{"doi":"10.1681/asn.2020020139","title":"Pulling the Hood off Genetic Susceptibility to Hypertensive Renal Disease","abstract":"The effect of elevated BP on morbidity and mortality is not uniformly distributed across the hypertensive population. Susceptibility to progressive hypertensive renal disease (HRD) is influenced by heritable factors: the occurrence of family members who have experienced ESKD is a robust predictor of risk1,2 and provides the rationale for large-scale population studies that have sought to identify genetic variation contributing to loss of renal function.3 These studies face many challenges. Risk arises from the effects within individuals of plural concurrent genetic susceptibilities. The genetic variation creating risk may differ between pedigrees and populations. The phenotypic information regarding renal function and disease that is available at the population level is limited to indirect assessments (eGFR and proteinuria) and does not include information obtained directly from kidney tissue. Finally, the impressive numbers of genetic markers assessed in genome-wide association studies do not mean that these markers saturate the genome. In fact, they leave significant parts inadequately covered. For example, the Illumina Infinium HumanCore single nucleotide polymorphism (SNP) array interrogates the human genome with an average density of approximately one SNP per 1 kb. Antibodies are known to be the pathogenic agent of several progressive renal diseases, and the Ig heavy-chain gene (IGH) is highly polymorphic. However, in this array, SNP density across IGH is 1 per 46 kb, with gaps as large as 250 kb left unexamined. In the immune-focused Infinium Immunoarray, the corresponding density of markers in this region is 1 per 260 kb with one interval of >1 Mb, representing approximately 80% of IGH, lacking markers. Consequently, alternative opportunities to understand the genetic risk of progressive renal disease are essential. Rodent genetic models may provide opportunities to address these challenges and identify mechanisms by which HRD arises. This is especially so when genetic risk arises from natural genetic variation that can reveal the involvement of genes or mechanisms not previously anticipated to participate in disease. Opportunities beyond the reach of human population genetics include reduced genetic complexity because the maternal and paternal autosomes in inbred rodent models are genetically identical. Both selective breeding and targeted genetic modification can be performed in model organisms to investigate specific genetic variation. These approaches include low-resolution replacement of an entire chromosome (consomic line) or a chromosomal segment (congenic line) from a rodent strain that lacks disease susceptibility. Higher resolution obtained by targeted gene deletion and replacement of single genes are also important tools after the potential target has been refined. Several useful rat models of HRD have been identified that result from natural genetic variation. Fan et al.4 report in this issue of JASN an extensive investigation that develops convincing evidence that a single-nucleotide variant in γ-adducin, a widely expressed cytoskeletal protein encoded by the gene Add3, contributes to renal injury in the Fawn-Hooded Hypertensive (FHH) rat. They show how this variant perturbs cellular function and impairs physiologic autoregulation of renal blood flow. This inbred rat model experiences FSGS and proteinuria with increasing BP and proteinuria as animals age.5,6 Several genomic loci have been mapped in FHH that create susceptibility, indicating polygenic inheritance. Genetic variation in Shroom3 in FHH alters its interactions with actin and contributes to podocyte foot process fusion and albuminuria.7 Variation in Rab38 in FHH is also involved in albuminuria; however, this does not affect glomerular permeability, but rather, it acts to reduce tubular reuptake of filtered protein.8 The polygenic nature of HRD in FHH gains a new dimension from the study reported by Fan et al.,4 which introduces an additional gene","journal":"Journal of the American Society of Nephrology","year":2020,"id":116601,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9478,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":525485,"name":"Peter A. Doris","orcid":"0000-0002-0565-7939","position":1,"is_corresponding":false},{"id":525480,"name":"Isha S. Dhande","orcid":"0000-0001-9436-4080","position":0,"is_corresponding":true}],"reference_count":9,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:13:44.286758Z","pmid":"32123053","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}