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Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes
BACKGROUND: The NPC1 gene encodes a protein involved in intracellular lipid trafficking; its second endosomal loop (loop 2) is a receptor for filoviruses. A polymorphism (His215Arg) in NPC1 was associated with obesity in Europeans. Adaptations to diet and pathogens represented powerful selective for...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520752/ https://www.ncbi.nlm.nih.gov/pubmed/23153210 http://dx.doi.org/10.1186/1741-7015-10-140 |
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author | Al-Daghri, Nasser M Cagliani, Rachele Forni, Diego Alokail, Majed S Pozzoli, Uberto Alkharfy, Khalid M Sabico, Shaun Clerici, Mario Sironi, Manuela |
author_facet | Al-Daghri, Nasser M Cagliani, Rachele Forni, Diego Alokail, Majed S Pozzoli, Uberto Alkharfy, Khalid M Sabico, Shaun Clerici, Mario Sironi, Manuela |
author_sort | Al-Daghri, Nasser M |
collection | PubMed |
description | BACKGROUND: The NPC1 gene encodes a protein involved in intracellular lipid trafficking; its second endosomal loop (loop 2) is a receptor for filoviruses. A polymorphism (His215Arg) in NPC1 was associated with obesity in Europeans. Adaptations to diet and pathogens represented powerful selective forces; thus, we analyzed the evolutionary history of the gene and exploited this information for the identification of variants/residues of functional importance in human disease. METHODS: We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia. RESULTS: Maximum-likelihood ratio tests indicated the action of positive selection on loop 2 and identified three residues as selection targets; these were confirmed by an independent random effects likelihood (REL) analysis. No selection signature was detected in present-day human populations, but analysis of nonsynonymous polymorphisms showed that a variant (Ile642Met, rs1788799) in the sterol sensing domain affects a highly conserved position. This variant and the previously described His215Arg polymorphism were tested for association with obesity and type 2 diabetes (T2D) in a cohort from Saudi Arabia. Whereas no association with obesity was detected, 642Met allele was found to predispose to T2D. A significant interaction was noted with sex (P = 0.041), and stratification on the basis of gender indicated that the association is driven by men (P = 0.0021, OR = 1.5). Notably, two NPC1 haplotypes were also associated with T2D in men (rs1805081-rs1788799, His-Met: P = 0.0012, OR = 1.54; His-Ile: P = 0.0004, OR = 0.63). CONCLUSIONS: Our data indicate a sex-specific effect of NPC1 variants on T2D risk and describe putative binding sites for filoviruses entry. |
format | Online Article Text |
id | pubmed-3520752 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-35207522012-12-13 Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes Al-Daghri, Nasser M Cagliani, Rachele Forni, Diego Alokail, Majed S Pozzoli, Uberto Alkharfy, Khalid M Sabico, Shaun Clerici, Mario Sironi, Manuela BMC Med Research Article BACKGROUND: The NPC1 gene encodes a protein involved in intracellular lipid trafficking; its second endosomal loop (loop 2) is a receptor for filoviruses. A polymorphism (His215Arg) in NPC1 was associated with obesity in Europeans. Adaptations to diet and pathogens represented powerful selective forces; thus, we analyzed the evolutionary history of the gene and exploited this information for the identification of variants/residues of functional importance in human disease. METHODS: We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia. RESULTS: Maximum-likelihood ratio tests indicated the action of positive selection on loop 2 and identified three residues as selection targets; these were confirmed by an independent random effects likelihood (REL) analysis. No selection signature was detected in present-day human populations, but analysis of nonsynonymous polymorphisms showed that a variant (Ile642Met, rs1788799) in the sterol sensing domain affects a highly conserved position. This variant and the previously described His215Arg polymorphism were tested for association with obesity and type 2 diabetes (T2D) in a cohort from Saudi Arabia. Whereas no association with obesity was detected, 642Met allele was found to predispose to T2D. A significant interaction was noted with sex (P = 0.041), and stratification on the basis of gender indicated that the association is driven by men (P = 0.0021, OR = 1.5). Notably, two NPC1 haplotypes were also associated with T2D in men (rs1805081-rs1788799, His-Met: P = 0.0012, OR = 1.54; His-Ile: P = 0.0004, OR = 0.63). CONCLUSIONS: Our data indicate a sex-specific effect of NPC1 variants on T2D risk and describe putative binding sites for filoviruses entry. BioMed Central 2012-11-15 /pmc/articles/PMC3520752/ /pubmed/23153210 http://dx.doi.org/10.1186/1741-7015-10-140 Text en Copyright ©2012 Al-Daghri et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Al-Daghri, Nasser M Cagliani, Rachele Forni, Diego Alokail, Majed S Pozzoli, Uberto Alkharfy, Khalid M Sabico, Shaun Clerici, Mario Sironi, Manuela Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title | Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title_full | Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title_fullStr | Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title_full_unstemmed | Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title_short | Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
title_sort | mammalian npc1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3520752/ https://www.ncbi.nlm.nih.gov/pubmed/23153210 http://dx.doi.org/10.1186/1741-7015-10-140 |
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