Email updates

Keep up to date with the latest news and content from BMC Medicine and BioMed Central.

Journal App

google play app store
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

For all author emails, please log on.

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

Published: 15 November 2012

Abstract

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.

Keywords:
NPC1; filovirus; natural selection; type 2 diabetes