Gene by BMI Interactions Influencing C-Reactive Protein Levels in European-Americans

C-Reactive Protein (CRP) is a biomarker indicating tissue damage, inflammation, and infection. High-sensitivity CRP (hsCRP) is an emerging biomarker often used to estimate an individual’s risk for future coronary heart disease (CHD). hsCRP levels falling below 1.00 mg/l indicate a low risk for developing CHD, levels ranging between 1.00 mg/l and 3.00 mg/l indicate an elevated risk, and levels exceeding 3.00 mg/l indicate high risk. Multiple Genome-Wide Association Studies (GWAS) have identified a number of genetic polymorphisms which influence CRP levels. SNPs implicated in such studies have been found in or near genes of interest including: CRP, APOE, APOC, IL-6, HNF1A, LEPR, and GCKR. A strong positive correlation has also been found to exist between CRP levels and BMI, a known risk factor for CHD and a state of chronic inflammation. We conducted a series of analyses designed to identify loci which interact with BMI to influence CRP levels in a subsample of European-Americans in the ARIC cohort. In a stratified GWA analysis, 15 genetic regions were identified as having significantly (p-value < 2.00*10-3) distinct effects on hsCRP levels between the two obesity strata: lean (18.50 kg/m2 < BMI < 24.99 kg/m2) and obese (BMI ≥ 30.00 kg/m2). A GWA analysis performed on all individuals combined (i.e. not a priori stratified for obesity status) with the inclusion of an additional parameter for BMI by gene interaction, identified 11 regions which interact with BMI to influence hsCRP levels. Two regions containing the genes GJA5 and GJA8 (on chromosome 1) and FBXO11 (on chromosome 2) were identified in both methods of analysis suggesting that these genes possibly interact with BMI to influence hsCRP levels. We speculate that atrial fibrillation (AF), age-related cataracts and the TGF-β pathway may be the biological processes influenced by the interaction of GJA5, GJA8 and FBXO11, respectively, with BMI to cause changes in hsCRP levels. Future studies should focus on the influence of gene x bmi interaction on AF, age-related cataracts and TGF-β.

A case-control study of hepatitis C virus and its interaction with hepatitis B virus on the development of hepatocellular carcinoma in the USA

Objective. The aim of this study was to assess the independent risk of hepatitis C virus (HCV) infection in the development of hepatocellular carcinoma (HCC). The independent risk of hepatitis B virus (HBV), its interaction with hepatitis C virus and the association with other risk factors were examined.^ Methods. A hospital-based case-control study was conducted between January 1994 and December 1995. We enrolled 115 pathologically confirmed HCC patients and 230 nonliver cancer controls, who were matched by age ($\pm$5 years), gender, and year of diagnosis. Both cases and controls were recruited from The University of Texas M. D. Anderson Cancer Center at Houston. The risk factors were collected through personal interviews and blood samples were tested for HCV and HBV markers. Univariate and multivariate analyses were performed through conditional logistic regression.^ The prevalence of anti-HCV positive is 25.2% in HCC cases compared to 3.0% in controls. The univariate analysis showed that anti-HCV, HBsAg, alcohol drinking and cigarette smoking were significantly associated with HCC, however, family history of cancer, occupational chemical exposure, and use of oral contraceptive were not. Multivariate analysis revealed a matched odds ratio (OR) of 10.1 (95% CI 3.7-27.4) for anti-HCV, and an OR of 11.9 (95% CI 2.5-57.5) for HBsAg. However, dual infection of HCV and HBV had only a thirteen times increase in the risk of HCC, OR = 13.9 (95% CI 1.3-150.6). The estimated population attributable risk percent was 23.4% for HCV, 12.6% for HBV, and 5.3% for both viruses. Ever alcohol drinkers was positively associated with HCC, especially among daily drinkers, matched OR was 5.7 (95% CI 2.1-15.6). However, there was no significant increase in the risk of HCC among smokers as compared to nonsmokers. The mean age of HCC patients was significantly younger among the HBV(+) group and among the HCV(+)/HBV(+) group, when compared to the group of HCC patients with no viral markers. The association between past histories of blood transfusion, acupuncture, tattoo and IVDU was highly significant among the HCV(+) group and the HBV(+)/HCV(+) group, as compared to HCC patients with no viral markers. Forty percent of the HCC patients were pathologically or clinically diagnosed with liver cirrhosis. Anti-HCV(+) (OR = 3.6 95% CI 1.5-8.9) and alcohol drinking (OR = 2.7 95% CI 1.1-6.7), but not HBsAg, are the major risk factors for liver cirrhosis in HCC patients.^ Conclusion. Both hepatitis B virus and hepatitis C virus were independent risk factors for HCC. There was not enough evidence to determine the interaction between both viruses. Only daily alcoholic drinkers showed increasing risk for HCC development, as compared to nondrinkers. ^

Developmental effects of estrogen and PCBs in the reproductive tract of BALB/C mice

Many of the tumorigenic effects that result from neonatal exposure to both natural and synthetic estrogens resemble those found in humans exposed to diethylstilbestrol (DES) in utero. Using this established DES neonatal mouse model, my goal was to investigate long-term molecular and morphological effects of certain polychlorinated biphenyls (PCBs) that are weakly estrogenic in adult mice. Focusing on the cervicovaginal (CV) tract, since this is where tumors develop in the BALB/c mouse, I first assessed the 17β-estradiol (E2) dose-response for expression of lactoferrin (LTF). LTF is a highly inducible estrogen biomarker that is permanently altered in uteri from neonatally treated mice. Treatments were administered via 5 subcutaneous injections beginning within 16 hrs after birth, days 1–5. ^ The ontogeny of LTF expression from mouse CV tracts was determined by examining three different stages of life: pups, immature, and mature mice. Northern RNA analysis and immunohistochemistry showed that neonatal E 2 treatment both increases and decreases LTF expression. Early expression of LTF in the CV tract at all doses occurred in pups. In both immature and adult mice, increased LTF expression was dependent on whether E2 induced ovary-dependent or ovary-independent persistent vaginal cornification. ^ Next, I studied biological responses from neonatally PCB exposed adult mice. As expected, using a neonatal uterine bioassay I showed that 2 ′4′6′-trichloro-4-biphenylol (OH-PCB-30), 2′3′4′ 5-tetrachloro-4-biphenyloI (OH-PCB-61), and OH-PCB-30/61 (50/50 mixture), were estrogenic causing a dose-dependent increase in uterine weight. ^ Long-term effects of OH-PCB 30 [200 μg/pup/day] were most similar to E2 as seen by an increased uterine wet weight in day 50 mice similar to E2 [5 μg/pup/day] (141% and 140% of control, respectively). Another similarity between OH-PCB 30 and E2 neonatally treated mice was found in those sacrificed at 20 months of age. At these same doses CV tract squamous cell carcinoma induction was 43% of E2 treated mice and 47% of OH-PCB 30 treated mice. Differences were noted in adenoaquamous; cell carcinoma development, where 16% of OH-PCB-30 neonatally treated mice developed tumors versus 8% for E2. Based on these results using the neonatal mouse model, I conclude that the OH-PCBs tested are strongly estrogenic and tumorigenic showing dose-response relationships when exposure occurs during development of the reproductive tract in mice. These results may have important implications for risk assessment in determining the effects of xenoestrogens exposure early versus later in life. ^