Borges Vinicius Magalhães, Horimoto Andrea R V R, Wijsman Ellen Marie, Kimura Lilian, Nunes Kelly, Nato Alejandro Q, Mingroni-Netto Regina Célia
Human Genome and Stem Cells Research Center, Institute of Biosciences University of Séo Paulo São Paulo Brazil.
Department of Biomedical Sciences, Joan C. Edwards School of Medicine Marshall University Huntington WV USA.
J Am Heart Assoc. 2025 Apr;14(7):e036193. doi: 10.1161/JAHA.124.036193. Epub 2025 Mar 21.
Essential hypertension (EH) is a global health issue. Despite extensive research, much of EH heritability remains unexplained. We investigated the genetic basis of EH in African-derived individuals from partially isolated quilombo populations in Vale do Ribeira (São Paulo, Brazil).
Samples from 431 individuals (167 affected, 261 unaffected, 3 unknown) were genotyped using a 650 000 single-nucleotide polymorphism array. Estimated global ancestry proportions were 47% African, 36% European, and 16% Native American. We constructed 6 pedigrees using additional data from 673 individuals and created 3 nonoverlapping single-nucleotide polymorphism subpanels. We phased haplotypes and performed local ancestry analysis to account for admixture. Genome-wide linkage analysis and fine-mapping via family-based association studies were conducted, prioritizing EH-associated genes through a systematic approach involving databases like PubMed, ClinVar, and GWAS (Genome-Wide Association Studies) Catalog. Linkage analysis identified 22 regions of interest with logarithm of the odds scores ranging from 1.45 to 3.03, encompassing 2363 genes. Fine-mapping (family-based association studies) identified 60 EH-related candidate genes and 117 suggestive/significant variants. Among these, 14 genes, including , , , and , were strongly related to hypertension harboring 29 suggestive/significant single-nucleotide polymorphisms.
Through a complementary approach combining admixture-adjusted Genome-wide linkage analysis based on Markov chain Monte Carlo methods, family-based association studies on known and imputed data, and gene prioritizing, new loci, variants, and candidate genes were identified. These findings provide targets for future research, replication in other populations, facilitate personalized treatments, and improve public health toward African-derived underrepresented populations. Limitations include restricted single-nucleotide polymorphism coverage, self-reported pedigree data, and lack of available EH genomic studies on admixed populations for independent validation, despite the performed genetic correlation analyses using summary statistics.
原发性高血压（EH）是一个全球性的健康问题。尽管进行了广泛的研究，但EH的许多遗传因素仍未得到解释。我们调查了来自巴西圣保罗里贝拉河谷部分孤立的基隆博人群中非洲裔个体的EH遗传基础。
使用65万个单核苷酸多态性阵列对431名个体（167名患病，261名未患病，3名情况不明）的样本进行基因分型。估计全球祖先比例为47%非洲血统、36%欧洲血统和16%美洲原住民血统。我们利用来自673名个体的额外数据构建了6个家系，并创建了3个不重叠的单核苷酸多态性子面板。我们对单倍型进行了分型，并进行了本地祖先分析以考虑混合情况。进行了全基因组连锁分析，并通过基于家系的关联研究进行精细定位，通过涉及PubMed、ClinVar和GWAS（全基因组关联研究）目录等数据库的系统方法对与EH相关的基因进行优先排序。连锁分析确定了22个感兴趣的区域，优势对数得分范围为1.45至3.03，涵盖2363个基因。精细定位（基于家系的关联研究）确定了60个与EH相关的候选基因和117个提示性/显著性变异。其中，包括 、 、 和 在内的14个基因与高血压密切相关，含有29个提示性/显著性单核苷酸多态性。
通过结合基于马尔可夫链蒙特卡罗方法的混合调整全基因组连锁分析、对已知和推算数据进行的基于家系的关联研究以及基因优先排序的互补方法，确定了新的基因座、变异和候选基因。这些发现为未来的研究提供了靶点，便于在其他人群中进行复制，促进个性化治疗，并改善针对非洲裔代表性不足人群的公共卫生。局限性包括单核苷酸多态性覆盖范围有限、自我报告的家系数据，以及尽管使用汇总统计数据进行了遗传相关性分析，但缺乏针对混合人群的可用EH基因组研究进行独立验证。
