| Summary: | <p>Abstract</p> <p>Background</p> <p>The <it>NPC1 </it>gene encodes a protein involved in intracellular lipid trafficking; its second endosomal loop (loop 2) is a receptor for filoviruses. A polymorphism (His215Arg) in <it>NPC1 </it>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.</p> <p>Methods</p> <p>We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia.</p> <p>Results</p> <p>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 (<it>P </it>= 0.041), and stratification on the basis of gender indicated that the association is driven by men (<it>P </it>= 0.0021, OR = 1.5). Notably, two <it>NPC1 </it>haplotypes were also associated with T2D in men (rs1805081-rs1788799, His-Met: <it>P </it>= 0.0012, OR = 1.54; His-Ile: <it>P </it>= 0.0004, OR = 0.63).</p> <p>Conclusions</p> <p>Our data indicate a sex-specific effect of <it>NPC1 </it>variants on T2D risk and describe putative binding sites for filoviruses entry.</p>
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