Genetic effects on treatment response of umeclidinium/vilanterol in chronic obstructive pulmonary disease

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• 作者：Lynn Condreay^a ; ¹ ; ^{Lynn.Condreay@parexel.com" class="auth_mail" title="E-mail the corresponding author} ; Lingkang Huang^a ; ² ; Elizabeth Harris^a ; ¹ ; Jean Brooks^b ; John H. Riley^b ; Alison Church^a ; Soumitra Ghosh^c
• 关键词：Chronic obstructive pulmonary disease ; ADRB2 ; Genome-wide association study ; Single nucleotide polymorphism ; Umeclidinium ; Vilanterol
• 刊名：Respiratory Medicine
• 出版年：2016
• 出版时间：May 2016
• 年：2016
• 卷：114
• 期：Complete
• 页码：123-126
• 全文大小：356 K

文摘

Treatment with long-acting β₂-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) for chronic obstructive pulmonary disease (COPD) is standard, but response varies. We investigated genetic association with treatment response to umeclidinium (UMEC, a LAMA), vilanterol (VI, a LABA), and combination therapy.

Methods

Data from 17 clinical trials (N = 6075) in patients with COPD receiving once-daily UMEC/VI (125/25mcg or 62.5/25mcg), UMEC (125 or 62.5mcg), VI (25mcg) or placebo were used. Genetic association with change from baseline in trough forced expiratory volume in 1 s (FEV₁) ∼24 h post-dosing was assessed for: (i) 3 β₂-adrenoceptor (ADRB2) gene variants; (ii) 298 single-nucleotide polymorphisms (SNPs) with prior evidence of associations; (iii) human leukocyte antigen (HLA) alleles and (iv) genome-wide association study (GWAS) SNPs. Other endpoints were (i) reversibility at screening; and at baseline: (ii) FEV₁; (iii) forced vital capacity (FVC), and (iv) FEV₁/FVC ratio. Using linear regression, the inverse normal transformed residuals were pooled together, first across treatment group, then across studies for each monotherapy, then combination therapy and finally for every treated patient.

Results

Of 6075 patients, 1849 received UMEC/VI, 1390 received UMEC, 1795 received VI, and 1041 received placebo. None of the ADRB2 variants, HLA alleles or GWAS variants tested were associated with treatment response or baseline endpoints. Four SNPs in FAM13A (rs7671167, rs2869967, rs1964516, rs1903003) were significantly associated with baseline FEV₁/FVC ratio (p < 3 × 10⁻⁵) after adjusting for multiple testing.

Conclusions

No genetic association was found with treatment response to UMEC or VI when administered as monotherapies or in combination.