Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample
Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated...
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Elsevier
2025-05-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S246802492500107X |
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| author | Dariush Ghasemi-Semeskandeh Eva König Luisa Foco Nikola Dordevic Martin Gögele Johannes Rainer Markus Ralser Dianne Acoba Francisco S. Domingues Dorien J.M. Peters Peter P. Pramstaller Cristian Pattaro |
| author_facet | Dariush Ghasemi-Semeskandeh Eva König Luisa Foco Nikola Dordevic Martin Gögele Johannes Rainer Markus Ralser Dianne Acoba Francisco S. Domingues Dorien J.M. Peters Peter P. Pramstaller Cristian Pattaro |
| author_sort | Dariush Ghasemi-Semeskandeh |
| collection | DOAJ |
| description | Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with. Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models. Results: We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures. Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles. |
| format | Article |
| id | doaj-art-477fbab3fef241b8a678eaf40ad9bb1d |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Kidney International Reports |
| spelling | doaj-art-477fbab3fef241b8a678eaf40ad9bb1d2025-08-20T03:47:10ZengElsevierKidney International Reports2468-02492025-05-011051495150810.1016/j.ekir.2025.02.018Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population SampleDariush Ghasemi-Semeskandeh0Eva König1Luisa Foco2Nikola Dordevic3Martin Gögele4Johannes Rainer5Markus Ralser6Dianne Acoba7Francisco S. Domingues8Dorien J.M. Peters9Peter P. Pramstaller10Cristian Pattaro11Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands; Institute for Biomedicine, Eurac Research, Bolzano, Italy; Integrative Data Analysis Unit, Health Data Science Centre, Human Technopole, Milan, Italy; Correspondence: Dariush Ghasemi-Semeskandeh, Human Technopole, Health Data Science Centre, V.le Rita Levi-Montalcini, 1, Milan 20157, Italy.Institute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute of Biochemistry, Charité - Universitätsmedizin Berlin, Berlin, GermanyClinical Renal, Late-stage Development, Cardiovascular, Renal and Metabolism, Bio Pharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; Institut Necker Enfants-Malades, Institut National de la Santé et de la Recherche Médicale U1151, Université Paris Cité, Paris, FranceInstitute for Biomedicine, Eurac Research, Bolzano, ItalyDepartment of Human Genetics, Leiden University Medical Center, Leiden, The NetherlandsInstitute for Biomedicine, Eurac Research, Bolzano, ItalyInstitute for Biomedicine, Eurac Research, Bolzano, Italy; Cristian Pattaro, Eurac Research, Institute for Biomedicine, Via Volta 21, 39100 Bozen/Bolzano, Italy.Introduction: Genome-wide association studies (GWAS) identified a locus on chromosome 4q21.1, spanning the Family With Sequence Similarity 47 Member E (FAM47E), Starch Binding Domain 1 (STBD1), Coiled-Coil Domain Containing 158 (CCDC158), and Shroom Family Member 3 (SHROOM3) genes, to be associated with kidney function markers. Functional studies implicated SHROOM3 as the effector gene, demonstrating its developmental role to guarantee podocyte barrier integrity. However, the locus has also been associated with other clinical traits, including electrolytes, hematological, cardiovascular, and neurological traits, not all of which can be easily traced to the regulation of kidney function. We therefore conducted a systematic analysis of the whole locus’ genetic profiles (haplotypes) to assess which phenotypic profiles they were associated with. Methods: For the 4 genes, we reconstructed haplotypes spanning 71 exonic and intronic variants for 12,834 participants in the Cooperative Health Research in South Tyrol (CHRIS) study based on genotypes imputed on a local whole-exome sequencing (WES) reference panel. Haplotypes were tested for associations with 72 clinical traits, 170 serum metabolites, and 148 plasma protein concentrations, using linear regression models. Results: We identified 11 haplotypes with a population frequency between 2% and 24%. Compared with the most common haplotype, most haplotypes were associated with higher creatinine-based estimated glomerular filtration rate (eGFR) and lower serum magnesium levels. In addition, specific haplotypes were also associated with biologically diverse groups of traits, including albuminuria, blood pressure, red blood cell traits, carnitines, and amino acids. Cluster analysis highlighted the existence of distinct genetic profiles in which individuals with specific haplotypes presented with specific phenotypic and metabolic signatures. Conclusion: The genetic variability of the FAM47E–SHROOM3 locus indicates the existence of population subgroups with distinct biomarker profiles.http://www.sciencedirect.com/science/article/pii/S246802492500107XCCDC158FAM47EhaplotypekidneySHROOM3STBD1 |
| spellingShingle | Dariush Ghasemi-Semeskandeh Eva König Luisa Foco Nikola Dordevic Martin Gögele Johannes Rainer Markus Ralser Dianne Acoba Francisco S. Domingues Dorien J.M. Peters Peter P. Pramstaller Cristian Pattaro Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample Kidney International Reports CCDC158 FAM47E haplotype kidney SHROOM3 STBD1 |
| title | Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample |
| title_full | Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample |
| title_fullStr | Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample |
| title_full_unstemmed | Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample |
| title_short | Clinical and Metabolic Signatures of FAM47E–SHROOM3 Haplotypes in a General Population Sample |
| title_sort | clinical and metabolic signatures of fam47e shroom3 haplotypes in a general population sample |
| topic | CCDC158 FAM47E haplotype kidney SHROOM3 STBD1 |
| url | http://www.sciencedirect.com/science/article/pii/S246802492500107X |
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