title: Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes.
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.
authors.affiliation: Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, King Abdullah road, Riyadh 11451, Kingdom of Saudi Arabia. aldaghri2011@gmail.com
authors.forename: Nasser M
authors.initials: NM
authors.lastname: Al-Daghri
authors.forename: Rachele
authors.initials: R
authors.lastname: Cagliani
authors.forename: Diego
authors.initials: D
authors.lastname: Forni
authors.forename: Majed S
authors.initials: MS
authors.lastname: Alokail
authors.forename: Uberto
authors.initials: U
authors.lastname: Pozzoli
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Alkharfy
authors.forename: Shaun
authors.initials: S
authors.lastname: Sabico
authors.forename: Mario
authors.initials: M
authors.lastname: Clerici
authors.forename: Manuela
authors.initials: M
authors.lastname: Sironi
mesh_terms: D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics*; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D019143:Evolution, Molecular; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D000077296:Niemann-Pick C1 Protein; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D011110:Polymorphism, Genetic; D011991:Receptors, Virus / Q000235:genetics; D012529:Saudi Arabia; D012641:Selection, Genetic; D012737:Sex Factors
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D011991:Receptors, Virus