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Biomedical subjects

Scott R Diehl

Publications and source records attributed to Scott R Diehl.

16 recordsLinked to original sources
PubMed2006

Distribution of Epstein-Barr viral load in serum of individuals from nasopharyngeal carcinoma high-risk families in Taiwan.

The utility of EBV load as a tumor marker in nasopharyngeal carcinoma (NPC) patients suggests that it might also serve as a screening test for individuals who are at high risk for developing NPC. We previously demonstrated that unaffected individuals from high-risk families had elevated anti-EBV antibody levels compared to community controls. In this study, we measured EBV load using 2 different real-time PCR assays (targeting BamH1W and polymerase gene sequences, respectively) carried out in 2 independent research labs in serum samples from 19 untreated NPC cases, 11 healthy community controls and 100 unaffected individuals from families in which 2 or more individuals were affected with NPC. EBV genomes were detectable in 68% of NPC cases by the EBV BamH1W assay and in 74% by the EBV polymerase assay (kappa = 0.64). Patients with stage III or IV disease had significantly higher EBV load compared to those with stage I or II disease (p = 0.008). EBV DNA was detected in a single community control sample by the EBV BamH1W assay and in none of the samples by the EBV polymerase assay. Only one of 100 unaffected family members tested positive by both assays. An additional 14 were positive by only one of the 2 EBV load assays used and usually in only one of the duplicate wells tested, all with very low viral loads (3-50 copies/ml). In addition, EBV load did not correlate with EBV serology results (anti-VCA, anti-DNase, anti-EBNA-1) among these unaffected family members. In conclusion, our study suggests limited clinical utility of the EBV load test, in its current configuration, to screen individuals from high-risk families. Should a more sensitive or specific molecular assay be developed that is capable of detecting and distinguishing tumor-derived EBV genomes or gene products from true negatives, it could be evaluated as a possible screening tool for asymptomatic and early-stage NPC.

Antibodies, Viral↗
PubMed2005

Correlation of susceptibility to 6-aminonicotinamide and hydrocortisone-induced cleft palate.

Our previous genome-wide Quantitative Trait Locus (QTL) mapping study using mouse A/J by C57BL/6J recombinant inbred (RI) lines suggested several chromosomal regions contain genes influencing susceptibility to phenytoin (PT)-induced cleft lip with or without cleft palate [CL(P)] and 6-aminonicotinamide (6-AN)-induced isolated cleft palate (CP). Importantly, the same chromosomal regions but different RI parental strain alleles were sometimes implicated in susceptibility to these different kinds of orofacial clefting. Here we report the susceptibility to hydrocortisone (HC)-induced CP in these RI lines. We treated pregnant females with HC and studied the incidence of CP in day 17 fetuses. RI lines showed highly correlated responses to HC and 6-AN. The A/J parental line and five RI lines showed very high levels of clefting in response to both of these teratogens. The C57BL/6J parental line and five other RI lines exhibited low incidence of CP for these teratogens. In contrast, there was no significant correlation between incidence of PT-induced CL(P) and HC-induced CP.

6-Aminonicotinamide↗
PubMed2005

Microsatellite polymorphisms in the epidermal growth factor receptor (EGFR) gene and the transforming growth factor-alpha (TGFA) gene and risk of oral cancer in Puerto Rico.

OBJECTIVES AND METHODS: Risks of oral cancer related to a CA microsatellite repeat polymorphism in intron 1 of the epidermal growth factor receptor (EGFR) gene and a TaqI polymorphism in the transforming growth factor-alpha (TGFA) gene were evaluated in a population-based case-control study consisting of 157 cases and 149 controls recruited in Puerto Rico. RESULTS: Carriers of > or = 16 CA repeats in EGFR showed a 1.9-fold increased risk for oral cancer (OR=1.9, 95% CI=1.0-3.5). Risks also tended to increase with decreasing number of alleles with > or = 16 CA repeats (P for trend=0.06). Our data suggested a non-significant reduction in risk for subjects heterozygous for the TGFA polymorphism (OR=0.6, 95% CI=0.2-1.3). CONCLUSIONS: The EGFR-associated risk appeared to be independent of tobacco and alcohol use and may be restricted primarily to subjects who consumed low amounts of fresh fruits and vegetables (OR=5.9, 95%CI: 2.3-15.2). These data implicate dietary and molecular targets for oral cancer prevention.

Adult↗
PubMed2005

Quantitative measures of aggressive periodontitis show substantial heritability and consistency with traditional diagnoses.

BACKGROUND: Aggressive periodontitis (AgP) research nearly always classifies subjects into traditional discrete categories of localized or generalized, based upon degree of attachment loss (AL) and types of affected teeth. Since AL is continuous and quantitative, however, useful information is lost. We developed quantitative measures of AgP, compared these to traditional methods, and estimated heritabilities in families. METHODS: We examined 237 healthy, 169 localized AgP, and 204 generalized AgP subjects. We used the site of maximum AL of each tooth to calculate means for each subject for different groups of teeth. We also applied principal components analysis (PCA) to condense variation among 28 teeth into three orthogonal (uncorrelated) variables. We used discriminant function analysis (DFA) to evaluate how well the quantitative measures match with traditional classifications. Quantitative trait heritabilities were estimated by variance components. RESULTS: PCA clustered first molars, incisors, and the other teeth into three groups. DFA showed that quantitative measures classified subjects consistent with traditional methods (87% to 94% agreement). Heritabilities ranged from 13.7% (P = 0.10) to 30.0% (P = 0.008) for quantitative measures, with highest values obtained for first molars. A combination of the principal component variables most heavily weighted on first molars and incisors gave the best model of disease susceptibility, with good separation of healthy versus diseased subjects, independent of disease extent or severity. CONCLUSIONS: Quantitative measures may provide improved precision and power for many kinds of periodontal research. Our finding of significant heritability supports their use in gene mapping studies of AgP susceptibility.

Acute Disease↗
PubMed2004

Epstein-Barr virus seroreactivity among unaffected individuals within high-risk nasopharyngeal carcinoma families in Taiwan.

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.

Adolescent↗
PubMed2004

Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer: a HuGE review.

Possession of the fast metabolizing alleles for alcohol dehydrogenase (ADH), ADH1B*2 and ADH1C*1, and the null allele for aldehyde dehydrogenase (ALDH), ALDH2*2, results in increased acetylaldehyde levels and is hypothesized to increase the risk of head and neck cancer. To examine this association, the authors undertook a Human Genome Epidemiology review on these three genes and a pooled analysis of published studies on ADH1C. The majority of Asians had the fast ADH1B*2 and ADH1C*1 alleles, while the majority of Caucasians had the slow ADH1B*1/1 and ADH1C*1/2 genotypes. The ALDH2*2 null allele was frequently observed among Asians, though it was rarely observed in other populations. In a pooled analysis of data from seven case-control studies with a total of 1,325 cases and 1,760 controls, an increased risk of head and neck cancer was not observed for the ADH1C*1/2 genotype (odds ratio = 1.00, 95% confidence interval: 0.81, 1.23) or the ADH1C*1/1 genotype (odds ratio = 1.14, 95% confidence interval: 0.92, 1.41). Increased relative risks of head and neck cancer were reported for the ADH1B*1/1 and ALDH2*1/2 genotypes in several studies. Recommendations for future studies include larger sample sizes and incorporation of relevant ADH and ALDH genes simultaneously, as well as other genes. These considerations suggest the potential for the organization of a consortium of investigators conducting studies in this field.

Alcohol Dehydrogenase↗
PubMed2004

Metabolic polymorphisms, smoking, and oral cancer in Puerto Rico.

Genetic polymorphisms resulting in variation in metabolism of tobacco carcinogens may influence oral cancer risk. In a population-based case-control study in Puerto Rico, genotypes of CYP1A1, GSTM1, and GSTT1 were determined by a PCR-based method for 132 oral cancer patients and 143 control subjects. Genotype-associated risks were estimated by logistic regression. The null variant of GSTM1 was associated with a marginally significant decrease in oral cancer risk [odds ratio (OR) = 0.6, 95% confidence interval (CI) = 0.3-1.0, and P for trend = 0.09]. Risks increased with increasing cigarette use among subjects with the GSTM1-present genotype (P for trend <0.0001), rising to OR = 9.5, 95% CI = 3.0-30, among the heaviest cigarette users. In contrast, among subjects with the GSTM1-null genotype, risks did not clearly increase with increasing cigarette use (P for trend <0.61; OR = 1.8, 95% CI = 0.6-5.2 among the heaviest tobacco users). The GSTT1-null variant (OR = 1.0, 95% CI = 0.5-1.9) and CYP1A1(462Val) variant (OR = 0.9, 95% CI = 0.5-1.7) were not associated with the risk. Risks rose with increasing cigarette use in a similar manner for subjects with or without the CYP1A1(462Val) variant (P for interaction = 0.3) and for subjects with or without the GSTT1-null genotype (P for interaction = 0.4). In conclusion, cigarette use significantly increased the risk of oral cancer in this population. The GSTM1-present genotype was associated with higher tobacco-associated risk for oral cancer among heavy smokers than the null genotype.

Aged↗
PubMed2003

Alcohol concentration and risk of oral cancer in Puerto Rico.

Alcohol consumption is a major risk factor for cancers of the mouth and pharynx (oral cancer), but the differential risks by beverage type are unclear. In this 1992-1995 study, the authors examined oral cancer risk in Puerto Rico, comparing alcohol intake among 286 male cases aged 21-79 years and 417 population-based male controls, frequency matched by age. Heavy consumers of liquor (>/=43 drinks per week) had strongly increased risks of oral cancer (odds ratio = 6.4, 95% confidence interval: 2.4, 16.8); beer/wine showed only modest effects. Among liquor drinkers, risks were consistently greater for those who drank straight (undiluted) liquor than for those who usually drank mixed (diluted) liquor (odds ratio = 4.0, 95% confidence interval: 2.4, 6.7). Risks associated with combined exposure to tobacco were also more pronounced when subjects drank liquor straight. The elevated risks associated with drinking homemade rum were similar to those for other types of liquor. These results suggest that alcohol concentration is a risk factor for oral cancer independent of the total quantity of alcohol consumed.

Adult↗
PubMed2003

Insulin-like growth factor II receptor gene-167 genotype increases the risk of oral squamous cell carcinoma in humans.

Our purpose was to evaluate inherited short tandem repeat polymorphisms of the insulin-like growth factor II receptor gene (IGF2R) in oral cancer risk. The 197 individuals that consented to participate in a hospital-based, case-control study were interviewed with a structured questionnaire and provided blood and saliva. DNA was extracted for genotyping using a PCR-based method. Odds ratios were calculated using multivariate logistic regression. Subjects carrying the heterozygous 167-bp IGF2R genotype had a 2.7-fold higher risk of oral cancer compared with subjects with other genotypes (odds ratio = 2.7, 95% confidence interval: 1.16-6.48), controlling for major confounders. Our results suggest that genetic variation of IGF2R may influence significantly the risk of oral cancer.

Adult↗
PubMed2003

Robustness of inference on measured covariates to misspecification of genetic random effects in family studies.

Family studies to identify disease-related genes frequently collect only families with multiple cases. It is often desirable to determine if risk factors that are known to influence disease risk in the general population also play a role in the study families. If so, these factors should be incorporated into the genetic analysis to control for confounding. Pfeiffer et al. [2001 Biometrika 88: 933-948] proposed a variance components or random effects model to account for common familial effects and for different genetic correlations among family members. After adjusting for ascertainment, they found maximum likelihood estimates of the measured exposure effects. Although it is appealing that this model accounts for genetic correlations as well as for the ascertainment of families, in order to perform an analysis one needs to specify the distribution of random genetic effects. The current work investigates the robustness of the proposed model with respect to various misspecifications of genetic random effects in simulations. When the true underlying genetic mechanism is polygenic with a small dominant component, or Mendelian with low allele frequency and penetrance, the effects of misspecification on the estimation of fixed effects in the model are negligible. The model is applied to data from a family study on nasopharyngeal carcinoma in Taiwan.

Analysis of Variance↗
PubMed2002

The role of diet and specific micronutrients in the etiology of oral carcinoma.

BACKGROUND: Carcinoma of the oral cavity is one of the most common cancers worldwide. Tobacco smoking and the consumption of alcoholic beverages are significant risk factors but to the authors' knowledge the role of nutrition is not adequately understood. The authors undertook an epidemiologic study of oral carcinoma occurring in Greece, where tobacco smoking and alcohol consumption are common but the incidence of the disease is among the lowest reported in Europe. METHODS: One hundred six patients with histologically confirmed incident oral carcinoma and an equal number of control subjects matched for age and gender were studied. Dietary information was assessed through a validated extensive food frequency questionnaire and the data were analyzed using conditional logistic regression. RESULTS: After adjustment for energy intake, tobacco smoking, and alcohol consumption, there was evidence that the consumption of cereals, fruits, dairy products, and added lipids (which in Greece are represented mostly by olive oil) was found to be associated inversely with the risk of oral carcinoma. Only with respect to meat and meat products was there adequate evidence of a positive association with the risk of oral carcinoma. Among the micronutrients studied, riboflavin, magnesium, and iron appeared to be correlated inversely with the disease. CONCLUSIONS: Fruits, cereals, dairy products, and olive oil appear to convey protection against oral carcinoma and their effects may be mediated through higher intakes of riboflavin, iron, and magnesium. The low incidence of oral carcinoma reported in Greece may be explained in part by the higher consumption of the food groups and micronutrients that appear to protect against the disease.

Adult↗
PubMed2002

Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk.

We investigated effects on oral cancer (OC) risk of an interaction between a single nucleotide polymorphism (SNP) in the alcohol dehydrogenase 3 (ADH3) gene and alcohol consumption levels using a hospital-based study of 93 cases and 99 controls conducted in Athens, Greece. This SNP affects ethanol metabolism in vitro and appeared to interact with alcohol consumption in a previous OC study. We also evaluated a SNP in CYP2E1, another gene involved in ethanol metabolism, reported to be associated with OC risk in a European population. Data on genotypes and risk factors obtained from interviews were analyzed using multivariate logistic regression, accounting for potential confounders. No overall (marginal) association was found between OC risk and ADH3 genotypes. An interaction between ADH3 genotypes and alcohol consumption levels, however, was suggested. In non-drinkers, the ADH3(1-1) genotype has higher risk than ADH3(1-2) or ADH3(2-2) genotypes, but for subjects consuming alcohol, lower risk was observed for ADH3. We fit a logistic regression model to estimate the increase in OC risk associated with each alcohol drink consumed per week. We estimated that OC risk increased by 31.5% per drink/week for the ADH3(2-2) genotype, 4.1% for the ADH3(1-2) genotype and 1.6% for the ADH3(1-1) genotype. Evidence of genotype-environment interaction was suggestive (p = 0.048, Wald chi p = 0.145, likelihood ratio). This finding is opposite to that reported for a population in Puerto Rico, where the ADH3(1-1) genotype seemed more sensitive to ethanol exposure. In Greece, genetic variation at the CYP2E1 SNP is almost entirely absent, with only 1 case and 1 control heterozygous for the variant. By contrast, in a population in France where an OC association was reported, the frequency of CYP2E1 heterozygotes was 5% in controls and 9% in OC cases. These findings illustrate the importance of replicating SNP associations both within and between different racial and ethnic groups and geographic regions.

Alcohol Dehydrogenase↗
PubMed2002

Associations of serum concentrations of IgG, IgA, IgM and interleukin-1beta with early-onset periodontitis classification and race.

BACKGROUND: The significance of serum concentrations of various antibodies and cytokines in the pathogenesis of early-onset periodontitis (EOP) is not well understood. Recent reports suggest differences between young blacks and whites in certain humoral responses, regardless of periodontal status. This study was undertaken to compare the serum concentrations of IgG, IgA, IgM, and IL-1beta in EOP subjects with that of healthy controls, and to study the effect of race on these levels. MATERIAL AND METHODS: This case-control study included 228 individuals, 19-25 years old who were selected from a larger population examined in the National Survey of Oral Health of United States Children in 1986/1987. The subjects were classified by their EOP status and they included 166 subjects with EOP and 62 healthy controls. Blood samples were used to assess the serum concentrations of IgG, IgM, IgA, IgG subclass, and IL-1beta. RESULTS: The serum concentrations of IgG, IgG subclasses, IgA, and IgM in blacks were not significantly different in the generalized, localized and incidental EOP groups as compared to the healthy controls. The serum IL-1beta concentration was slightly and uniformly lower in the EOP groups than in the control group, although not statistically significant. Blacks had significantly higher serum concentrations of total IgG, and of IgG1, IgG2 and IgG3 than whites and Hispanics. Hispanics had significantly higher serum concentrations of IgM and IgG4 than whites and blacks. Hispanics also had a significantly higher serum concentration of IL-1beta than blacks. CONCLUSIONS: Total antibody response in blacks is not associated with EOP classification. Race has a significant effect on serum antibody concentrations irrespective of disease classification, with blacks having significantly higher serum concentrations of IgG1, IgG2 and IgG3 than whites and Hispanics.

Adult↗
PubMed2002

Folate intake, serum homocysteine and methylenetetrahydrofolate reductase (MTHFR) C677T genotype are not associated with oral cancer risk in Puerto Rico.

We examined the relationships between folate and methionine intake, serum homocysteine levels (as a biomarker for folate metabolism), and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism genotype and risk of oral cancer in a population-based, case-control study in Puerto Rico. Structured questionnaires were used to collect information on demographic factors, usual adult diet, and tobacco and alcohol use. Oral epithelial cells and blood samples were collected from a subset of subjects. Analyses were conducted by logistic regression, adjusting for age, sex, lifetime smoking and lifetime alcohol intake, with the following numbers of cases/controls, respectively: dietary data (341/521); MTHFR genotype (148/149); and homocysteine (60/90). Although increased folate intake was associated with decreased oral cancer risk [adjusted odds ratio (OR) in highest vs. lowest quartile = 0.6, 95% confidence interval (CI): 0.4, 1.0, P(trend) = 0.05)], this finding was due almost entirely to folate intake from fruit (adjusted OR = 0.4, 95% CI: 0.2, 0.6; P(trend) = 0.0001), whereas other dietary folate sources showed no clear association. Methionine intake and serum homocysteine levels were not associated with oral cancer risk. Subjects with the MTHFR C677T homozygous variant (TT) genotype had a nonsignificantly lower risk, and risk patterns tended to differ by level of folate, methionine, alcohol intake and smoking, although the power to detect significant associations in subgroups of these variables was low. Risks for oral cancer are not folate specific; preventive recommendations for this disease should emphasize the importance of a healthy diet, including substantial intake of fruits.

Aged↗
PubMed2001

Mapping a gene for neuropathic pain-related behavior following peripheral neurectomy in the mouse.

Total hindpaw denervation in rodents elicits an abnormal behavior of licking, scratching and self-injury of the anesthetic limb ("autotomy"). Since the same denervation produces phantom limb pain and anesthesia dolorosa in humans, autotomy has been used as a model of human neuropathic pain. Autotomy is an inherited trait in rodents, attributable to a few genes of major effect. Here we used recombinant inbred (RI) mouse lines of the AXB-BXA RI set to map a gene for autotomy. Autotomy levels following unilateral sciatic and saphenous nerve section were scored daily for 36 days, using a standardized scale, in all 23 RI lines available for this set. We used a genetic map of 395 marker loci and a permutation-based statistical method for categorical data to assess the statistical significance of mapping results. We identified a marker on chromosome 15 with statistical support (P=0.0003) in the range considered significant for genome-wide scans in the mouse. Several genes located in this chromosomal region encode for neural functions related to neuropathic pain and may indicate targets for development of novel analgesics.

Animals↗