PubMed Health⌕ Search

Biomedical subjects

Jeannette Bigler

Publications and source records attributed to Jeannette Bigler.

At least 19 recordsLinked to original sources
PubMed2006

Inherited variation in carcinogen-metabolizing enzymes and risk of colorectal polyps.

Exposures such as cigarette smoke and meat contain a variety of procarcinogens, which are thought to play a role in elevation of risk for colorectal polyps and/or cancer. These procarcinogens (including heterocyclic amines and polycyclic aromatic hydrocarbons) are metabolized by a variety of polymorphic enzymes including N-acetyltransferases, sulfotransferases, cytochrome P450 enzymes and epoxide hydrolase. We hypothesized that genetic variation in the encoding genes NAT1, NAT2, SULT1A1, SULT1A2, CYP1A1 or EPHX1 is associated with risk of colorectal polyps and interacts with cigarette use or meat intake to modify risk of colorectal polyps. We examined the role of these genes in a clinic-based study of 651 Caucasian cases with hyperplastic polyps, adenomatous polyps or both types of polyps and 556 polyp-free controls. We found evidence for interaction between NAT acetylator status and SULT1A1 genotype in risk of hyperplastic polyps: individuals with SULT1A1 638AA genotype and NAT1 and NAT2 intermediate/fast phenotypes had 3.5-fold increased risk (95% CI 1.2-10.3) compared with individuals with SULT1A1 638GG genotype and NAT1 and NAT2 slow phenotypes. Data were also consistent with interactions between smoking and variation in SULT1A1, CYP1A1 and EPHX1 and between meat intake and variation in CYP1A1 and EPHX1. No interactions were statistically significant. Although results should be interpreted with caution considering sample size and the number of hypotheses examined, our study suggests future avenues of investigation in larger investigations of genetic and lifestyle factors in the pathway to colorectal cancer.

Adult↗
PubMed2006

Risk of microsatellite-unstable colorectal cancer is associated jointly with smoking and nonsteroidal anti-inflammatory drug use.

Smoking has been consistently associated with an increased risk of colorectal adenomas and hyperplastic polyps as well as colorectal cancer. Conversely, nonsteroidal anti-inflammatory drugs (NSAID) have been associated with reduced colorectal cancer risk. We conducted a population-based case-control study to evaluate the joint association between smoking and regular NSAID use with colorectal cancer risk; we also examined these associations stratified by tumor microsatellite instability (MSI). We analyzed 1,792 incident colorectal cancer cases and 1,501 population controls in the Seattle, Washington area from 1998-2002. MSI, defined as MSI high (MSI-H) or MSI-low/microsatellite stable (MSI-L/MSS), was assessed in tumors of 1,202 cases. Compared with nonsmokers, colorectal cancer risk was modestly increased among individuals who had ever smoked. Current NSAID use was associated with a 30% lower risk compared with nonusers. There was a statistically significant interaction between smoking duration and use of NSAIDs (P(interaction) = 0.05): relative to current NSAID users who never smoked, individuals who had both smoked for >40 years and had never used NSAIDs were at the highest risk for colorectal cancer (adjusted odds ratio, 2.8; 95% confidence intervals, 1.8-4.1). Compared with nonsmokers, there was a stronger association within MSI-H tumors with current smoking than there was within MSI-L/MSS tumors. Smokers of long duration were at elevated risk of MSI-H tumors even with NSAID use. The risk of MSI-L/MSS tumors was not elevated among long-duration smokers with long exposure to NSAIDs but was elevated among long-duration smokers who had never used NSAIDs. There seems to be a synergistic inverse association (implying protection) against colorectal cancer overall as a result of NSAID use and nonsmoking, but risk of MSI-H colorectal cancer remains elevated among smokers even when they have a history of NSAID use.

Adult↗
PubMed2006

Genetic variability, haplotypes, and htSNPs for exons 1 at the human UGT1A locus.

UDP-Glucuronosyltransferases (UGTs) are a superfamily of enzymes responsible for glucuronidation of xenobiotics and endobiotics. Genetic polymorphisms have been identified in the promoter and exonic regions of several UGT genes. The UGT1As on chromosome 2q37 have unique exons 1 but share the remainder of their coding sequence. We screened exon 1 of each of the nine functional UGT1As in Asians (n=46) and Caucasians (n=92) with the aim of determining linkage disequilibrium (LD) and haplotypes across the entire locus in both populations. For polymorphisms in UGT 1A3, 1A4, 1A5, 1A7, and 1A8, we observed significant differences in the allele frequency between the two populations. The haplotype block structure across the UGT1A locus was constructed using all 83 polymorphisms and showed four and five haplotype blocks in Caucasians and Asians, respectively. There was long-distance LD between UGT pairs: 1A8 and 1A10; 1A1 and 1A3; 1A1 and 1A6; 1A6 and 1A7; and 1A7 and 1A9. Whereas both ethnic groups shared some haplotype-tagging SNPs (htSNPs), Caucasians and Asians also had unique htSNPs. This was partly due to the fact that rare variants (<5% allele frequency) were included in our analyses. Haplotypes with frequencies >5% represented only 60% of Caucasian and 65% of Asian UGT1A haplotypes. Differences in haplotype distribution patterns suggest individual and ethnic differences in glucuronidation capacity.

Asian People↗
PubMed2006

Methylenetetrahydrofolate reductase and thymidylate synthase genotypes and risk of acute graft-versus-host disease following hematopoietic cell transplantation for chronic myelogenous leukemia.

Methylenetetrahydrofolate reductase (MTHFR) and thymidylate synthase (TS) play key roles in intracellular folate metabolism. Polymorphisms in these enzymes have been shown to modify toxicity of methotrexate (MTX) after hematopoietic cell transplantation. In this study, we evaluated the risk of acute graft-versus-host disease (GVHD) associated with genetic variation in recipient and donor MTHFR and TS genotypes to assess whether genotype alters the efficacy of MTX in acute GVHD prophylaxis. Data on the transplantation course were abstracted from medical records for 304 adults who received allogeneic hematopoietic cell transplants. MTHFR (C677T and A1298C) and TS (enhancer-region 28-base pair repeat, TSER, and 1494del6) genotypes were determined using polymerase chain reaction/restriction fragment length polymorphism and TaqMan assays. Multivariable logistic regression was used to assess the associations between genotypes and risk of acute GVHD. Compared with recipients with the wild-type MTHFR 677CC genotype, those with the variant 677T allele showed a decreased risk of detectable acute GVHD (677CT: odds ratio, 0.8; 95% confidence interval, 0.4-1.6; 677TT: odds ratio, 0.4; 95% confidence interval, 0.2-0.8; P for trend = .01). The variant MTHFR 1298C allele in recipients was associated with an increased risk of acute GVHD compared with the wild-type MTHFR 1298AA genotype (1298AC: odds ratio, 2.0; 95% confidence interval, 1.1-3.9; 1298CC: odds ratio, 3.6; 95% confidence interval, 1.0-12.7; P for trend < .01). No association with risk of acute GVHD was observed for donor MTHFR genotypes or for recipient or donor TS genotypes, with the exception of an increase in acute GVHD among recipients whose donors had the TSER 3R/2R genotype (odds ratio, 3.0; 95% confidence interval, 1.3-7.2). These findings indicate that host, but not donor, MTHFR genotypes modify the risk of acute GVHD in recipients receiving MTX, in a manner consistent with our previously reported associations between MTHFR genotypes and MTX toxicity. A direct trade-off between drug toxicity and drug efficacy may play a role. Alternatively, the systemic folate environment, regulated by host tissues, might influence donor T-cell growth and activity.

Acute Disease↗
PubMed2006

Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics.

Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) show indisputable promise as chemopreventive agents. Possible targets include cancers of the colon, stomach, breast and lung. However, recent studies raise concern about potential cardiovascular toxicity associated with the use of NSAIDs that specifically target the enzyme cyclooxygenase 2. These findings, and others that show that inherited genetic characteristics might determine preventive success, argue for new strategies that are tailored to individual medical history and genetic make-up.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

Mismatch repair polymorphisms and colorectal polyps: hMLH1-93G>A variant modifies risk associated with smoking.

BACKGROUND AND AIM: Mutations in the mismatch repair (MMR) enzymes hMLH1 and hMSH6 are known causes of hereditary nonpolyposis colorectal cancer and act by inducing a mutator phenotype characterized by microsatellite instability. The aim of our study was to determine if polymorphisms in the DNA MMR genes hMLH1 and hMSH6 are associated with an increased risk of colorectal polyps, and to evaluate interactions with exposures known to cause DNA damage. METHODS: In a Minnesota-based case-control study of individuals with adenomas (N=401), hyperplastic polyps (N=195), or both adenomas and hyperplastic polyps (N=123) versus polyp-free controls (N=624), we investigated the role of hMLH1-93G>A, hMLH1 I219V, and hMSH6 G39E polymorphisms in increasing the risk of colorectal polyps. Polytomous multivariate logistic regression analysis was used, adjusting for age, sex, body mass index, postmenopausal hormone use, aspirin use, and NSAID use. RESULTS: Overall, no evidence of an association between any of the three polymorphisms or hMLH1 haplotypes and colorectal polyps was observed. However, risk associated with the hMLH1-93A variant differed by smoking: smoking-associated risks were stronger among those with variant -93AA or -93AG genotypes, showing a twofold greater risk of adenoma with >25 pack-years of smoking compared with nonsmokers, and a corresponding eightfold greater risk of hyperplastic polyps (genotype smoking: p-interaction=0.02 for hyperplastic polyps and p-interaction=0.08 for adenomas). CONCLUSIONS: These data are consistent with the observation that smoking is associated with MMR in colorectal neoplasia and suggest that the risk increase with smoking may differ by hMLH1-93G>A genotype.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Prostacyclin synthase and arachidonate 5-lipoxygenase polymorphisms and risk of colorectal polyps.

Prostacyclin synthase (PGIS) and arachidonate 5-lipoxygenase (ALOX5) are enzymes relevant to prostaglandin and leukotriene synthesis, both important pathways for colon cancer risk. We hypothesized that genetic variation altering the function of these enzymes would modify risk of colorectal polyps. In a Minnesota-based case-control study of adenomatous (n = 517) or hyperplastic (n = 192) polyps versus polyp-free controls (n = 618), we investigated the role of promoter repeat polymorphisms in PGIS and ALOX5 as well as ALOX5 -1700 G>A. Having fewer than six repeats on both PGIS alleles (<6R/<6R) was associated with an increased risk of adenomas compared with the 6R/6R (wild-type) genotype (OR, 1.90; 95% CI, 1.09-3.30). Having more repeats (>6R/> or =6R) reduced risk (OR, 0.73; 95% CI, 0.40-1.35; P(trend) = 0.03). In allele-based analyses, fewer repeats were associated with a modestly increased risk of adenomas and perhaps hyperplastic polyps. There were no risk differences for either the ALOX5 VNTR or -1700 G>A polymorphisms. Associations with regular use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) differed by PGIS genotype. Among individuals with at least one wild-type allele, NSAID use was associated with a decreased risk; however, those with fewer PGIS repeats (<6R/<6R) did not benefit (P(interaction) = 0.06). There was also evidence of an interaction between the COX-2 -765 G>C and ALOX5 -1700 G>A genotypes (P(interaction) = 0.07). The PGIS promoter polymorphism may affect risk of colorectal polyps and modify the effects of NSAID use on polyp risk. A more comprehensive investigation of genetic variability in prostaglandin synthesis in relation to risk of colorectal neoplasia and NSAID pharmacogenetics is warranted.

Adenomatous Polyps↗
PubMed2006

Ascending the learning curve--MSI testing experience of a six-laboratory consortium.

According to recently published guidelines, microsatellite instability (MSI) testing of colorectal cancers may be clinically indicated on a significant proportion of all colorectal tumors. To date, nothing has been published regarding the reproducibility of MSI testing between laboratories. We present MSI quality control activities experience of a six center multinational consortium, as laboratories developed competency with MSI testing and interpretation. The aim of this paper is to share lessons learned and to describe the final concordance rates in scoring MSI markers within this consortium.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2005

Glucuronidation of the aspirin metabolite salicylic acid by expressed UDP-glucuronosyltransferases and human liver microsomes.

Acetylsalicylic acid (aspirin) is a common nonsteroidal anti-inflammatory drug used for treatment of pain and arthritis. In the body, acetylsalicylic acid is rapidly deacetylated to form salicylic acid. Both compounds have been proposed as anti-inflammatory agents. Major metabolites of salicylic acid are its acyl and phenolic glucuronide conjugates. Formation of these conjugates, catalyzed by UDP-glucuronosyltransferases (UGTs), decreases the amount of pharmacologically active salicylic acid present. We aimed to identify the UGTs catalyzing the glucuronidation of salicylic acid using both heterologously expressed enzymes and pooled human liver microsomes (HLMs) and to develop a liquid chromatography-tandem mass spectrometry method to quantify glucuronidation activity of UGTs 1A1, 1A3, 1A4, 1A6, 1A7, 1A8, 1A9, 1A10, 2B4, 2B7, 2B15, and 2B17 Supersomes. All UGTs tested, except 1A4, 2B15, and 2B17, catalyzed salicylic acid phenolic and acyl glucuronidation. Ratios of salicylic acid phenolic to acyl glucuronide formation varied more than 12-fold from 0.5 for UGT1A6 to 6.1 for UGT1A1. These results suggest that all UGTs except 1A4, 2B15, and 2B17 might be involved in the glucuronidation of salicylic acid in vivo. From comparisons of apparent Km values determined in pooled HLMs and in expressed UGTs, UGT2B7 was suggested as a likely catalyst of salicylic acid acyl glucuronidation, whereas multiple UGTs were suggested as catalysts of phenolic glucuronidation. The results of this UGT screening may help target future evaluation of the effects of UGT polymorphisms on response to aspirin in clinical and population-based studies.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

FDR-controlling testing procedures and sample size determination for microarrays.

Microarrays are used increasingly to identify genes that are truly differentially expressed in tissues under different conditions. Planning such studies requires establishing a sample size that will ensure adequate statistical power. For microarray analyses, false discovery rate (FDR) is considered to be an appropriate error measure. Several FDR-controlling procedures have been developed. How these procedures perform for such analyses has not been evaluated thoroughly under realistic assumptions. In order to develop a method of determining sample sizes for these procedures, it needs to be established whether these procedures really control the FDR below the pre-specified level so that the determined sample size indeed provides adequate power. To answer this question, we first conducted simulation studies. Our simulation results showed that these procedures do control the FDR at most situations but under-control the FDR when the proportion of positive genes is small, the most likely scenarios. Thus, these existing procedures can overestimate the power and underestimate the sample size. Accordingly, we developed a simulation-based method to provide more accurate estimates for power and sample size.

Algorithms↗
PubMed2005

Glucuronidation of nonsteroidal anti-inflammatory drugs: identifying the enzymes responsible in human liver microsomes.

Nonsteroidal anti-inflammatory drugs (NSAIDs), used for the treatment of pain and inflammation, are eliminated primarily through conjugation with polar sugar moieties to form glucuronides. Glucuronidation is catalyzed by the UDP-glucuronosyltransferases (UGT) superfamily. An inverse relationship may exist between glucuronidation activity and NSAID efficacy; however, specific UGTs catalyzing conjugation of the structurally diverse NSAIDs have yet to be identified systematically. Therefore, NSAID glucuronidation activity by 12 individually expressed UGTs was investigated by liquid chromatography-tandem mass spectrometry. The relative rates of NSAID glucuronidation varied among UGT enzymes examined, demonstrating specificity of the individual UGTs toward selected NSAIDs. Kinetic parameters were determined for expressed UGT Supersomes and compared with parameters determined in pooled human liver microsomes (HLMs). Comparison of K(m) values suggested roles for UGTs 1A3 and 2B7 in indene glucuronidation and UGTs 1A9, 2B4, and 2B7 in profen glucuronidation. Inhibitory studies in pooled HLMs support the role of UGTs 1A1, 1A3, 1A9, 2B4, and 2B7 in the glucuronidation of ibuprofen, flurbiprofen, and ketoprofen. Bilirubin did not inhibit indomethacin or diclofenac glucuronidation, suggesting that UGT1A1 was not involved in catalysis. Imipramine did not inhibit glucuronidation of sulindac, sulindac sulfone, indomethacin, or naproxen in pooled HLMs, suggesting that UGT1A3 was not a principal hepatic catalyst. Nevertheless, multiple UGT enzymes, most notably UGTs 1A1, 1A9, 2B4, and 2B7, seem to be involved in the hepatic catalysis of NSAID glucuronidation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Thromboxane synthase (TBXAS1) polymorphisms in African-American and Caucasian populations: evidence for selective pressure.

Thromboxane synthase (TBXAS1), a cytochrome P450 enzyme, converts prostaglandin H2 into thromboxane A2, a potent vasoconstrictor and inducer of platelet aggregation. Thromboxane A2 has been implicated in modulating cell cytotoxicity and in tumor growth and metastasis. Twelve coding-region variants were identified in the human TBXAS1 gene in 48 African-American and 46 Caucasian individuals, of which eight were amino-acid substitutions. The latter were confirmed in an independent Caucasian population (n=94 unrelated individuals). We performed an evolutionary analysis of patterns of nucleotide diversity and identified patterns of amino acid replacement in human-mouse comparisons consistent with purifying selection on an inter-species time scale using the McDonald-Kreitman test. We also observed patterns of nucleotide diversity within humans consistent with purifying selection acting on existing polymorphism using Tajima's D within coding regions. These evolutionary tests suggest that some of the rare coding variations observed in the human population are deleterious. We used two sequence-homology-based software programs and molecular modeling to predict the potential impact of these polymorphisms on TBXAS1 function. The c.772C>T (p.Lys258Glu), c.1249C>G (p.Gln417Glu), and c.1348G>A (p.Glu450Lys) substitutions are predicted as most likely to alter protein function; another, c.1352C>A (p.Thr451Asn), may also affect function. Given the evolutionary evidence, these variants may be functional and therefore of relevance for disease endpoints related to inflammation and angiogenesis, as well as for the pharmacogenetics of non-steroidal anti-inflammatory drugs.

Black or African American↗
PubMed2005

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: personal and lifestyle factors (United States).

Insulin-like growth factors (IGFs) play an important role in cell proliferation and apoptosis, and recent epidemiologic studies have suggested that circulating IGF-1 and IGF binding protein-3 (IGFBP-3) may be related to colorectal, breast, and prostate cancer risk. The purpose of this analysis was to investigate the role of various personal and lifestyle factors in the inter-individual variation of circulating IGF-1 and IGFPB-3. We measured plasma levels of IGF-1 and IGFBP-3 in a sequential sample of 333 population-based control subjects enrolled in the Seattle Colorectal Cancer Family Registry from August 1999 through December 2001, who had provided a blood sample. Total IGF-1 and IGFBP-3 were measured from plasma samples using ELISA assays. Interviewer-administered questionnaires collected data on various personal and lifestyle factors. Multivariate-adjusted linear regression was used to assess the associations between specific personal and lifestyle factors with IGF-1 and IGFBP-3 levels. Age, body mass index, and postmenopausal hormone use were statistically significantly inversely related to IGF-1 concentrations, and milk consumption was significantly positively related to IGF-1 levels. Only age was significantly related to circulating IGFBP-3. Although the sources of inter-individual variation of IGF-1 and IGFB-3 are not yet fully understood, this analysis provides some insights into factors that may contribute.

Adult↗
PubMed2005

Cruciferae interact with the UGT1A1*28 polymorphism to determine serum bilirubin levels in humans.

UDP-glucuronosyltransferase (UGT) 1A1 is a conjugating biotransformation enzyme that plays a role in maintaining levels of endogenous compounds (e.g., bilirubin) and handling exogenous compounds, including carcinogens. The UGT1A1*28 polymorphism results in decreased UGT1A1 promoter activity due to 7 thymine-adenine (TA) repeats instead of the commonly found 6 repeats. Studies indicate that foods from the botanical families Cruciferae (e.g., broccoli), Rutaceae (citrus), Liliaceae (e.g., onions), and Leguminosae (legumes) may increase UGT activity. We investigated, in an observational study, whether foods from these botanical groups were associated with increased UGT1A1 activity as indicated by serum bilirubin concentrations and whether the effect varied by UGT1A1*28 genotype, comparing those homozygous for the [TA](7)-repeat allele (7/7) to homozygous wild-types (6/6) and heterozygotes (6/7) combined. Healthy volunteers completed 3-d food records. Blood samples were drawn for genomic DNA collection and bilirubin measures. For total, direct, and indirect bilirubin measures, there was no significant association with any botanical group independently. There was a significant inverse association between all 3 bilirubin measures and interaction of UGT1A1*28 genotype with Cruciferae intake (P < 0.02 for each measure); individuals with the 7/7 genotype had reduced bilirubin concentrations with increased intake of cruciferous vegetables, whereas individuals with the 6/6 or 6/7 genotype did not. With regard to UGT1A1-conjugated carcinogens (e.g., heterocyclic amines, polycyclic aromatic hydrocarbons), individuals with decreased UGT1A1 activity due to the 7/7 genotype may be at greater risk for carcinogenesis, but our results imply that they also may have greater opportunity to decrease that risk through dietary intervention.

Adult↗
PubMed2005

PTGS2 (COX-2) -765G > C promoter variant reduces risk of colorectal adenoma among nonusers of nonsteroidal anti-inflammatory drugs.

Prostaglandin H synthase 2 (PTGS2) or cyclooxygenase-2 (COX-2) has been shown to play a key role in the regulation of inflammation, and its inhibition is associated with a reduced risk of colon cancer. The PTGS2 (COX-2) -765G > C promoter variant is located in a putative SP1 binding site and reduces PTGS2 expression. In a Minnesota-based case-control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 -765G > C promoter polymorphism. Multiple logistic regression analysis was used, adjusting for age, body mass index, caloric intake, alcohol, fiber, sex, hormone use, and smoking. For colorectal adenoma, odds ratios (OR) compared with PTGS2 -765GG as reference were GC 1.00 [95% confidence interval (95% CI), 0.74-1.35] and CC 0.53 (95% CI, 0.22-1.28). For hyperplastic polyps, the comparable adjusted odds ratios were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05-1.11). Risk associated with the -765G > C variant differed by aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use. Among nonusers of aspirin or other NSAIDs, the CC genotype conferred a significant decrease in risk of adenoma (OR, 0.26; 95% CI, 0.07-0.89). Use of aspirin or other NSAIDs reduced risk of adenoma only among those with the -765GG (wild type) and possibly -765CG genotypes (OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% CI, 0.40-1.02, respectively). These data suggest that COX-2 expression or activity may be beneficially suppressed, and risk of colorectal polyps reduced, by aspirin or other NSAIDs in PTGS2 -765GG (wild type) individuals and by the -765 CC variant genotype in nonusers of NSAIDs.

Adenoma↗
PubMed2005

Variation in plasma insulin-like growth factor-1 and insulin-like growth factor binding protein-3: genetic factors.

Insulin-like growth factors (IGFs) play key roles in cell proliferation and apoptosis. Whereas relatively stable within individuals, IGFs vary substantially between individuals, and a large component of this variation may be determined by genetic factors. Several polymorphisms in IGF genes have been identified, although their functional significance is not clear. We evaluated the association of polymorphisms in IGF-1 and IGFBP-3 and circulating levels of IGF-1 and IGFBP-3 in 323 population-based control subjects enrolled in a case-control study of colorectal cancer from September 1999 through February 2002. Total IGF-1 and IGFBP-3 levels were measured using ELISA assays, and all subjects were genotyped for a microsatellite polymorphism in IGF-1 and a single nucleotide polymorphism in IGFBP-3. Multiple linear regression was used to assess the association of genotype with circulating IGFs. IGF-1 levels were unrelated to either polymorphism. IGFBP-3 was significantly associated with IGFBP-3 genotype, with IGFBP-3 levels increasing from CC (1,895 ng/mL) --> GC (2,029 ng/mL) --> GG (2,182 ng/mL), (p-trend < 0.001). Having an IGF-1 genotype other than homozygous for the 19-repeat allele was associated with higher IGFBP-3 levels (1,945 versus 2,052 ng/mL). Furthermore, both IGF-1 and IGFBP-3 genotypes modified the relationship between postmenopausal hormone use and IGFs. This analysis provides evidence that common variation in IGF genes may contribute to the variation in circulating levels observed between individuals.

Adult↗
PubMed2005

Insulin-like growth factor polymorphisms and colorectal cancer risk.

Several modifiable lifestyle factors, such as physical activity, obesity, and postmenopausal hormone use, have been associated with colorectal cancer risk. It has been hypothesized that some or all of these factors may mediate their effects through alterations in insulin-like growth factor-1 (IGF-1) and its binding proteins (IGFBP). To evaluate the role of IGFs in colorectal cancer, we examined the relationship of two common genetic polymorphisms in IGF-1 (a cytosine-adenosine dinucleotide repeat) and IGFBP-3 (a G --> C single nucleotide polymorphism) with colorectal cancer risk, as well as their potential modification by physical activity, body mass index (BMI), and postmenopausal hormone use. Subjects included 782 male and female colorectal cancer cases diagnosed between 1998 and 2002 and reported to the statewide registry in the metropolitan Seattle area, and 503 age- and sex-matched cancer-free population controls. Colorectal cancer was modestly associated with having an IGF-1 genotype other than homozygous for 19 repeats (odds ratio, 1.3; 95% confidence interval, 1.0-1.6) and having the GG IGFBP-3 genotype (odds ratio, 1.3; 95% confidence interval, 1.0-1.8). There was evidence that IGF-1 genotype modified the relationship between BMI and colorectal cancer among women, such that high BMI increased risk of colorectal cancer only among those with the 19/19 genotype (P(interaction) = 0.02). IGFBP-3 genotype was also a significant effect modifier of the relationship between risk factors and colorectal cancer: The positive association between BMI and colorectal cancer was observed only among men (P(interaction) < 0.01) and women (P(interaction) = 0.06) with the GG genotype; the inverse association between postmenopausal hormone use and colorectal cancer was observed only among women with the GG genotype (P = 0.01) and the inverse association between physical activity and colorectal cancer was observed only among men who carried the C allele (P < 0.01). The current study provides some support for a role of IGFs in colorectal cancer etiology, particularly in mediating the relationship of common risk factors (physical activity, BMI, and postmenopausal hormone use).

Adult↗