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Acquisition and natural history of human papillomavirus type 16 variant infection among a cohort of female university students.

Analogous to the epidemiology of different types of human papillomaviruses (HPVs), variants of a single type such as HPV16 may differ in the natural course of infection. A prospective study was conducted in a cohort of female university students who did not have HPV16 DNA or antibody at enrollment. Subjects were followed every 4 months with Pap smear and colposcopic examinations and tests for HPV DNA and antibody. Of 528 women, 62 acquired HPV16 infection during follow-up. The 5-year cumulative incidence was 12.6% for infection with HPV16 prototype-like variants and 3.1% for infection with non-prototype-like (NPL) variants. Among those with incident HPV16 infection, the adjusted odds ratio of detecting NPL variants was 6.0 [95% confidence interval (CI), 1.3-27.5)] for nonwhite women or white women who had had nonwhite sex partners compared with white women who had not had nonwhite sex partners. As compared with women who had not used hormonal contraceptives in the 8 months prior to the first HPV16-positive detection, the adjusted odds ratio of detecting NPL variants increased from 1.6 (95% CI, 0.3-9.1) for those who had used hormonal contraceptives for 1-4 months to 5.4 (95% CI, 1.0-28.3) for those who had used hormonal contraceptives for 5-8 months (P for trend = 0.04). There was no difference in HPV16 seroconversion rates between women with prototype-like variants and women with NPL variants. The increased risk for biopsy-confirmed cervical intraepithelial neoplasia grades 2 or 3 associated with detection of incident infection by NPL variants was not explained by differences in persistence between the two variant groups, indicating that biological mechanisms other than viral persistence may be responsible for the observed difference in risk for cervical intraepithelial neoplasia grades 2 or 3.

Adolescent↗

Variant angina is not associated with angiotensin I converting enzyme gene polymorphism but rather with smoking.

BACKGROUND: Angiotensin converting enzyme (ACE) perhaps plays roles in regulating coronary vasomotor tone by producing angiotensin II and degrading bradykinin. OBJECTIVES: We sought to investigate the role of ACE gene polymorphism in the pathogenesis of variant angina and to compare it with that of other clinical risk factors for male patients with variant angina and age-matched and sex-matched control subjects. METHODS: We studied 78 male patients with variant angina who exhibited spontaneous or provoked coronary spasms during coronary angiography and compared prevalences of ACE gene genotype (deletion D and insertion I) and other risk factors between this group of patients with variant angina and age-matched and sex-matched control subjects whose angiograms were normal and in whom the ergonovine test did not cause spasms (n = 80). RESULTS: Smokers were more prevalent in the group of patients with variant angina (P < 0.05). Genotype and allele prevalences of the group of patients with variant angina (0.14, 0.53 and 0.33 for DD, DI and II and 0.41 and 0.59 for D and I, respectively) were no different from those of the control group (0.16, 0.49 and 0.35 for DD, DI and II and 0.40 and 0.60 for D and I). Multiple logistic regression analysis showed that smoking was a significant risk factor for variant angina (odds ratio 2.61, 95% confidence interval 1.03-6.66) whereas ACE genotype was not. CONCLUSIONS: Variant angina is associated with an environmental factor, such as smoking, rather than a genetic factor, such as ACE gene polymorphism.

Aged↗

Risk of anal carcinoma in situ in relation to human papillomavirus type 16 variants.

Infection with human papillomavirus (HPV), especially HPV16, is central to the development of squamous anogenital cancers and their precursor lesions, termed "squamous intraepithelial neoplasias." Men who have sex with men, particularly those who are infected with HIV, are at a high risk for anal infection with HPV16 and for low-grade anal neoplasia; however, only a subset of these men develop anal invasive cancer or its immediate precursor lesion, anal carcinoma in situ (CIS). To examine the hypothesis that certain variants of HPV16 are most strongly associated with development of anal CIS, we followed 589 men who have sex with men whose initial anal cytological smears did not show anal CIS. Anoscopy, anal cytology, and PCR-based assays for detection and classification of HPV types were performed every 4-6 months, with HPV16 further classified by single-stranded conformation polymorphism analysis as being a prototype-like (PL) or non-prototype-like (NPL) variant. Anal CIS was histologically confirmed in 6 of 384 (1.6%) consistently HPV16-negative men, in 12 of 183 (6.6%) men with HPV16 PL variants, and in 4 of 22 (18.2%) men with HPV16 NPL variants. After adjustment for anal cytological diagnoses at study entry, HIV status and CD4 count, and detection of HPV types other than type 16, men with HPV16 NPL variants were 3.2 times (95% confidence interval, 1.0-10.3) more likely to develop anal CIS than were those with PL variants. Neither detection of HPV16 DNA at high levels nor detection of HPV16 DNA for a prolonged period, factors that we previously demonstrated to be associated with risk of high-grade anal squamous intraepithelial neoplasia, was significantly associated with HPV16 NPL variants. The biological mechanism relating to Ihis excess risk remains undetermined.

Anus Neoplasms↗

Studies of the variability of the genes encoding the insulin-like growth factor I receptor and its ligand in relation to type 2 diabetes mellitus.

Insulin-like growth factor I (IGF-I) is an important regulator of many aspects of growth, differentiation, and development, and as low birth weight has been associated with impaired glucose tolerance and overt type 2 diabetes in adult life, we considered the genes encoding the IGF-I and the IGF-I receptor (IGF-IR) as candidates for low birth weight, insulin resistance, and type 2 diabetes. Here we report the mutational analysis of the coding regions of the IGF-I and IGF-IR performed on genomic DNA from probands of 82 Danish type 2 diabetic families. No mutations predicting changes in the amino acid sequences of the IGF-I or IGF-IR genes were detected, but several silent and intronic polymorphisms were found. The impact of the most prevalent polymorphism, GAG1013GAA of the IGF-IR, was evaluated in a population-based sample of 349 young healthy subjects, where the variant had an allele frequency of 0.44 (95% confidence interval, 0.40-0.48). No significant relationships between this variant and birth weight, birth length, or insulin sensitivity index were detected. In addition, we did not observe any significant differences in allelic frequencies of the codon 1013 variant between 395 type 2 diabetic patients (allele frequency, 0.52; 95% confidence interval, 0.49-0.55) and 238 matched glucose-tolerant control subjects (allelic frequency, 0.47; 95% confidence interval, 0.43-0.50). In conclusion, variability in the coding regions of IGF-I and the IGF-IR does not associate with reduced birth weight, insulin sensitivity index, or type 2 diabetes in the Danish population.

Adult↗

Avoidance as a predictor of the biological course of HIV infection over a 7-year period in gay men.

The present study prospectively investigated the relation between avoidance coping and active cognitive and behavioral coping and the progression of HIV infection over 7 years in 181 gay men. Findings revealed that for a number of medical and behavioral factors, (a) avoidance coping predicted a lower rate of decline in CD4 cells, (b) the proportional hazard (PH) attributable to avoidance of developing a syncytium-inducing HIV variant was 0.72 (95% confidence interval [CI]: 0.53 - 0.99, p < .05), and (c) the PH attributable to avoidance of dropping below 200 CD4 cells/microl was 0.66 (95% CI: 0.50 - 0.89, p < .01). Avoidance coping was not related to the development of AIDS-defining clinical symptoms. Active cognitive and behavioral coping was not related to the outcome measures.

Adaptation, Psychological↗

Role of estradiol metabolism and CYP1A1 polymorphisms in breast cancer risk.

The endogenous metabolism of estrogens is primarily oxidative and involves hydroxylation of the steroid at either C2 (2-OHE1) or C16 (16-OHE1). While the 2-OHE1 metabolites are essentially devoid of peripheral biological activity, 16-OHE1 is an estrogen agonist. There is evidence of an association between the 2-OHE1/16-OHE1 metabolites ratio and breast cancer risk. The CYP1A1 gene may play a role in the 2-hydroxylation (2-OH) of estradiol. African-American women with the wild-type CYP1A1 gene showed a significant increase in the 2-OHE1/16-OHE1 ratio, from 1.35 +/- 0.56 at baseline to 2.39 +/- 0.98 (p = 0.006) after 5 days of treatment with indole-3-carbinol (400 mg/day), a 2-OHE1 inducer. Women with the Msp1 polymorphism showed no significant increase, (0.37% +/- 0.17%). In a case-control study involving 57 women with breast cancer and 312 female controls, the frequency of the homozygous Msp1 polymorphism was 4.2% in African-American controls and 16% in African-American breast cancer cases. The odds ratio of breast cancer with the Msp1 homozygous variant was 8.4 (95% confidence interval: 1.7-41.7). This association was not observed in Caucasian women. The other CYP1A1 polymorphisms were not associated with breast cancer. The CYP1A1 Msp1 polymorphism may be a marker of altered estradiol metabolism and of increased susceptibility to estrogen-related breast cancer in African-Americans.

Adult↗

Polymorphisms and haplotypes of serine hydroxymethyltransferase and risk of squamous cell carcinoma of the head and neck: a case-control analysis.

Low dietary intake of fruits and vegetables, particularly folate deficiency, has been associated with the risk of squamous cell carcinoma of the head and neck (SCCHN). We hypothesized that polymorphisms of the cytosolic serine hydroxymethyltransferase (SHMT1) gene involved in folate-dependent, one-carbon metabolism are associated with SCCHN risk. In a hospital-based, case-control study of 721 non-Hispanic white SCCHN patients and 1,234 control subjects, frequency-matched by age and sex, three known SHMT1 polymorphisms (34761C>T, 34840C>G and 34859C>T) were genotyped. It was found that none of these three polymorphisms alone had a significant main effect on the risk of SCCHN. However, when the three polymorphisms were evaluated together by the number of the variant (risk) haplotype alleles (i.e. 34761 T, 34840G or 34859 T), the risk of SCCHN was significantly increased in a dose-response manner as the number of variant haplotype alleles increased compared to those with zero variant alleles [adjusted odd ratio (OR)=1.39, 95% confidence interval (CI)=1.14-1.70 for 1-3 variant alleles and OR=1.46, 95% CI=1.09-1.97 for 4-6 variant alleles; Ptrend=0.001]. In stratification analysis, this significant association was confined to younger men (<or=64 years), ever smokers, ever drinkers and patients whose primary tumor site was in the pharynx or larynx. In conclusion, these three SHMT1 polymorphisms may play a joint role in the etiology of SCCHN in a non-Hispanic white population.

Aged↗

Evidence for association of OCTN genes and IBD5 with ulcerative colitis.

BACKGROUND AND AIMS: Genetic association between Crohn's disease (CD) and OCTN1 (SLC22A4) C1672T/OCTN2 (SLC22A5) G-207C variants in IBD5 has recently been reported. These genes encode solute carriers and the association was suggested to be distinct from the background IBD5 risk haplotype. There have been conflicting reports of the association between markers in the IBD5 region and ulcerative colitis (UC) and interaction (epistasis) between this locus and CARD15. Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci. METHODS: A total of 1104 unrelated Caucasian subjects with inflammatory bowel disease (IBD) (496 CD, 512 UC, 96 indeterminate) and 750 ethnically matched controls were genotyped for three single nucleotide polymorphisms (SNPs) in the CD associated genes (OCTN1+1672, OCTN2-207, and IGR2230), and two flanking IBD5 tagging SNPs, IGR2096 and IGR3096. Data were analysed by logistic regression methods within STATA. RESULTS: OCTN variants were as strongly associated with UC and IBD overall as they were with CD (p = 0.0001; OR 1.3 (95% confidence interval 1.1-1.5)). OCTN variants were in tight linkage disequilibrium with the extended IBD5 risk haplotype D' 0.79 and 0.88, and r2 = 0.62 and 0.72 for IGR2096 and 3096, respectively. There was no deviation from a multiplicative model of interaction between CARD15 and IBD5 on the penetrance scale. CONCLUSIONS: The OCTN variants were associated with susceptibility to IBD overall. The effect was equally strong in UC and CD. Although OCTN variants may account for the increased risk of IBD associated with IBD5, a role for other candidate genes within this extended haplotype was not excluded. There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD.

Adult↗

Induced sputum inflammatory mediator concentrations in chronic cough.

Previous studies have shown evidence of airway inflammation in patients with chronic cough and have suggested that the cough may be due to release of tussive mediators and activation of afferent sensory nerve endings. We measured the concentration of various proinflammatory and tussive mediators in induced sputum supernatants from 20 patients with cough variant asthma or eosinophilic bronchitis, 20 patients with nonasthmatic chronic cough, 22 patients with idiopathic chronic cough, and 18 healthy control subjects. We measured histamine, cysteinyl-leukotrienes, prostanoids (prostaglandin D2 and prostaglandin E2), and interleukin-8 by enzyme immunoassay. The median sputum histamine concentrations were significantly higher in patients with idiopathic chronic cough (8.0 ng/ml) and cough variant asthma/eosinophilic bronchitis (10.2 ng/ml) than in normal subjects (2.6 ng/ml; 95% confidence interval of difference from idiopathic chronic cough, 0.8 to 25.8 [p = 0.009] and 95% confidence interval of difference from cough variant asthma/eosinophilic bronchitis, 1.1 to 20.1 [p = 0.01]). Median sputum prostaglandin D2 and prostaglandin E2 concentrations were significantly higher in all categories of chronic cough. Our findings support the view that there is release of inflammatory and tussive mediators in patients with chronic cough and suggest that there might be similarities in the mechanism of cough in a diverse range of conditions.

Adult↗

Branching plasticity and candidate gene-hormone networks associated with shade responses in soybean under relay strip intercropping.

BACKGROUND: Branching is a key determinant of high-yield plant architecture in soybean, particularly in maize- soybean relay strip intercropping where plants experience an "initially shaded-then fully illuminated" light regime. However, the genetic regulation of branching responses to shading remains poorly understood. METHODS: We evaluated 11 branching-related traits across 202 soybean accessions grown under monoculture (SS) and relay strip intercropping (RI). Branch number (BN), branching incidence (BI), and total branch length (TBL) were assessed together with stress tolerance indices (STI) and relative distance plasticity index (RDPI). Genome-wide association studies (GWAS) using mixed linear model (MLM) and three-variance-component MLM (3VmrMLM) were combined with haplotype and protein structural analyses to refine candidate genes. RESULTS: Based on Pearson correlation analysis of all 11 traits, BN, BI, and TBL measured before maize harvest showed the strongest and most consistent associations with branch seed weight within the corresponding cropping system (BSW_SS under SS and BSW_RI under RI), whereas other traits showed weaker or environment-dependent associations. Higher STI values calculated from these traits during the co-growth phase were negatively associated with BSW_RI, suggesting weaker compensatory recovery after light restoration in genotypes with more stable early branching patterns between SS and RI. In contrast, mediation analysis indicated that RDPI was positively associated with BSW_RI mainly through improved mature branching architecture (MB_index), which accounted for approximately 70% of the total positive effect. GWAS identified 57 and 74 significant QTNs using MLM and 3VmrMLM, respectively, and LD-window genes were filtered for exonic nonsynonymous or premature stop-codon variants, yielding 883 genes with putative functional variants. Two high-confidence genes emerged: Glyma.02G058600 (PP2C55), exhibiting shading-specific haplotype effects likely linked to GA-mediated branch-stem balance, and Glyma.02G059900 (DA1-related protein), showing stable effects across environments and implicated in ABA-mediated suppression of axillary meristems. CONCLUSIONS: These results provide insight into the genetic and physiological basis of soybean branching responses under relay strip intercropping, clarify that branching plasticity and relative shade tolerance represent distinct response dimensions in this system, and identify putative loci that may be useful for breeding soybean cultivars with improved shade adaptation and yield stability.

Glycine max↗

A CYP1A1 restriction fragment length polymorphism is associated with breast cancer in African-American women.

We examined the role of CYP1A1 polymorphisms as potential molecular markers of breast cancer susceptibility in Caucasian and African-American women. The case-control study involved 51 women with breast cancer and 269 female controls. In African-Americans, the frequency of the homozygous MspI polymorphism was 3.5% in controls and 19% in breast cancer cases. The odds ratio of breast cancer with the MspI homozygous variant was 9.7 (95% confidence interval: 2.0-47.9). This association was not observed in Caucasian women. The exon 7 and AA polymorphisms were not associated with breast cancer in either group. The mechanism for the observed association between the MspI polymorphism and breast cancer is unclear. It is possible that the CYP1A1 MspI RFLP is linked with other polymorphisms in the African-American population, either in the CYP1A1 gene, which is involved in estrogen metabolism, or other genes related to risk of breast cancer.

Adult↗

The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis.

OBJECTIVE: Mannose-binding lectin (MBL) enhances opsonization and activates complement. Dysfunctional alleles of MBL have been associated with low plasma concentrations of MBL and increased risk of systemic lupus erythematosus (SLE), but genotyping studies have shown inconsistent results. We performed case-control studies of the MBL polymorphisms in 2 Caucasian cohorts and a meta-analysis incorporating all published results of MBL genotyping in SLE to explore whether the MBL functional variants are associated with SLE. METHODS: MBL genotypes at 7 single-nucleotide polymorphisms were sequenced in 96 European American patients with SLE and 96 age-, race-, and sex-matched controls. MBL codons 52, 54, and 57 were genotyped in 285 German patients with SLE and 200 race-matched controls. Allele frequencies of all known variants were tallied for meta-analysis. RESULTS: Although there was a trend toward association with MBL polymorphisms in both patient cohorts evaluated, none of them was significantly associated with SLE on its own. Seventeen comparisons from 15 studies were included in the meta-analysis. Publication bias was excluded by Egger's regression test (P = 0.14). The overall odds ratio for MBL codon 54 variant B was 1.406 (95% confidence interval 1.221-1.608; P < 0.001). Stratification by ethnicity showed significantly increased odds ratios for association of the MBL codon 54 B variant with SLE in African, Asian, and Caucasian cohorts. CONCLUSION: Meta-analysis of all available studies on MBL polymorphisms and SLE shows that MBL variant alleles such as MBL exon 1 codon 54 B, promoter -550 L, and promoter -221 X are SLE risk factors. This association is robust and persists after incorporation of data from our 2 cohorts in which the association failed to reach significance.

Adult↗

Relation of alleles of the sodium-potassium adenosine triphosphatase alpha 2 gene with blood pressure and lead exposure.

Lead is associated with elevated blood pressure, although the mechanism of action is unknown. Genetic differences in sodium-potassium adenosine triphosphatase (Na(+)-K(+)ATPase) could explain some of the variation in the strength of the blood pressure-blood lead relation that has been observed in previous studies. In 1996-1997, the authors studied the association of blood pressure, hypertension prevalence, and polymorphisms in the gene for the alpha 2 subunit of Na(+)-K(+)ATPase (ATP1A2) among 220 former organolead manufacturing workers from New Jersey. Subjects were genotyped for a restriction fragment length polymorphism (RFLP) on the ATP1A2 gene. The association between blood lead and blood pressure was stronger among persons who were homozygous for the variant allele. Genotype was also associated with hypertension (adjusted odds ratio = 7.7; 95% confidence interval: 1.9, 31.4). Finally, the variant allele was 1.8 times more common among African Americans than among Caucasians. The RFLP may indicate susceptibility to the effect of lead on blood pressure. Moreover, the alpha 2 gene (or a closely linked gene) may contribute to the pathophysiology of hypertension. However, because the number of subjects (especially African Americans) with the susceptible genotype in this study was small, these observations should be considered preliminary.

Adult↗

Influence of an insertion variant in the 5'UTR of the endothelin-1 gene on orthostatic intolerance.

BACKGROUND: Orthostatic intolerance is a multifactorial disease in which the genetic contribution is probably the result of a number of genes acting in combination. Recent work has shown that orthostatic intolerance is influenced by endothelial nitric oxide synthase gene polymorphisms. Since endothelin-1 (ET-1) is one of the most important vasoconstrictor peptides, a frequent adenine insertion polymorphism within the 5'-untranslated region (5'UTR), which is of functional importance for ET-1 expression, could influence orthostatic intolerance. The aim of this study was therefore to ascertain whether this frequent variant of the endothelin-1 gene influences the risk for orthostatic intolerance. METHODS: We studied 257 white patients (120 cases with orthostatic intolerance and 137 controls) for genotyping of the 5'UTR I variant. From this cohort, 111 patients and 99 control subjects underwent a tilt-table test or an upright posture study, including monitoring of blood pressure, heart rate, and plasma catecholamines, in the supine position and during 30 minutes of standing. Genotyping was performed in all participants. Chi tests of independence were used to test for associations between orthostatic intolerance and genotype. In addition, an association of the insertion polymorphism with hemodynamic variables (heart rate, supine and upright blood pressure) was ascertained using one-way analysis of variance. RESULTS: The 5'UTR I variant was significantly less common in patients with orthostatic intolerance (allele frequency 0.36 and 0.28, in controls and cases, respectively). Additionally, we found a significant decrease in the risk of orthostatic intolerance among people who were homozygous for the 5'UTR variant (I/I) compared with the wild-type variant (D/D) (odds ratio, 0.41; 95% confidence interval, 0.17 to 0.97; P = 0.04). No association between the 5'UTR variant and heart rate or blood pressure regardless of diagnosis was found. CONCLUSIONS: Our current results suggest that the hereditary adenine insertion variant in the 5'-UTR of the endothelin-1 gene is protective for orthostatic intolerance. The increased ET-1 protein expression that has been linked with the I variant might be associated with a more efficient hemodynamic response to standing. This is likely one of several common genetic loci that may represent modifiers of orthostatic intolerance phenotypes.

5' Untranslated Regions↗

Maternal and fetal variants of genetic thrombophilias and the risk of preeclampsia.

BACKGROUND: A woman's thrombophilic genes may increase her risk of preeclampsia in pregnancy. Vascular conditions of the placenta related to thrombophilic genes of the fetus could also be relevant for preeclampsia. The case-parent triad study design provides separate estimation of maternal and fetal genes. METHODS: We recruited 92 mother-father-child triads of preeclamptic pregnancies from a birth clinic in Stavanger, Norway. All parents were of Norwegian origin. Maternal, paternal, and fetal DNA were genotyped for the methylenetetrahydrofolate reductase (MTHFR) C677T and Factor V Leiden (FVL) G1691A SNPs. Estimation of the relative risk (RR) associated with fetal and maternal genetic variants was performed by log-linear models. RESULTS: There was no indication of an effect of the child's FVL alleles on preeclampsia risk. For case babies with 2 copies of the variant allele, the association with the MTHFR variant was inconclusive (RR = 1.6; 95% confidence interval [CI] = 0.6-4.3). Case mothers who were homozygous for the MTHFR variant had a relative risk of 2.0 (CI = 1.0-4.1) assuming a recessive gene effect. A 2.5-fold risk (CI = 1.1-5.7) of preeclampsia was estimated when the mother carried one copy of the FVL. Among mothers homozygous for the MTHFR variant, the relative risk of the FVL variant was 4.6-fold (CI = 1.0-21). CONCLUSIONS: We found little evidence of an effect of the child's MTHFR or FVL alleles on the risk of preeclampsia. Our estimates of effects of maternal MTHFR and FVL alleles were consistent with estimates from case-control studies. The case-parent triad design may be a useful tool for studies of pregnancy complications such as preeclampsia.

Adult↗

Polyadenylation polymorphism in the acetyltransferase 1 gene (NAT1) increases risk of colorectal cancer.

Exposure to carcinogens present in the diet, cigarette smoke, or the environment may be associated with increased risk of colorectal cancer. Aromatic amines (aryl- and heterocyclic) are a class of carcinogens that are important in these exposures. These compounds can be N- or O-acetylated by the NAT1 or NAT2 enzymes, resulting in activation or in some cases detoxification. Recent studies have shown that both NAT2 and NAT1 genes exhibit variation in human populations and that rapid acetylation by the NAT2 enzyme may be a risk factor for colorectal cancer. In this study we have analyzed for genetic polymorphism in both NAT1 and NAT2 in a group of 202 colorectal cancer patients and 112 control subjects from Staffordshire, England. We find significantly increased risk (odds ratio, 1.9; 95% confidence interval, 1.2-3.2; P = 0.009) associated with the NAT1*10 allele of NAT1, an allele that contains a variant polyadenylation signal. Individuals with higher stage tumors (Duke's C) were more likely to inherit this variant allele (odds ratio, 2.5; 95% confidence interval, 1.3-4.7; P = 0.005). In contrast, rapid acetylation genotypes of NAT2 were not a significant risk factor in this English population. However, we found that the risk associated with the NAT1 variant allele (NAT1*10) was most apparent among NAT2 rapid acetylators (odds ratio, 2.8; 95% confidence interval, 1.4-5.7; P = 0.003), suggesting a possible gene-gene interaction between NAT1 and NAT2 (test for interaction; P = 0.12). This is the first study to test for cancer risk associated with the NAT1 gene, and these positive findings suggest that NAT1 alleles may be important genetic determinents of colorectal cancer risk.

Adenocarcinoma↗

High-order interactions among genetic variants in DNA base excision repair pathway genes and smoking in bladder cancer susceptibility.

Cancer is a common multifactor human disease resulting from complex interactions between many genetic and environmental factors. In this study, we used a multifaceted analytic approach to explore the relationship between eight single nucleotide polymorphisms in base excision repair (BER) pathway genes, smoking, and bladder cancer susceptibility in a hospital-based case-control study. Overall, we did not find an association between any single BER gene single nucleotide polymorphism and bladder cancer risk. However, in stratified analysis, the OGG1 S326C variant genotypes in ever smokers (odds ratio, 0.74; 95% confidence interval, 0.56-0.99) and ADP-ribosyltransferase (ADPRT) V762A variant genotypes in never smokers (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) conferred a significantly reduced risk. Using logistic regression, we observed that there was a two-way interaction between ADPRT V762A and smoking status. We next used classification and regression tree analysis to explore high-order gene-gene and gene-environment interactions. We found that smoking is the most important influential factor for bladder cancer risk. Consistent with the above findings, we found that the ADPRT V762A was only significantly involved in bladder cancer risk in never smokers and the OGG1 S326C was only significantly involved in ever smokers. We also observed gene-gene interactions among OGG1 S326C, XRCC1 R194W, and MUTYH H335Q in ever smokers. Using multifactor dimensionality reduction approach, the four-factor model, including smoking status, OGG1 S326C (rs1052133), APEX1 D148E (rs3136820), and ADPRT762 (rs1136410), had the best ability to predict bladder cancer risk with the highest cross-validation consistency (100%) and the lowest prediction error (37.02%; P < 0.001). These results support the hypothesis that genetic variants in BER genes contribute to bladder cancer risk through gene-gene and gene-environmental interactions.

Algorithms↗

Somatic likelihood tiering: an interpretable post-calling triage protocol for tumor-only whole-exome variant review.

Tumor-only whole-exome sequencing (WES) is used when matched normal tissue is unavailable, but one sample can produce thousands of variants. Somatic likelihood tiering (SLT) is an interpretable post-calling protocol that ranks Mutect2 calls into four review-priority tiers using population-frequency, germline-quality, cancer-knowledge, PureCN posterior, and clonal-hematopoiesis evidence. Layer 2 distinguishes common, rare-callable, and unevaluable gnomAD states; missing or unmatchable gnomAD evidence is not positive rarity evidence. On the SEQC2 HCC1395 benchmark, the callability-aware SLT-A row contained 101 calls, 78 truth variants, 77.2% PPV (95% Wilson confidence interval 68.1%-84.3%), and a Number Needed to Review (NNR) of 1.29 (1.19-1.47). The conservative SLT-C catchment retained 352 of 455 truth variants (77.4%, 73.3%-81.0%) and all tiers together retained 430 of 455 truth variants. SNV performance is the primary calibration frame: SLT-C retained 341 of 439 SNV truth variants, whereas indel results were exploratory because only 16 truth indels were available. Clinical cohorts are reported as recall and concordance versus partially dependent matched-normal Mutect2 references, not independent clinical sensitivity. Patient-level bootstrap intervals were principal: HdM-BLCA-1 SLT-A recall was 18.2% (14.0%-23.5%), and LUAD-TW SLT-A recall was 49.1% (26.6%-63.3%) among 32 evaluable patients. The HdM-BLCA-1 median SLT-A queue remained 1277 variants per patient, so SLT reduces first-pass candidate counts but does not measure review time or eliminate FFPE candidate-count burden. SLT provides an auditable tumor-only WES review queue, not a substitute for matched-normal sequencing, independent orthogonal validation, or definitive somatic classification.

Humans↗