Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
University of California, San Francisco
ClinicalTrials.gov Identifier:
NCT00187733
First received: September 14, 2005
Last updated: September 11, 2012
Last verified: September 2012
  Purpose

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 (i.e., 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.


Condition Intervention
Carnitine Transporter Deficiency
Other: Fasting blood and urine collection

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Influence of OCTN2 Variants on Carnitine Status and Plasma Triglycerides

Resource links provided by NLM:


Further study details as provided by University of California, San Francisco:

Biospecimen Retention:   Samples With DNA

Blood Draw (10cc) to determine eligibility (CBC, blood chemistries). Blood draw (20cc) at t=0 in fasting state for baseline measurement of biochemical markers (including carnitine, acylcarnitines, creatinine, and total lipid panel) Urine collection at t=0 Blood draw (20cc) at t=2 hours for measurement of biochemical markers (including carnitine, acylcarnitines, creatinine, and total lipid panel) Urine collection at t=2 hours Transformation of blood to establish lymphoblastoid cell lines (from blood samples collected at t=0 and t=2 hours)


Enrollment: 16
Study Start Date: January 2005
Study Completion Date: February 2008
Primary Completion Date: February 2008 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Fasting
Other: Fasting blood and urine collection
Other: Fasting blood and urine collection
Not applicable no drugs dispensed

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, -207G>C. 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 < 0.05). Further studies of the Phe17Leu polymorphism showed a reduced V(max) 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 -207C/C homozygotes (p < 0.05). 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.

  Eligibility

Ages Eligible for Study:   18 Years to 40 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Sampling Method:   Non-Probability Sample
Study Population

Healthy individuals per screening laboratory results and health questionnaire

Criteria

Inclusion Criteria:

  • Previous participation in the "SOPHIE" study
  • Between the ages of 18 and 40 years old
  • Have a pre-selected genotype for OCTN1 and OCTN2
  • Have been selected as healthy by medical history questionnaire and screening blood work (complete blood count [CBC], comprehensive metabolic panel).

Exclusion Criteria:

  • Pregnant at the time of the study
  • Have a new history indicating they are no longer healthy
  • Taking a medication that could confound study results
  • Individuals with anemia (hemoglobin < 12 g/dL), an elevation in liver enzymes to higher than double the respective normal value, or elevated creatinine concentrations (males ≥ 1.5 mg/dL, females ≥ 1.4 mg/dL).
  • Do not consent to participate in the study.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00187733

Locations
United States, California
San Francisco General Hospital
San Francisco, California, United States, 94143
Sponsors and Collaborators
University of California, San Francisco
Investigators
Principal Investigator: Kathleen Giacomini, PhD University of California, San Francisco
  More Information

Publications:
Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT00187733     History of Changes
Other Study ID Numbers: 1005
Study First Received: September 14, 2005
Last Updated: September 11, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, San Francisco:
L-carnitine

Additional relevant MeSH terms:
Muscular Diseases
Cardiomyopathies
Hyperammonemia
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Carnitine
Vitamin B Complex
Vitamins
Micronutrients
Growth Substances
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on April 17, 2014