Department of Clinical Biochemistry, Copenhagen University Hospital-Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
JAMA Ophthalmol. 2023 Jan 1;141(1):13-21. doi: 10.1001/jamaophthalmol.2022.4602.
The association of major lipid genes with and their potential as drug targets for age-related macular degeneration (AMD) is unknown. These associations are important to study because AMD is the leading cause of irreversible late-onset blindness in high-income countries.
To determine whether the full range of structural genetic variation in apolipoprotein E (APOE), a master gene in peripheral and cerebral lipid metabolism, is associated with risk of AMD.
DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS) cohorts. Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021.
The exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.
Cox regression was applied to estimate risk of AMD associated with APOE genotype.
A total of 105 546 participants (mean [SD] age, 57.7 [13.4] years; 58 140 [55%] female participants) were included. Compared with participants with the common ɛ33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45-0.96) and ε43 (aHR, 0.80; 95% CI, 0.71-0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00-1.31) genotype. Compared with noncarriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53; 95% CI, 1.14-10.96) and Arg154Cys (aHR, 4.52; 95% CI, 1-13-18.13) heterozygotes. Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12; 95% CI, 1.05-1.19), the adjusted model plus APOE ɛ2/ɛ3/ɛ4 status (aHR, 1.82; 95% CI, 1.20-2.76), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77; 95% CI, 1.14-2.75).
These findings highlight that structural variation in APOE beyond the ε2/ε3/ε4 variants may be important for risk of AMD in a population of European ancestry. Rare functional ɛ2-like variants in APOE have previously been reported to have protective associations for Alzheimer disease but the present findings suggest a simultaneous high risk of AMD. This would limit the drug target potential of mechanisms resembling these variants.
主要脂质基因与年龄相关性黄斑变性（AMD）的关联及其作为药物靶点的潜力尚不清楚。这些关联很重要，因为 AMD 是高收入国家导致不可逆转的晚期发病失明的主要原因。
确定载脂蛋白 E（APOE）的全范围结构遗传变异是否与 AMD 的发病风险相关，APOE 是周围和大脑脂质代谢的主基因。
设计、地点和参与者：这项队列研究使用了哥本哈根城市心脏研究（CCHS）和哥本哈根一般人群研究（CGPS）队列的数据。参与者从采血时开始纳入研究，直到发生事件、死亡、移民或 2018 年 12 月 7 日（以先发生者为准）。对于 CCHS 的参与者，APOE 基因进行了测序，CGPS 中对杂合频率至少为 0.0002 的 9 个变体进行了基因分型。观察者对患者分组进行了盲法。数据分析于 2021 年 3 月至 9 月进行。
暴露情况为 APOE 状态，所有参与者均测量了血浆中直接的基因产物 apoE 水平。
应用 Cox 回归估计 APOE 基因型与 AMD 相关的风险。
共纳入 105546 名参与者（平均[标准差]年龄为 57.7[13.4]岁；58140[55%]为女性参与者）。与常见的ɛ33 基因型相比，与 ε44（多因素调整后的危险比[aHR]，0.66；95%CI，0.45-0.96）和 ε43（aHR，0.80；95%CI，0.71-0.90）基因型相关的 AMD 风险较低，与 ε32（aHR，1.15；95%CI，1.00-1.31）基因型相关的 AMD 风险较高。与非携带者相比，Gly145Asp（aHR，3.53；95%CI，1.14-10.96）和 Arg154Cys（aHR，4.52；95%CI，1-13-18.13）杂合子的 AMD 发病风险更高。进一步调整脂质特征和 APOE ε2/ε3/ε4 变体后，结果相似。在调整模型中，每增加 1 毫克/分升遗传上更高的血浆 apoE，AMD 的发病风险增加（aHR，1.12；95%CI，1.05-1.19），调整模型加 APOE ε2/ε3/ε4 状态（aHR，1.82；95%CI，1.20-2.76），以及仅在 ε33 基因型个体的调整模型中（aHR，1.77；95%CI，1.14-2.75）。
这些发现强调了 APOE 除了 ε2/ε3/ε4 变体之外的结构变异可能对欧洲血统人群 AMD 的发病风险很重要。APOE 中先前报道的罕见功能性 ε2 样变体与阿尔茨海默病的保护相关，但本研究结果表明同时存在高 AMD 风险。这将限制类似这些变体的机制的药物靶点潜力。
