Mucin VNTR haplogroup associations with idiopathic pulmonary fibrosis are not independent of rs35705950

Background: The MUC5B promoter variant (rs35705950) is the strongest common genetic risk factor for idiopathic pulmonary fibrosis (IPF). MUC5B and MUC5AC contain variable number tandem repeat (VNTR) regions. Long-read sequencing resolves MUC5AC into three SNP-tagged haplogroups (H1, H2, H3) differing in repeat length, and MUC5B into two (H1, H2) differing in lineage but not length. The tags correlate with rs35705950, so whether a haplogroup effect is distinguishable from the promoter variant is unclear. Methods: We assigned MUC5AC and MUC5B haplogroups from imputed chromosome 11 array data in 771 European-ancestry IPF Job Exposures Study participants (385 cases, 386 controls). Logistic regression adjusted for age, smoking, principal components and centre, with and without rs35705950. The same models were fitted in TOPMed (1,961 cases, 3,816 controls). Results: MUC5AC H3 and MUC5B H1 were each associated with IPF (H3 OR 1.63, 95% CI 1.26-2.09, p=1.8x10-4; MUC5B H1 OR 0.71, 0.52-0.98, p=0.038). Both attenuated on adjustment for rs35705950 (H3 OR 1.10, 0.83-1.45, p=0.52; MUC5B H1 OR 0.82, 0.58-1.15, p=0.25). A MUC5AC H2 association persisted after adjustment (OR 0.69, 0.51-0.94, p=0.017). In TOPMed the H3 findings replicated (unadjusted OR 1.62, 1.47-1.78, p<10-15; adjusted 0.94, 0.84-1.05, p=0.26), but the rs35705950-adjusted H2 association did not: the estimate was null overall (OR 0.99, 0.88-1.11, p=0.87) and in men and women separately (1.00, 0.87-1.16; 0.97, 0.79-1.19). The MUC5B tag failed quality control in TOPMed. Conclusions: The MUC5AC H3 and MUC5B H1 associations are not independent of rs35705950. The MUC5AC H2 association seen here did not replicate. VNTR haplogroup does not appear to contribute to IPF risk independently of rs35705950.