Gyroscope Therapeutics Limited, London, United Kingdom.
Finnish Biobank Cooperative-FINBB, Turku, Finland.
PLoS One. 2022 Sep 6;17(9):e0272260. doi: 10.1371/journal.pone.0272260. eCollection 2022.
Advanced age-related macular degeneration (AAMD) risk is associated with rare complement Factor I (FI) genetic variants associated with low FI protein levels (termed 'Type 1'), but it is unclear how variant prevalences differ between AMD patients from different ethnicities.
Collective prevalence of Type 1 CFI rare variant genotypes were examined in four European AAMD datasets. Collective minor allele frequencies (MAFs) were sourced from the natural history study SCOPE, the UK Biobank, the International AMD Genomics Consortium (IAMDGC), and the Finnish Biobank Cooperative (FINBB), and compared to paired control MAFs or background population prevalence rates from the Genome Aggregation Database (gnomAD). Due to a lack of available genetic data in non-European AAMD, power calculations were undertaken to estimate the AAMD population sizes required to identify statistically significant association between Type 1 CFI rare variants and disease risk in different ethnicities, using gnomAD populations as controls.
Type 1 CFI rare variants were enriched in all European AAMD cohorts, with odds ratios (ORs) ranging between 3.1 and 7.8, and a greater enrichment was observed in dry AMD from FINBB (OR 8.9, 95% CI 1.49-53.31). The lack of available non-European AAMD datasets prevented us exploring this relationship more globally, however a statistical association may be detectable by future sequencing studies that sample approximately 2,000 AAMD individuals from Ashkenazi Jewish and Latino/Admixed American ethnicities.
The relationship between Type 1 CFI rare variants increasing odds of AAMD are well established in Europeans, however the lack of broader genetic data in AAMD has adverse implications for clinical development and future commercialisation strategies of targeted FI therapies in AAMD. These findings emphasise the importance of generating more diverse genetic data in AAMD to improve equity of access to new treatments and address the bias in health care.
与低 FI 蛋白水平相关的罕见补体因子 I (FI) 遗传变异与年龄相关性黄斑变性 (AMD) 风险相关，尤其是与高级别 AMD (AAMD) 风险相关（称为“Type 1”），但尚不清楚不同种族的 AMD 患者中变异的流行率有何不同。
在四个欧洲 AAMD 数据集检查了 Type 1 CFI 罕见变异基因型的总体流行率。从 SCOPE 自然史研究、英国生物银行、国际 AMD 基因组联盟 (IAMDGC) 和芬兰生物银行合作组织 (FINBB) 中获取了罕见变异的次要等位基因频率 (MAF)，并与配对对照 MAF 或基因组聚集数据库 (gnomAD) 中的背景人群流行率进行了比较。由于缺乏非欧洲 AAMD 患者的可用遗传数据，因此进行了功效计算，以使用 gnomAD 人群作为对照，估计在不同种族中确定 Type 1 CFI 罕见变异与疾病风险之间存在统计学显著关联所需的 AAMD 人群规模。
Type 1 CFI 罕见变异在所有欧洲 AAMD 队列中均富集，优势比 (OR) 范围为 3.1 至 7.8，在 FINBB 的干性 AMD 中观察到更大的富集（OR 8.9，95%CI 1.49-53.31）。缺乏非欧洲 AAMD 数据集使我们无法更全面地探索这种关系，但是未来的测序研究可能会发现统计学关联，这些研究将从阿什肯纳兹犹太人和拉丁裔/混合裔美国人中大约 2000 名 AAMD 个体中进行采样。
在欧洲人中，Type 1 CFI 罕见变异增加 AAMD 发病几率的关系已经确立，但是 AAMD 中缺乏更广泛的遗传数据对靶向 FI 治疗的 AAMD 临床开发和未来商业化策略具有不利影响。这些发现强调了在 AAMD 中生成更多多样化遗传数据的重要性，以提高获得新治疗方法的公平性，并解决医疗保健中的偏见。
