Single nucleotide polymorphisms of one-carbon metabolism and cancers of the esophagus, stomach, and liver in a Chinese population.

One-carbon metabolism (folate metabolism) is considered important in carcinogenesis because of its involvement in DNA synthesis and biological methylation reactions. We investigated the associations of single nucleotide polymorphisms (SNPs) in folate metabolic pathway and the risk of three GI cancers in a population-based case-control study in Taixing City, China, with 218 esophageal cancer cases, 206 stomach cancer cases, 204 liver cancer cases, and 415 healthy population controls. Study participants were interviewed with a standardized questionnaire, and blood samples were collected after the interviews. We genotyped SNPs of the MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes, using PCR-RFLP, SNPlex, or TaqMan assays. To account for multiple comparisons and reduce the chances of false reports, we employed semi-Bayes (SB) shrinkage analysis. After shrinkage and adjusting for potential confounding factors, we found positive associations between MTHFR rs1801133 and stomach cancer (any T versus C/C, SB odds-ratio [SBOR]: 1.79, 95% posterior limits: 1.18, 2.71) and liver cancer (SBOR: 1.51, 95% posterior limits: 0.98, 2.32). There was an inverse association between DNMT1 rs2228612 and esophageal cancer (any G versus A/A, SBOR: 0.60, 95% posterior limits: 0.39, 0.94). In addition, we detected potential heterogeneity across alcohol drinking status for ORs relating MTRR rs1801394 to esophageal (posterior homogeneity P = 0.005) and stomach cancer (posterior homogeneity P = 0.004), and ORs relating MTR rs1805087 to liver cancer (posterior homogeneity P = 0.021). Among non-alcohol drinkers, the variant allele (allele G) of these two SNPs was inversely associated with the risk of these cancers; while a positive association was observed among ever-alcohol drinkers. Our results suggest that genetic polymorphisms related to one-carbon metabolism may be associated with cancers of the esophagus, stomach, and liver. Heterogeneity across alcohol consumption status of the associations between MTR/MTRR polymorphisms and these cancers indicates potential interactions between alcohol drinking and one-carbon metabolic pathway

Relations of Sex Hormone Levels to Leukocyte Telomere Length in Black, Hispanic, and Asian/Pacific Islander Postmenopausal Women

Background Sex hormones may play important roles in sex-specific biological aging. We specifically examined the associations between circulating concentrations of sex hormones and leukocyte telomere length (TL). Methods We conducted a cross-sectional study of 1124 black, 444 Hispanic, and 289 Asian/Pacific Islander women in the Women's Health Initiative Observational Cohort. Concentrations of estradiol and testosterone were measured using electrochemiluminescence immunoassays. TL was measured using quantitative PCR. Results Women included in the study were 50 to 79 years of age. Levels of estradiol were not significantly associated with TL in this sample of women. The associations between total and free testosterone and TL differed by race/ethnicity (P for interaction = 0.03 for total testosterone and 0.05 for free testosterone). Total and free testosterone concentrations were not associated with TL in black and Hispanic women, whereas in Asian/Pacific Islanders, their concentrations were inversely associated with TL (P-trend = 0.003 for both). These associations appeared robust in multiple subgroup analysis and multivariable models adjusted for potential confounding factors. In Asian/Pacific Islanders, doubling of serum free testosterone concentration was associated with 202 bp shorter TL (95% CI, 51 to 353 bp), and doubling of total testosterone concentration was associated with 203 bp shorter TL (95% CI, 50 to 355 bp). Conclusions Serum concentration of estradiol was not associated with leukocyte TL in this large sample of postmenopausal women. Total and free testosterone levels were inversely associated with TL in Asian/Pacific Islander women but not in black and Hispanic women, although future studies to replicate our observations are warranted particularly to address potential ethnicity-specific relations. The significant findings of the study This study elucidates the potential roles of sex hormones in biological aging, and identified that total and free testosterone levels were inversely associated with telomere length in Asian/Pacific Islander women but not in black and Hispanic women. The study adds The findings of this study suggest that Asian/Pacific Islander women may be susceptible to the potential detrimental effects of high testosterone level on biologic aging

A Prospective Study of Leukocyte Telomere Length and Risk of Type 2 Diabetes in Postmenopausal Women

Telomere length (TL) has been implicated in the pathogenesis of age-related disorders. However, there are no prospective studies directly investigating the role of TL and relevant genes in diabetes development. In the multiethnic Women’s Health Initiative, we identified 1,675 incident diabetes case participants in 6 years of follow-up and 2,382 control participants matched by age, ethnicity, clinical center, time of blood draw, and follow-up duration. Leukocyte TL at baseline was measured using quantitative PCR, and Mendelian randomization analysis was conducted to test whether TL is causally associated with diabetes risk. After adjustment for matching and known diabetes risk factors, odds ratios per 1-kilobase increment were 1.00 (95% CI 0.90–1.11) in whites, 0.95 (0.85–1.06) in blacks, 0.96 (0.79–1.17) in Hispanics, and 0.88 (0.70–1.10) in Asians. Of the 80 single nucleotide polymorphisms (SNPs) in nine genes involved in telomere regulation, 14 SNPs were predictive of TL, but none were significantly associated with diabetes risk. Using ethnicity-specific SNPs as randomization instruments, we observed no statistically significant association between TL and diabetes risk (P = 0.52). Although leukocyte TL was weakly associated with diabetes risk, this association was not independent of known risk factors. These prospective findings indicate limited clinical utility of TL in diabetes risk stratification among postmenopausal women

Genetic Variation At 8Q24, Family History Of Cancer, And Upper Gastrointestinal Cancers In A Chinese Population

Genetic variation at 8q24 is associated with prostate, bladder, breast, colorectal, thyroid, lung, ovarian, UADT, liver and stomach cancers. However, a role for variation at 8q24 in familial clustering of upper gastrointestinal cancers has not been studied. In order to explore potential inherited susceptibility, we analyzed epidemiologic data from a population-based case-control study of upper gastrointestinal cancers from Taixing, China. The study population includes 204 liver, 206 stomach, and 218 esophageal cancer cases and 415 controls. Associations between 8q24 rs1447295, rs16901979, rs6983267 and these cancers were stratified by family history of cancer. Odds ratios and 95% confidence intervals were adjusted for potential confounders: age, sex, education, tobacco smoking, alcohol consumption, and BMI at interview. We also adjusted for hepatitis B and aflatoxin (liver cancer) and Helicobacter pylori (stomach cancer). In a dominant model, among those with a family history of cancer, rs1447295 was positively associated with liver cancer (ORadj 2.80; 95% CI 1.15–6.80). Heterogeneity was observed (Pheterogeneity=0.029) with rs6983267 and liver cancer, with positive association in the dominant model among those with a family history of cancer and positive association in the recessive model among those without a family history of cancer. When considered in a genetic risk score model, each additional 8q24 risk genotype increased the odds of liver cancer by two-fold among those with a family history of cancer (ORadj 2.00; 95% CI 1.15–3.47). These findings suggest that inherited susceptibility to liver cancer may exist in the Taixing population and that variation at 8q24 might be a genetic component of that inherited susceptibility

S: Common variations in the genes encoding C-reactive protein, tumor necrosis factor-alpha

sensitivity C-reactive protein (CRP), tumor necrosis factor (TNF-), and interleukin-6 (IL-6) have been associated with an increased risk of diabetes. METHODS: To examine the roles of genetic variation in the genes encoding CRP, TNF- , and IL-6 in the de-velopment of diabetes, we conducted a prospective case–control study nested within the Women’s Health Initiative Observational Study. We followed 82 069 postmenopausal women (50–79 years of age) with no history of diabetes for incident diabetes for a mean follow-up of 5.5 years. We identified 1584 cases and matched them with 2198 controls with respect to age, ethnicity, clinical center, time of blood draw, and length of follow-up. We genotyped 13 haplotype-tagging single-nucleotide polymorphisms (tSNPs

Common genetic variants in peroxisome proliferator-activated receptor-gamma (PPARG) and type 2 diabetes risk among Women\u27s Health Initiative postmenopausal women

CONTEXT: Peroxisome proliferator-activated receptor-gamma (PPARG) plays a pivotal role in adipogenesis and glucose homeostasis. OBJECTIVE: We investigated whether PPARG gene variants were associated with type 2 diabetes (T2D) risk in the multiethnic Women\u27s Health Initiative (WHI). RESEARCH DESIGN AND METHODS: We assessed PPARG single-nucleotide polymorphisms (SNPs) in a case-control study nested in the prospective WHI observational study (WHI-OS) (1543 T2D cases and 2170 matched controls). After identifying 24 tagSNPs, we used multivariable logistic regression models and haplotype-based analyses to estimate these tagSNP-T2D associations. Single-SNP analyses were also conducted in another study of 5642 African American and Hispanic American women in the WHI SNP Health Association Resource (WHI-SHARe). RESULTS: We found a borderline significant association between the Pro12Ala (rs1801282) variant and T2D risk in WHI-OS [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.31-0.83, P = .01, combined group, additive model; P = .04, Hispanic American] and WHI-SHARe (OR 0.25, 95% CI 0.08-0.77, P = .02, Hispanic American) participants. In promoter region, rs6809631, rs9817428, rs10510411, rs12629293, and rs12636454 were also associated with T2D risk (range ORs 0.68-0.78, 95% CIs 0.52-0.91 to 0.60-1.00, P CONCLUSIONS: The association between PPARG Pro12Ala SNP and increased T2D susceptibility was confirmed, with Pro12 as risk allele. Additional significant loci included 5 PPARG promoter variants

Plasma Folate, Vitamin B12, and Homocysteine and Cancers of the Esophagus, Stomach, and Liver in a Chinese Population

Evidence is accumulating regarding a role of micronutrients in folate metabolism in cancer risk. We investigated the associations of plasma folate, vitamin B12, and homocysteine with upper gastrointestinal (GI) cancers in a population-based case-control study in Taixing City, China. With informed consent, we recruited cases with cancers of esophagus (n = 218), stomach (n = 206), and liver (n = 204), and one common healthy control group (n = 405). A standardized epidemiologic questionnaire was used in face-to-face interviews, and blood samples were collected during interviews. We observed an inverse association between plasma folate levels and liver cancer. The adjusted odds ratio (aOR) was 0.46 [95% confidence interval (CI) = 0.24-0.88] comparing individuals in the highest quartile to those in the lowest. We found a positive association between plasma vitamin B12 levels and all three cancers. The aORs for those in the highest quartile were 2.80 (95% CI = 1.51-5.18) for esophageal cancer, 2.17 (1.21-3.89) for stomach cancer, and 9.97 (4.82-20.60) for liver cancer, comparing to those in the lowest quartile. We further observed interaction between plasma folate and vitamin B12 on these cancers. Our data indicated associations between plasma folate and vitamin B12 with upper GI cancers in Chinese population. Further research is warranted considering the debate over the necessity of food fortification

Associations between SNPs of MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes and cancers of the esophagus, stomach, and liver –the comparison between results from single SNP model¹ and joint SNPs model².

1<p>: Single SNP model: models included one SNP only; Semi-Bayes odds ratio (SBOR) adjusted for age (5-year categories and deviation from stratum mean), sex, residency (city, rural), alcohol drinking frequency, smoking pack-years, BMI, education, H. <i>pylori</i> infection (in stomach cancer analyses), HBsAg (in liver cancer analyses), and plasma AFB1 levels (in liver cancer analyses), based on the assumption that genotype did not affect any of these variables.</p>2<p>: Joint SNPs model: models included all of the 8 SNPs; SBOR adjusted for the same set of covariates. All of the SNPs combined together were under the same genetic models (genotype-specific, log-additive, dominant, or recessive).</p><p>*: One-sided semi-Bayes <i>P</i>-values; the posterior probability that the point estimate is on the wrong side of the null <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland4" target="_blank">[26]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland5" target="_blank">[27]</a>.</p>†<p>: <i>P</i>-value from Chi-Square test for trend.</p><p>Associations between SNPs of MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes and cancers of the esophagus, stomach, and liver –the comparison between results from single SNP model^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#nt107" target="_blank">1</a>} and joint SNPs model^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#nt108" target="_blank">2</a>}.</p

Associations between SNPs of MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes and cancers of the esophagus, stomach, and liver.

1<p>: Semi-Bayes odds ratio (SBOR) adjusted for age (5-year categories and deviation from stratum mean) and sex.</p>2<p>: SBOR further adjusted for residency (city, rural), alcohol drinking frequency, smoking pack-years, BMI, education, H. <i>pylori</i> infection (in stomach cancer analyses), HBsAg (in liver cancer analyses), and plasma AFB1 levels (in liver cancer analyses), based on the assumption that genotype did not affect any of these variables.</p><p>*: One-sided semi-Bayes <i>P</i>-values; the posterior probability that the point estimate is on the wrong side of the null <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland4" target="_blank">[26]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland5" target="_blank">[27]</a>.</p>†<p>: <i>P</i>-value from Chi-Square test for trend.</p><p>Associations between SNPs of MTHFR, MTR, MTRR, DNMT1, and ALDH2 genes and cancers of the esophagus, stomach, and liver.</p

Association between polygenetic risk score and cancers of the esophagus, stomach, and liver^¶.

†<p>: Semi-Bayes odds ratio (SBOR) adjusted for age (5-year categories and deviation from stratum mean), sex, residency (city, rural), alcohol drinking frequency, smoking pack-years, BMI, education, H. <i>pylori</i> infection (in stomach cancer analyses), HBsAg (in liver cancer analyses), and plasma AFB1 levels (in liver cancer analyses), based on the assumption that genotype did not affect any of these variables.</p><p>*: One-sided semi-Bayes <i>P</i>-values; the posterior probability that the point estimate is on the wrong side of the null <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland4" target="_blank">[26]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#pone.0109235-Greenland5" target="_blank">[27]</a>.</p>¶<p>: Polygenetic risk score (PRS) was calculated only among subjects with complete data on all 8 SNPs.</p><p>Association between polygenetic risk score and cancers of the esophagus, stomach, and liver^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0109235#nt113" target="_blank">¶</a>}.</p