Variants associated with HHIP expression have sex-differential effects on lung function.
Variants associated with HHIP expression have sex-differential effects on lung function.
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DOI：
10.12688/wellcomeopenres.15846.2
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发表时间：
2020
影响因子：
--
通讯作者：
Wain LV
中科院分区：
文献类型：
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作者：
Fawcett KA;Obeidat M;Melbourne C;Shrine N;Guyatt AL;John C;Luan J;Richmond A;Moksnes MR;Granell R;Weiss S;Imboden M;May-Wilson S;Hysi P;Boutin TS;Portas L;Flexeder C;Harris SE;Wang CA;Lyytikäinen LP;Palviainen T;Foong RE;Keidel D;Minelli C;Langenberg C;Bossé Y;Van den Berge M;Sin DD;Hao K;Campbell A;Porteous D;Padmanabhan S;Smith BH;Evans DM;Ring S;Langhammer A;Hveem K;Willer C;Ewert R;Stubbe B;Pirastu N;Klaric L;Joshi PK;Patasova K;Massimo M;Polasek O;Starr JM;Karrasch S;Strauch K;Meitinger T;Rudan I;Rantanen T;Pietiläinen K;Kähönen M;Raitakari OT;Hall GL;Sly PD;Pennell CE;Kaprio J;Lehtimäki T;Vitart V;Deary IJ;Jarvis D;Wilson JF;Spector T;Probst-Hensch N;Wareham NJ;Völzke H;Henderson J;Strachan DP;Brumpton BM;Hayward C;Hall IP;Tobin MD;Wain LV
背景：肺功能具有高度遗传性，并且在整个生命过程中存在性别差异。然而，关于性别差异对肺功能的遗传影响知之甚少。我们的目的是进行第一个全基因组基因型与性别的肺功能相互作用研究，以确定男性和女性之间不同的遗传效应。 研究方法：我们在UK Biobank（N= 303，612）中测试了7，745，864种变异与性别之间的相互作用，并在SpiroMeta联盟的75，696名独立个体中进行了复制。 结果如下：5个独立的单核苷酸多态性（SNPs）在全基因组范围内与性别对肺功能有显著的交互作用（P<5 × 10 - 8），21个显示提示性交互作用（P<1 × 10 - 6）。在SpiroMeta中复制了rs7697189（chr 4：145436894）对1秒用力呼气量（FEV 1）的最强信号（P=3.15x10 - 15）（P=0.016）。C等位基因使男性FEV 1增加的幅度（未转换的FEV 1 β=0.028 [SE 0.0022]升）大于女性（β=0.009 [SE 0.0014]升），这种效应不能通过对身高、吸烟或青春期年龄的差异效应来解释。rs7697189位于刺猬相互作用蛋白（HHIP）基因的上游，先前与肺功能和HHIP肺表达相关。结果发现HHIP基因在不同性别间的表达差异有统计学意义（P= 6.90 × 10 - 6），但未发现rs7697189对HHIP基因表达的性别差异作用。 结论：我们确定了一种新的基因型与性别的相互作用在一个假定的增强子区域上游的HHIP基因。建立HHIP SNPs对男性和女性肺功能具有不同影响的机制对于我们理解两性的肺健康和疾病将是重要的。
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 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.