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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
AAPI’S NUTRITION GUIDE TO OPTIMAL HEALTH: USING PRINCIPLES OF FUNCTIONAL MEDICINE AND NUTRITIONAL GENOMICS helpful marker of risk of IBD but not necessarily the final criteria for diagnosis. This also shows that not all individuals with IBD have exactly the same genetic variations, nor do they present with the same exact symptoms, thus demonstrating individual biochemical and genetic uniqueness. Ultimately, it appears that the defective bacterial signal in turn leads to an excessive 91 immune response, presenting as chronic gut inflammation in susceptible individuals (25). Figure 1. Illustration of the IBD-susceptibility genes. The confirmed IBD-susceptibility genes discussed in this paper (CARD15/NOD2, DLG5, SLC22A4/A5) are indicated by italicized, black letters. (image credit – 35) DLG5 A typical characteristic of IBD is a disturbed epithelial barrier function. DLG5 is a member of the membrane-associated guanylate kinase gene family that is important in the maintenance of epithelial cell integrity (47). The DLG5 gene is located on chromosome 10q23 (40) and has been implicated in regulating cell growth and maintaining cell shape and polarity (48). DLG5 proteins are localized at cell-cell junctions and are thought to be involved in the maintenance of epithelial integrity (47) and, thus, in preserving selective gastrointestinal permeability. Variants in the DLG5 gene are suspected of interfering with this function and resulting in disrupted epithelial barrier 2012
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