Exome sequencing of three cases of familial exceptional longevity |
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Authors: | Timothy P Cash Guillermo Pita Orlando Domínguez Maria R Alonso Leticia T Moreno Consuelo Borrás Leocadio Rodríguez‐Mañas Catalina Santiago Nuria Garatachea Alejandro Lucia Juan A Avellana Jose Viña Anna González‐Neira Manuel Serrano |
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Institution: | 1. Tumour Suppression Group;2. Human Genotyping‐CEGEN Unit;3. Genomics Core Unit, Spanish National Cancer Research Centre (CNIO), , 28029 Madrid, Spain;4. Department of Physiology, School of Medicine, University of Valencia/INCLIVA, , 46010 Valencia, Spain;5. Department of Geriatrics, University Hospital of Getafe, , Getafe, 28905 Madrid, Spain;6. European University, , 28670 Madrid, Spain;7. Faculty of Health and Sport Science, University of Zaragoza, , 22001 Huesca, Spain;8. Geriatric Unit, University Hospital Ribera, , Alzira, 46600 Valencia, Spain |
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Abstract: | Exceptional longevity (EL) is a rare phenotype that can cluster in families, and co‐segregation of genetic variation in these families may point to candidate genes that could contribute to extended lifespan. In this study, for the first time, we have sequenced a total of seven exomes from exceptionally long‐lived siblings (probands ≥ 103 years and at least one sibling ≥ 97 years) that come from three separate families. We have focused on rare functional variants (RFVs) which have ≤ 1% minor allele frequency according to databases and that are likely to alter gene product function. Based on this, we have identified one candidate longevity gene carrying RFVs in all three families, APOB. Interestingly, APOB is a component of lipoprotein particles together with APOE, and variants in the genes encoding these two proteins have been previously associated with human longevity. Analysis of nonfamilial EL cases showed a trend, without reaching statistical significance, toward enrichment of APOB RFVs. We have also identified candidate longevity genes shared between two families (5–13) or within individual families (66–156 genes). Some of these genes have been previously linked to longevity in model organisms, such as PPARGC1A, NRG1, RAD52, RAD51, NCOR1, and ADCY5 genes. This work provides an initial catalog of genes that could contribute to exceptional familial longevity. |
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Keywords: | apolipoprotein B centenarians exome sequencing longevity rare variants |
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