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.
Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes / N. Al-Daghri, R. Cagliani, D. Forni, M. Alokail, U. Pozzoli, K. Alkharfy, S. Sabico, M. Clerici, M. Sironi. - In: BMC MEDICINE. - ISSN 1741-7015. - 10:(2012 Nov 15), pp. 140.1-140.11.
|Titolo:||Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes|
CLERICI, MARIO SALVATORE (Penultimo)
|Parole Chiave:||filovirus; natural selection; NPC1; type 2 diabetes|
|Settore Scientifico Disciplinare:||Settore MED/03 - Genetica Medica|
|Data di pubblicazione:||15-nov-2012|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1186/1741-7015-10-140|
|Appare nelle tipologie:||01 - Articolo su periodico|