Case-control Logistic Regression Research Articles

Abstract 95: Associations of Ischemic Stroke With Known Stroke Susceptibility Loci Vary by Age

Objective: The goal of this study was to test whether the strength of association of stroke-associated genetic variants differs by age of stroke onset. Background: In the MEGASTROKE GWAS study, 55 variants were robustly associated with ischemic stroke in predominantly older populations. Yet limited research has been carried out to date to understand how these genetic associations are modified by age, which could provide clues to the underlying biological mechanisms of these associations. Methods: Analyses were based on 16,000 stroke cases of European ancestry identified from the Stroke Genetics Network (SiGN) and Early Onset Ischemic Stroke Consortium and 24,838 stroke-free controls. We tested if the associations of each variant with stroke differed by age using two complementary approaches. First, we used a case-control logistic regression model testing for the associations of stroke with variant, age, and a variant*age interaction term and second, we used a case-only approach, testing for an association of variant with age of stroke onset. All analyses were adjusted for sex and population structure. Results: We identified six variants whose associations were significantly modified by age (p ≤ 0.001) by either analysis; 5 variants by the case-control analysis and 4 variants by the case-only analysis. Among these were 2 variants at the ABO locus that have been previously shown to be more strongly associated with early compared to late onset stroke, tagging blood groups A and O, respectively, and a variant in WNT2B that has previously been associated with early, but not late, onset ischemic stroke in a small case-control study. Conclusions: Six out of 55 variants previously associated with ischemic stroke in large GWAS studies show differential effects by age, with the stroke risk allele more strongly associated with early onset stroke for 5 variants or more strongly associated with older onset stroke (1 variant). Future work is needed to understand the reasons for this age dependency. Disclosures: None. Study Supported By: R01NS100178, R01NS105150, R01NS114045

APOE Genotype and Alzheimer Disease Risk Across Age, Sex, and Population Ancestry

Apolipoprotein E (APOE)*2 and APOE*4 are, respectively, the strongest protective and risk-increasing, common genetic variants for late-onset Alzheimer disease (AD), making APOE status highly relevant toward clinical trial design and AD research broadly. The associations of APOE genotypes with AD are modulated by age, sex, race and ethnicity, and ancestry, but these associations remain unclear, particularly among racial and ethnic groups understudied in the AD and genetics research fields. To assess the stratified associations of APOE genotypes with AD risk across sex, age, race and ethnicity, and global population ancestry. This genetic association study included case-control, family-based, population-based, and longitudinal AD-related cohorts that recruited referred and volunteer participants. Data were analyzed between March 2022 and April 2023. Genetic data were available from high-density, single-nucleotide variant microarrays, exome microarrays, and whole-exome and whole-genome sequencing. Summary statistics were ascertained from published AD genetic studies. The main outcomes were risk for AD (odds ratios [ORs]) and risk of conversion to AD (hazard ratios [HRs]), with 95% CIs. Risk for AD was evaluated through case-control logistic regression analyses. Risk of conversion to AD was evaluated through Cox proportional hazards regression survival analyses. Among 68 756 unique individuals, analyses included 21 852 East Asian (demographic data not available), 5738 Hispanic (68.2% female; mean [SD] age, 75.4 [8.8] years), 7145 non-Hispanic Black (hereafter referred to as Black) (70.8% female; mean [SD] age, 78.4 [8.2] years), and 34 021 non-Hispanic White (hereafter referred to as White) (59.3% female; mean [SD] age, 77.0 [9.1] years) individuals. There was a general, stepwise pattern of ORs for APOE*4 genotypes and AD risk across race and ethnicity groups. Odds ratios for APOE*34 and AD risk attenuated following East Asian (OR, 4.54; 95% CI, 3.99-5.17),White (OR, 3.46; 95% CI, 3.27-3.65), Black (OR, 2.18; 95% CI, 1.90-2.49) and Hispanic (OR, 1.90; 95% CI, 1.65-2.18) individuals. Similarly, ORs for APOE*22+23 and AD risk attenuated following White (OR, 0.53, 95% CI, 0.48-0.58), Black (OR, 0.69, 95% CI, 0.57-0.84), and Hispanic (OR, 0.89; 95% CI, 0.72-1.10) individuals, with no association for Hispanic individuals. Deviating from the global pattern of ORs, APOE*22+23 was not associated with AD risk in East Asian individuals (OR, 0.97; 95% CI, 0.77-1.23). Global population ancestry could not explain why Hispanic individuals showed APOE associations with less pronounced AD risk compared with Black and White individuals. Within Black individuals, decreased global African ancestry or increased global European ancestry showed a pattern of APOE*4 dosage associated with increasing AD risk, but no such pattern was apparent for APOE*2 dosage with AD risk. The sex-by-age-specific interaction effect of APOE*34 among White individuals (higher risk in women) was reproduced but shifted to ages 60 to 70 years (OR, 1.48; 95% CI, 1.10-2.01) and was additionally replicated in a meta-analysis of Black individuals and Hispanic individuals (OR, 1.72; 95% CI, 1.01-2.94). Through recent advances in AD-related genetic cohorts, this study provided the largest-to-date overview of the association of APOE with AD risk across age, sex, race and ethnicity, and population ancestry. These novel insights are critical to guide AD clinical trial design and research.

Genome-wide interaction analysis of folate for colorectal cancer risk

BackgroundEpidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate’s role in CRC. ObjectivesOur aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. MethodsWe applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). ResultsInverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. ConclusionsVariation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

Abstract 817: Probing the diabetes - colorectal cancer link using gene - environment interaction analyses

Abstract Background: Type 2 diabetes mellitus (T2D) is an established risk factor for colorectal cancer. However, the mechanisms underlying this relationship are unclear and it is not known if the association is modified by genetic variants. To provide insights into the molecular pathways potentially linking diabetes and colorectal cancer, we undertook a large-scale gene-environment interaction analysis (GxE). Methods: We tested multiplicative statistical interactions between approximately 7 million common (allele frequency &amp;gt;1%) genetic variants and T2D status in 31,529 colorectal cancer cases and 42,861 controls of European ancestry from 3 genetic consortia (GECCO/CCFR/CORECT). Statistical methods included traditional case-control logistic regression, case-only analyses, joint tests (2df/3df), and two-step approaches. We also explored additive and multiplicative interactions between polygenic risk score (PRS) of the known genome-wide significant loci for colorectal cancer and T2D. Results: Overall, T2D was positively associated with colorectal cancer risk [odds ratio [OR]: 1.25 (95% confidence interval [CI]: 1.14-1.36)]. A statistically significant interaction was identified between T2D status and an intronic variant in LRCH1 (rs9526201) and colorectal cancer risk using the 2-d.f. joint test (p-value:1.44x10-8). A statistically significant additive scale interaction between PRS for colorectal cancer and T2D was found (p-value: 1.8x10-10) such that the observed risk of developing colorectal cancer for individuals with T2D and a 1 standard deviation (SD) higher increment of PRS compared to non-diabetics with the lowest PRS was 0.184 more than if there was no interaction between T2D and PRS. Conclusion: These results suggest that variation in a gene related to immune function may modify the association of T2D with colorectal cancer and potentially provide novel insights into the biology underlying this relationship. Furthermore, our data show that genetic risk prediction models for CRC may need to consider non-genetic risk factors. Citation Format: Niki Dimou, Andre E. Kim, Orlagh Flanagan, Neil Murphy, Emmanouil Bouras, Peter T. Campbell, Graham Casey, Steven Gallinger, Stephen B. Gruber, Li Hsu, Mark A. Jenkins, Yi Lin, Victor Moreno, Conghui Qu, Edward Ruiz-Narvaez, Mariana C. Stern, Yu Tian, Kostas Tsilidis, W. James Gauderman, Marc J. Gunter, Ulrike Peters. Probing the diabetes - colorectal cancer link using gene - environment interaction analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 817.

Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia.

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R2) of the case-control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R2) of 0.027 (P value = 4.6 × 10-8), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96-5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.

Association of Body Mass Index With Colorectal Cancer Risk by Genome-Wide Variants.

Body mass index (BMI) is a complex phenotype that may interact with genetic variants to influence colorectal cancer risk. We tested multiplicative statistical interactions between BMI (per 5 kg/m2) and approximately 2.7 million single nucleotide polymorphisms with colorectal cancer risk among 14059 colorectal cancer case (53.2% women) and 14416 control (53.8% women) participants. All analyses were stratified by sex a priori. Statistical methods included 2-step (ie, Cocktail method) and single-step (ie, case-control logistic regression and a joint 2-degree of freedom test) procedures. All statistical tests were two-sided. Each 5 kg/m2 increase in BMI was associated with higher risks of colorectal cancer, less so for women (odds ratio [OR] = 1.14, 95% confidence intervals [CI] = 1.11 to 1.18; P = 9.75 × 10-17) than for men (OR = 1.26, 95% CI = 1.20 to 1.32; P = 2.13 × 10-24). The 2-step Cocktail method identified an interaction for women, but not men, between BMI and a SMAD7 intronic variant at 18q21.1 (rs4939827; Pobserved = .0009; Pthreshold = .005). A joint 2-degree of freedom test was consistent with this finding for women (joint P = 2.43 × 10-10). Each 5 kg/m2 increase in BMI was more strongly associated with colorectal cancer risk for women with the rs4939827-CC genotype (OR = 1.24, 95% CI = 1.16 to 1.32; P = 2.60 × 10-10) than for women with the CT (OR = 1.14, 95% CI = 1.09 to 1.19; P = 1.04 × 10-8) or TT (OR = 1.07, 95% CI = 1.01 to 1.14; P = .02) genotypes. These results provide novel insights on a potential mechanism through which a SMAD7 variant, previously identified as a susceptibility locus for colorectal cancer, and BMI may influence colorectal cancer risk for women.

Glaucoma in large-scale population-based epidemiology: a questionnaire-based proxy

PurposeTo improve upon self-reported glaucoma status in population-based cohorts by developing a questionnaire-based proxy incorporating self-reported status in conjunction with glaucoma-specific visual complaints.MethodsA vision specific questionnaire, including questions from the National Eye Institute Visual Functioning Questionnaire-25 (NEI-VFQ-25) was administered to 79,866 Lifelines participants, a population-based cohort study in the Northern Netherlands. We compared NEI-VFQ-25 responses between ‘definite’ glaucoma cases (n = 90; self-reported surgical cases) and an age- and gender-matched subset of controls (n = 1,800) to uncover glaucoma-specific visual complaints, using a case–control logistic regression. We defined ‘probable glaucoma’ as both self-reported disease status and visual complaints, and ‘possible glaucoma’ as either. To evaluate the resulting proxy, we determined age-stratified glaucoma prevalences in the remaining cohort and compared the result to the literature.ResultsPer unit increase in the vision subscales (range 0–100) distance, peripheral and low luminance, we observed significantly increased odds of definite glaucoma (2% [P = 0.03], 4% [P = 1.2 × 10−8] and 2% [P = 0.02], respectively); the associated area under the curve was 0.73. We identified 300 probable and 3,015 (1,434 by self-report) possible glaucoma cases. Standardised prevalences of definite, probable and possible glaucoma for 55+ were 0.4%, 1.1% and 7.3%, respectively. For self-reported glaucoma (combining definite, probable and possible by self-report), this was 5.2%.ConclusionsThe combination of self-reported glaucoma status and visual complaints can be used to capture glaucoma cases in population-based settings. The resulting prevalence of combined definite and probable glaucoma (1.5%) appears to be more consistent with previous reports than the prevalence estimate of 5.2% based only on self-report.

Keeping cool in the warming Arctic: thermoregulatory behaviour by Svalbard reindeer (Rangifer tarandus platyrhynchus)

In animals with long generation times, evolution of physiological and morphological traits may not be fast enough to keep up with rapid climate warming, but thermoregulatory behaviour can possibly serve as an important buffer mitigating warming effects. In this study, we investigated if the cold-adapted Svalbard reindeer (Rangifer tarandus platyrhynchus (Vrolik, 1829)) used cool bed sites as a thermoregulatory behaviour in the summer. We recorded habitat variables and ground temperature at 371 bed sites with random “control” sites 10 and 100 m distant. Using case-control logistic regression, we found that reindeer selected bed sites on cool substrates (snow and mire), as well as cold, dry ground on days with warm ambient temperatures, while they avoided such sites on cold days. Selection of both cool substrates and cool ground did not depend on age or sex. The study was conducted in an environment where neither predatory threat nor insect harassment influenced bed site selection. Our findings suggest that the thermal landscape is important for habitat selection of cold-adapted Arctic ungulates in summer. Thus, behavioural strategies may be important to mitigate effects of climate change, at least in the short term.

Interactions Between Genetic Variants and Environmental Factors Affect Risk of Esophageal Adenocarcinoma and Barrett’s Esophagus

Background & AimsGenome-wide association studies (GWAS) have identified more than 20 susceptibility loci for esophageal adenocarcinoma (EA) and Barrett’s esophagus (BE). However, variants in these loci account for a small fraction of cases of EA and BE. Genetic factors might interact with environmental factors to affect risk of EA and BE. We aimed to identify single nucleotide polymorphisms (SNPs) that may modify the associations of body mass index (BMI), smoking, and gastroesophageal reflux disease (GERD), with risks of EA and BE.MethodsWe collected data on single BMI measurements, smoking status, and symptoms of GERD from 2284 patients with EA, 3104 patients with BE, and 2182 healthy individuals (controls) participating in the Barrett’s and Esophageal Adenocarcinoma Consortium GWAS, the UK Barrett’s Esophagus Gene Study, and the UK Stomach and Oesophageal Cancer Study. We analyzed 993,501 SNPs in DNA samples of all study subjects. We used standard case–control logistic regression to test for gene-environment interactions.ResultsFor EA, rs13429103 at chromosome 2p25.1, near the RNF144A-LOC339788 gene, showed a borderline significant interaction with smoking status (P = 2.18×10-7). Ever smoking was associated with an almost 12-fold increase in risk of EA among individuals with rs13429103-AA genotype (odds ratio=11.82; 95% CI, 4.03–34.67). Three SNPs (rs12465911, rs2341926, rs13396805) at chromosome 2q23.3, near the RND3-RBM43 gene, interacted with GERD symptoms (P = 1.70×10-7, P = 1.83×10-7, and P = 3.58×10-7, respectively) to affect risk of EA. For BE, rs491603 at chromosome 1p34.3, near the EIF2C3 gene, and rs11631094 at chromosome 15q14, at the SLC12A6 gene, interacted with BMI (P = 4.44×10-7) and pack-years of smoking history (P = 2.82×10-7), respectively.ConclusionThe associations of BMI, smoking, and GERD symptoms with risks of EA and BE appear to vary with SNPs at chromosomes 1, 2, and 15. Validation of these suggestive interactions is warranted.

Bayesian Estimation of Pneumonia Etiology: Epidemiologic Considerations and Applications to the Pneumonia Etiology Research for Child Health Study.

In pneumonia, specimens are rarely obtained directly from the infection site, the lung, so the pathogen causing infection is determined indirectly from multiple tests on peripheral clinical specimens, which may have imperfect and uncertain sensitivity and specificity, so inference about the cause is complex. Analytic approaches have included expert review of case-only results, case–control logistic regression, latent class analysis, and attributable fraction, but each has serious limitations and none naturally integrate multiple test results. The Pneumonia Etiology Research for Child Health (PERCH) study required an analytic solution appropriate for a case–control design that could incorporate evidence from multiple specimens from cases and controls and that accounted for measurement error. We describe a Bayesian integrated approach we developed that combined and extended elements of attributable fraction and latent class analyses to meet some of these challenges and illustrate the advantage it confers regarding the challenges identified for other methods.

Modeling lane-change-related crashes with lane-specific real-time traffic and weather data

ABSTRACTThis study investigates the relationship between lane-change-related crashes and lane-specific, real-time traffic factors. It is anticipated that the real-time traffic data for the two lanes—the vehicle's lane (subject lane) and the lane to which that a vehicle intends to change (target lane)—are more closely related to lane-change-related crashes, as opposed to congregated traffic data for all lanes. Lane-change-related crash data were obtained from a 62-mile long freeway in Southeast Wisconsin in 2012 and 2013. One-minute traffic data from the 5- to 10-minute interval prior to the crashes were extracted from an immediately upstream detector station and two immediately downstream stations from the crash location. Weather information was collected from a major historical weather database. A matched case-control logistic regression was used for analysis. Results show that the following factors significantly affect the probability of a lane-change-related crash: average flow into the target lane at the first downstream station, the flow ratio at the second downstream station, and snow conditions. Additionally, the average speed in the target lane at the first downstream station contributes to the occurrence of lane-change crashes during snowy conditions. According to the model, the probability of a lane-change-related crash under real-time traffic conditions can aid in flagging potential crash-prone conditions. The identified contributing factors can help traffic operators select traffic control and management countermeasures to proactively mitigate lane-change-related crashes.

Peripheral inflammatory cytokines and immune balance in Generalised Anxiety Disorder: Case-controlled study

Introduction: Previous investigations have demonstrated that major depression is associated with particular patterns of cytokine signalling. The primary aim of this study was to examine peripheral pro-inflammatory and anti-inflammatory cytokines and immune balance in Generalised Anxiety Disorder (GAD). Methods: A case-controlled cross-sectional study design was employed: 54 patients with GAD and 64 healthy controls were recruited. Participants completed self-report measures of anxiety and depression. Two pro-inflammatory and two anti-inflammatory cytokines were measured using multiplex technology. Results: Case-control logistic regression analyses revealed significant differences in serum levels of IL-10, TNF-α, and IFN-γ between GAD and control groups after adjusting for age, gender, body mass index, smoking and alcohol consumption: these group differences were independent of the presence or degree of depression. Comparison of pro-inflammatory to anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF-α/IL10, TNF-α/IL4, IFN-γ/IL10, and IFN-γ/IL4 in the GAD group compared to the control group. Conclusions: This study is the first to investigate both pro- and anti-inflammatory cytokines and their balance in patients with GAD in comparison to healthy controls. The findings indicate a relatively increased pro-inflammatory response and decreased anti-inflammatory response and provide the first demonstration of an altered cytokine balance in GAD. Serum cytokine levels in GAD were independent of the presence of depression.

Abstract # 1866 How is the immune balance affected in patients with generalised anxiety disorder?

Introduction Greater understanding of the role of cytokines in interactions between the nervous and immune systems has led to integrative and explanatory models for neuropsychiatric disorders. Our study aimed to examine peripheral inflammatory cytokines and immune balance in generalised anxiety disorder (GAD). Methods A case-controlled cross-sectional study investigated associations between psychological and biological variables. 54 patients with GAD and 64 healthy controls were recruited. Participants completed self-report measures of anxiety and depression. A panel of two pro-inflammatory and two anti-inflammatory cytokines were measured using multiplex technology. Results Case-control logistic regression analyses revealed significant differences in serum levels of IL-10, TNF- α , and IFN- γ between GAD and control groups after adjusting for age, gender and body mass index: these group differences were independent of the presence or degree of depression. Comparison of pro- and anti-inflammatory cytokine ratios indicated that there were significantly higher ratios of TNF- α /IL10, TNF- α /IL4, IFN- γ /IL10, and IFN- γ /IL4 in the GAD group compared to the control group. Conclusions This study is the first to investigate both pro- and anti-inflammatory cytokines and their balance in patients with GAD in comparison to healthy controls. The findings indicate a relatively increased pro-inflammatory response and diminished anti-inflammatory response and provide the first demonstration of a Th1/Th2 cytokine imbalance in GAD. The changes in serum cytokine levels in GAD were independent of the presence of depression.

Analysis of Sideswipe Collision Precursors Considering the Spatial-Temporal Characteristics of Freeway Traffic

AbstractTo avoid bias caused by the high percentage of rear-end collisions in the generic models, only the observed sideswipe collisions on Highway I-5 in the central Puget Sound, Washington State, area are used to analyze the matched case-control logistic regression model. Considering the spatial-temporal characteristics of traffic flow and short-term variation of the sideswipe collision occurrence, a comprehensive analysis of sideswipe collision occurrence and its relationship with the freeway flow across lanes and detector locations are studied. The results imply that sideswipe collisions are more likely to occur at straight and level segments of multilane freeways in off-peak hours. High average occupancy and low average flow and speed variance upstream of collision location tend to increase the probability of sideswipe collision in congested scenarios. In contrast, high average speed and coefficient of variation in speed, low speed variance and coefficient of variation in occupancy, and high average ...

Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis

Hashimoto's thyroiditis (HT) is the most common form of autoimmune thyroid diseases (AITD) characterized by progressive destruction of thyroid tissue that may lead to hypothyroidism. High thyroid autoantibodies against thyroid peroxidase (TPOAb) levels are present in 90% of patients with HT and serve as a clinical marker for the detection of early AITD/HT. The main aim of our study was to test whether recently identified genetic variants associated with TPOAb are also involved in HT development.A total of 504 unrelated individuals, including 200 patients with HT and 304 controls, were involved in this study. Diagnosis of HT cases was based on clinical examination, measurement of thyroid hormones (TSH and fT4) and antibodies (TgAb, TPOAb) and ultrasound examination. We selected and genotyped 14 known TPOAb-associated genetic variants. Case–control logistic regression model was used to test the association of selected genetic variants with HT. Additionally, we tested association of the same genetic variants with thyroid related quantitative traits (TPOAb levels, TgAb levels and thyroid gland volume) using linear regression.Three genetic variants showed nominal association with HT; rs10774625 in ATXN2 gene (p = 0.0149, OR = 0.73, CI = 0.56–0.94), rs7171171 near RASGRP1 gene (p = 0.0356, OR = 1.4, CI = 1.02–1.92) and rs11675434 in TPO gene (p = 0.041, OR = 1.31, CI = 1.01–1.69). Two of these SNPs (rs1077462, rs11675434) also showed association with TPOAb levels (p = 0.043, β = −0.39; p = 0.042, β = 0.40, respectively) and one (rs7171171) was associated with thyroid gland volume (p = 0.0226, β = −0.21).Our findings suggest that variants inside or near TPO, ATXN2 and RASGRP1 genes are associated with HT. Identified loci are novel to HT and represent good basis for further exploration of HT susceptibility.

CYP24A1 variant modifies the association between use of oestrogen plus progestogen therapy and colorectal cancer risk.

Background:Menopausal hormone therapy (MHT) use has been consistently associated with a decreased risk of colorectal cancer (CRC) in women. Our aim was to use a genome-wide gene–environment interaction analysis to identify genetic modifiers of CRC risk associated with use of MHT.Methods:We included 10 835 postmenopausal women (5419 cases and 5416 controls) from 10 studies. We evaluated use of any MHT, oestrogen-only (E-only) and combined oestrogen–progestogen (E+P) hormone preparations. To test for multiplicative interactions, we applied the empirical Bayes (EB) test as well as the Wald test in conventional case–control logistic regression as primary tests. The Cocktail test was used as secondary test.Results:The EB test identified a significant interaction between rs964293 at 20q13.2/CYP24A1 and E+P (interaction OR (95% CIs)=0.61 (0.52–0.72), P=4.8 × 10−9). The secondary analysis also identified this interaction (Cocktail test OR=0.64 (0.52–0.78), P=1.2 × 10−5 (alpha threshold=3.1 × 10−4). The ORs for association between E+P and CRC risk by rs964293 genotype were as follows: C/C, 0.96 (0.61–1.50); A/C, 0.61 (0.39–0.95) and A/A, 0.40 (0.22–0.73), respectively.Conclusions:Our results indicate that rs964293 modifies the association between E+P and CRC risk. The variant is located near CYP24A1, which encodes an enzyme involved in vitamin D metabolism. This novel finding offers additional insight into downstream pathways of CRC etiopathogenesis.

Selected vitamin D metabolic gene variants and risk for autism spectrum disorder in the CHARGE Study

BackgroundVitamin D is essential for proper neurodevelopment and cognitive and behavioral function. We examined associations between autism spectrum disorder (ASD) and common, functional polymorphisms in vitamin D pathways. MethodsChildren aged 24–60months enrolled from 2003 to 2009 in the population-based CHARGE case–control study were evaluated clinically and confirmed to have ASD (n=474) or typical development (TD, n=281). Maternal, paternal, and child DNA samples for 384 (81%) families of children with ASD and 234 (83%) families of TD children were genotyped for: TaqI, BsmI, FokI, and Cdx2 in the vitamin D receptor (VDR) gene, and CYP27B1 rs4646536, GC rs4588, and CYP2R1 rs10741657. Case–control logistic regression, family-based log-linear, and hybrid log-linear analyses were conducted to produce risk estimates and 95% confidence intervals (CI) for each allelic variant. ResultsPaternal VDR TaqI homozygous variant genotype was significantly associated with ASD in case–control analysis (odds ratio [OR] [CI]: 6.3 [1.9–20.7]) and there was a trend towards increased risk associated with VDR BsmI (OR [CI]: 4.7 [1.6–13.4]). Log-linear triad analyses detected parental imprinting, with greater effects of paternally-derived VDR alleles. Child GC AA-genotype/A-allele was associated with ASD in log-linear and ETDT analyses. A significant association between decreased ASD risk and child CYP2R1 AA-genotype was found in hybrid log-linear analysis. There were limitations of low statistical power for less common alleles due to missing paternal genotypes. ConclusionsThis study provides preliminary evidence that paternal and child vitamin D metabolism could play a role in the etiology of ASD; further research in larger study populations is warranted.

Occurrence and risk factors of thyroid dysfunction in chronic hepatitis C patient received interferon treatment

Objective To investigate the antiviral treatment for patients with chronic hepatitis c(CHC) the influence of thyroid function and its related risk factors. Methods Used polyethylene glycol(peg)interferon (PegIFNα-2a)plus ribavirin(RBV)for the treatment of 122 cases of patients with CHC data were retrospectively analyzed.All of the patients before treatment thyroid function were normal.According to the thyroid function after treatment they were divided into normal thyroid function and abnormal thyroid function groups.Adopting the method of case-control study and Logistic regression we analyzed correlative risk factors of thyroid dysfunction. Results 122 CHC patients completed 48 weeks of treatment, and follow-up of 24 weeks,34 patients with thyroid dysfunction, rate of 27.9%. Logistic regression analysis showed that women, a positive thyroid autoantibodies, health care and smoking might be risk factor for thyroid dysfunction(OR=4.470,4.470,4.757 and 7.306,P<0.05 or P<0.01). Conclusion Interferon plus RBV during the treatment of CHC patients with a high incidence of thyroid dysfunction, including women, a positive thyroid autoantibodies, the health, and smoking could be a risk factor for thyroid dysfunction. Key words: Hepatitis C; Interferon; Thyroid Function; Factor analysis, statistical

Multivariate analysis on the association between acquired multi-drug resistant organism infection and ventilator-associated pneumonia:evidence from a nested case-control study of eight ICUs

The aim of this study was to explore the association between acquired multi-drug resistant organism (MDRO) and ventilator-associated pneumonia (VAP) in patients hospitalized at the intensive care unit(ICU). Real-time monitoring system for hospital infection was used to track VAP patients. The period of study was from January 1, 2013 to December 31, 2013. Both a nested case-control study design and logistic multivariable regression model were performed to explore the association. A total of 142 VAP cases and 342 non-VAP controls were available in this study. Duration of Hospital stay, ICU stay and mechanical days were statistically significant between the case and the control group (P≤0.001). Compared with MDRO negative patient, the MDRO colonization or infection patients showed an 3.05-time increase on the risk of VAP (adjusted OR = 4.05, 95% CI:2.51-5.46). Remarkably,MDRO-positive patients were significantly associated with increased duration of mechanical ventilation and antimicrobial drug use (P < 0.001). MDRO colonized and infection patients would significantly increase the risks of VAP, with prolonged hospitalization and ICU stay. Effective measures should be taken to promote and control patient's safety at the hospital.

Tumor size as a recommendable variable for accuracy of the prognostic prediction of gastric cancer: a retrospective analysis of 1,521 patients.

It is still controversial whether tumor size (Ts) should be considered an important indicator for evaluation the prognosis of gastric cancer (GC). The purpose of this study was to elucidate the prognostic prediction superiority of Ts in the large-scale cohort of GC patients. Data from 1,521 patients who underwent the curative resection were analyzed for demonstration the prognostic value of Ts. In addition, a tumor size-node-metastasis (TsNM) classification system was proposed to evaluate the comparative superiorities of the prognostic prediction of GC patients. With the univariate and multivariate analyses, Ts was identified as an independently prognostic predictor of GC patients, as was T stage. Ts was demonstrated to have smaller Akaike information criterion and Bayesian Information Criterion values within the Cox regression analyses than shown by T stage, which represented the optimum prognostic stratification. TsNM classification was also found to be competent for accurately prognostic evaluation of GC patients. The matched case-control logistic regression showed that TsNM classification could provide very powerful discriminations of patients' overall survival, compared with TNM classification. Additionally, Ts stage was found to enhance the survival discriminations in patients with certain clinicopathological characteristics, including male gender, T4a stage, N0 stage, diffuse type of Lauren classification, or age≤60years. Ts should be recommended as an important clinicopathologic variable to enhance the accuracy of the prognostic prediction of GC clinical patients.