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• W3208152686 abstract "<ns4:p><ns4:bold>Background: </ns4:bold>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.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> 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.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10<ns4:sup>-8</ns4:sup>) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10<ns4:sup>-6</ns4:sup>). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV<ns4:sub>1</ns4:sub>) (P=3.15x10<ns4:sup>-15</ns4:sup>), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV<ns4:sub>1</ns4:sub> more in males (untransformed FEV<ns4:sub>1</ns4:sub> 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 (<ns4:italic>HHIP</ns4:italic>) gene and was previously associated with lung function and <ns4:italic>HHIP</ns4:italic> lung expression. We found <ns4:italic>HHIP</ns4:italic> expression was significantly different between the sexes (P=6.90x10<ns4:sup>-6</ns4:sup>), but we could not detect sex differential effects of rs7697189 on expression.</ns4:p><ns4:p> <ns4:bold>Conclusions:</ns4:bold> We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the <ns4:italic>HHIP</ns4:italic> gene. Establishing the mechanism by which <ns4:italic>HHIP</ns4:italic> 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.</ns4:p>" @default.
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• W3208152686 date "2020-06-01" @default.
• W3208152686 modified "2023-10-14" @default.
• W3208152686 title "Variants associated with HHIP expression have sex-differential effects on lung function" @default.
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