functional medicine and nutritional genomics - American Association ...

AAPI’S NUTRITION GUIDE TO OPTIMAL HEALTH: USING PRINCIPLES OF FUNCTIONAL MEDICINE AND NUTRITIONAL GENOMICS
organic cation
transporters
ATP-binding cassette
subfamily B member 1
Drosophila discs large
homologue 5
(also called
OCTN1/OCTN2)
This review is focused specifically on three IBDassociated
genes that appear to identify major
susceptibility loci for CD: 1) CARD15/NOD2, 2)
DLG5, and 3) SLC22A4/A5 (OCTN1/OCTN2).
CARD15/NOD2
The CARD15/NOD2 gene located on chromosome
16q12 was the first IBD susceptibility gene to be
associated with Crohn’s disease (35). The CARD15
gene encodes the NOD2 protein, which is thought to
provide protection against invasive bacteria by
eliminating intracellular pathogens in epithelial cells at
the gastrointestinal mucosa barrier (25). NOD2
protein is expressed by monocytes, granulocytes,
dendritic cells and by epithelial cells. It functions as an
intracellular sensor of peptidoglycan components of
bacterial cell walls, known as muramyl dipeptide (25).
Muramyl dipeptide (MDP) is a peptidoglycan
component that specifically signals throughout the
CARD15/NOD2 pathway. It is involved in modulating
activity of the immune related transcription factor,
nuclear factor-κB (NF-κB) (25).
There are 3 major polymorphisms that induce structural
changes in the leucine-rich repeats for the
CARD15/NOD2 gene (13,38). They are (see Table
2):
i. Arg702Trp (35,41)
ii. Gly908Arg (35,41)
iii. 1007finsC (35) or
c.3020insC (40,42)
90
1672 C>T
� SLC22A5
-207 G>C
transport or polarity of
the intestinal wall
ABCB1 Affects mucosal
transport or polarity of
the intestinal wall
DLG5 � DLG5 113G>A
� P.P1371Q
� P.G1066G
� Rs2289308
� DLG_e26
� P.D1507D
Affects mucosal
transport or polarity of
the intestinal wall
2012
The above described polymorphisms in the
CARD15/NOD2 gene are all associated with a
decreased functional response in stimulating MDP which
appears to lead to NF-КB overexpression and
inflammation (43,44). In a study by Kobayashi et al.,
the authors concluded that because the protein Nod2,
encoded by the CARD15 gene, is critical in protecting
the host from intestinal bacterial infection, variations in
Nod2 might promote CD due to a defective response
to commensal and/or pathogenic bacteria and may
contribute to Th1 skewing (45). Therefore, it appears
that defects in the initial innate response and
subsequent signaling of the adaptive immune response
are associated with increased susceptibility to chronic
gut inflammation (46).
The CARD15/NOD2 polymorphisms are more
prevalent in individuals with IBD as compared with
non-IBD controls, but are not present in all cases of
CD, either in humans or in mouse models. Intestinal
inflammation is not always present in mice that have
CARD15/NOD2 polymorphisms (45) and Hugot et
al. (13) reported that 0%-5% of the general
Caucasian population are homozygous for CDassociated
mutations and 60%-70% of CD patients
are heterozygous, in that they do not have both
CARD15/NOD2 alleles mutated‛.
Given these discrepancies, it appears that the presence
of CARD15/NOD2 gene variants may be a