Identification and Metabolic Characterization of a Cohort of Human Subjects With Mutations in PRDM-16
Condition: Mutation; Obesity; Dyslipidemia; Diabetes
MeSH terms: Dyslipidemias
Study type: Observational

Summary: 
      Chinese male subjects will be invited to participate in a research study of brown fat, a
      special tissue in the body that is designed to burn energy to make heat. The objective is to
      learn the importance of a gene called "PRDM-16" for the function of brown fat. Subjects were
      selected as a possible subject in this study because they fulfil the age and weight criteria.

      500 subjects from the Singhealth Investigational Medicine Unit healthy volunteer database
      will be recruited over a period of 2 years. All of the subjects will have their PRDM-16 gene
      sequenced. The objective is to identify subjects with mutations, or changes, in their PRDM-16
      gene. About 12 subjects with PRDM-16 mutations are expected to be identified.

      Samples of blood obtained during the course of this study will be stored and analysed only
      for the purposes of this study for a period not exceeding 2 years, and will be destroyed
      after completion of the study, unless subject is agreeable to donate the samples to the
      National Heart Centre Singapore for continuous storage for future studies that are approved
      by the institutional review board..
    

Detailed description: 
      The long-term objective of this study is to develop new treatments for obesity and
      obesity-associated disorders such as diabetes and dyslipidemia. The recent finding of active
      brown fat depots in adult humans provides an exciting new strategy for the treatment of these
      diseases. Brown fat is a specialized organ found primarily in small mammals. Brown fat has
      the unique capability to burn fuel at high rates in order to generate heat. The role of brown
      fat in mammals is to defend against cold exposure. Human infants have active brown fat
      deposits located in the intra-scapular region. This brown fat depot regresses with age and it
      was long thought that adult humans had no brown fat tissue. Recent studies have demonstrated
      the presence of brown fat activity in adult humans following exposure to cold. Brown fat in
      adult humans is concentrated in the cervical region and displays some sex-specific
      differences. Furthermore the size of the depot is inversely correlated with BMI and age of
      the subjects. This finding has generated intense interest as it opens up the possibility of
      harnessing brown fat as a means of combating obesity and obesity-related disorders in man.
      Indeed, maneuvers that activate brown fat in humans have been shown to cause reductions in
      fat mass.

      Much of our understanding of brown fat biology comes from work in mice. Of particular
      relevance for the treatment of human disease are several findings. First, increasing brown
      fat activity in mice renders the animals resistant to the development of obesity on a high
      fat diet. Second, levels of insulin sensitivity are directly related to brown fat activity.
      Finally, the transcription factor factor PR-domain containing protein 16 (PRDM-16) is crucial
      for directing the biology of brown fat.

      The overall goal of the study is to translate the findings from mouse studies of brown fat
      into human subjects. This is an important first step in the process of developing brown
      fat-targeted therapies to treat human metabolic diseases such as obesity and insulin
      resistance. In view of this the investigators are interested in answering several questions.
      First, do humans with mutations in PRDM-16 have defects in brown fat activity? Recently,
      humans with mutations in PRDM-16 were identified and found to have a cardiomyopathy
      phenotype. The brown fat function in these individuals has not been described. By employing a
      genetic screen of volunteers the investigators hope to identify subjects in Singapore with
      defects in PRDM-16. Prior studies in humans suggest that the size of the brown fat depot is
      inversely correlated with BMI and age of the subjects and that depot size varies between the
      sexes. In order to eliminate BMI, age and sex as confounding variables the investigators will
      include male subjects of Chinese race between the ages of 21 and 50 and with BMI greater than
      18.5 but less than 30. The investigators will include only Chinese subjects to avoid
      confounding our initial study with variables that relate to race of the subjects. The
      identification of human subjects carrying mutations in PRDM-16 will set the stage for further
      studies that will attempt to several research questions. These include whether humans with
      PRDM-16 mutations have defects in brown fat and the metabolic consequences for humans with
      defective brown fat.
    

Intervention name(s): Blood Sample Collection
Intervention type(s): Other
Intervention description(s): Blood draw #1 Site of blood draw: IMU Volume of blood: 20mL Purpose of blood draw: Isolation of genomic DNA Site of storage: NHRIS biobank Coding: Specimens will be identified using a research ID that will be affixed to samples using bar-coding. After the blood is collected, stored the blood at 4 degree Celsius and contact the NHCS biobank coordinator to collect the blood samples. The blood samples must be collected within 1 hour of collection.
Observational model: Case-Control
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        500 subjects will be recruited from the IMU healthy volunteer database. The investigators
        will enroll male Chinese volunteers. Women, children and the elderly are excluded from our
        initial study since prior research suggests that age and sex has an effect on brown fat
        function. In order to study the role of PRDM-16 in brown fat function the investigators
        wish to keep other contributing variables static in our study.
      
Biospecimen description: 
      A blood sample will be obtained and processed to isolate genomic DNA. A PCR-based strategy
      will be employed to sequence the entire PRDM-16 locus to identify variants. Variant alleles
      of PRDM-16 will be classified as having benign or deleterious mutations. Subjects who harbor
      deleterious mutations in both alleles of PRDM-16 will be identified for further study.

      For subjects who withdraw from the study, no further testing of the blood samples will occur.
      The blood will be stored at the NHRIS biobank. After the study is complete the samples will
      remain in storage at the NHRIS biobank.