Big data from small animals: integrating multi-level environmental data into the Dog Aging Project.

Environmental exposures can have large impacts on health outcomes. While many resources have been dedicated to understanding how humans are influenced by the environment, few efforts have been made to study the role of built and natural environmental features on animal health. The Dog Aging Project (DAP) is a longitudinal community science study of aging in companion dogs. Using a combination of owner-reported surveys and secondary sources linked through geocoded coordinates, DAP has captured home, yard and neighbourhood variables for over 40,000 dogs. The DAP environmental data set spans four domains: the physical and built environment; chemical environment and exposures; diet and exercise; and social environment and interactions. By combining biometric data, measures of cognitive function and behaviour, and medical records, DAP is attempting to use a big-data approach to transform the understanding of how the surrounding world affects the health of companion dogs. In this paper, the authors describe the data infrastructure developed to integrate and analyse multi-level environmental data that can be used to improve the understanding of canine co-morbidity and aging.

L'impact des expositions environnementales sur la santé est parfois considérable. Si diverses ressources ont été consacrées à décrire l'influence de l'environnement sur les humains, les efforts visant à étudier l'effet des paramètres environnementaux, tant naturels qu'anthropiques, sur la santé animale sont plus rares. Le Dog Aging Project (DAP) est une étude scientifique longitudinale à base communautaire portant sur le vieillissement du chien de compagnie. À partir d'observations notifiées par les propriétaires de chiens et de sources secondaires reliées par des coordonnées de géocodage, le DAP a réuni des variables sur le foyer d'habitation, l'environnement extérieur immédiat et le voisinage de plus de 40 000 chiens. Les séries de données environnementales du DAP couvrent quatre domaines : l'environnement physique et bâti ; l'environnement chimique et les expositions ; le régime alimentaire et la dépense physique ; et les interactions et l'environnement social. En combinant les données biométriques, les mesures du fonctionnement cognitif et comportemental et les dossiers médicaux, le DAP cherche à utiliser l'approche des mégadonnées pour transformer notre perception de la manière dont le monde qui nous entoure affecte la santé des chiens de compagnie. Les auteurs décrivent l'infrastructure des données mise au point pour intégrer et analyser des données environnementales multi-niveaux, afin de mieux comprendre les phénomènes de comorbidité et de vieillissement chez le chien.

La exposición a factores ambientales puede tener muchas e importantes repercusiones en los resultados sanitarios. Si bien se han dedicado cuantiosos recursos a aprehender la influencia del entorno en las personas, poco se ha hecho para estudiar el modo en que las características del medio, tanto natural como artificial, repercuten en la salud de los animales. El proyecto sobre Envejecimiento canino [Dog Aging Project: DAP] es un estudio longitudinal de ciencia ciudadana centrado en el envejecimiento de los perros de compañía. Combinando la información de encuestas realizadas a propietarios y de fuentes secundarias y vinculando los datos a coordenadas geográficas codificadas, el DAP ha permitido reunir información de variables ligadas al hogar, el jardín y el barrio de más de 40 000 perros. El conjunto de datos ambientales del DAP cubre cuatro grandes ámbitos: medio físico y urbanizado; condiciones químicas del entorno y exposición a sustancias químicas; régimen alimentario y ejercicio; y medio e interacciones sociales. Pasando por el uso combinado de datos biométricos, historias clínicas y mediciones de la función cognitiva y el comportamiento, el DAP apunta ahora a emplear técnicas de trabajo con macrodatos para hacer evolucionar nuestras ideas sobre la influencia del mundo que nos rodea en la salud de los perros de compañía. Los autores describen la infraestructura de datos establecida para integrar y analizar datos ambientales multiestratificados que nos ayuden a conocer mejor los procesos de comorbilidad y envejecimiento en el perro.

Muscle-building supplement use and increased risk of testicular germ cell cancer in men from Connecticut and Massachusetts.

BACKGROUND: No analytic epidemiological study has examined the relationship between use of muscle-building supplements (MBSs) and testicular germ cell cancer (TGCC) risk. METHODS: We conducted a population-based case-control study including 356 TGCC cases and 513 controls from Connecticut and Massachusetts. RESULTS: The odds ratio (OR) for ever use of MBSs in relation to risk of TGCC was significantly elevated (OR=1.65, 95% confidence interval (CI): 1.11-2.46). The associations were significantly stronger among early users, men with more types of MBSs used, and longer periods of use. CONCLUSIONS: MBS use is a potentially modifiable risk factor that may be associated with TGCC.

Predictive value of bronchoscopy after infant cardiac surgery: a prospective study.

BACKGROUND AND AIMS: Airway evaluation following infant cardiac surgery often reveals evidence of tracheobronchial narrowing. We studied the association between airway narrowing and extubation failure (EF) in this population. METHODS: Prospective cohort study of infants (age ≤6 months) from March-September 2009. Flexible bronchoscopy (FB) evaluations were obtained using a standardised protocol after operative intervention. The primary endpoint was the development of extubation failure (EF; defined as the need for invasive mechanical ventilation ≤48 h after primary extubation) and several secondary endpoints. RESULTS: Fifty-three patients were evaluated at a median age of 81 [interquartile range (IQR) 13-164] days and weight of 4.2 (IQR 3.2-6.0) kg; 13 (25 %) of the patients had single ventricle palliations and two subsequently underwent heart transplantation. Significant airway narrowing was noted in 15 of 30 [50 %, 95 % confidence interval (CI) 31-69 %] patients who underwent FB; ten of the 53 patients (19 %, 95 %CI 10-32 %) subsequently developed EF. Narrowed airway calibre on bronchoscopy had a sensitivity and specificity of 50 % (95 %CI 28-71 %) and 50 % (95 %CI 28-71 %), respectively, for EF. The single greatest predictor of EF by univariate analysis was the need for preoperative ventilation [odds ratio (OR) 6.5, 95 %CI 1.3-33.2, p = 0.03]. Patients with EF had a greater likelihood of intensive care readmission (OR 4.8, 95 %CI 1.1-21, p < 0.04) during the same hospital admission. CONCLUSIONS: Airway narrowing on FB is noted frequently after infant cardiac surgery. Overall assessment and presence of narrowing on bronchoscopy had poor sensitivity and specificity for EF in our cohort. Expert assessment of tracheobronchial narrowing on FB has poor to moderate inter-rater reliability.

Pragmatic study of orlistat 60 mg on abdominal obesity.

BACKGROUND/OBJECTIVES: It is well established that combining a reduced calorie, low-fat diet with the lipase inhibitor orlistat results in significantly greater weight loss than placebo plus diet. This weight loss is accompanied by changes in adipose tissue (AT) distribution. As 60 mg orlistat is now available as an over-the-counter medication, the primary objective of this study was to determine whether 60 mg orlistat is effective as a weight loss option in a free-living community population with minimal professional input. METHODS: AT and ectopic lipid content were measured using magnetic resonance imaging and (1)H MR spectroscopy, respectively, in 27 subjects following 3 months treatment with orlistat 60 mg and a reduced calorie, low-fat diet. RESULTS: Significant reductions in intra-abdominal AT (-10.6%, P=0.023), subcutaneous (-11.7% P<0.0001) and pericardial fat (-9.8%, P=0.034) volumes and intrahepatocellular lipids (-43.3%, P=0.0003) were observed. These changes in body fat content and distribution were accompanied by improvements in plasma lipids and decreases in blood pressure and heart rate. CONCLUSION: These findings suggest that over-the-counter 60 mg orlistat, in combination with the type of advice a subject could expect to be given when obtaining 60 mg orlistat in a community setting, does indeed result in potentially clinically beneficial changes in body composition and risk factors for metabolic diseases.

Prospective association of serum androgens and sex hormone-binding globulin with subclinical cardiovascular disease in young adult women: the "Coronary Artery Risk Development in Young Adults" women's study.

CONTEXT: The role of endogenous androgens and SHBG in the development of cardiovascular disease in young adult women is unclear. OBJECTIVE: Our objective was to study the prospective association of serum androgens and SHBG with subclinical coronary and carotid disease among young to middle-aged women. DESIGN AND SETTING: This was an ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort study with 20 yr of follow-up. PARTICIPANTS: Participants included 1629 women with measurements of serum testosterone and SHBG from yr 2, 10, or 16 and subclinical disease assessment at yr 20 (ages 37-52 yr). MAIN OUTCOME MEASURES: Coronary artery calcified plaques (CAC) and carotid artery intima-media thickness (IMT) were assessed at yr 20. The IMT measure incorporated the common carotid arteries, bifurcations, and internal carotid arteries. RESULTS: SHBG (mean of yr 2, 10, and 16) was inversely associated with the presence of CAC (multivariable adjusted odds ratio for women with SHBG levels above the median = 0.59; 95% confidence interval = 0.40-0.87; P = 0.008). SHBG was also inversely associated with the highest quartile of carotid-IMT (odds ratio for women with SHBG levels in the highest quartile = 0.56; 95% confidence interval = 0.37-0.84; P for linear trend across quartiles = 0.005). No associations were observed for total or free testosterone with either CAC or IMT. CONCLUSION: SHBG levels were inversely associated with subclinical cardiovascular disease in young to middle-aged women. The extent to which low SHBG is a risk marker or has its own independent effects on atherosclerosis is yet to be determined.

Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study.

CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case-control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3'-untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population-based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk.

Left ventricular morphology influences mortality after the Norwood operation.

BACKGROUND: Within the spectrum of congenital heart disease referred to as hypoplastic left heart syndrome (HLHS), there is variation in the morphology and function of the left ventricle which could influence outcomes after stage I Norwood palliation. OBJECTIVE: To determine if left ventricular (LV) morphology is associated with outcome after stage I Norwood palliation for HLHS. METHODS: Echocardiograms were reviewed from 108 patients who had undergone Norwood palliation at our institution over the past 11 years. Total cardiac diameter, thickness of the interventricular septum (IVS), LV area and LV myocardial area were calculated. Competing risk analysis was performed for survival to a stage II operation and to determine potential predictors. RESULTS: From the Norwood operation up to stage II operation, mortality was predicted by IVS thickness, while the absence of right ventricular (RV) dysfunction was predictive of survival to stage II operation. For the complete pathway, from Norwood to the Fontan operation, mortality was predicted by IVS, a lower RV fractional area change and the presence of significant tricuspid regurgitation. Cardiac transplantation during this period was predicted by a lower RV fractional area change (p = 0.02) and a larger LV area in diastole. CONCLUSIONS: These results indicate that LV hypertrophy and decreased RV function adversely effect survival after the Norwood operation. They suggest that LV morphology, especially septal hypertrophy, can influence outcomes in HLHS and should be considered when evaluating treatment options.

Cholesteryl ester transfer protein (CETP) genetic variation and early onset of non-fatal myocardial infarction.

Although Cholesteryl Ester Transfer Protein (CETP) mediates the transfer of cholesteryl esters and triglycerides between lipoprotein particles and thus plays a crucial role in reverse cholesterol transport, the association of variations in the CETP gene with acute myocardial infarction (MI) remains unclear. In this study we examined whether common genetic variation in the CETP gene is related to early-onset non-fatal MI risk in a population-based case-control study from western Washington State. Genotyping for the CETP -2708 G/A, -971 A/G, -629 A/C, Intron-I TaqI G/A and exon-14 A/G (I405V) SNPs was performed in 578 cases with first acute non-fatal MI and in 666 demographically similar controls, free of clinical cardiovascular disease, identified randomly from the community. In-person interviews and non-fasting blood specimens provided data on coronary heart disease risk factors. In men, there was little evidence for an association between single SNPs and MI risk, but in women the age- and race-adjusted OR was found to be significant in 4 out of the 5 CETP single variants. Haplotype analysis revealed two haplotypes associated with MI risk among men. As compared to men homozygous for the most common haplotype D (-2708 G, -971 G, -629 C, TaqI G and exon-14 A), the fully-adjusted multiplicative model identified haplotype G (-2708 G, -971 A, -629 A, TaqI G and exon-14 G) was associated with a 4.0-6.0-fold increased risk of MI for each additional copy; [95%CI 2.4-14.8] and haplotype B (-2708 G, -971 G, -629 A, TaqI A and exon-14 A) showed a significant decreased risk for early onset MI [OR = 0.18; 95%CI 0.04 - 0.75]. An evolutionary-based haplotype analysis indicated that the two haplotypes associated with the MI risk are most evolutionarily divergent from the other haplotypes. Variation at the CETP gene locus is associated with the risk of early-onset non-fatal MI. This association was found to be independent of HDL-C levels. These data and the sex-specific findings require confirmation in other populations.

Micro magnetic resonance angiography of the finger in systemic sclerosis.

OBJECTIVE: To characterize vascular lesions in SSc disease with high-resolution magnetic resonance angiography (Micro-MRA) of the finger. METHODS: Eight SSc subjects and eight age- and sex-matched healthy controls were recruited for this study. Among the SSc subjects, the mean +/- s.d. age was 54.5 +/- 4.9 yrs, and the mean +/- s.d. duration of disease was 8.3 +/- 8.4 yrs. The numbers of SSc subjects that had telangiectasia, calcinosis and impaired finger flexion were 3, 2 and 3, respectively. The 2D time-of-flight micro-MRA was performed on a 3T clinical MRI scanner using a custom-designed finger coil with an in-plane resolution of 0.16 x 0.21 mm(2) and slice thickness of 1.2 mm. The data for the proper palmar digital artery lumen area, the number of visible dorsal digital veins and a semi-quantitative vascular score, which evaluates the overall integrity of digital vessels, were independently evaluated by two experienced reviewers who were blinded to the status of the subject. RESULTS: Micro-MRA detected significant differences in the digital vasculature between SSc subjects and healthy volunteers. The SSc subjects had a significantly decreased digital artery lumen area (0.13 +/- 0.06 vs 0.53 +/- 0.26 mm(2), P < 0.001), a reduced number of digital veins (0.63 +/- 1.06 vs 3.13 +/- 0.99, P = 0.001) and a lowered overall vascular score (1.75 +/- 1.04 vs 3.5 +/- 0.53, P = 0.001). The study also found that both the digital artery lumen area (Pearson's; r = -0.72, P = 0.044) and vascular scores (Spearman's; rho = -0.75, P = 0.047) of the SSc subjects were inversely correlated with the duration of the disease. CONCLUSIONS: Micro-MRA can be used to identify and quantitatively characterize the vascular disease in SSc fingers. The parameters derived from micro-MRA could potentially be used as prospective biomarkers for clinical evaluation.

Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults. OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals. PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications. RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low. CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

Coagulation factor VII gene haplotypes, obesity-related traits, and cardiovascular risk in young women.

BACKGROUND: Associations between common F7 haplotypes, plasma factor VII (FVII) levels, and cardiovascular risk have recently been reported in population studies involving predominantly European men. METHODS: We assessed associations between F7 haplotypes and cardiovascular risk in two US population-based studies: a case-control study of these alleles related to a decreased risk of arterial thrombotic outcomes such as myocardial infarction (MI) in young-to-middle-aged women (n = 671), and a cohort study of cardiovascular disease risk factors in young women (n = 1040). RESULTS: The high-expression F7 haplotype B (containing the promoter variant allele -402A) was associated with an increased FVII level among controls, but not with MI risk. Women carrying a> or =1 copy of the low FVII expression level haplotype C (containing the -401T/-323del/-122C and Gln353 alleles) had decreased FVII levels and decreased risk of MI (odds ratio 0.54, 95% CI 0.31-0.93) compared with women homozygous for the most common haplotype A. Haplotype C was also associated with a decreased body mass index (BMI) and an increased high-density lipoprotein (HDL) cholesterol level, but not with MI risk after adjustment for these metabolic risk factors. In a cohort study composed of young US women, individuals homozygous for haplotype C had a lower BMI and lower systolic blood pressure, but the association between the F7 haplotype and HDL cholesterol was not confirmed. CONCLUSION: Common FVII haplotypes may contribute to the risk of MI in women, but the mechanisms appear complex. The association between F7 haplotypes and MI susceptibility may be mediated in part through an influence on atherogenic risk factors such as BMI.

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Facilitators and barriers to cervical cancer screening among Chinese Canadian women.

BACKGROUND: Chinese Canadian women have higher cervical cancer incidence, and lower Pap testing, rates than the general Canadian population. Predisposing, enabling and reinforcing factors associated with ever having a Pap test, and having a recent Pap test within the last 2 years, were assessed in Chinese women in British Columbia using the PRECEDE-PROCEED model. METHOD: Chinese women (n=512) between the ages of 20 and 79 years and residing in Greater Vancouver were interviewed about Pap testing, health care, traditional health beliefs, acculturation and sociodemographic characteristics. Two analyses were done, comparing women who had ever and never had a Pap test, and comparing women who had and had not received a recent Pap test. Focus groups and qualitative interviews ensured cultural sensitivity in the survey questionnaire. RESULTS: Seventy-six percent reported ever having a Pap test and 57% reported having a Pap test within the last 2 years. Traditional health beliefs were not associated with ever or recent Pap testing. However, belief that Pap testing prevented cancer and general knowledge about the Pap test were associated with screening. Concern about pain/discomfort with the test, availability of time, culturally sensitive health care services and recommendation for Pap testing by a physician were also associated with screening. Factors differed for ever, and recently, having a Pap test. INTERPRETATION: Pap testing is less common among Chinese Canadian women. Continuing education about Pap testing is recommended for physicians serving underscreened Chinese women. Culturally and linguistically appropriate educational materials are needed for the Chinese community.

RNA amplification, fidelity and reproducibility of expression profiling.

We quantitatively address the effect of T7 RNA amplification on expression profiling data, and answer the following questions: (1) What fraction of genes sampled is amplified non-linearly? (2) What is the effect of RNA amplification on comparative expression measurements? (3) If there is amplification bias, is the bias dependent on the degree of amplification or the amount of starting material and (4) Does amplification increase the overall variability of the results? We show that while there is significant amplification bias, the bias is consistent and generally has little effect on array comparisons between amplified samples.

Serologic evidence of herpes simplex virus 1 infection and oropharyngeal cancer risk.

In vitro and animal models suggest that the herpes simplex virus 1 (HSV1) may contribute to the development of oropharyngeal squamous cell carcinoma (OSCC). To determine whether the risk of OSCC is related to infection with HSV1 in humans, we recruited 260 patients from 18 to 65 years old who were newly diagnosed with OSCC between 1990-1995 while residing in three western Washington State counties. For comparison, we recruited at random 445 controls frequency matched to cases on age and sex. Participants completed in-person interviews and provided serum samples that were tested for antibody response to HSV1. After adjusting for sex, cigarette smoking, alcohol consumption, age, and income, HSV1 antibody positivity was associated with a slightly increased risk of OSCC [adjusted odds ratio (OR), 1.3; 95% confidence interval (CI), 0.9-2.0]. The adjusted association between HSV1 antibody positivity and OSCC risk among those who were current cigarette smokers (OR, 4.2; CI, 2.4-7.1) was stronger than would be predicted based on the additive combination of smoking alone (OR, 2.3; CI, 1.2-4.2) and HSV1 seropositivity alone (OR, 1.0; CI, 0.6-1.7). There was suggestive evidence that the association between HSV1 infection and OSCC was similarly modified by evidence of HPV infection but no evidence of effect modification with alcohol consumption. This population-based study suggests that HSV1 may enhance the development of OSCC in individuals who are already at increased risk of the disease because of cigarette smoking or HPV infection.

N-Acetyltransferase 2 polymorphisms, cigarette smoking and alcohol consumption, and oral squamous cell cancer risk.

The risk of squamous cell cancers of the oral cavity (OSCC) is strongly related to the use of tobacco and alcohol. N-Acetyl transferases 1 and 2 (NAT2) metabolize aryl- and heterocyclic amines that are present in tobacco smoke. NAT2 slow acetylator phenotype or genotype is related to reduced ability to detoxify these xenobiotics that are carcinogenic in tissues in which smoking-related cancers develop (e.g. bladder). We studied the association between the deduced NAT2 acetylator phenotypes and OSCC risk in a population-based study of 341 cases and 552 controls. In-person interviews provided information on tobacco use and alcohol consumption. Nucleotide substitutions at position 191, 341, 590, 803 and 857 were determined by a combination of oligonucleotide ligation assays and PCR/RFLP assays. There was no overall association between acetylator status with OSCC risk; the odds ratios for slow and intermediate acetylators, as compared with the rapid acetylators, were 1.2 (95% CI 0.7-2.2) and 1.1 (95% CI 0.6-2.0), respectively. The percent increase in risk of OSCC per pack-year cigarette smoking was similar among slow acetylators (3.0%, 95% CI 2.1-4.0) and the combined intermediate and rapid acetylators (3.5%, 95% CI 2.4-5.0). In contrast, the risk of OSCC per weekly alcoholic drink was stronger among the combined rapid and intermediate acetylators (3.3%, 95% CI 1.8-4.9) compared with slow acetylators (1.6%, 95% CI 0.6-2.7) (interaction P = 0.055). These data raise the possibility that NAT2 may be involved in the activation of one or more pro-carcinogens associated with alcohol consumption.

Oral squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3 genotypes.

Heavy alcohol consumption, particularly in combination with cigarette smoking, increases the risk of oral squamous cell carcinoma (OSCC). Alcohol dehydrogenase 3 (ADH3) converts ethanol to acetaldehyde, which is a suspected oral carcinogen. The ADH3*1 allele is associated with increased conversion of ethanol to acetaldehyde, but whether the risk of OSCC is increased among ADH3*1 carriers, or whether the risk of OSCC attributable to alcohol consumption is modified by ADH3 genotype is unclear from previous studies. We examined the association between ADH3 genotypes, alcohol consumption, and OSCC risk in a population-based study of 333 cases and 541 controls from the state of Washington. The distribution of ADH3 genotypes was similar among cases and controls: ADH3*1/*1: 32.7% cases, 36.5% controls; ADH3*1/*2: 49.0% cases, 43.1% controls: ADH3*2/*2: 18.3% cases, 20.3% controls. The age-, sex-, and race-adjusted odds ratios (OR), relative to ADH3*2/*2 carriers, were as follows: ADH*1/*1: OR, 1.0 [95% confidence interval (CI) = 0.7, 1.5]; and ADH3*1/*2: OR, 1.3 (95% CI = 1.0, 1.8). We modeled the risk of OSCC associated with alcohol consumption as modified by ADH3 genotype adjusting for age, sex, race, and cigarette smoking. Among ADH3*2 homozygotes, the risk of OSCC increased 5.3% (2.1-8.5%) with each additional alcoholic drink/week, compared with 2.5% (1.5-2.6%) and 1.2% (0.0-2.4%) among persons carrying the ADH3*1/*2 and ADH3*1/*1 genotypes, respectively. These data suggest that the ADH3*2 allele confers increased susceptibility to the effect of alcohol on OSCC risk in our population.

Polymorphisms of coagulation factor XIII subunit A and risk of nonfatal hemorrhagic stroke in young white women.

BACKGROUND AND PURPOSE: Although family studies have suggested a genetic influence on hemorrhagic stroke, the underlying genetic risk factors remain poorly defined. Coagulation factor XIII, which is involved in hemostasis, fibrinolysis, vascular remodeling, and tissue repair, represents a candidate gene for hemorrhagic stroke. We assessed the potential role of 3 factor XIII subunit A coding-sequence polymorphisms, along with a promoter polymorphism of plasminogen activator inhibitor-1 (PAI-1, which is also involved in fibrin stabilization and vascular remodeling), in young white women with hemorrhagic stroke. METHODS: Genotype analysis for factor XIII subunit A Val34Leu, Tyr204Phe, and Pro564Leu and for PAI-1 -675 4G/5G was performed in a population-based case-control study of 42 white women aged <45 years with nonfatal hemorrhagic stroke and 345 demographically similar control subjects. RESULTS: Compared with the respective homozygous wild-type genotypes, the Tyr204/Phe204 genotypes (age-adjusted odds ratio [OR] 2.9, 95% 95% CI 1.1 to 7.5) and the Leu564/Leu564 genotype (OR 4.3, 95% CI 1.4 to 13.7) were each associated with an increased risk of nonfatal hemorrhagic stroke. The risk estimate associated with the Phe204 variant was highest in women with subarachnoid hemorrhage and in nonsmokers, whereas the risk estimate of the Leu564/Leu564 genotype was highest in women with intracerebral hemorrhage and in smokers. Women who carried either the Phe204 allele or the Leu564/Leu564 genotype in combination with the PAI-1 5G/5G genotype had a nearly 20-fold increased risk of hemorrhagic stroke (OR 18.9, 95% CI 3.8 to 95.1). CONCLUSIONS: Our findings suggest that the Phe204 and Leu564 variants of coagulation factor XIII may be markers for genetic susceptibility to hemorrhagic stroke in women aged <45 years.