Association between Airport Ultrafine Particles and Lung Cancer Risk: The Multiethnic Cohort Study.

BACKGROUND: Ultrafine particles (UFPs) are unregulated air pollutants abundant in aviation exhaust. Emerging evidence suggests that UFPs may impact lung health due to their high surface area-to-mass ratio and deep penetration into airways. This study aimed to assess long-term exposure to airport-related UFPs and lung cancer incidence in a multiethnic population in Los Angeles County. METHODS: Within the California Multiethnic Cohort, we examined the association between long-term exposure to airport-related UFPs and lung cancer incidence. Multivariable Cox proportional hazards regression models were used to estimate the effect of UFP exposure on lung cancer incidence. Subgroup analyses by demographics, histology and smoking status were conducted. RESULTS: Airport-related UFP exposure was not associated with lung cancer risk [per one IGR HR = 1.01, 95% CI: 0.97-1.05] overall and across race/ethnicity. A suggestive positive association was observed between a one IQR increase in UFP exposure and lung squamous cell carcinoma (SCC) risk [HR = 1.08, 95% CI: 1.00-1.17] with a Phet for histology=0.05. Positive associations were observed in 5-year lag analysis for SCC [HR = 1.12, CI: 1.02-1.22] and large cell carcinoma risk [HR = 1.23, CI: 1.01-1.49] with a [Phet for histology = 0.01]. CONCLUSIONS: This large prospective cohort analysis suggests a potential association between airport-related UFP exposure and specific lung histologies. The findings align with research indicating that UFPs found in aviation exhaust may induce inflammatory and oxidative injury leading to SCC. IMPACT: These results highlight the potential role of airport-related UFP exposure in the development of lung SCC.

Genetic analyses of diverse populations improves discovery for complex traits.

Genome-wide association studies (GWAS) have laid the foundation for investigations into the biology of complex traits, drug development and clinical guidelines. However, the majority of discovery efforts are based on data from populations of European ancestry1-3. In light of the differential genetic architecture that is known to exist between populations, bias in representation can exacerbate existing disease and healthcare disparities. Critical variants may be missed if they have a low frequency or are completely absent in European populations, especially as the field shifts its attention towards rare variants, which are more likely to be population-specific4-10. Additionally, effect sizes and their derived risk prediction scores derived in one population may not accurately extrapolate to other populations11,12. Here we demonstrate the value of diverse, multi-ethnic participants in large-scale genomic studies. The Population Architecture using Genomics and Epidemiology (PAGE) study conducted a GWAS of 26 clinical and behavioural phenotypes in 49,839 non-European individuals. Using strategies tailored for analysis of multi-ethnic and admixed populations, we describe a framework for analysing diverse populations, identify 27 novel loci and 38 secondary signals at known loci, as well as replicate 1,444 GWAS catalogue associations across these traits. Our data show evidence of effect-size heterogeneity across ancestries for published GWAS associations, substantial benefits for fine-mapping using diverse cohorts and insights into clinical implications. In the United States-where minority populations have a disproportionately higher burden of chronic conditions13-the lack of representation of diverse populations in genetic research will result in inequitable access to precision medicine for those with the highest burden of disease. We strongly advocate for continued, large genome-wide efforts in diverse populations to maximize genetic discovery and reduce health disparities.

The contribution of common genetic variation to nicotine and cotinine glucuronidation in multiple ethnic/racial populations.

BACKGROUND: The lung cancer risk of smokers varies by race/ethnicity even after adjustment for smoking. Evaluating the role of genetics in nicotine metabolism is likely important in understanding these differences, as disparities in risk may be related to differences in nicotine dose and metabolism. METHODS: We conducted a genome-wide association study in search of common genetic variants that predict nicotine and cotinine glucuronidation in a sample of 2,239 smokers (437 European Americans, 364 African Americans, 453 Latinos, 674 Japanese Americans, and 311 Native Hawaiians) in the Multiethnic Cohort Study. Urinary concentration of nicotine and its metabolites were determined. RESULTS: Among 11,892,802 variants analyzed, 1,241 were strongly associated with cotinine glucuronidation, 490 of which were also associated with nicotine glucuronidation (P < 5×10(-8)). The vast majority were within chromosomal region 4q13, near UGT2B10. Fifteen independent and globally significant SNPs explained 33.2% of the variation in cotinine glucuronidation, ranging from 55% for African Americans to 19% for Japanese Americans. The strongest single SNP association was for rs115765562 (P = 1.60 × 10(-155)). This SNP is highly correlated with a UGT2B10 splice site variant, rs116294140, which together with rs6175900 (Asp67Tyr) explains 24.3% of the variation. The top SNP for nicotine glucuronidation (rs116224959, P = 2.56 × 10(-43)) was in high LD (r(2) = 0.99) with rs115765562. CONCLUSIONS: Genetic variation in UGT2B10 contributes significantly to nicotine and cotinine glucuronidation but not to nicotine dose. IMPACT: The contribution of genetic variation to nicotine and cotinine glucuronidation varies significantly by racial/ethnic group, but is unlikely to contribute directly to lung cancer risk.

Nicotine N-glucuronidation relative to N-oxidation and C-oxidation and UGT2B10 genotype in five ethnic/racial groups.

Nicotine metabolism influences smoking behavior and differences in metabolism probably contribute to ethnic variability in lung cancer risk. We report here on the proportion of nicotine metabolism by cytochrome P450 2A6-catalyzed C-oxidation, UDP-glucuronosyl transferase 2B10 (UGT2B10)-catalyzed N-glucuronidation and flavin monooxygenase 3-catalyzed N-oxidation in five ethnic/racial groups and the role of UGT2B10 genotype on the metabolic patterns observed. Nicotine and its metabolites were quantified in urine from African American (AA, n = 364), Native Hawaiian (NH, n = 311), White (n = 437), Latino (LA, n = 453) and Japanese American (JA, n = 674) smokers. Total nicotine equivalents, the sum of nicotine and six metabolites, and nicotine metabolism phenotypes were calculated. The relationship of UGT2B10 genotype to nicotine metabolic pathways was determined for each group; geometric means were computed and adjusted for age, sex, creatinine, and body mass index. Nicotine metabolism patterns were unique across the groups, C-oxidation was lowest in JA and NH (P < 0.0001), and N-glucuronidation lowest in AA (P < 0.0001). There was no difference in C-oxidation among Whites and AA and LA. Nicotine and cotinine glucuronide ratios were 2- and 3-fold lower in AA compared with Whites. Two UGT variants, a missense mutation (Asp67Tyr, rs61750900) and a splice variant (rs116294140) accounted for 33% of the variation in glucuronidation. In AA, the splice variant accounted for the majority of the reduced nicotine glucuronidation. UGT2B10 variant allele carriers had increased levels of C-oxidation (P = 0.0099). Our data indicate that the relative importance of nicotine metabolic pathways varies by ethnicity, and all pathways should be considered when characterizing the role of nicotine metabolism on smoking behavior and cancer risk.

Altered temporal characteristics of the rectoanal inhibitory reflex in patients with abdominal distension.

The rectoanal inhibitory reflex (RAIR) is important in gas and stool evacuation. We examined RAIR features in patients with chronic constipation who exhibited bloating with and without abdominal distension, to determine whether alterations in RAIR may be a factor in the pathogenesis of abdominal distension. Seventy-five female patients with chronic constipation with or without abdominal distension were included in the study. The presence or absence of abdominal distension was assessed according to the Rome II questionnaire. All patients underwent both RAIR and rectal sensitivity testing, and specific RAIR parameters were analyzed. Patients were divided into two groups: abdominal bloating with distension (D, n = 55) and abdominal bloating without distension (ND, n = 20). D had a longer time to the onset of anal sphincter inhibition (latency of inhibition) (P = 0.03) compared with ND. In logistic regression analysis, a combination of age, latency of inhibition and the time measured from onset of inhibition to the point of maximum inhibition predicted abdominal distension (P = 0.002). There were no differences between groups for the time from point of maximum inhibition to recovery and for the percentage of internal anal sphincter relaxation. This is the first study to examine the role of RAIR in patients with abdominal distension. Female patients with constipation and abdominal distension exhibited differences in the temporal characteristics of, but not in the degree of, anal sphincter relaxation compared with patients without distension. Since this study was uncontrolled, further studies are necessary to determine the contribution of altered anorectal reflexes to abdominal distension.

Predictors of outcome of anorectal biofeedback therapy in patients with constipation.

BACKGROUND: Anorectal biofeedback therapy (BFT) is a safe and effective treatment in patients with constipation. Given the high prevalence of constipation and therefore high demand for BFT, there is a need to prioritise patients. AIMS: To explore clinical features and anorectal physiology which predict success or failure of BFT and to derive a statistical model which helps to predict the success of BFT. METHODS: A total of 102 patients with constipation referred for BFT were evaluated. All patients underwent comprehensive clinical and anorectal function assessment, including balloon expulsion testing. The BFT protocol consisted of a comprehensive 6-weekly visit programme comprising instruction on toilet behaviour and abdominal breathing, achieving adequate rectal pressure and anal relaxation, and balloon expulsion and rectal sensory retraining. Success of BFT was based on an improvement in global bowel satisfaction. RESULTS: Harder stool consistency (P=0.009), greater willingness to participate (P<0.001), higher resting anal sphincter pressure (P=0.04) and prolonged balloon expulsion time (P=0.02) correlated with an improvement in bowel satisfaction score. A longer duration of laxative use (P=0.049) correlated with no improvement in bowel satisfaction score. Harder stools, shorter duration of laxative use, higher straining rectal pressure and prolonged balloon expulsion independently predicted successful BFT. A model (S(i) = (p)∑ ß(j)X(ij), where ß represents a regression coefficient, X is a given predictive variable and S(i) is the weighted index score for each individual) incorporating these four variables enabled prediction of successful BFT, with sensitivity and specificity of 0.79 and 0.81, respectively. CONCLUSIONS: Important clinical and anorectal physiological features were found to be associated with outcome of anorectal biofeedback therapy in patients with constipation. This information and the predictive model will assist clinicians to prioritise patients for anorectal biofeedback therapy.

Relationships between pelvic floor symptoms and function in irritable bowel syndrome.

BACKGROUND: Pelvic floor dyssynergia (PFD) within irritable bowel syndrome (IBS) is often overlooked and the relationship between symptoms and physiology is relatively unexplored. Our aims were to determine relationships between clinical features and anorectal function in non-diarrhea predominant IBS (non-D IBS) patients and whether certain clinical or physiological features predict PFD in IBS. METHODS: Two groups of patients were evaluated. Group I: 32 female non-D IBS patients with >or=2 symptoms suggesting PFD underwent comprehensive symptom and anorectal function assessment. Group II: 32 female non-D IBS patients recruited from the community underwent symptom assessment. KEY RESULTS: Prevalence of PFD symptoms was similar in both groups. In group I patients, increased frequency of digitation was associated with a longer balloon expulsion time (P = 0.03). Higher scores for anal pain were associated with both a low resting anal pressure (P = 0.04) and a shorter duration of maximum squeeze (P = 0.03). Reduced perineal descent was associated with anxiety (P = 0.03) and depression (P = 0.01). A shorter duration of maximum squeeze was associated with higher parity (P = 0.02) and previous hysterectomy (P = 0.047). Duration of PFD symptoms was higher (P = 0.02) and maximum tolerated volume was lower (P = 0.05) in 22 patients with a physiological diagnosis of PFD compared to 10 without PFD. No symptoms independently predicted a physiological diagnosis of PFD. CONCLUSIONS & INFERENCES: Important relationships between certain PFD symptoms and disordered anorectal physiology have been demonstrated in these non-D IBS patients. However, symptoms alone could not predict PFD, and certain clinical features should therefore highlight the need for comprehensive anorectal function tests.

Prolonged balloon expulsion is predictive of abdominal distension in bloating.

OBJECTIVES: Abdominal bloating and distension are common in patients with constipation. The precise mechanism of abdominal distension remains uncertain. We hypothesized that constipated patients with bloating plus distension exhibit a greater degree of anorectal dysfunction, potentially affecting gas evacuation, than those without distension. Therefore, our aim was to evaluate anorectal function and other clinical features in patients with constipation who exhibit bloating with and without distension. METHODS: In all, 88 female patients with abdominal bloating and either non-diarrhea irritable bowel syndrome (IBS) or functional constipation were included in the study. The presence or absence of abdominal distension was assessed according to the Rome II questionnaire, and all patients underwent comprehensive clinical assessment and anorectal function studies. RESULTS: Patients were divided into two groups: abdominal bloating with distension (D; n=53) and abdominal bloating without distension (ND; n=35). D featured a prolonged balloon expulsion time (P=0.005), a higher resting anal sphincter pressure (P=0.002), and a higher maximum anal sphincter squeeze pressure (P=0.015) than ND. They also experienced more bloating (P<0.001), more abdominal pain (P=0.004), harder stools (P=0.01), and more incomplete emptying (P=0.005). In logistic regression modeling, prolonged balloon expulsion time was a significant predictor of abdominal distension (P=0.018). CONCLUSIONS: This is the first study to show that prolonged balloon expulsion time predicts abdominal distension in patients with bloating and constipation. Hence, ineffective evacuation of gas and stool associated with prolonged balloon expulsion may be an important mechanism underlying abdominal distension.