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Open Access Research article

Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes

Nasser M Al-Daghri123*, Rachele Cagliani4, Diego Forni4, Majed S Alokail123, Uberto Pozzoli4, Khalid M Alkharfy1235, Shaun Sabico123, Mario Clerici67 and Manuela Sironi4

Author Affiliations

1 Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, King Abdullah road, Riyadh 11451, Kingdom of Saudi Arabia

2 Prince Mutaib Chair for Biomarkers of Osteoporosis Research, King Saud University, King Abdullah road, Riyadh 11451, Kingdom of Saudi Arabia

3 Center of Excellence in Biotechnology, King Saud University, King Abdullah road, Riyadh 11451, Kingdom of Saudi Arabia

4 Bioinformatics, Scientific Institute IRCCS E.MEDEA, Via Don L. Monza 20, Bosisio Parini 23842, Italy

5 Clinical Pharmacy Department, College of Pharmacy, King Saud University, King Abdullah road, Riyadh 11451, Kingdom of Saudi Arabia

6 Department of Molecular Medicine, Don Gnocchi Foundation IRCCS, ONLUS, Piazetta Morandi, Milano 20100, Italy

7 Department of Pathophysiology and Transplantation, Milano University Medical School, Via Fratelli Cervi, Milano 20090, Italy

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BMC Medicine 2012, 10:140  doi:10.1186/1741-7015-10-140

Published: 15 November 2012



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.


We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia.


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).


Our data indicate a sex-specific effect of NPC1 variants on T2D risk and describe putative binding sites for filoviruses entry.

NPC1; filovirus; natural selection; type 2 diabetes