Abstract:
Hyperparathyroidism (HPT) manifests as a complex condition with a substantial disease burden. While advances have been made in surgical interventions and non-surgical pharmacotherapy for the management of hyperparathyroidism, radical options to halt underlying disease progression remain lacking. Identifying putative genetic drivers and exploring novel drug targets that can impede HPT progression remain critical unmet needs. A Mendelian randomization (MR) analysis was performed to uncover putative therapeutic targets implicated in hyperparathyroidism pathology. Cis-expression quantitative trait loci (cis-eQTL) data serving as genetic instrumental variables were obtained from the eQTLGen Consortium and Genotype-Tissue Expression (GTEx) portal. Hyperparathyroidism summary statistics for single nucleotide polymorphism (SNP) associations were sourced from the FinnGen study (5590 cases; 361,988 controls). Colocalization analysis was performed to determine the probability of shared causal variants underlying SNP-hyperparathyroidism and SNP-eQTL links. Five drug targets (CMKLR1, FSTL1, IGSF11, PIK3C3 and SLC40A1) showed significant causation with hyperparathyroidism in both eQTLGen and GTEx cohorts by MR analysis. Specifically, phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3) and solute carrier family 40 member 1 (SLC40A1) showed strong evidence of colocalization with HPT. Multivariable MR and Phenome-Wide Association Study analyses indicated these two targets were not associated with other traits. Additionally, drug prediction analysis implies the potential of these two targets for future clinical applications. This study identifies PIK3C3 and SLC40A1 as potential genetically proxied druggable genes and promising therapeutic targets for hyperparathyroidism. Targeting PIK3C3 and SLC40A1 may offer effective novel pharmacotherapies for impeding hyperparathyroidism progression and reducing disease risk. These findings provide preliminary genetic insight into underlying drivers amenable to therapeutic manipulation, though further investigation is imperative to validate translational potential from preclinical models through clinical applications.
摘要:
甲状旁腺功能亢进症(HPT)表现为具有严重疾病负担的复杂病症。虽然在甲状旁腺功能亢进的手术干预和非手术药物治疗方面取得了进展,仍然缺乏阻止潜在疾病进展的激进选择。确定推定的遗传驱动因素和探索可以阻碍HPT进展的新型药物靶标仍然是关键的未满足需求。进行了孟德尔随机化(MR)分析,以揭示与甲状旁腺功能亢进病理有关的推定治疗靶标。从eQTLGen联盟和基因型组织表达(GTEx)门户获得用作遗传工具变量的顺式表达定量性状基因座(cis-eQTL)数据。甲状旁腺功能亢进的单核苷酸多态性(SNP)关联汇总统计来自FinnGen研究(5590例;361,988例对照)。进行共定位分析以确定SNP-甲状旁腺功能亢进和SNP-eQTL链接潜在的共有因果变异的概率。通过MR分析,五个药物靶标(CMKLR1,FSTL1,IGSF11,PIK3C3和SLC40A1)在eQTLGen和GTEx队列中均显示出与甲状旁腺功能亢进的显着因果关系。具体来说,磷脂酰肌醇3激酶催化亚基3型(PIK3C3)和溶质载体家族40成员1(SLC40A1)显示出与HPT共定位的有力证据。多变量MR和全表型关联研究分析表明,这两个目标与其他性状无关。此外,药物预测分析暗示了这两个靶标在未来临床应用中的潜力。这项研究确定了PIK3C3和SLC40A1是潜在的遗传代理药物基因和甲状旁腺功能亢进的有希望的治疗靶标。靶向PIK3C3和SLC40A1可能为阻止甲状旁腺功能亢进进展和降低疾病风险提供有效的新型药物疗法。这些发现提供了对适合治疗操作的潜在驱动因素的初步遗传见解,尽管必须进行进一步的研究,以验证从临床前模型到临床应用的转化潜力。