St Jean Pamela L, Roth David A, McCarthy Linda C, Hughes Arlene R
Genomic Medicine, PAREXEL International, Durham, North Carolina.
GlaxoSmithKline, Upper Providence, Pennsylvania, USA.
Pharmacogenet Genomics. 2019 Aug;29(6):132-135. doi: 10.1097/FPC.0000000000000378.
GlaxoSmithKline (GSK) conducted pharmacogenetic (PGx) analyses to determine whether genetic variants influence response to belimumab treatment in patients with systemic lupus erythematosus (SLE). We conducted an exploratory genome-wide meta-analysis (GWAS) of 10.9 million genetic variants and the efficacy data from 816 belimumab-treated SLE patients in three phase 3 belimumab clinical studies. Two highly correlated variants, rs293983 and rs364370, in the ANO3 (anoctamin 3) gene region were significantly associated with efficacy as measured by the SLE Response Index (SRI4) with a per-T-allele odds ratio (OR) of 2.15 [95% confidence interval (CI): 1.66-2.79, P=8.0×10]. In contrast, there was no association with SRI4 response in 577 placebo-treated patients (per-T-allele OR: 0.98; 95% CI: 0.74-1.29, P=0.87). A post-hoc analysis by geographic region revealed a strong SRI4 response signal in 157 belimumab-treated patients from Asia (per-T-allele OR=2.85, 95% CI: 1.41-5.74, P=0.0021). On the basis of this encouraging finding in Asian patients, we conducted a confirmatory analysis of the SRI4 end point in an independent phase 3 study of SLE patients from northeast Asia. We found no evidence of an association between rs293983 and SRI4 response in 204 belimumab-treated patients (per-T-allele OR: 0.90, 95% CI: 0.52-1.57, P=0.64). The inability to replicate the observed GWAS effect suggests this was a false positive result; hence, we failed to identify any genetic variants significantly associated with belimumab efficacy.
葛兰素史克公司（GSK）开展了药物遗传学（PGx）分析，以确定基因变异是否会影响系统性红斑狼疮（SLE）患者对贝利尤单抗治疗的反应。我们对1090万个基因变异以及来自三项贝利尤单抗3期临床研究中816例接受贝利尤单抗治疗的SLE患者的疗效数据进行了探索性全基因组荟萃分析（GWAS）。ANO3（anoctamin 3）基因区域中的两个高度相关变异rs293983和rs364370，与以SLE反应指数（SRI4）衡量的疗效显著相关，每个T等位基因的优势比（OR）为2.15 [95%置信区间（CI）：1.66 - 2.79，P = 8.0×10⁻⁹]。相比之下，577例接受安慰剂治疗的患者中，该变异与SRI4反应无关联（每个T等位基因OR：0.98；95% CI：0.74 - 1.29，P = 0.87）。按地理区域进行的事后分析显示，在157例来自亚洲的接受贝利尤单抗治疗的患者中存在强烈的SRI4反应信号（每个T等位基因OR = 2.85，95% CI：1.41 - 5.74，P = 0.0021）。基于亚洲患者这一令人鼓舞的发现，我们在一项针对东北亚SLE患者的独立3期研究中对SRI4终点进行了验证性分析。我们发现在204例接受贝利尤单抗治疗的患者中，没有证据表明rs293983与SRI4反应存在关联（每个T等位基因OR：0.90，95% CI：0.52 - 1.57，P = 0.64）。无法重复观察到的GWAS效应表明这是一个假阳性结果；因此，我们未能识别出任何与贝利尤单抗疗效显著相关的基因变异。
