Ignite Creation Date:
2024-05-05 @ 11:56 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00187733
Status:
COMPLETED
Last Update Posted:
2012-09-13
First Post:
2005-09-14
Brief Title:
Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides
Sponsor:
University of California San Francisco
Organization:
University of California San Francisco
Study Overview
Official Title:
Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides
Status:
COMPLETED
Status Verified Date:
2012-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The current study is part of a large multi-investigator grant to look at the pharmacogenetics of a number of membrane transporters Previously the investigators have recruited a cohort of healthy volunteers Studies of Pharmacogenetics in Ethnically-Diverse Populations or SOPHIE and have resequenced the coding region of a number of membrane transporter genes to identify genetic polymorphisms in these genes Subjects in this cohort have agreed to be called back for recruitment in further studies based on their own genetic sequence allowing the investigators the possibility to prospectively study the influence of genetic polymorphisms on particular phenotypes ie genotype-to-phenotype studies The investigators plan to take a genotype-to-phenotype approach to study the influence of specific polymorphisms in the novel organic cation transporter 2 OCTN2 gene on carnitine and lipid metabolism in healthy subjects
Detailed Description:
Although OCTN2 is fairly well studied in its relationship with SCD little is known about the carrier frequency of disease-causing alleles of OCTN2 or of more common functional polymorphisms in this gene To address these issues we screened for genetic variants in the OCTN2 coding region by direct sequencing of the exons and flanking intronic region of OCTN2 in a large sample n 276 of ethnically diverse subjects In addition we established lymphoblastoid cell lines from subjects homozygous for either allele of the previously identified promoter region variant -207GC We found eight amino acid sequence variants of OCTN2 of which three Phe17Leu Leu144Phe and Pro549Ser were polymorphic in at least one ethnic group When assayed for functional activity by expression in human embryonic kidney 293 cells using as probes both the endogenous substrate l-carnitine and the organic cation tetraethylammonium three variants showed functional differences from the reference OCTN2 Phe17Leu Tyr449Asp Val481Phe p 005 Further studies of the Phe17Leu polymorphism showed a reduced Vmax for l-carnitine transport to approximately 50 of the reference OCTN2 Confocal microscopy studies using an OCTN2-GFP fusion protein showed that Phe17Leu had distinct subcellular localization from the reference OCTN2 with diffuse cytoplasmic retention of Phe17Leu in contrast to reference OCTN2 which localized specifically to the plasma membrane Lymphoblasts from subjects homozygous for the -207G allele showed increased l-carnitine transport compared with the -207CC homozygotes p 005 This study suggests that although loss-of-function mutations in OCTN2 are likely to be rare common variants of OCTN2 found in healthy populations may contribute to variation in the disposition of carnitine and some clinically used drugs
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None