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Unique Lipoprotein Phenotype and Genotype 
Associated with Exceptional Longevity

November 6, 2003

Abstraction Template
     
Key variables & Description Article

Reference
Complete the bibliographic reference for the article according to AJE format.

 

Barzilai N., Atzmon G., Schechter C., et. al.  Unique Lipoprotein Phenotype and Genotype Associated With Exceptional Longevity JAMA. 2003;290:2030-2040.  Link to PubMed abstract

Category of HuGE information
Specify the types of information (from the list below) available in the article:

  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 

  1. Prevalence of gene variant
  2. Gene-disease association

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

 

To determine factors associated with human longevity.

Gene(s)
Identification of the following:

  1. Gene name
  2. Chromosome location
  3. Gene product/function
  4. Alleles
  5. OMIM #

 

  1. Gene name: cholesteryl ester transfer protein (CETP)
  2. Chromosome location: 16q21
  3. Gene product/function:Transfers of insoluble cholesteryl esters between lipoprotein particles as a part of cholesterol homeostasis
    Alleles: In the promoter region -631C/A (NCBI dbsSNP rs1800776), -629 C/A (rs1800775) were genotyped. In the exons codon 405 isoleucine to valine (1405V) (rs5882) in exon 14 and D442G (rs2303790) in exon 15 were genotyped.
  4. Alleles: IL-6 - 174 G/G, IL-6 - 174 G/C, and IL-6 - 174 C/C
  5. OMIM #: 118470

 

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

 

  1. Body Mass Index
  2. Metabolic Syndrome Diagnosis
  3. History of Cardiovascular Disease
  4. Standard Lipid profile, plus ApoA1 and ApoB measures
  5. Nuclear Magnetic resonance spectroscopy of lipid size
  6. Blood Pressure
  7. Use of Cholesterol Lowering Drugs

 

Health outcome(s)
Identification of the major health outcome(s) studied

 

The major health outcome was independent living at 95 years of age
Study design
Specification of the type of study design(s)
  1. Case-control
  2. Cohort 
  3. Cross-sectional
  4. Descriptive or case series
  5. Clinical trial
  6. Population screening

 

  1. Case-control
Case definition
For study designs 1, 4, and 5, define the following if available:
  1. Disease case definition
  2. Exclusion criteria
  3. Gender
  4. Race/ethnicity
  5. Age
  6. Time period
  7. Geographic location
  8. Number of participants

 

  1. Disease case definition: Individuals of Ashkenazi Jewish descent who lived independently until 95 years or age or more.
  2. Exclusion criteria: individuals were excluded who did not have a first degree offspring willing to participate in the study
  3. Gender: 157 females, 56 males
  4. Race/ethnicity: Ashkenazi Jewish
  5. Age: mean age SD, 98.2 years (5.3), range 95-107 years,
  6. Time period: 1998-2002
  7. Geographic location: not specified
  8. Number of participants: n=213 propands , percent of total eligible not specified.
  9. Possible Cases: 216 offspring of probands, mean age, 68.3 years (6.7), range 51-89 years, 122 females, 94 males

 

Control definition
For study design 1, define the following if available:
  1. Control selection criteria
  2. Matching variables
  3. Exclusion criteria
  4. Gender
  5. Race/ethnicity
  6. Age
  7. Time period
  8. Geographic location
  9. Number of participants
  1. Control selection criteria: Individuals of Ashkenazi Jewish descent. 75 spouses of the offspring, 189 other Individuals enrolled in the Einstein Aging Study.
  2. Matching variables: Age
  3. Exclusion criteria: Parents living past 95 years of age.
  4. Exclusion criteria: spouses 53% female, others 57% female
  5. Race/ethnicity: Ashkenazi Jewish
  6. Age: spouses mean age, (SD); 70.2 (10.2), others 71.3 (9.1)
  7. Time period: 1998-2002
  8. Geographic location: not specified
  9. Number of participants: spouses n=75 other n=189, percent of total eligible not specified in both cases.
  1. Control selection criteria: Age matched individuals from the Framingham Study.
  2. Matching variables: Age
  3. Exclusion criteria: not specified
  4. Gender: 48% female
  5. Race/ethnicity: White
  6. Age: mean 67.8 years, SD (3.5)
  7. Time period: 1998-2002
  8. Geographic location: not specified
  9. Number of participants: n=589, percent of total eligible not specified

 

Assessment of environment factors
For studies that include gene-environment interactions, define the following, if available:
  1. Environmental factor
  2. Exposure assessment
  3. Exposure definition
  4. Number of participants with exposure data (%
    of total eligible)

 

  1. Environmental factor: Not applicable
  2. Exposure assessment:
  3. Exposure definition:
  4. Number of participants with exposure data: N (% of total eligible)
  5. Environmental factor: [Repeat for additional environmental factor, if applicable]
  6. Not applicable

 

Genotyping
Specify the following:
  1. Gene
  2. DNA source
  3. Methodology
  4. Number of participants genotyped (% of total eligible) 

The hepatic lipase promoter region was sequenced in 100 centenarians and controls, no significant polymorphism were found.

  1. Gene: Cholesteryl ester transfer protein (CETP) polymorphic markers: in the promoter region -631C/A (NCBI dbsSNP rs1800776), -629 C/A (rs1800775) were genotyped and in the exons codon 405 isoleucine to valine (1405V) (rs5882) in exon 14 and D442G (rs2303790) in exon 15.
  2. DNA source: DNA from blood samples.
  3. Methodology: DNA was amplified with biotinylated primers and produces of the PCR reaction were detected colorimetrically with sequence specific oligonucleotide probes immobilized on a nylon membrane in a linear array.
  4. Number of participants genotyped: All of the probands (centenarians), their offspring and Ashkenazi controls (group 1) were genotyped for CETP polymorphisms. None of the Framingham Control were genotyped.

 

Results
Describe the major results under each of the following HuGE categories. Include tables when data are provided:
  1. Prevalence of gene variant
  2. Gene-disease association
  3. Gene-environment interaction
  4. Gene-gene interaction
  5. Genetic test evaluation/monitoring

 

  1. Gene-disease association – Centenarians and their offspring had significantly larger lipoproteins than either control group. It was determined that 26% of the centenarians (probands) were homozygous for the I450V variant of CETP as were 20.7% of their offspring while only 8.6% of the Ashkenazi controls were homozygous.

 

Conclusion
State the author's overall conclusions from the study

 

Long health life is correlated with increased lipoprotein particle size and this can be inherited, in part, through a variant in CETP.

Comments
Provide additional insight, including methodologic issues and/or concerns about the study
  • The selection of the study participants varied between and within control groups. The Ashkenazi control consisted of both the spouses of the offspring as well as other from an unrelated study. This may have introduced selection bias, although both groups are from the same ethnic background. The second control group was of whites recruited from the Framingham Offspring Study. The inclusion of both control groups strengthens the study.
  • The numbers of centenarians and first degree offspring included is high and strengthens the study.
  • The biological plausibility of the suggested mechanism also strengthens the study. It is hypothesized that the larger lipoproteins are less predisposed to adhere to the vascular wall and this could reducing the incidence of cardiovascular disease and stroke in this population.
The authors estimated that the population attributable “risk” (fraction) for longevity of homozygosity for CETP I450V was 18.1 percent. This can be estimated in this type of study assuming the rareness of longevity. The equation published in the article, Risk= PxOR(1+PxOR), is incorrect. One common formula for estimating population attributable fraction (Levin) is AF= P(OR-1)/1+P(OR-1). Using this equation and data provided in the article (OR for longevity = 3.56 and the prevalence of the homozygous genotype = 0.086 in Ashkenazi Jewish controls), the attributable fraction is approximately 18.0 percent, similar to the 18.1 percent reported by the authors.

 

Last Updated August 25, 2004