Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes.
PMID 23153210 | PMCID PMC3520752 | DOI 10.1186/1741-7015-10-140 · BMC medicine · 2012
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.
Validated evidence
| Type | Entity | Source evidence | Confidence | Extractor |
|---|---|---|---|---|
| gene | NPC1 | “Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes.” | 0.98 | hgnc_dict_v1 |
| phenotype | obesity | “A polymorphism (His215Arg) in NPC1 was associated with obesity in Europeans.” | 0.98 | phenotype_alias_lexicon_v2 |
| phenotype | diabetes mellitus | “Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes.” | 0.93 | phenotype_alias_lexicon_v2 |
| population | Saudi Arabia | “METHODS: We performed phylogenetic analysis, population genetic tests, and genotype-phenotype analysis in a population from Saudi Arabia. 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.” | 0.95 | saudi_context_rules_v1 |
| variant | rs1788799 | “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.” | 0.90 | hgvs_regex_v1 |
| variant | rs1805081 | “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).” | 0.90 | hgvs_regex_v1 |