Interaction Odds Ratio Research Articles

Excess mortality and its causes among older adults with schizophrenia versus those with bipolar disorder and major depressive disorder: a 5-year prospective multicenter study.

Excess mortality observed in people with schizophreniamay persist in later life. The specific causes of increased mortality observed in older adults with schizophrenia and the potential influence of psychotropic medications remain partly unknown. We compared 5-year mortality and its causes of older adults with schizophrenia to bipolar disorder (BD) or major depressive disorder (MDD). We used a 5-year prospective cohort, including 564 older inpatients and outpatients with schizophrenia, BD or MDD (mean age: 67.9years, SD = 7.2years). Causes of death were cardiovascular disorder (CVD) mortality, non-CVD disease-related mortality (e.g., infections), suicide, and unintentional injury. The primary analysis was a multivariable logistic model with inverse probability weighting (IPW) to reduce the effects of confounders, including sociodemographic factors, duration and severity of the disorder, and psychiatric and non-psychiatric comorbidity. Five-year all-cause mortality among older participants with schizophrenia and with BD or MDD were 29.4% (n = 89) and 18.4% (n = 45), respectively. Following adjustments, schizophrenia compared to MDD or BD was significantly associated with increased all-cause mortality (AOR = 1.35; 95%CI = 1.04-1.76; p = 0.024) and cardiovascular mortality (AOR = 1.50; 95%CI = 1.13-1.99; p = 0.005). These associations were significantly reduced among patients taking antidepressants [interaction odds ratio (IOR) = 0.42; 95%CI = 0.22-0.79; p = 0.008 and IOR = 0.39: 95%CI = 0.16-0.94; p = 0.035, respectively]. Schizophrenia was associated with higher mortality compared to BD or MDD. Cardiovascular diseases explained most of this excess mortality. Exploratory analyses suggested that psychotropic medications did not influence this excess mortality, except for antidepressants, which were associated with significantly reduced between-group difference in all-cause and cardiovascular mortality.

Association between genetic risk of alcohol consumption and alcohol-related morbidity and mortality under different alcohol policy conditions: Evidence from the Finnish alcohol price reduction of 2004.

Harmful alcohol consumption is influenced by both genetic susceptibility and the price of alcohol. Many previous studies have observed that genetic susceptibility to consumption of alcohol is more predictive in less restrictive drinking conditions. We assess whether such a pattern applies when the prices of alcoholic beverages are decreased. Data consist of genetically informed population-representative surveys (FINRISK 1992, 1997, 2002 and Health 2000) linked to administrative registers. We analysed the interaction between a polygenic score (PGS) for alcoholic drinks per week consumed and price reduction in predicting the incidence of alcohol-related hospitalizations and deaths in difference-in-difference and interrupted time-series frameworks. Individuals in Finland were followed quarter-yearly from 1 March 2000 to 31 May 2008. A total of 22 152 individuals (607 132-person quarter-years, 1399 outcome events) aged 30-79 years. A natural experiment stemming from the alcohol tax reduction in March 2004 and import deregulation in May 2004. Outcome was quarter-yearly-measured alcohol-related death or hospitalization. The independent variables of main interest were PGS and a price reform indicator. We adjusted for gender, age, age squared, season, 10 first principal components of the genome, data collection round and genotyping batch. Both alcohol price reduction and one standard deviation change in PGS were associated with alcohol-related health outcomes; odds ratios (ORs) were 1.32, 95% confidence interval (CI) = 1.13, 1.53 and 1.26, 95% CI = 1.12, 1.42 in the 8-year follow-up, respectively. The association between PGS and alcohol-related morbidity was similar before and after the alcohol price reform (PGS × price reform interaction OR = 0.96, 95% CI = 0.81, 1.14). These results were robust across different follow-up periods and measurement and analysis strategies. Although the decrease of alcohol price in Finland in 2004 substantially increased overall alcohol-related morbidity and mortality, the genetic susceptibility to alcohol consumption did not become more manifest in predicting them.

Association of Interpregnancy Interval With Adverse Birth Outcomes

Many studies have reported an association of interpregnancy interval (IPI) between 2 consecutive births with adverse birth outcomes in low- and middle-income countries. However, most of these studies ignore the implications of some unmeasured confounders. To explore the association of IPI with adverse perinatal outcomes. This large-scale cohort study used the Guangdong Provincial Women and Children Health Information System in Guangdong Province, China, to obtain birth data recorded between January 1, 2014, and December 31, 2020. Matched-sibling design was used. The final cohort included first-born and second-born sibling pairs delivered by mothers who were permanent residents of Guangdong Province. The exposure variable was IPI, which was categorized as follows: less than 6, 6 to 11, 12 to 17, 18 to 23, 24 to 29, 30 to 35, and 36 or more months. The outcome variables were adverse birth outcomes: preterm birth (PTB, gestational age <37 weeks), low birth weight (LBW, <2500 g), and small for gestational age (SGA). Adjusted odds ratio (OR) and interaction odds ratio (IOR) associated with IPI were calculated. The study consisted of 725 392 sibling pairs of multiparous mothers. Among these mothers, 718 111 (99.0%) were aged 20 to 34 years, and 715 583 (98.7%) were of Han Chinese ethnicity. Unmatched analysis showed that a short IPI of less than 6 months was associated with higher risks of PTB (adjusted OR, 1.96; 95% CI, 1.87-2.06), LBW (adjusted OR, 1.88; 95% CI, 1.79-1.98), and SGA (adjusted OR, 1.34; 95% CI, 1.30-1.38) compared with an IPI of 18 to 23 months. These associations were attenuated in the matched-sibling analysis. An association of short IPI (<6 months) with PTB (adjusted IOR, 1.40; 95% CI, 1.30-1.51), LBW (adjusted IOR, 1.30; 95% CI, 1.21-1.40), and SGA (adjusted IOR, 1.16; 95% CI, 1.11-1.22) remained in the matched analysis. For IPI of 36 months or more, the odds of PTB (adjusted OR, 1.08; 95% CI, 1.03-1.14) and LBW (adjusted OR, 1.13; 95% CI, 1.07-1.19) in the unmatched analysis were also greater than the reference interval (18-23 months), but not for SGA (adjusted OR, 0.96; 95% CI, 0.93-0.99). Associations between a long IPI (≥36 months) and PTB (adjusted IOR, 1.10; 95% CI, 1.02-1.19) and LBW (adjusted IOR, 1.16; 95% CI, 1.07-1.26) remained through the sibling comparisons. Results of this study indicated that mothers with a short (<6 months) or long (≥36 months) IPI had greater odds of adverse birth outcomes. The findings may inform family planning policies and guide individuals and families who are planning for another pregnancy in China.

Metagenomic analysis of the fecal microbiome in patients with colorectal cancer compared to healthy controls as a function of age.

3532 Background: Colorectal cancer (CRC) incidence is increasing in young patients ( &lt; 50 years old) without a clear etiology. Emerging data has implicated the fecal microbiome in CRC carcinogenesis. However, its impact on young onset CRC (YO-CRC) is poorly defined. Colibactin producing E. Coli and fadA producing Fusobacterium nucleatum can drive CRC carcinogenesis, however their effects across the age spectrum are unknown. Methods: We performed a meta-analysis of fecal metagenomics sequencing from n = 692 patients with CRC and n = 602 healthy controls from eleven studies to evaluate species and known microbial derived factors (colibactin and FadA) associated with CRC as a function of age. Generalized linear mixed effects regression was used to model the predicted prevalence of gene families and taxa as a non-linear function of age. Two-stage individual patient data meta-analysis (IPDMA) with adjustment for gender, CRC status, and body mass index was also used to estimate summary odds ratios for colibactin, F. nucleatum, and E. Coli. Interaction ORs were obtained to assess the difference in the effect of each gene or taxa on CRC case status in YO-CRC. Shannon Diversity index and metabolic pathway differences in the fecal metagenome for YO-CRC patients were assessed using phyloseq and MetaCyc respectively using an IPDMA approach. Results: Summary odds ratios (OR) for CRC were increased relative to controls with the presence of colibactin (OR 1.92 95%CI 1.08-3.38), fadA (OR 4.57 95%CI 1.63-12.85), and F. nucleatum (OR 6.93 95%CI 3.01-15.96) in models of all patients adjusted for age, gender, and body mass index. The OR for CRC for the presence of E.coli was 2.02 (0.92-4.45). An increase in the prevalence of F. nucleatum (OR = 1.40 [1.18; 1.65] and Escherichia coli (OR = 1.14 [1.02; 1.28]) per 10-year increase in age was observed in models including samples from both CRC and healthy controls. No difference was observed for Shannon Diversity (OR 1.36 95%CI 0.68-2.72) or MetaCyc pathways in YO-CRC patients. Species relative abundance was differentially enriched in YO-CRC relative to old CRC patients and controls for five species- Intestinimonas butyriciproducens, Holdemania filiformis, Firimicutues bacterium CAG 83, Bilophilia wadsworthia, and Alistipes putredinis. Conclusions: Strong associations with CRC status were observed for colibactin, fadA, and F. nucleatum with increased F. nucleatum in older patients. Several species were enriched in YO-CRC patients including B. wadsworthia which can produce carcinogenic sulfur metabolites and is increased with adherence to a sulfur microbial diet-low in vegetables and legumes. A sulfur microbial diet has also been associated with higher incidence of YO-CRC in population studies (Nguyen Gastroenterology 2021). Additional study is warranted to understand causal mechanisms of enriched species observed in YO-CRC patients.

Interaction of biomass fuels use and metals exposure on hypertension: A prospective cohort study in rural areas along the Yangtze River, China

Humans maybe simultaneously exposed to multiple-metals and indoor air pollution in daily life. However, limited prospective studies have assessed the interaction between multiple metals exposure and biomass fuels use on hypertension in China. The prospective cohort study in rural areas along the Yangtze River included 2625 adults in 2014–2015, and they were followed up till 2019. Among 1248 rural residents who were without hypertension at baseline, 377 hypertension events (30.21%) were observed after 4.5 years of average follow-up time. First-morning urine samples of residents were collected at baseline, the association between urinary metals level and hypertension were assessed using quantile g-computation. Additionally, we also examined the effect of biomass fuels use, fuels switching, and cookstove ventilation on the association of metals exposure with hypertension. Quantile g-computation analyses showed a positive joint effect of 17 metals on hypertension, with the odds ratio (OR) of 1.68 (95% CI: 0.89, 3.14) when increasing all seventeen metals by one quartile, and cadmium, lithium, copper contributed the largest positive weights. Biomass fuels use can interact with cadmium exposure on hypertension with OR for interaction of 1.28 (95%CI: 1.00, 1.73), and increase the association between copper, manganese and zinc exposure and systolic blood pressure, lithium exposure and diastolic blood pressure at the follow-up visit. Moreover, switching from biomass fuels to clean fuels during follow up, cookstove ventilation can alleviate the risk of higher blood pressure from metals exposure. In rural areas along the Yangtze River, China, biomass fuels use for cooking can interact with multiple-metals exposure on hypertension. Residents who switched from biomass fuels to clean fuels and who used ventilation had a lower risk of hypertension. Further cohort studies are needed to clarify the mechanism of combined effects of metals exposure and biomass fuels use on the human health.

The Association of Aging-Related Polymorphisms with Susceptibility to Lung Cancer: A Case-Control Study in a Japanese Population.

Background:Telomere length is associated with cancer as well as aging. Telomerase reverse transcriptase (TERT), telomere RNA component (TERC) and oligonucleotide/oligosaccharide-binding fold containing 1 (OBFC1) are known to be involved in telomere length regulation. The tumor suppressor p53 (TP53), which has been shown to interact with tumor protein p53-binding protein 1 (TP53BP1), is implicated in the response to telomere shortening and aging. Polymorphisms in the TP53 and TP53BP1 genes are associated with various types of cancer. The aim of this study is to evaluate the impact of aging-related polymorphisms on lung cancer risk. Materials and Methods:This case-control study consists of 462 lung cancer cases and 379 controls from Japan. We examined the effect of TERT rs2736100, TERC rs1881984, OBFC1 rs11191865, TP53 rs1042522 and TP53BP1 rs560191 on the risk of lung cancer using a Taq-Man real-time PCR assay. Unconditional logistic regression was used to assess the adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: None of the main effects of any of the telomere-related polymorphisms were related to the risk of lung cancer. Similarly, none of the interactive effects of any of the telomere-related polymorphisms with smoking were associated with lung cancer risk. The significant multiplicative interaction between TERT rs2736100 and TP53BP1 rs560191 was statistically significant (OR for interaction = 0.34, 95% CI = 0.14–0.84). The multiplicative interaction between OBFC1 rs11191865 and TP53BP1 rs560191 was also statistically significant (OR for interaction = 2.44, 95% CI = 1.02–5.87) but the OR for interaction was in the opposite direction. Conclusions:Our findings indicate that TP53BP1 rs560191 may predispose to lung cancer risk depending on the genotypes of telomere-related polymorphisms. Additional studies are warranted to confirm the findings suggested in the present study.

Contribution of Polygenic Risk to Hypertension Among Long-Term Survivors of Childhood Cancer

BackgroundChildhood cancer survivors experience significantly higher rates of hypertension, which potentiates cardiovascular disease, but the contribution and relationship of genetic and treatment factors to hypertension risk are unknown. ObjectivesThis study sought to determine the contribution of a blood pressure polygenic risk score (PRS) from the general population and its interplay with cancer therapies to hypertension in childhood cancer survivors. MethodsUsing 895 established blood pressure loci from the general population, we calculated a PRS for 3,572 childhood cancer survivors of European ancestry from the Childhood Cancer Survivor Study (CCSS) original cohort, 1,889 from the CCSS expansion cohort, and 2,534 from the St. Jude Lifetime Cohort. Hypertension was assessed using National Cancer Institute criteria based on self-report of a physician diagnosis in CCSS and based on blood pressure measurement in the St. Jude Lifetime Cohort. ResultsIn the combined sample of 7,995 survivors, those in the top decile of the PRS had an odds ratio (OR) of 2.66 (95% confidence interval [CI]: 2.03 to 3.48) for hypertension compared with survivors in the bottom decile. The PRS-hypertension association was modified by being overweight/obese (per standard deviation interaction OR: 1.13; 95% CI: 1.01 to 1.27) and exposure to hypothalamic-pituitary axis radiation (per standard deviation interaction OR: 1.18; 95% CI: 1.05 to 1.33). Attributable fractions for hypertension to the PRS and cancer therapies were 21.0% and 15.7%, respectively; they jointly accounted for 40.2% of hypertension among survivors. ConclusionsA blood pressure PRS from the general population is significantly associated with hypertension among childhood cancer survivors and contributes to approximately one quarter of hypertension risk among survivors. These findings highlight the importance of screening for hypertension in all childhood cancer survivors and identifying higher-risk subgroups.

The interactive effect of location, alcohol consumption and non-traffic injury.

This study aimed to assess the extent to which the association between recent alcohol consumption and risk of non-traffic injury varies according to location at the time of the injury. Case-cross-over design. A total of 15 625 injury patients from 49 emergency departments (EDs) in 22 countries. Recent alcohol consumption and location at the time of the injury were assessed for when the injury occurred and for the same time 1week prior to this. The confounding and interactive effects of location were examined by estimating the adjusted odds ratio (OR) of injury from alcohol consumption adjusting for location and then by examining the alcohol consumption×location interaction. There were significant interactive effects of location and alcohol consumption on injury risk. For example, the ORs for volume 0.1-3.0 drinks and street/public place each were 3.0 and 14.2, respectively, whereas the OR for their joint effect was 44.1, suggesting a positive additive interaction [relative excess risk due to interaction (RERI)=27.9, P<0.05] and zero multiplicative interaction (OR=1.0, P=0.895). The interactions of alcohol consumption with drinking establishment location, work-place and other locations were mostly additive and negative on the multiplicative scale (e.g. for interaction between volume 0.1-3.0 drinks and drinking establishment location: RERI=1.19, P=0.529; multiplicative interaction OR=0.54, P<0.05). Location appears to influence the relationship between alcohol consumption and risk of injury. The association between alcohol consumption and injury appears to be greater in locations such as streets and public places compared with private residences.

The influence of time to adrenaline administration in the Paramedic 2 randomised controlled trial

PurposeTo examine the time to drug administration in patients with a witnessed cardiac arrest enrolled in the Pre-Hospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug Administration in Cardiac Arrest (PARAMEDIC2) randomised controlled trial.MethodsThe PARAMEDIC2 trial was undertaken across 5 NHS ambulance services in England and Wales with randomisation between December 2014 and October 2017. Patients with an out-of-hospital cardiac arrest who were unresponsive to initial resuscitation attempts were randomly assigned to 1 mg intravenous adrenaline or matching placebo according to treatment packs that were identical apart from treatment number. Participants and study staff were masked to treatment allocation.Results8016 patients were enrolled, 4902 sustained a witnessed cardiac arrest of whom 2437 received placebo and 2465 received adrenaline. The odds of return of spontaneous circulation decreased in both groups over time but at a greater rate in the placebo arm odds ratio (OR) 0.93 (95% CI 0.92–0.95) compared with the adrenaline arm OR 0.96 (95% CI 0.95–0.97); interaction OR: 1.03, 95% CI 1.01–1.05, p = 0.005. By contrast, although the rate of survival and favourable neurological outcome decreased as time to treatment increased, the rates did not differ between the adrenaline and placebo groups.ConclusionThe rate of return of spontaneous circulation, survival and favourable neurological outcomes decrease over time. As time to drug treatment increases, adrenaline increases the chances of return of spontaneous circulation. Longer term outcomes were not affected by the time to adrenaline administration. (ISRCTN73485024).

Education Level and Cigarette Smoking: Diminished Returns of Lesbian, Gay and Bisexual Individuals.

Background: Education level is one of the strongest protective factors against high-risk behaviors such as cigarette smoking. Minorities’ Diminished Returns (MDRs), however, suggest that the protective effects of education level tend to be weaker for racial and ethnic minority groups relative to non-Hispanic White people. Only two previous studies have shown that MDRs may also apply to lesbian, gay, and bisexual (LGB) individuals; however, these studies have focused on outcomes other than tobacco use. Aims: To compare LGB and non-LGB American adults for the effects of education level on cigarette-smoking status. Methods: Population Assessment of Tobacco and Health (PATH; 2013) entered 31,480 American adults who were either non-LGB (n = 29,303, 93.1%) or LGB (n = 2,177; 6.9%). The independent variable was education level. The dependent variable was current established cigarette smoking. Race, ethnicity, age, gender, poverty status, employment, and region were the covariates. LGB status was the moderator. Results: Overall, individuals with higher education level (odds ratio (OR) = 0.69) had lower odds of current established smoking. We found a significant interaction between LGB status and education level suggesting that the protective effect of education level on smoking status is systemically smaller for LGB people than non-LGB individuals (OR for interaction = 1.19). Conclusions: Similar to the patterns that are shown for racial and ethnic minorities, MDRs can be observed for the effects of education level among sexual minorities. In the United States, highly educated LGB adults remain at high risk of smoking cigarettes, a risk which is disproportionate to their education level. In other terms, high education level better helps non-LGB than LGB individuals to avoid cigarette smoking. The result is a relatively high burden of tobacco use in highly educated LGB individuals.

The Impact of Dysphagia on Mortality of Nursing Home Residents: Results From the nutritionDay Project

ObjectivesDysphagia is a frequent finding in nursing home residents. The aim of this study is to evaluate the association of dysphagia and mortality in nursing home residents and identify further risk factors for mortality in residents with dysphagia. DesignOne-day, annually repeated cross-sectional study, evaluating the nutritional situation of nursing home residents with 6-month mortality as outcome. Setting191 nursing homes from 14 countries in Europe and the United States participating in the nutritionDay study between 2007 and 2012. ParticipantsData of all nursing home residents in the nutritionDay study aged 65 years or older with available information about dysphagia and outcome were analyzed. MeasurementsResidents’ characteristics and mortality rate were calculated by group comparison, and mortality risk was calculated by multivariate regression analysis with adjustment for potential confounding factors. Results10,185 residents (78% female) with a mean age of 85 ± 8.1 years were included in the analysis. Dysphagia was reported in 15.4% of residents. The 6-month mortality of residents with dysphagia was significantly higher than of those without dysphagia (24.7% vs 11.9%; P < .001). The multivariate regression analysis revealed dysphagia [odds ratio (OR) 1.44, 95% confidence interval (CI) 1.24-1.68, P < .001] along with body mass index <20 (OR 1.78, 95% CI 1.55-2.03, P < .001) and weight loss >5 kg (OR 1.61, 95% CI 1.37-1.88, P < .001) as independent and significant risk factors for mortality. Because of significant interaction, a disproportionately high mortality of 38.9% was found in residents with dysphagia accompanied by previous weight loss >5 kg (OR for interaction 1.44; 95% CI 1.03-2.01; P = .032). Tube feeding was reported in 14.6% of residents with dysphagia. The mortality rate of dysphagic residents receiving tube feeding vs those who were not was not significantly different (21.4% vs 25.3%; P = .244). ConclusionIn this nutritionDay study, dysphagia was identified as an independent risk factor for mortality in nursing home residents. Residents with dysphagia accompanied by weight loss are at a particularly high risk of mortality and should therefore receive special attention.

Abstract P2-09-01: T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial

Abstract Background: Dual anti-HER2 blockade resulted in increased pathologic complete response rate (pCR) in the 3 arm NeoALTTO trial. High immune gene expression and the absence of PIK3CA pathway mutations are predictive of pCR in all treatment arms but no markers were identified that could predict which patients require dual HER2 targeted therapy. The goal of this analysis was to examine if TRBV expression could add to the predictive function of previously identified immune markers. Patients and Methods: We analyzed RNA and Whole Exome sequencing data from 245 cancers (54% of all patients) included in the trial. The TRBV reference sequences were obtained from the International ImMunoGeneTics information system. Reads were aligned using a custom BLAST mapping pipeline and normalized by the total number of aligned reads in each sample. We calculated 3 T cell receptor metrics for each tumor including (i) total TRBV chain expression level, (ii) Shannon entropy of the normalized unique TRBV-expression frequencies which reflect TCR diversity and (iii) we also used non-negative matrix factorization (NMF) to define TRBV co-expression metagenes (TRBVMG). We evaluated correlation between these metrics and immune and proliferation gene expression signatures and genomic features of the cancer including clonal heterogeneity and mutation load. We assessed association between TRBV and pCR using multivariate logistic regression. Results: 65 distinct TRBV variants showed heterogeneous expression levels across cancers with strong co-expression patterns. Total TRBV expression correlated strongly with immune metagene expression (Spearman's ρ=0.93, P&amp;lt;0.001), but entropy had a weaker, inverse correlation with immune metagene expression (Spearman's ρ=-0.40, P&amp;lt;0.001). Associations between TRBV metrics and mutation load and clonal heterogeneity were weak. pCR correlated with higher total TRBV expression (Spearman's ρ=0.17, P&amp;lt;0.05). Correlation between entropy and pCR was non-significant (odds ratio (OR) for regressing entropy with pCR was &amp;lt;1). NMF identified 4 distinct TRBVMGs that showed substantial expression variation within immune cell rich cancers. ER-status, proliferation and immune-gene expression adjusted logistic regression analysis including a treatment-arm interaction term revealed that TRBVMG-2, characterized by high expression of TRBV4.3, TRBV6.3 and TRBV7.2 variants, was associated with higher pCR rate in patients treated with trastuzumab plus lapatinib (Interaction OR=3.23 adjusted P=0.03). In immune-rich cancers, TRBVMG-2 expression above the median was associated with higher pCR rate in the dual HER2 targeted treatment arm compared to the other arms (68% vs 21%, Fisher exact test P&amp;lt;0.001). Patients with immune cell rich cancers but TRBVMG-2 expression below the median had similar pCR rates in all arms (42% monotherapy vs. 28% dual therapy, P=0.46). Conclusions: TRBV expression pattern can provide predictive information beyond known immune gene expression signatures. High expression of TRBV4.3, TRBV6.3 and TRBV7.2 variants is associated with higher pCR rate with dual HER2 targeted and paclitaxel neoadjuvant therapy. Citation Format: Powles R, Redmond D, Sotiriou C, Loi S, Fumagalli D, Nuciforo P, Harbeck N, de Azambuja E, Sarp S, Di Cosimo S, Huober J, Baselga J, Piccart-Gebhart M, Elemento O, Hatzis C, Pusztai L. T-cell receptor beta chain variable region (TRBV) expression patterns predict response to combined trastuzumab/lapatinib treatment in the NeoALTTO/BIG-1-06 trial [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-01.

Chronic pelvic pain in women of reproductive and post‐reproductive age: a population‐based study

Epidemiological studies on chronic pelvic pain (CPP) have focused on women of reproductive age. We aimed to determine the prevalence of chronic pelvic pain (CPP) in adult women and the differences in associated factors among women of reproductive age and older women. In addition, to determine whether distinct subgroups existed among CPP cases. A cross-sectional postal survey was conducted among 5300 randomly selected women aged ≥25years resident in the Grampian region, UK. Multivariable logistic regression was used to determine pregnancy-related and psychosocial factors associated with CPP. To identify subgroups of CPP cases, we performed cluster analysis using variables of pain severity, psychosocial factors and pain coping strategies. Of 2088 participants, 309 (14.8%) reported CPP. CPP was significantly associated with being of reproductive age (odds ratios (OR) 2.43, 95% CI 1.69-3.48), multiple non-pain somatic symptoms (OR 3.58 95% CI 2.23-5.75), having fatigue (OR mild 1.74 95% CI 1.24-2.44, moderate/severe 1.82, 95% CI 1.25-2.63) and having depression (OR 1.61, 95% CI 1.09-2.38). CPP was less associated with multiple non-pain somatic symptoms in women of reproductive age compared to older women (interaction OR 0.51, 95% CI 0.28-0.92). We identified two clusters of CPP cases; those having little/no psychosocial distress and those having high psychosocial distress. CPP is common in both age groups, though women of reproductive age are more likely to report it. Heightened somatic awareness may be more strongly associated with CPP in older women. There are distinct groups of CPP cases characterized by the absence/presence of psychosocial distress. Heightened somatic awareness may be more strongly associated with CPP in women of post-reproductive years compared to women of reproductive years. Two subgroups of CPP cases can be differentiated by the absence/presence of psychosocial distress suggesting that stratified management approach may be more efficient.

Polymorphic variants in the vitamin D pathway genes and the risk of ovarian cancer among non-carriers of BRCA1/BRCA2 mutations.

Previous studies have produced inconsistent results regarding the contribution of single-nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene to ovarian cancer (OC) in various ethnicities. Additionally, little has been established with regard to the role of SNPs located in the retinoid X receptor α (RXRA), vitamin D-binding protein [also know as group-specific component (GC)] and VDR genes in non-carriers of the breast cancer 1/2 early onset (BRCA1/BRCA2) gene mutations. All participating individuals in the present study were evaluated for BRCA1 mutations (5382incC, C61G and 4153delA) with HybProbe assays, and for BRCA2 mutation (5946delT) using high-resolution melting (HRM) analysis. The associations of 8 SNPs located in RXRA, GC and VDR were investigated in OC patients without the BRCA1/BRCA2 mutations (n=245) and healthy controls (n=465). Genotyping of RXRA rs10881578 and rs10776909, and GC rs1155563 and rs2298849 SNPs was conducted by HRM analysis, while RXRA rs749759, GC rs7041, VDR BsmI rs1544410 and FokI rs2228570 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. In addition, the gene-gene interactions among all tested SNPs were studied using the epistasis option in PLINK software. The lowest P-values of the trend test were identified for VDR rs1544410 and GC rs2298849 as Ptrend=0.012 and Ptrend=0.029, respectively. It was also found that, in the dominant inheritance model, VDR BsmI contributed to an increased risk of OC [odds ratio (OR), 1.570; 95% confidence interval (CI), 1.136-2.171; P=0.006; Pcorr=0.048]. The gene-gene interaction analysis indicated a significant interaction between RXRA rs749759 and VDR FokI rs2228570 (OR for interaction, 1.687; χ2=8.278; asymptotic P-value=0.004; Pcorr=0.032). In conclusion, this study demonstrated that certain VDR and RXRA SNPs may be risk factors for OC in non-carriers of BRCA1/BRCA2 mutations in the Polish population.

Correlates of gambling on high-school grounds

ObjectiveThis study examined adolescent gambling on school grounds (GS+) and how such behavior was associated with gambling-related attitudes. Further, we examined whether GS+ moderated associations between at-risk problem-gambling (ARPG) and gambling behaviors related to gambling partners. MethodParticipants were 1988 high-school students who completed survey materials. Demographic, perceptions, attitudes, and gambling variables were stratified by problem-gambling severity (ARPG versus recreational gambling) and GS+ status. Chi-square and adjusted logistic regression models were used to examine relationships among study variables. ResultsNearly 40% (39.58%) of students reported past-year GS+, with 12.91% of GS+ students, relative to 2.63% of those who did not report gambling on school grounds (GS−), meeting DSM-IV criteria for pathological gambling (p<0.0001). In comparison to GS− students, GS+ students were more likely to report poorer academic achievement and more permissive attitudes towards gambling behaviors. Weaker links in GS+ students, in comparison with GS−, students, were observed between problem-gambling severity and gambling with family members (interaction odds ratio (IOR)=0.60; 95% CI=0.39–0.92) and gambling with friends (IOR=0.21; 95% CI=0.11–0.39). ConclusionsGS+ is common and associated with pathological gambling and more permissive attitudes towards gambling. The finding that GS+ (relative to GS−) youth show differences in how problem-gambling is related to gambling partners (friends and family) warrants further investigation regarding whether and how peer and familial interactions might be improved to diminish youth problem-gambling severity. The high frequency of GS+ and its relationship with ARPG highlights a need for school administrators and personnel to consider interventions that target school-based gambling.

Gene-environment interactions between JAZF1 and occupational and household lead exposure in prostate cancer among African American men.

A single nucleotide polymorphism, rs10486567, in JAZF1 has consistently been associated with increased risk of prostate cancer. The physical interaction of zinc finger proteins, such as JAZF1, with heavy metals may play a role in carcinogenesis. This study assessed potential gene-environment statistical interactions (G×E) between rs10486567 and heavy metals in prostate cancer. In a case-only study of 228 African American prostate cancer cases, G×E between rs10486567 and sources of cadmium and lead (Pb) were assessed. Unconditional logistic regression was used to estimate interaction odds ratios (IORs), and generalized estimating equations were used for models containing nested data. Case-control validation of IORs was performed, using 82 controls frequency matched to cases on age-race. Among cases, a potential G×E interaction was observed between rs10486567 CC genotype and living in a Census tract with a high proportion of housing built before 1950, a proxy for household Pb exposure, when compared to CT or TT carriers (OR 1.81; 95% CI 1.04-3.16; p = 0.036). A stronger G×E interaction was observed when both housing and occupational Pb exposure were taken into account (OR 2.62; 95% CI 1.03-6.68; p = 0.04). Case-control stratified analyses showed the odds of being a CC carrier were higher in cases compared to controls among men living in areas with older housing (OR 2.03; CI 0.99-4.19; p = 0.05) or having high occupational Pb exposure (OR 2.50; CI 1.01-6.18; p = 0.05). In African American men, the association between JAZF1 rs10486567 and prostate cancer may be modified by exposure to heavy metals such as Pb.

Maternal–fetal metabolic gene–gene interactions and risk of neural tube defects

Single-gene analyses indicate that maternal genes associated with metabolic conditions (e.g., obesity) may influence the risk of neural tube defects (NTDs). However, to our knowledge, there have been no assessments of maternal–fetal metabolic gene–gene interactions and NTDs. We investigated 23 single nucleotide polymorphisms among 7 maternal metabolic genes (ADRB3, ENPP1, FTO, LEP, PPARG, PPARGC1A, and TCF7L2) and 2 fetal metabolic genes (SLC2A2 and UCP2). Samples were obtained from 737 NTD case-parent triads included in the National Birth Defects Prevention Study for birth years 1999–2007. We used a 2-step approach to evaluate maternal–fetal gene–gene interactions. First, a case-only approach was applied to screen all potential maternal and fetal interactions (n=76), as this design provides greater power in the assessment of gene–gene interactions compared to other approaches. Specifically, ordinal logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (CI) for each maternal–fetal gene–gene interaction, assuming a log-additive model of inheritance. Due to the number of comparisons, we calculated a corrected p-value (q-value) using the false discovery rate. Second, we confirmed all statistically significant interactions (q<0.05) using a log-linear approach among case-parent triads. In step 1, there were 5 maternal–fetal gene–gene interactions with q<0.05. The “top hit” was an interaction between maternal ENPP1 rs1044498 and fetal SLC2A2 rs6785233 (interaction OR=3.65, 95% CI: 2.32–5.74, p=2.09×10−8, q=0.001), which was confirmed in step 2 (p=0.00004). Our findings suggest that maternal metabolic genes associated with hyperglycemia and insulin resistance and fetal metabolic genes involved in glucose homeostasis may interact to increase the risk of NTDs.

Gene-environment interaction between body mass index and transforming growth factor beta 1 (TGFβ1) gene in knee and hip osteoarthritis

IntroductionThe objective was to investigate potential gene-environment interaction between body mass index (BMI) and each of eight TGFβ1 polymorphisms in knee and hip osteoarthritis (OA).MethodsWe conducted a case-control study of Caucasian men and women aged 45 to 86 years from Nottingham, United Kingdom (Genetics of OA and Lifestyle (GOAL) study). Cases had clinically severe symptoms and radiographic knee or hip OA; controls had no symptoms and no radiographic knee/hip OA. We used logistic regression to investigate the association of TGFβ1 polymorphisms and OA when stratifying by BMI. Knee and hip OA were analyzed separately with adjustment for potential confounders. Additive and multiplicative interactions were examined.Results2,048 cases (1,042 knee OA, 1,006 hip OA) and 967 controls were studied. For hip OA, the highest risk was in overweight (BMI ≥25 kg/m2) individuals with the variant allele of single-nucleotide polymorphism (SNP) rs1800468 (odds ratio (OR) 2.21, 95% confidence interval (CI) 1.55, 3.15). Evaluation of gene-environment interaction indicated significant synergetic interaction (relative excess risk due to interaction (RERI) = 0.93, synergy index (SI) = 4.33) with an attributable proportion due to interaction (AP) of 42% (AP = 0.42; 95% CI 0.16, 0.68). Multiplicative interaction was also significant (OR for interaction (ORINT) = 2.27, P = 0.015). For knee OA, the highest risk was in overweight individuals with homozygous genotype 11 of SNP rs2278422 (OR = 6.95, P <0.001). In contrast, the variant allele indicated slightly lower risks (OR = 4.72, P <0.001), a significant antagonistic interaction (RERI = -2.66, SI = 0.59), AP = -0.56 (95%CI -0.94, -0.17) and a significant multiplicative interaction (ORINT = 0.47, P = 0.013).ConclusionTGFβ1 gene polymorphisms interact with being overweight to influence the risk of large joint OA.

Abstract P3-08-02: Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets

Abstract Background: E-cadherin is a tumor suppressor gene involved in cell-cell adhesion, epithelial-to-mesenchymal transitions (EMT) and invasion. Loss of E-cadherin expression is strongly associated with lobular breast cancers, which exhibit single cell patterns of infiltration and are often estrogen receptor positive. We sought to determine if relative risk estimates for 19 established breast cancer susceptibility loci were modified by E-cadherin breast tumor tissue expression. Methods: Case-control analyses included up to 1885 invasive breast cancer cases and 2366 age and site matched controls aged 20–74 years from the Polish Breast Cancer Study (PBCS), a population based case-control study conducted in Poland from 2000–2003. Genotyping of the 19 single nucleotide polymorphisms (SNPs) was performed using TaqMan® assays. Tissue expression of E-cadherin was assessed using immunohistochemical (IHC) staining of tissue microarrays and IHC results were scored as the product of percent positive tumor cells × intensity. Tumors having a score of &amp;lt;10 were classified as E-cadherin low and those with a score ≥10 as E-cadherin high. Polytomous logistic regression models adjusted for age and study site were used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for each breast cancer subtype, defined by E-cadherin expression levels, compared to controls. Case-only data from the PBCS (N = 797) and the Study of Epidemiology and Risk Factors in Cancer Heredity, SEARCH (N = 2155) was used in logistic regression models to test for heterogeneity of SNPs by E-cadherin expression. Results: Three SNPs suggested significant heterogeneity by E-cadherin expression in the PBCS: rs2046210 at 6q25.1(ESR1) [per-allele ORs (95% CI); 1.53 (1.19–1.98) for E-cadherin low tumors and 0.99 (0.86–1.14) for E-cadherin high tumors, P-heterogeneity = 0.002]; rs1045485 at 10p14 (CASP8) [per-allele ORs (95% CI); 0.62 (0.41–0.93) for E-cadherin low tumors and 0.98 (0.81–1.18) for E-cadherin high tumors, P-heterogeneity = 0.04]; and rs11249433 at 1p11.2 (NOTCH2/FCGR1B) [per-allele ORs (95% CI); 1.29 (1.02–1.64) for E-cadherin low tumors and 1.01 (0.88–1.15) for E-cadherin high tumors, P-heterogeneity = 0.06]. Combined case-only analysis of PBCS and SEARCH for these three SNPs showed significant heterogeneity by E-cadherin expression for rs11249433 [Interaction OR (95% CI); 1.19 (1.05–1.36), P-heterogeneity = 0.007] and rs1045485 [Interaction OR (95% CI); 0.69 (0.53–0.90), P-heterogeneity = 0.007]. The association with rs2046210 [Interaction OR (95% CI); 1.12 (0.61–2.03), P-heterogeneity = 0.73] did not remain significant in combined analyses. Conclusion: Our findings provide evidence that associations for breast cancer susceptibility loci vary by E-cadherin tumor tissue expression, which has not been described previously. Specifically, our results suggest that the genetic markers rs11249433 and rs1045485 may preferentially modify risk for tumors with low or absent E-cadherin expression in two independent data sets. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-02.

Epistasis between neurochemical gene polymorphisms and risk for ADHD

A number of genes with function related to synaptic neurochemistry have been genetically associated with attention deficit/hyperactivity disorder. However, susceptibility to the development of common psychiatric disorders by single variants acting alone, can so far only explain a small proportion of the heritability of the phenotype. It has been postulated that the unexplained 'dark heritability' may at least in part be due to epistatic effects, which may account for the small observed marginal associations, and the difficulties with replication of positive findings. We undertook a comprehensive exploration of pair-wise interactions between genetic variants in 24 candidate genic regions involved in monoaminergic catabolism, anabolism, release, re-uptake and signal transmission in a sample of 177 parent-affected child trios using a case-only design and a case-pseudocontrol design using conditional logistic regression. Marker-pairs thresholded on interaction odds ratio (OR) and P-value are presented. We detected a number of interaction ORs >4.0, including an interesting correlation between markers in the ADRA1B and DBH genes in affected individuals, and several further interesting but smaller effects. These effects are no larger than you would expect by chance under the assumption of independence of all pair-wise relations; however, independence is unlikely. Furthermore, the size of these effects is of interest and attempts to replicate these results in other samples are anticipated.