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Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma

机译：神经肽S（NPS）变体修饰哮喘中NPS受体1（NPSR1）变体的信号传导和风险效应

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摘要

Single nucleotide polymorphisms (SNPs) close to the gain-of-function substitution, Asn(107)Ile (rs324981, A>T), in Neuropeptide S Receptor 1 (NPSR1) have been associated with asthma. Furthermore, a functional SNP (rs4751440, G>C) in Neuropeptide S (NPS) encodes a Val(6)Leu substitution on the mature peptide that results in reduced bioactivity. We sought to examine the effects of different combinations of these NPS and NPSR1 variants on downstream signaling and genetic risk of asthma. In transfected cells, the magnitude of NPSR1-induced activation of cAMP/PKA signal transduction pathways and downstream gene expression was dependent on the combination of the NPS and NPSR1 variants with NPS-Val(6)/NPSR1-Ile(107) resulting in strongest and NPS-Leu(6)/NPSR1-Asn(107) in weakest effects, respectively. One or two copies of the NPS-Leu(6) (rs4751440) were associated with physician-diagnosed childhood asthma (OR: 0.67, 95%CI 0.49–0.92, p = 0.01) and together with two other linked NPS variants (rs1931704 and rs10830123) formed a protective haplotype (p = 0.008) in the Swedish birth cohort BAMSE (2033 children). NPS rs10830123 showed epistasis with NPSR1 rs324981 encoding Asn(107)Ile (p = 0.009) in BAMSE and with the linked NPSR1 rs17199659 (p = 0.005) in the German MAGIC/ISAAC II cohort (1454 children). In conclusion, NPS variants modify asthma risk and should be considered in genetic association studies of NPSR1 with asthma and other complex diseases.
机译：神经肽S受体1（NPSR1）中接近功能获得替代的Asn（107）Ile（rs324981，A> T）单核苷酸多态性（SNP）与哮喘有关。此外，神经肽S（NPS）中的功能性SNP（rs4751440，G> C）编码成熟肽上的Val（6）Leu取代，导致生物活性降低。我们试图检查这些NPS和NPSR1变体的不同组合对下游信号传导和哮喘遗传风险的影响。在转染的细胞中，NPSR1诱导的cAMP / PKA信号转导途径激活和下游基因表达的强度取决于NPS和NPSR1变体与NPS-Val（6）/ NPSR1-Ile（107）的组合，从而产生最强的和NPS-Leu（6）/ NPSR1-Asn（107）的作用最弱。一或两份NPS-Leu（6）（rs4751440）与医师诊断的儿童哮喘有关（OR：0.67，95％CI 0.49-0.92，p = 0.01），以及其他两个相关的NPS变异体（rs1931704和rs10830123）在瑞典出生队列BAMSE（2033名儿童）中形成了保护性单倍型（p = 0.008）。 NPS rs10830123在BAMSE中显示为编码Asn（107）Ile的NPSR1 rs324981（p = 0.009），在德国MAGIC / ISAAC II队列中有相关的NPSR1 rs17199659（p = 0.005），（1454名儿童）。总之，NPS变异会改变哮喘风险，因此在NPSR1与哮喘和其他复杂疾病的遗传关联研究中应考虑这些变异。

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