Outline

1
Nutrigenomics Hot Kids on the Functional
Block Canadian Society for Clinical
Nutrition Vancouver April 26, 2003
Ken Kornman Boston USA
2
Functional Foods and Supplements
Beyond adequate nutritional effects----- A
functional food/supplement
Beneficially affects target functions in the body
AND
Leads to an improved state of health or well-being
Diplock et al. 1999
3
Individuals are on different paths that determine
long-term wellness
Disease Initiator e.g. cholesterol
Genetic variations
? Ken Kornman, Interleukin Genetics 2003
4
One gene variation determines clinical response
to Kineret therapy in Arthritis
cases with gt50 reduction in joint swelling
IL-1A Gene Variation
OR4.85 (1.85-12.70) plt0.001
Camp et al 1999
5
Pharmacogenetics

• Pharmaceutical company
• Improve clinical trialsreduce variability
• Develop new drugs that benefit people with modest
  responses to primary drug
• Patient
• Less trial and error in my response
• Less chance of side-effects
• Physician
• Less time required to manage failed response
• Happier and healthier patients
• Fewer side-effects to manage
• Payers
• reduced health care costs

6
Mega-trends Supporting Nutrigenomics
Consumer interests
Technology
1st international Conference on Nutrigenomics,
The Netherlands, March 2002
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Genetic variations and inflammation A Practical
Nutrigenomics Opportunity

• A few genetic variations exist in critical
  inflammation genes
• are known
• are found in substantial segments of the
  population
• alter the clinical level of inflammatory
  mediators
• alter inflammation-controlled diseases
• Inflammation is modifiable---in complex ways---
  by various nutritional products

8
Inflammation is a critical component of
cardiovascular disease
9
Atherosclerotic heart disease follows multiple
paths
Cholesterol
Artery
Inflammation
? Ken Kornman, Interleukin Genetics 2003
10
Inflammatory Gene Activity Determines Clinical
Expression of Major Human Diseases
Initiating Factor
Disease
Inflammation
? Ken Kornman, Interleukin Genetics 2003
11
Inflammation Genetics Development of nutritional
products to prevent common diseases

• Inflammation is a critical component of several
  common diseases
• Inflammation genetics determine disease
  trajectory and response to therapeutic and
  preventive agents

12
The human inflammatory response employs a
powerful cascade of signal-amplification
Local Tissue
Gene Activation
? Ken Kornman, Interleukin Genetics 2003
13
Nine genes involved in IL-1 biological activity
are clustered on chromosome 2
Nicklin, Duff, Kornman et al. 2002
SNPs in the extensively studied genes for IL-1?,
IL-1?, and IL-1ra Define inherited patterns of
IL-1 gene variations (haplotypes) That appear to
be of functional and clinical importance Camp,
Cox, diGiovine, Nicklin, Duff Am J Human
Genetics 1999
14
Inflammation Genetics Development of nutritional
products to prevent common diseases

• Inflammation is a critical component of several
  common diseases
• Inflammation genetics determine disease
  trajectory and therapeutic response

• IL-1 Genotype Pattern 1 is pro-inflammatory
• ? increased inflammatory biomarkers
• increased trajectory of major common diseases
• increased response to new arthritis drug

15
The IL-1 Pattern 1 genetic variations have a
strong and significant influence on the
distribution of CRP values
? Ken Kornman, Interleukin Genetics 2003
Berger et al. 2002 N504 plt0.001
CRP Quartile
of patients in the specific group who are
within the indicated CRP quartile
46.4
7.1
Pattern 1 Tag Positive2.2 Negative1.1/1.2
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Interleukin Genetics The application of
inflammation genetics to the treatment and
prevention of common diseases

• Inflammation is a critical component of several
  common diseases
• Inflammation genetics determine disease
  trajectory and therapeutic response

• IL-1 Genotype Pattern 1 is pro-inflammatory
• ? increased inflammatory biomarkers
• increased trajectory of major common diseases
• increased response to new arthritis drug

17
IL-1 Pattern 1 genotype is associated with
Alzheimers Disease

• Griffin WS, Nicoll JA, Grimaldi LM, Sheng JG,
  Mrak RE. The pervasiveness of interleukin-1 in
  alzheimer pathogenesis a role for specific
  polymorphisms in disease risk. Exp Gerontol 2000
  Jul35(4)481-487.
• Nicoll JA, Mrak RE, Graham DI, Stewart J, Wilcock
  G, MacGowan S, Esiri MM, Murray LS, Dewar D, Love
  S, Moss T, Griffin WS. Association of
  interleukin-1 gene polymorphisms with Alzheimers
  disease. Ann Neurol 2000 47365-368.
• Grimaldi LM, Casadei VM, Ferri C, Veglia F,
  Licastro F, Annoni G, Biunno I, De Bellis G,
  Sorbi S, Mariani C, Canal N, Griffin WS,
  Franceschi M. Association of early-onset
  Alzheimers disease with an interleukin-1 alpha
  gene polymorphism. Ann Neurol 2000 47 361-365.
• Rebeck GW. Confirmation of the genetic
  association of interleukin-1A with early onset
  sporadic Alzheimers disease. Neurosci Lett 2000
  293(1) 75-77.
• Tanzi RE. Alzheimers disease risk and the
  interleukin-1 genes. Ann Neurol 2000 47
  283-285.
• Kolsch H, Ptok U, Bagli M, Papassotiropoulos A,
  Schmitz S, Barkow K, Kockler M, Rao ML, Maier W,
  Heun R. Gene polymorphisms of interleukin-1alpha
  influence the course of Alzheimer's disease. Ann
  Neurol 2001 Jun49(6)818-819.

18
IL-1 genetic variations increase the risk of a
first heart attack
? Ken Kornman, Interleukin Genetics 2003
1987-89 Age 45-64 Total Cholesterol lt200 N955
11 Years
Relative risk 4.47 (1.54-12.96) p0.0058
ILGN Unpublished 2002
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Polyunsaturated fatty acids inhibit IL-1
From James M Am J Clin Nutrition 2000
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Variations in key inflammatory genes alter tissue
responses and change the course of disease
? Ken Kornman, Interleukin Genetics 2003