Chapter 15 - Functional nutrigenomics: A personalized shift in treating inflammation

The effects of polymorphisms in genes coding for key folate metabolism enzymes such as thymidylate synthetase (TS) on colorectal neoplasia risk are likely to be influenced by gene–gene and gene–nutrient interactions. We investigated the combined effects of three polymorphisms in the TS gene region, TSER, TS 3R G>C, and TS 1494del6, dietary intakes of folate and other B vitamins, and genotype for other folate metabolism variants, in a colorectal adenoma (CRA) case–control study. Individuals homozygous for TS 1494del6 del/del were at significantly reduced CRA risk compared to those with either ins/del or ins/ins genotypes (odds ratio 0.52; 95% confidence interval: 0.31–0.85, P=0.009). We also observed evidence of interactions between TS 1494del6 genotype and intake of folate, and vitamins B6 and B12, and MTHFR C677T genotype, with the reduction in risk in del/del homozygotes being largely confined to individuals with high nutrient intakes and MTHFR 677CC genotype (Pinteraction=0.01, 0.006, 0.03, and 0.07, respectively). TSER genotype, when considered either alone or in combination with TS 3R G>C genotype, did not significantly influence CRA risk. These findings support a role for TS in colorectal carcinogenesis, and provide further evidence that functional polymorphisms in folate metabolism genes act as low-risk alleles for colorectal neoplasia and participate in complex gene–gene and gene–nutrient interactions.

Genetic polymorphisms in one-carbon metabolizing pathway genes have been associated with risk of malignant lymphoma. However, the results have been inconsistent. The objectives of this study were to examine the potential relationship between gene-nutrient interactions and the risk of non-Hodgkin lymphoma (NHL). We examined 25 polymorphisms in 16 one-carbon metabolism genes for their main effect and gene-nutrient interactions in relation to NHL risk among 518 incident cases and 597 population-based controls of Connecticut women enrolled between 1996 and 2000. A significantly reduced risk of NHL was associated with the homozygous TT genotype in CBS (rs234706, Ex9+33C>T) (OR = 0.51, 95 % CI 0.31-0.84), the homozygous CC genotype in MBD2 (rs603097, -2176C>T) (OR = 0.37, 95 % CI 0.17-0.79), the heterozygote AG genotype in FTHFD (rs1127717, Ex21+31A>G) (OR = 0.73, 95 % CI 0.55-0.98), and a borderline significantly reduced risk of NHL was observed for the homozygous CC genotype in MTRR (rs161870, Ex5+136T>C) (OR = 0.23, 95 % CI 0.05-1.04). The reduced risk of NHL associated with these genotypes was predominately in those with higher dietary vitamin B6 and methionine intakes, as well as with higher dietary folate intake although results were less stable. A borderline significantly increased risk of NHL was also observed for CBS (rs1801181, Ex13+41C>T), FTHFD (rs2305230, Ex10-40G>T), SHMT1 (rs1979277, Ex12+138C>T), and SHMT1 (rs1979276, Ex12+236T>C), and these associations appeared to be contingent on dietary nutrient intakes. Our results suggest that variation in several one-carbon metabolizing pathway genes may influence the risk of NHL through gene-nutrient interactions involving dietary nutrient intakes.

The objective of the study was to assess the role of variations in serum folate, vitamin B12, homocysteine and the presence of genetic polymorphisms as risk factors for congenital heart disease (CHD) in children. A total of 32 children with CHD, and their mothers and 32 normal children and their mothers formed the study and control groups, respectively. Serum folate, vitamin B12 and homocysteine as well as genetic polymorphisms MTHFR C677→︀T, MTHFR A1298→︀C, MTR A2756→︀G and MTRR A66→︀G were assessed. Low serum folate and genetic polymorphisms MTHFR C677→︀T and MTRR A66→︀G among children and their mothers and high homocysteine among mothers were noted as risk factors for CHD (P<0.05). Vitamin B12 levels were normal and showed no association. Presence of MTHFR C677→︀T and MTRR A66→︀G, both concurrently among children as well as mothers and simultaneously among mother-child pairs, showed several fold increase in the risk for CHD. On multivariate analysis, the risk factors noted for CHD were presence of MTHFR C677→︀T among children and their mothers and MTRR A66→︀G among mothers. Analyses for nutrient-gene interaction revealed significant associations between low serum folate and high serum homocysteine levels, and the presence of selected genetic polymorphisms. Low serum folate, high homocysteine and presence of selected genetic polymorphisms among children and their mothers were noted as risk factors for CHD. Nutrient-gene interaction being a modifiable risk factor, the study recommends the use of peri-conceptional folate supplementation with vitamin B12 sufficiency for primary prevention of CHD.

The metabolic syndrome (MetS) is a complex disorder characterised by abdominal obesity, insulin resistance, hypertension, dyslipidaemia and inflammation (1) . Development of the MetS is thought to be influenced by both genetic and environmental effects, with diet being a major environmental factor. Multiple genes are involved in the disease and interactions between gene variants and dietary fatty acids may modulate the risk of the disease. The LIPGENE WP1.2 project (Diet, genomics and the metabolic syndrome: an integrated nutrition, agro-food, social and economic analysis) aims to investigate associations between polymorphisms in candidate genes and gene‐nutrient interactions with biomarkers of the MetS, by means of a dietary intervention to alter fat composition in a cohort of patients with MetS. The adiponectin gene (ACDC, ADIPOQ) codes for the adiponectin protein, the most abundant adipokine secreted by adipocytes (2) . Levels of circulating adiponectin are reduced in obese subjects and subjects with type 2 diabetes, as well as in patients suffering from a variety of obesity-related malignancies. This hormone may be a key player in the aetiology of the MetS, being an important regulator of insulin sensitivity and inflammation. An investigation has been conducted into whether polymorphisms in ACDC are associated with biomarkers of the MetS, and whether polymorphisms in other genes are associated with plasma levels of adiponectin, taking into account both dietary fat intake and plasma fatty acid levels in 486 individuals at baseline. In total four single-nucleotide polymorphisms (SNP) within the adiponectin gene (ACDC: rs266729) and its 2 receptors (ADIPOR1: rs10753929, rs10920533 and ADIPOR2: rs6489323) showed significant associations (P £ 0.006) with fasting insulin levels when levels of plasma SFA were taken into account. In general, higher plasma SFA was accompanied by higher fasting insulin; however, this association was only demonstrated in a subset of the population, with the effect being dependent on genotype. Thus, some genotypes appear to interact with plasma SFA to exert a modifiable effect on fasting insulin, while others are unresponsive to SFA levels. A combination of the four SNP with plasma SFA demonstrated an even greater significant effect (P = 0.001, h 2 0.186). Levels of circulating adiponectin were also found to be associated with particular combinations of genotypes and SFA. Individuals showed significant tendencies (P £ 0.02) towards either stable or varying levels of adiponectin in response to differences in plasma SFA levels, depending on genotype in the following SNP: rs2241766 in ACDC, rs10920533 in ADIPOR1 and rs1800783 in NO synthase 3. Combination of these three SNP further increased the effect (P = 0.000, h 2 0.11). Using information from single SNP or SNP combinations could thus potentially identify individuals who are more likely to respond to dietary therapy. These results provide further evidence towards the emerging role of adiponectin in obesity and related disorders, and provide optimism for the use of nutrigenomic approaches in disease management. While alterations in fat composition may not be sufficient to improve symptoms in all patients, the results demonstrate that certain genotypes may give rise to more modifiable phenotypes that are more sensitive to levels of SFA. These individuals might respond more positively to dietary interventions, reducing the need for drug treatment, or slowing disease progression.

Background: Autoimmune diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are a serious global health issue, arising from complex gene-environment interactions involving nutrition. Pharmacological interventions are first-line, but dietary manipulation is a relevant modifiable factor. Aim: The current review strives to synthesize recent evidence (2020-2024) of the interaction between specific genetic polymorphisms and eating patterns on influencing disease activity and symptoms in RA and SLE. Methods: A narrative review was conducted by systematically reviewing scientific literature between 2020 and 2024. The focus was on studies investigating interactions between genetic polymorphisms and food intakes on clinical outcomes in RA and SLE patients. Results: Evidence confirms that genetic polymorphisms in pathways of nutrient metabolism (e.g., VDR, MTHFR), oxidative stress (GPX1), and inflammation (FADS1) significantly modify reactions to nutrients like vitamin D, folate, selenium, and omega-3 fatty acids. Dietary patterns, particularly the Mediterranean dietary pattern, are supportive of genetically modulating risk, and the gut microbiota is an important intermediary in these mechanisms. The reaction to elimination diets may also be genetically controlled. Conclusion: A uniform dietary approach is not adequate for RA and SLE management. The evidence points to the potential of personalized nutrition, where genetic testing can guide individually designed dietary protocols in order to reduce disease activity, dampen flares, and improve patient quality of life.

Functional variants in genes of the renin-angiotensin (RAS) and kallikrein-kinin (KKS) systems have already been implicated in blood pressure (BP) modulation, but few studies have focused on a nutrigenetics approach. Thus, the aim of this study is to verify the effects of the interaction between genetic polymorphisms (rs4340-ACE, rs699-AGT, and rs1799722-BDKRB2) and micronutrient consumption (sodium, potassium, calcium, and magnesium) on BP values of normotensive adult individuals. The study included 335 adults, men and women, 25.5 (6.6) years old. Biochemical, anthropometric, BP measurements, and food intake data were assessed for all participants. Gene-nutrient interaction on BP outcome was tested by multiple linear regression with manual backward stepwise modeling. Our results indicated that individuals with G allele for rs699 polymorphism, in the increase of sodium and magnesium consumption, both in the genotypic model (sodium, p = 0.035; magnesium, p = 0.016) and in the dominant model (sodium, p = 0.009; magnesium, p = 0.006) had higher systolic BP (SBP) levels compared to AA homozygotes (sodium, p = 0.001; magnesium, p < 0.001). Also, individuals with the T allele for the rs1799722 polymorphism, with higher calcium intake, had significantly higher levels of SBP and diastolic BP (DBP) when compared to CC homozygotes (p = 0.037). In conclusion, our findings pointed for significant interactions between genetic polymorphisms (rs699-AGT and rs1799722-BDKRB2) and the consumption of micronutrients (sodium, magnesium, and calcium) on the BP variation. These findings contribute to the understanding of the complex mechanisms involved in BP regulation, which probable include several gene-nutrition interactions.

Nutrigenomics is a tool to measure gene expressions in response to dietary intake and better understand the human body's nutrient-gene interactions. Nutrigenetics is a tool to assess how genetic variations influence nutrients' interaction result of developing various chronic diseases. Dietary factors alter genes' expression, including nutritional factors such as antioxidants, vitamins, phytochemicals, caffeine, sterols, fatty acids, and alcohol. Furthermore, genetic polymorphisms in nutrient action targets such as enzymes could alter molecular pathways that influence the physiological response to dietary intake. Identifying relevant diet-gene interactions will benefit individuals seeking personalized nutritional advice.

Prevalence and effects of gene-gene and gene-nutrient interactions on serum folate and serum total homocysteine concentrations in the United States: findings from the third National Health and Nutrition Examination Survey DNA Bank

Nutrients and Gene Interactions in Cancer, E. Giovannucci Candidate Mechanisms for Interactions between Nutrients and Genes, J.C. Mathers Biomarkers for Nutrient-Gene Interactions, C.E. Robertson and P. Vineis Interaction between Folate and Methylene-tetrahydrofolate Reductase (MTHFR) Gene in Cancer, S. Friso and S.-W. Choi Genetic Variability in Folate-Mediated One-Carbon Metabolism and Cancer Risk, C.M. Ulrich S-Adenosylmethionine and Methionine Adenosyltransferase Genes, J.M. Mato, M.L. Martinez-Chantar, and S.C. Lu Effects of Carotenoid Supplementation on Signal Transduction Pathways: Significance in Lung Cancer Prevention, X.-D. Wang and S. King The Actions of the Vitamin D Receptor in Health and Malignancy Polymorphic Associations and Gene Regulatory Actions, M.J. Campbell and K. W. Colston The Role of Alcohol Dehydrogenase Polymorphism in Alcohol-Associated Carcinogenesis, H.K. Seitz and F. Stickel Genetic Polymorphism of N-Acetyltransferase Genes as Risk Modifiers of Colorectal Cancer from Consumption of Well-Done Meat, L.C.R. Kidd, R.C.G. Martin, J.H. Moore, and D.W. Hein Ferritin and Serine Hydroxymethyltransferase, P.J. Stover Brassica-Gene Interactions and Cancer Risk, J.H. Fowke Conclusions and Future Perspectives, S. Friso, R. Corrocher, and S.-W. Choi Index

Hepatitis C virus (HCV) is a major cause of chronic liver disease, with about 170 million people infected worldwide. The standard regimen for treatment of HCV consists of a combination of pegylated interferon with ribavirin. Failure of interferon-α treatment in patients with chronic HCV infection remains a challenging obstacle. Both viral and host environmental factors have been implicated in reducing responsiveness to IFN-α therapy. Host genetic diversity is also believed to contribute to the different clinical outcomes in HCV infection. The objective of the study was to investigate the association of both IL-10 (-819 and -592) and MxA (-88 and -123) single-nucleotide polymorphisms (SNPs) of the promoter regions, with response to interferon (IFN) therapy in Egyptian patients infected with HCV genotype 4. Polymorphisms of both genes in 85 HCV patients and 100 controls were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. The frequency of SNP was compared between sustained responders (n = 52) and non-responders (n = 33), as determined by biochemical and virological response to IFN and ribavirin combined therapy. The frequency of the -819T/T and the -592A/A genotypes of IL-10 was significantly higher among responders compared to non-responders (51.92 vs 39.4 %, P = 0.03; 51.92 vs 42.42 %;P = 0.046 respectively). The G/G genotype at position -88 of the MxA gene was significantly lower in responders than in non-responders (25 vs 75.76 %, P = 0.046), whereas heterozygotes (G/T) were more likely responders (65.38 vs 18.18 %, P = 0). The -123C/A genotype was significantly associated with responders (48.08 vs 30.30 %, P = 0.014). Findings suggest that homozygosity for both -819T/T and -592A/A polymorphisms of IL-10 gene and that heterozygosity for both -88G/T and -123C/A polymorphisms of the MxA gene are important host factors that influence the response to IFN therapy in patients with chronic HCV infection.

The mechanisms responsible for development of inflammatory bowel disease (IBD) have not been fully elucidated, although the main cause of disease pathology is attributed to up-regulated inflammatory processes. The aim of this study was to investigate frequencies of polymorphisms in genes encoding pro-inflammatory and anti-inflammatory markers in IBD patients and controls. We determined genotypes of patients with IBD (n= 172) and healthy controls (n= 389) for polymorphisms in genes encoding various cytokines (interleukin (IL)-1beta, IL-6, tumour necrosis factor (TNF), IL-10, IL-1 receptor antagonist). Association of these genotypes to disease incidence and pathophysiology was investigated. No strong association was found with occurrence of IBD. Variation was observed between the ulcerative colitis study group and the control population for the TNF-alpha-308 polymorphism (p= 0.0135). There was also variation in the frequency of IL-6-174 and TNF-alpha-308 genotypes in the ulcerative colitis group compared with the Crohn's disease group (p= 0.01). We concluded that polymorphisms in inflammatory genes are associated with variations in IBD phenotype and disease susceptibility. Whether the polymorphisms are directly involved in regulating cytokine production, and consequently pathophysiology of IBD, or serve merely as markers in linkage disequilibrium with susceptibility genes remains unclear.

Methylenetetrahydrofolate Reductase Gene Polymorphism C677T is Associated with Increased Risk of Coronary Heart Disease in Chinese Type 2 Diabetic Patients

Background: The aim of this study was to explore the associations between the prevalence of chronic kidney disease (CKD) and polymorphisms in the genes encoding matrix metalloproteinases (MMPs) and tissue inhibitor of matrix metalloproteinases (TIMPs). MMPs degrade extracellular matrix proteins in the glomerulus, and play important roles in kidney disease progression. Methods: DNA samples from 3,309 subjects aged 35–69 years were genotyped for 10 potentially functional polymorphisms in MMP and TIMP genes. The prevalence of CKD (estimated glomerular filtration rate <60 ml/min/1.73 m²) was compared among the genotypes. Results: The prevalence of CKD decreased significantly with the number of minor alleles in MMP9 C–1562T (odds ratios (ORs) 0.77 for CT and 0.65 for TT compared with CC; p for trend = 0.023) and MMP9 R668Q (ORs, 0.79 for RQ and 0.64 for QQ compared with RR; p for trend = 0.024). The haplotype MMP9 –1562T/279R/668Q showed a reduced risk for CKD compared with the most common –1562C/279R/668R (OR 0.77, p = 0.008), and the genotype combination –1562TT/ 279RR/668QQ showed a halved risk for CKD compared with major allele homozygous –1562CC/279RR/668RR (OR 0.53, p = 0.091). Conclusion: The potentially functional polymorphisms of MMP9 were associated with the prevalence of CKD in a large Japanese population. These genotypes have been reported to increase MMP9 expression, supporting the hypothesis that MMP-9 has a protective role in the progression of kidney diseases.

Sarcoidosis is a chronic inflammatory disease characterised by granulomatous inflammation in various organs. As genetic factors have been implicated in its aetiology, in our study we investigated whether the promotor polymorphisms in three genes coding for inflammatory mediators interleukin-6 (IL-6), interleukin-12 (IL-12), and interleukin-18 (IL-18) could be associated with susceptibility to sarcoidosis. The study sample consisted of 104 patients with sarcoidosis and 100 healthy control subjects. Following DNA isolation from peripheral blood the IL-6/-174G>C single nucleotide polymorphism (SNP), the IL-12B/4 bp insertion polymorphism, and the IL-18/-137G>C SNP were characterised by polymerase chain reaction. Our results showed an increased frequency of IL-6/-174C allele (p<0.01, OR=2.05, 95% CI=1.32-3.16), and also an increased genotype frequency of IL-6/-174 CC and CG carriers (p<0.01, OR=2.78, 95% CI=1.49-5.19) among sarcoidosis patients in comparison with healthy controls. Allele and genotype frequencies did not differ significantly between cases and controls for either the IL-12B/4 bp insertion polymorphism or for the IL-18/-137G>C polymorphism. In conclusion, we demonstrated that the -174G>C promotor polymorphism in the IL-6 gene may be a risk factor for sarcoidosis.

Over the last 30 years it has become apparent that specific dietary fatty acids are capable of regulating, either directly or indirectly through various signal pathways, the expression of numerous genes, either positively or negatively. Such nutrient-gene interactions have important effects on cell metabolism, differentiation and growth, and ultimately on disease processes. The present review describes some of the more important fatty acid-gene interactions in relation to health and disease in mammalian species, and focuses on the underlying cell signal mechanisms, including various transcription factors, affected by fatty acids and some of their oxygenated derivatives, e.g. the eicosanoids. The review also attempts to clarify some of the complexities of the effects of fatty acids by suggesting a possible overriding regulation by the redox status of the cell. The latter will at least stimulate controversy in this exciting area of lipid research.