promoter polymorphism and pulmonary fibrosis.” The New England Journal of Medicine (2011)

Allele T

OR 6.80

p 1.2e-15

N 405

Small GWAS

European

Lou HQ et al. “The Association between MUC5B Rs35705950 and Risks of Idiopathic Interstitial Pneumonia, Systemic Sclerosis Interstitial Lung Disease, and Familial Interstitial Pneumonia: A Meta-Analysis.” Iranian Journal of Public Health (2020)

Allele T

OR 17.08

p 5.0e-2

N 94,747

Meta-analysis

multi-ancestry

Rheumatoid arthritis-associated interstitial lung disease

The MUC5B rs35705950-T allele is associated with interstitial lung disease in patients with rheumatoid arthritis (RA-ILD), particularly the usual interstitial pneumonia (UIP) histological pattern. A landmark 2018 NEJM study by Juge et al. (PMID 30345907) demonstrated this association in a large international multicenter cohort. A Korean/Japanese meta-analysis (Joo et al., 2022) found OR=4.90 for UIP in RA patients (p=0.024) and OR=3.51 in a combined meta-analysis, noting the variant is rare in Asians but highly enriched in those with UIP-pattern ILD. This association appears specific to UIP and is not observed for non-UIP RA-ILD subtypes.

Juge PA et al. “MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease.” The New England Journal of Medicine (2018)

Allele T

OR —

p —

Candidate gene study

multi-ancestry

Joo YB et al. “MUC5B promoter variant rs35705950, rare but significant susceptibility locus in rheumatoid arthritis-interstitial lung disease with usual interstitial pneumonia in Asian populations.” Rmd Open (2022)

Allele T

OR 3.51

p 2.3e-2

N 2,444

Preliminary work

East Asian

COVID-19 hospitalization

The MUC5B rs35705950-T allele (minor allele) is paradoxically associated with reduced COVID-19 hospitalization risk despite increasing fibrotic lung disease risk — meaning the common G allele is the risk allele for hospitalization. A 2022 MVP study (Verma et al.) found OR=0.89 (95% CI 0.82–0.97, p=6.86×10⁻³) in 4,325 cases/507,640 controls, with joint meta-analysis including HGI data (13,320 cases, 1,508,841 controls) confirming OR=0.90 (p=8.99×10⁻⁵). The T allele also reduced post-COVID-19 pneumonia risk in European ancestry (OR=0.82). No protective effect was seen against severe disease or mortality.

Verma A et al. “A MUC5B Gene Polymorphism, rs35705950-T, Confers Protective Effects Against COVID-19 Hospitalization but Not Severe Disease or Mortality.” American Journal of Respiratory and Critical Care Medicine (2022)

Allele G

OR 0.90

p 9.0e-5

N 1,522,161

Preliminary work

multi-ancestry

Neutrophil count

The rs35705950-T allele is associated with lower peripheral neutrophil count in large-scale GWAS studies, as catalogued in the EBI GWAS Catalog (p=1×10⁻¹⁶, beta= −0.045 per T allele, SE=0.0054). This finding likely reflects the MUC5B variant's role in modulating innate pulmonary immunity and mucosal defense, though the clinical significance of this quantitative blood cell trait is modest. The association is genome-wide significant and well-powered but the effect size is small.

Chen MH et al. “Trans-ethnic and Ancestry-Specific Blood-Cell Genetics in 746,667 Individuals from 5 Global Populations.” Cell 182(5):1198-1213.e14 (2020)

Allele T

OR —

β -0.045 ±0.005

p 1.0e-16

Large GWAS

European

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GWAS Catalog Trait Associations (15)

Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.

idiopathic pulmonary fibrosis

Allen RJ et al. “Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis.” Thorax 77(8):829-833 (2022)

Allele T

OR 5.06

p —

N 24,589

Large GWAS

European

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele T

OR 1.06

p 2.0e-178

N 449,368

Major Consortium StudyLarge GWAS

European

Allen RJ et al. “Genome-Wide Association Study of Susceptibility to Idiopathic Pulmonary Fibrosis.” American Journal of Respiratory and Critical Care Medicine 201(5):564-574 (2020)

Allele T

OR 4.84

p 1.0e-203

N 11,259

Large GWAS

European

Allen RJ et al. “Genetic variants associated with susceptibility to idiopathic pulmonary fibrosis in people of European ancestry: a genome-wide association study.” The Lancet. Respiratory Medicine 5(11):869-880 (2017)

Allele T

OR 2.89

p 1.0e-66

N 3,968

Large GWAS

European

Noth I et al. “Genetic variants associated with idiopathic pulmonary fibrosis susceptibility and mortality: a genome-wide association study.” The Lancet. Respiratory Medicine 1(4):309-317 (2013)

Allele T

OR 2.43

p 2.0e-50

N 1,084

Large GWAS

European

interstitial lung disease

Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)

Allele T

OR 1.01

p 1.0e-76

N 647,847

Large GWAS

multi-ancestry

Hobbs BD et al. “Overlap of Genetic Risk between Interstitial Lung Abnormalities and Idiopathic Pulmonary Fibrosis.” American Journal of Respiratory and Critical Care Medicine 200(11):1402-1413 (2019)

Allele T

OR 2.23

p 5.0e-29

N 10,709

Large GWAS

multi-ancestry

pulmonary fibrosis

Sakaue S et al. “A cross-population atlas of genetic associations for 220 human phenotypes.” Nature Genetics 53(10):1415-1424 (2021)

Allele T

OR 1.12

p 2.0e-65

N 646,226

Large GWAS

multi-ancestry

pulmonary surfactant-associated protein d measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele T

OR 0.05

p 1.0e-20

N 47,745

Large GWAS

European

blood protein amount

Gudjonsson A et al. “A genome-wide association study of serum proteins reveals shared loci with common diseases.” Nature Communications 13(1):480 (2022)

Allele T

OR 0.26

p 4.0e-19

N 5,367

Large GWAS

European

lysosome-associated membrane glycoprotein 3 measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele T

OR 0.07

p 2.0e-18

N 47,745

Large GWAS

European

Abnormal lung morphology

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele G

OR 0.09

p 3.0e-14

N 417,304

Major Consortium StudyLarge GWAS

European

COVID-19

Pairo-Castineira E et al. “GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.” Nature 617(7962):764-768 (2023)

Allele T

OR 0.86

p 4.0e-14

N 1,779,771

Meta-analysisLarge GWAS

multi-ancestry

“A first update on mapping the human genetic architecture of COVID-19.” Nature 608(7921):E1-E10 (2022)

Allele T

OR 0.89

p 6.0e-9

N 2,861,299

Large GWAS

multi-ancestry

Diz-de Almeida S et al. “Novel risk loci for COVID-19 hospitalization among admixed American populations.” Elife 13 (2024)

Allele T

OR 0.10

p 2.0e-12

N 73,303

Large GWAS

multi-ancestry

respiratory failure

Verma A et al. “Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.” Science (new York, N.y.) 385(6706):eadj1182 (2024)

Allele G

OR 0.09

p 8.0e-13

N 431,795

Major Consortium StudyLarge GWAS

European

mesothelin measurement

Loya H et al. “A scalable variational inference approach for increased mixed-model association power.” Nature Genetics 57(2):461-468 (2025)

Allele T

OR 0.06

p 2.0e-12

N 47,745

Large GWAS

European

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ClinVar annotation

Risk Factor★☆☆☆

4 submitters9 publications

Antisynthetase syndrome; Interstitial lung disease 2 (ILD2); Pulmonary fibrosis, idiopathic, susceptibility to; Susceptibility to coronavirus disease (COVID-19) severity and mortality due to low plasma levels of MUC5B

View on ClinVar →

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Research that mentions this SNP (3)

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Targeted resequencing reveals genetic risks in patients with sporadic idiopathic pulmonary fibrosis

AssociationN=378Yanhan Deng et al.(2018)· Human Mutation

Targeted resequencing of 92 IPF-related genes in 253 Chinese sporadic IPF patients and 125 controls identified 2 pathogenic variants (TERT rs121918666, rs199422294) and 10 loss-of-function variants in 4.74% of cases. Burden tests revealed rare missense variants in CSF3R, DSP, and LAMA3 were significantly associated with IPF. Four common SNPs (rs3737002, rs2296160, rs1800470, rs35705950) showed significant associations, with a cumulative risk model showing that high-risk subjects had 3.47-fold increased risk (95%CI: 2.07-5.81, p = 2.34×10⁻⁶) compared to low-risk subjects.

Traits studied:Idiopathic pulmonary fibrosis

PubMed DOI Metascience Observatory

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A meta-analysis examining the association between the MUC5B rs35705950 T/G polymorphism and susceptibility to idiopathic pulmonary fibrosis

Meta-analysisN=13,969Min-Gu Lee et al.(2015)· Inflammation Research

A meta-analysis of 12 studies (2,859 IPF patients, 6,901 controls) and 4 CTD-ILD studies (903 patients, 3,306 controls) examining the MUC5B rs35705950 T/G polymorphism found a significant association between the T allele and idiopathic pulmonary fibrosis (IPF) in Europeans and Asians (OR 3.768, 95% CI 2.935-4.836, p < 1.0 × 10⁻⁸), but no association with CTD-ILD. The T allele shows dose-dependent increased risk with OR 12.98 for TT vs GG genotype.

Traits studied:Connective tissue disease-associated interstitial lung diseaseIdiopathic pulmonary fibrosisSystemic sclerosis-associated ILD

PubMed DOI Metascience Observatory

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Association Between the MUC5B Promoter Polymorphism and Survival in Patients With Idiopathic Pulmonary Fibrosis

AssociationN=586Anna L. Peljto et al.(2013)· JAMA

Retrospective study of 586 IPF patients (INSPIRE cohort n=438, Chicago cohort n=148) examining the association between MUC5B rs35705950 polymorphism and survival. The T allele, a risk factor for IPF development, was significantly associated with improved survival (HR=0.48 for GT and HR=0.23 for TT vs. GG in INSPIRE; HR=0.39 for GT and HR=0.15 for TT in Chicago; P<0.001). MUC5B genotype improved predictive accuracy (C=0.71 vs. 0.68 in INSPIRE; C=0.73 vs. 0.69 in Chicago).

rs35705950

Key Literature Trait Associations

Idiopathic Pulmonary Fibrosis

Familial interstitial pneumonia

Rheumatoid arthritis-associated interstitial lung disease

COVID-19 hospitalization

Neutrophil count

GWAS Catalog Trait Associations (15)

idiopathic pulmonary fibrosis

interstitial lung disease

pulmonary fibrosis

pulmonary surfactant-associated protein d measurement

blood protein amount

lysosome-associated membrane glycoprotein 3 measurement

Abnormal lung morphology

COVID-19

respiratory failure

mesothelin measurement

ClinVar annotation

Research that mentions this SNP (3)

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