Variants associated with; HHIP; expression have sex-differential effects on lung function

Fawcett, K. A. and Obeidat, M. and Melbourne, C. and Shrine, N. and Guyatt, A. L. and John, C. and Luan, J. and Richmond, A. and Moksnes, M. R. and Granell, R. and Weiss, S. and Imboden, M. and May-Wilson, S. and Hysi, P. and Boutin, T. S. and Portas, L. and Flexeder, C. and Harris, S. E. and Wang, C. A. and Lyytikainen, L. P. and Palviainen, T. and Foong, R. E. and Keidel, D. and Minelli, C. and Langenberg, C. and Bosse, Y. and Van den Berge, M. and Sin, D. D. and Hao, K. and Campbell, A. and Porteous, D. and Padmanabhan, S. and Smith, B. H. and Evans, D. M. and Ring, S. and Langhammer, A. and Hveem, K. and Willer, C. and Ewert, R. and Stubbe, B. and Pirastu, N. and Klaric, L. and Joshi, P. K. and Patasova, K. and Massimo, M. and Polasek, O. and Starr, J. M. and Karrasch, S. and Strauch, K. and Meitinger, T. and Rudan, I. and Rantanen, T. and Pietilainen, K. and Kahonen, M. and Raitakari, O. T. and Hall, G. L. and Sly, P. D. and Pennell, C. E. and Kaprio, J. and Lehtimaki, T. and Vitart, V. and Deary, I. J. and Jarvis, D. and Wilson, J. F. and Spector, T. and Probst-Hensch, N. and Wareham, N. J. and Volzke, H. and Henderson, J. and Strachan, D. P. and Brumpton, B. M. and Hayward, C. and Hall, I. P. and Tobin, M. D. and Wain, L. V.. (2020) Variants associated with; HHIP; expression have sex-differential effects on lung function. Wellcome Open Res, 5. p. 111.

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Abstract

Background: Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. Methods: We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Results: Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 (-8)) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 (-6)). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV 1) (P=3.15x10 (-15)), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV 1 more in males (untransformed FEV 1 beta=0.028 [SE 0.0022] litres) than females (beta=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( HHIP) gene and was previously associated with lung function and HHIP lung expression. We found HHIP expression was significantly different between the sexes (P=6.90x10 (-6)), but we could not detect sex differential effects of rs7697189 on expression. Conclusions: We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the HHIP gene. Establishing the mechanism by which HHIP SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.

Faculties and Departments:	09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Biostatistics > Biostatistics Frequentist Modelling (Kwiatkowski) 09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Exposome Science (Probst-Hensch) 03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Exposome Science (Probst-Hensch)
UniBasel Contributors:	Imboden, Medea and Keidel, Dirk and Probst-Hensch, Nicole
Item Type:	Article, refereed
Article Subtype:	Research Article
ISSN:	2398-502X (Print)2398-502X (Linking)
Note:	Publication type according to Uni Basel Research Database: Journal article
Language:	English
Related URLs:	Document
Identification Number:	doi: 10.12688/wellcomeopenres.15846.1 pmid: 33728380
edoc DOI:	10.5451/unibas-ep91076
Last Modified:	28 Dec 2022 10:22
Deposited On:	28 Dec 2022 10:22

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