6533b871fe1ef96bd12d244f
RESEARCH PRODUCT
Variants associated with HHIP expression have sex-differential effects on lung function
Carl A. MelbourneCaroline HaywardStefan KarraschDirk KeidelDirk KeidelKatherine A. FawcettSusan M. RingYohan BosséCarol A. WangBen Michael BrumptonBen Michael BrumptonClaudia LangenbergPeter K. JoshiKe HaoIgor RudanDavid J. PorteousDon D. SinRaquel GranellBlair H. SmithJian'an LuanKristian HveemSarah E. HarrisSandosh PadmanabhanArchie CampbellSebastian May-wilsonVeronique VitartNicola PirastuArnulf LanghammerCraig E. PennellJohn M. StarrStefan WeissKarina PatasovaNicholas J. WarehamJames F. WilsonJames F. WilsonDeborah JarvisTim D. SpectorNick ShrineDavid P. StrachanMartin D. TobinMartin D. TobinBeate StubbeDavid M. EvansDavid M. EvansKirsi H. PietiläinenMangino MassimoIan P. HallGraham L. HallGraham L. HallJaakko KaprioRalf EwertRachel E. FoongRachel E. FoongClaudia FlexederLouise V. WainLouise V. WainMa'en ObeidatCristen J. WillerLeo-pekka LyytikäinenOlli T. RaitakariOlli T. RaitakariJohn HendersonKonstantin StrauchMarta R MoksnesCosetta MinelliNicole Probst-henschNicole Probst-henschPirro G. HysiAnna L. GuyattHenry VölzkeThomas MeitingerPeter D. SlyOzren PolasekAnne RichmondMika KähönenMaarten Van Den BergeMedea ImbodenMedea ImbodenThibaud BoutinLucija KlaricLaura PortasTerho LehtimäkiIan J. DearyTaina RantanenCatherine JohnTeemu Palviainensubject
0301 basic medicineSpirometrymedicine.medical_specialtyHHIPMedicine (miscellaneous)Expression ; Genome-wide Interaction Study ; Hhip ; Lung Function ; SexSingle-nucleotide polymorphismBiology3121 Internal medicineGeneral Biochemistry Genetics and Molecular Biology03 medical and health sciences0302 clinical medicineExpression ; Genome-wide interaction study ; HHIP ; Lung function ; SexInternal medicineexpressionmedicinesexAlleleEnhancerGeneLung functionLunggenome-wide interaction studymedicine.diagnostic_test1184 Genetics developmental biology physiologylung functionALSPAC/dk/atira/pure/core/keywords/alspacDifferential effects030104 developmental biologyEndocrinologymedicine.anatomical_structure030228 respiratory system3121 General medicine internal medicine and other clinical medicine3111 Biomedicinedescription
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 (FEV1) (P=3.15x10-15), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV1 more in males (untransformed FEV1 β=0.028 [SE 0.0022] litres) than females (β=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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-05-24 |