Departamento de Genética, Ecologia e Evolução, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Centro de Laboratórios Multiusuários, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Clin Transl Sci. 2022 Jun;15(6):1400-1405. doi: 10.1111/cts.13266. Epub 2022 Mar 28.
PDE4B (phosphodiesterase-4B) has an important role in cancer and in pharmacology of some disorders, such as inflammatory diseases. Remarkably in Native Americans, PDE4B variants are associated with acute lymphoblastic leukemia (ALL) relapse, as this gene modulates sensitivity of glucocorticoids used in ALL chemotherapy. PDE4B allele rs6683977.G, associated with genomic regions of Native American origin in US-Hispanics (admixed among Native Americans, Europeans, and Africans), increases ALL relapse risk, contributing to an association between Native American ancestry and ALL relapse that disappeared with an extra-phase of chemotherapy. This result insinuates that indigenous populations along the Americas may have high frequencies of rs6683977.G, but this has never been corroborated. We studied ancestry and PDE4B diversity in 951 healthy individuals from nine Latin American populations. In non-admixed Native American populations rs6683977.G has frequencies greater than 90%, is in linkage disequilibrium with other ALL relapse associated and regulatory variants in PDE4B-intron-7, conforming haplotypes showing their highest worldwide frequencies in Native Americans (>0.82). Our findings inform the discussion on the pertinence of an extra-phase of chemotherapy in Native American populations, and exemplifies how knowledge generated in US-Hispanics is relevant for their even more neglected and vulnerable Native American ancestors along the American continent.
磷酸二酯酶 4B（PDE4B）在癌症和某些疾病的药理学中具有重要作用，如炎症性疾病。值得注意的是，在美洲原住民中，PDE4B 变体与急性淋巴细胞白血病（ALL）的复发有关，因为该基因调节了 ALL 化疗中使用的糖皮质激素的敏感性。PDE4B 等位基因 rs6683977.G 与美国西班牙裔人群中的美洲原住民起源的基因组区域相关（在美洲原住民、欧洲人和非洲人之间混合），增加了 ALL 复发的风险，导致美洲原住民血统与 ALL 复发之间的关联，这种关联在化疗的额外阶段后消失。这一结果暗示美洲的土著人群可能具有较高频率的 rs6683977.G，但这从未得到证实。我们研究了来自九个拉丁美洲人群的 951 名健康个体的祖先和 PDE4B 多样性。在非混合的美洲原住民人群中，rs6683977.G 的频率大于 90%，与 PDE4B-intron-7 中的其他 ALL 复发相关和调节变体处于连锁不平衡状态，形成的单倍型显示出其在美洲原住民中的最高全球频率（>0.82）。我们的发现为讨论在美洲原住民人群中进行化疗的额外阶段提供了信息，并说明了在美国西班牙裔人群中产生的知识如何与他们在美洲大陆上被忽视和脆弱的美洲原住民祖先有关。
