Collapsing Glomerulopathy in Identical Twins With Lupus and High-Risk Apolipoprotein L1 (APOL1) Genotype.
Collapsing Glomerulopathy in Identical Twins With Lupus and High-Risk Apolipoprotein L1 (APOL1) Genotype.
复制标题
DOI：
10.1016/j.ekir.2021.06.005
复制
发表时间：
2021-09
影响因子：
6
通讯作者：
Sparks MA
中科院分区：
文献类型：
--
作者：
DeOliveira M;Feeney C;Leahy C;Nystrom S;Howell DN;Farouk SS;Wu M;Olabisi OA;Sparks MA
塌陷性肾小球病（CG）的特征是肾小球毛细血管簇整体或节段性塌陷以及上覆壁上皮细胞的增殖。它与多种病因有关，包括人类免疫缺陷病毒（HIV）、严重急性呼吸综合征冠状病毒-2（SARS-CoV-2）、自身免疫性疾病（包括系统性红斑狼疮（SLE））、恶性肿瘤、药物暴露和其他病毒性疾病。 1 患者通常表现为严重急性肾损伤 (AKI) 和蛋白尿。无论病因如何，CG 都是预后不良的标志。它主要见于近代西非血统的人。累积证据表明，携带 2 种载脂蛋白 L1 (APOL1) 肾脏风险变异 (KRV) 会增加 SLE、2 种 HIV、3 种移植供体肾脏、4、5 种和 SARS-CoV-2 的 CG 风险。 6 然而，并非所有拥有 2 架 APOL1 KRV 的运营商都开发了 CG。试图解释这种明显的不完全外显率引发了“两次打击假说”，该假说提出第二次打击——环境触发因素或除 2 个 APOL1 KRV 之外的其他遗传因素——对于 APOL1 相关 CG 的发病机制是必要的。由于 CG 与高炎症细胞因子的疾病相关，并且医源性干扰素与 CG、7、8、9 相关，因此推测环境因素或病症（例如 SLE）会提高循环干扰素水平，从而构成第二次打击。然而，2 个 APOL1 KRV 与 HIV 或 SLE 等已知的二次攻击相结合，仅在一小部分病例中导致 APOL1 相关肾病 (AAKD)，这增加了额外的遗传或表观遗传修饰对于 AAKD 的发病或进展至关重要的可能性。对异质患者群体的全基因组关联研究并未揭示 AAKD 的可重复的常见遗传修饰因子。 S1 这些全基因组关联研究的失败可能是由多种因素造成的，包括可能没有足够的力量来检测异质人群中效应大小适中的多基因风险调节剂。在这里，我们介绍了 2 例有 SLE 病史的同卵双胞胎，他们出现了 APOL1 相关的 CG。我们认为，这对双胞胎病例增加了证据，支持患者遗传背景在 APOL1 相关 CG 发病机制中可能发挥的作用，并且具有 APOL1 相关 CG 的同卵双胞胎的相同基因组可能是发现 AAKD 的此类遗传修饰因素的理想选择。
Collapsing glomerulopathy (CG) is characterized by global or segmental collapse of the glomerular capillary tuft along with proliferation of overlying parietal epithelial cells. It is associated with multiple etiologies including human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), autoimmune diseases including systemic lupus erythematosus (SLE), malignancy, drug exposures, and other viral illnesses. 1 Patients usually present acutely with severe acute kidney injury (AKI) and proteinuria. Irrespective of the etiology, CG is a marker of poor prognosis. It is predominantly seen in individuals of recent West African ancestry. Cumulative evidence demonstrates that carriage of 2 apolipoprotein L1 (APOL1) kidney risk variants (KRVs) increases the risk of CG in SLE, 2 HIV, 3 transplanted donor kidneys, 4, 5 and SARS-CoV-2. 6 However, not all carriers of 2 APOL1 KRVs develop CG. Attempts to explain this apparent incomplete penetrance gave rise to the “2-hit hypothesis” that proposes that a second hit—either environmental trigger or additional genetic factors other than 2 APOL1 KRVs—is necessary for pathogenesis of APOL1-associated CG. Because CG is associated with diseases with high inflammatory cytokines, and as iatrogenic interferons have been associated with CG, 7, 8, 9 it has been speculated that environmental factors or conditions such as SLE, which raise levels of circulating interferons, would constitute second hits. However, combination of 2 APOL1 KRVs and known second hits such as HIV or SLE results in APOL1-associated kidney disease (AAKD) in only a fraction of all cases, raising the possibility that the additional genetic or epigenetic modifiers are essential for onset or progression of AAKD. Genome-wide association studies of heterogenous patient population did not reveal reproducible common genetic modifier of AAKD. S1 The failure of these genome-wide association studies is likely driven by multiple factors including the possibility of insufficient power to detect polygenic risk modifiers with modest effect sizes in heterogenous population. Here, we present 2 cases of identical twins with a history of SLE who developed APOL1-associated CG. We propose that this twin-case adds evidence in support of the possible role of a patient’s genetic background in the pathogenesis of APOL1-associated CG and that the identical genome of monozygotic twins with APOL1-associated CG may be ideal for discovering such genetic modifiers of AAKD.
登录
查看更多内容
先天免疫途径调节肾病基因载脂蛋白L1。
影响因子：
19.6
作者：
通讯作者：
--
影响因子：
8.8
作者：
Shah, P. B.;Cooper, J. E.;Wiseman, A. C.
通讯作者：
Wiseman, A. C.
影响因子：
13.6
作者：
Kopp, Jeffrey B.;Nelson, George W.;Winkler, Cheryl A.
通讯作者：
Winkler, Cheryl A.
DOI：
10.2215/cjn.07311009
发表时间：
2010-04-01
影响因子：
9.8
作者：
Markowitz, Glen S.;Nasr, Samih H.;D'Agati, Vivette D.
通讯作者：
D'Agati, Vivette D.
影响因子：
13.6
作者：
Wu, Huijuan;Larsen, Christopher P.;Velez, Juan Carlos Q.
通讯作者：
Velez, Juan Carlos Q.