[Show abstract][Hide abstract] ABSTRACT: Previous observational studies suggest that vitamin C may reduce risk of colorectal cancer. Vitamin C transport is facilitated by membrane bound sodium-dependent transporters, SVCT1 (encoded by SLC23A1) and SVCT2 (encoded by SLC23A2). To investigate if common genetic variants in these two genes are associated with risk of colorectal tumor development, we conducted a case-control study of 656 Caucasian advanced distal colorectal adenoma cases and 665 Caucasian sigmoidoscopy-negative controls nested within the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. The analysis of common single nucleotide polymorphisms in SLC23A1 revealed no association. For SLC23A2, overall, there was no association with haplotypes, but two SNPs located in intron 8 and exon 11 could be associated (odds ratio = 0.49, 95% confidence interval = 0.25-0.95 for haplotype G-C vs. haplotype C-C). The findings should be confirmed in follow-up studies, and further investigation is required to probe the functional basis of this finding.
Nutrition and Cancer 02/2008; 60(5):652-9. DOI:10.1080/01635580802033110 · 2.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin C has been the focus of epidemiologic investigation in preterm delivery (<37 weeks' gestation), which is a leading cause of neonatal mortality and birth-related morbidity. There are two sodium-dependent membrane transporters encoded by SLC23A1 and SLC23A2, which have key roles in human vitamin C metabolism and which control dietary uptake, reabsorption, and tissue distribution of vitamin C. Using maternal DNA, the authors evaluated common single-nucleotide polymorphisms (SNPs) in SLC23A1 and SLC23A2 in a nested case-control analysis of the Pregnancy, Infection, and Nutrition Study (1995-2000) cohort. Of the associations observed for both haplotypes in SLC23A1 and individual SNPs in SLC23A2, the most robust finding is with an intron 2 variant in SLC23A2. Heterozygotes and homozygotes for this variant had a 1.7-fold (95% confidence interval: 0.9, 3.3) and a 2.7-fold (95% confidence interval: 1.2, 6.3) elevation in the risk of spontaneous preterm birth, respectively. Semi-Bayesian hierarchical regression analysis, which simultaneously adjusted for multiple SNPs within the same gene, gave comparable results. The authors' findings link genetic variants in the vitamin C transporters to spontaneous preterm birth, which may explain previous dietary associations. If the findings from this study are confirmed, they may serve as the foundation for genetic risk assessment of nutritional pathways in preterm birth.
American Journal of Epidemiology 02/2006; 163(3):245-54. DOI:10.1093/aje/kwj035 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Preliminary data suggest that common genetic variation in immune response genes can contribute to the risk for spontaneous preterm birth and possibly small-for-gestational age (SGA).
We investigated the relationship of polymorphisms in 6 cytokine genes associated with inflammation-interleukin (IL)1alpha, IL1beta, IL2, IL6, tumor necrosis factor (TNF), and lymphotoxin alpha (LTA)-with spontaneous preterm and SGA birth in a nested case-control study drawn from a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. We then compared haplotype frequency distributions and implemented semi-Bayesian hierarchical logistic regression analyses to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism.
Two haplotypes spanning the TNF/LTA genes were associated with increased risk for spontaneous preterm birth in white subjects (for the AGG haplotype, OR = 1.5 [95% CI=0.8-2.6]; for the GAC haplotype, 1.6 [0.9-2.9]). Additionally, carriers of the GAG haplotype were found to have decreased risk of spontaneous preterm birth (0.6; 0.3-1.0). The TNF(-488)A and LTA(IVS1-82)C variants, constituents of the AGG and GAC haplotypes respectively, were also strongly associated with increased risk of spontaneous preterm birth.
Our results suggest that common genetic variants in proinflammatory cytokine genes could influence the risk for spontaneous preterm birth. Selected TNF/LTA haplotypes were associated with spontaneous preterm birth in both African-American and white subjects. Our data do not support an inflammatory etiology for SGA.
[Show abstract][Hide abstract] ABSTRACT: Anti-inflammatory cytokines play a key role in pregnancy maintenance. Genetic variation in anti-inflammatory cytokines could influence a woman's risk of adverse reproductive outcomes.
We investigated the relationship of polymorphisms in interleukin 4 (IL4), IL5, IL10, IL13, and transforming growth factor (TGFbeta1) with spontaneous preterm birth and small-for-gestational age (SGA) in a nested case-control study of a prospective pregnancy cohort. Women were recruited between 24 and 29 weeks' gestation at the Wake County and University of North Carolina, Chapel Hill obstetric clinics between February 1996 and June 2000. We inferred haplotypes using the EM algorithm and the Bayesian method, PHASE. Semi-Bayesian hierarchical logistic regression was used to obtain odds ratio (OR) estimates and 95% confidence intervals (CIs) for each polymorphism.
African-American mothers who carried the IL4 GCC haplotype had greater risk of spontaneous preterm birth (OR = 2.9; 95% CI = 1.2-7.4). In white mothers, carriers of the "low-producing" IL4 CC and IL10 ATA haplotypes had markedly reduced risk of SGA (for the CC haplotype, 0.2 [0.0-1.2]; for the ATA haplotype, 0.5 [0.3-0.8]), whereas carriers of the "high-producing" IL4(-589)T variant had increased risk of SGA in both African-American and white mothers.
Variants related to decreased anti-inflammatory cytokine production may lower risk of SGA. Furthermore, the same mechanism that protects against SGA might increase risk of spontaneous preterm birth.
[Show abstract][Hide abstract] ABSTRACT: Vitamin C (L-ascorbic acid) is an essential co-factor for eight mammalian enzymes and quenches reactive oxygen species. Sodium-dependent vitamin C transport is mediated by two transporters, SVCT 1 and SVCT 2, encoded by SLC23A1 and SLC23A2. We characterized the genomic structures of SLC23A1 and SLC23A2, determined the extent of genetic variation and linkage disequilibrium across each gene, analyzed nucleotide diversity to estimate the effect of selective pressure, and compared sequence variation across species. In SLC23A1, the majority of single nucleotide polymorphisms (SNPs) are population-specific in either African Americans or Caucasians, including three of four non-synonymous SNPs. In contrast, most SNPs in SLC23A2 are shared between African Americans and Caucasians, and there are no non-synonymous SNPs in SLC23A2. Our analysis, combined with previous in vitro and in vivo studies, suggests that non-synonymous variation appears to be tolerated in SLC23A1 but not SLC23A2, and that this may be a consequence of different selective pressures following past gene duplication of the sodium-dependent vitamin C transporters. Genetic association studies of these two genes will need to account for the differences in haplotype structure and the population-specific variants. Our data represent a fundamental step toward the application of genetics to refining nutrient recommendations, specifically for vitamin C, and may serve as a paradigm for other vitamins.
Human Genetics 10/2004; 115(4):285-94. DOI:10.1007/s00439-004-1167-x · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Genetic variation in the human genome is an emerging resource for studying cancer, a complex set of diseases characterised by both environmental and genetic contributions. The number of common germ-line variants is great, on the order of 10-15 million per person, and represents a remarkable opportunity to investigate the aetiology, interindividual differences in treatment response and outcomes of specific cancers. The study of genetic variation can elucidate critical determinants in environmental exposure and cancer, which could have future implications for preventive and early intervention strategies. However, we are in the initial stages of characterising the tools (i.e., the single-nucleotide polymorphism, SNP) to rigorously analyse the genetic contributions to complex diseases, such as cancer. If the promise of the genomic era is to be realised, we must integrate this information into new strategies for implementation in both public health measures and, most importantly, provision of individual cancer-related care.
British Journal of Cancer 03/2004; 90(4):747-51. DOI:10.1038/sj.bjc.6601574 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chronic disseminated candidiasis (CDC) is a form of Candida species infection observed primarily in patients with acute leukemia. To investigate possible genetic factors associated with CDC, we conducted a pilot study of 40 patients with both leukemia and CDC and 50 control patients with leukemia only. A common haplotype of the IL4 promoter (-1098T/-589C/-33C) was overrepresented in patients with CDC (P= .01; odds ratio [OR], 2.16), whereas another common haplotype (-1098T/-589T/-33T) appeared to be protective against CDC (P= .018; OR, 0.47). Genetic variants of IL4 could contribute to the development of CDC in patients with acute leukemia.
The Journal of Infectious Diseases 05/2003; 187(7):1153-6. DOI:10.1086/368345 · 5.78 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vitamin C (L-ascorbic acid), a critical cofactor for intracellular enzymatic reactions, functions as a scavenger of free oxygen radicals and is an essential micronutrient. Vitamin C is actively transported into cells by one of two closely related sodium-dependent transporters, SVCT1 or SVCT2. In this paper, we report the complete sequencing and gene structure of SLC23A2, the gene encoding SVCT1. The1797-bp cDNA sequence (open reading frame) of the SLC23A2 gene was derived from a compact genomic sequence of 7966 bp [translation initiation codon (ATG) to poly A tail], which is divided into 14 exons. Furthermore, repetitive or masked elements constituted 17.98% of the gene; there were 4 Alu sequences and 5 MIR (Mammalian Interspersed Repetitive element) sequences. A search for common variants in SLC23A2, using current bioinformatic tools and direct resequencing of control populations, failed to identify common single nucleotide polymorphisms. The start of transcription was mapped to a position -47 relative to the ATG; the immediate 5' sequence was determined and analyzed for possible consensus binding sites for known transcription factors. Our findings will serve as the foundation for investigation of the regulation and expression of the tissue-specific sodium-dependent vitamin C transporter, SLC23A2.
Journal of Nutrition 11/2001; 131(10):2623-7. · 4.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Inflammatory cytokines and low-affinity Fcgamma receptor (FcgammaR) polymorphisms were investigated in 37 children with chronic immune thrombocytopenic purpura (cITP) and 218 controls. Genotype analysis included common variants in the regulatory regions of cytokines, TNF, LTA, IL1RN, IL1A, IL1B, IL4, IL6 and IL10, and structural variants of the low affinity FcgammaRs, FCGR2A, FCGR3A and FCGR3B. Associations were observed for TNF (P = 0.0032), LTA (P = 0.019), FCGR3A (P = 0.038) and FCGR3B (P = 0.0034). Two combinations of genotypes (TNF and FCGR3A; P = 0.0003, and LTA and FCGR3B; P = 0.011) were significantly associated with cITP. These results provide preliminary evidence that variant genotypes of FcgammaRs and cytokines contribute to cITP pathogenesis.
British Journal of Haematology 07/2001; 113(3):596-9. DOI:10.1046/j.1365-2141.2001.02807.x · 4.96 Impact Factor