Case-only Design Research Articles

Evidence of survival bias in the association between APOE-Є4 and age at ischemic stroke onset.

Large genome-wide association studies (GWASs) using case-control study designs have now identified tens of loci associated with ischemic stroke (IS). As a complement to these studies, we performed GWAS in a case-only design to identify loci influencing the age at onset (AAO) of ischemic stroke. Analyses were conducted in a discovery cohort of 10,857 ischemic stroke cases using a linear regression framework. We meta-analyzed all SNPs with p-value <1 x 10-5 in a sexcombined or sex-stratified analysis using summary data from two additional replication cohorts. In the women-only meta-analysis, we detected significant evidence for the association of AAO with rs429358, an exonic variant in apolipoprotein E (APOE) that encodes for the APOE-Є4 allele. Each copy of the rs429358:T>C allele was associated with a 1.29-year earlier stroke AAO (meta p-value = 2.48 x 10-11). This APOE variant has previously been associated with increased mortality and ischemic stroke AAO. We hypothesized that the association with AAO may reflect a survival bias attributable to an age-related decrease in mortality among APOE-Є4 carriers and have no association to stroke AAO per se. A simulation study showed that a variant associated with overall mortality might indeed be detected with an AAO analysis. A variant with a 2-fold increase in mortality risk would lead to an observed effect of AAO that is comparable to what we found. In conclusion, we detected a robust association of the APOE locus with stroke AAO and provided simulations to suggest that this association may be unrelated to ischemic stroke per se but related to a general survival bias.

Clinical and cognitive outcomes in first-episode psychosis: focus on the interplay between cannabis use and genetic variability in endocannabinoid receptors.

Research data show the impact of the endocannabinoid system on psychosis through its neurotransmission homeostatic functions. However, the effect of the endocannabinoid system genetic variability on the relationship between cannabis use and psychosis has been unexplored, even less in first-episode patients. Here, through a case-only design, we investigated the effect of cannabis use and the genetic variability of endocannabinoid receptors on clinical and cognitive outcomes in first-episode psychosis (FEP) patients. The sample comprised 50 FEP patients of European ancestry (mean age (sd) = 26.14 (6.55) years, 76% males), classified as cannabis users (58%) or cannabis non-users. Two Single Nucleotide Polymorphisms (SNP) were genotyped at the cannabinoid receptor type 1 gene (CNR1 rs1049353) and cannabinoid receptor type 2 gene (CNR2 rs2501431). Clinical (PANSS, GAF) and neuropsychological (WAIS, WMS, BADS) assessments were conducted. By means of linear regression models, we tested the main effect of cannabis use and its interaction with the polymorphic variants on the clinical and cognitive outcomes. First, as regards cannabis effects, our data showed a trend towards more severe positive symptoms (PANSS, p = 0.05) and better performance in manipulative abilities (matrix test-WAIS, p = 0.041) among cannabis users compared to non-users. Second, concerning the genotypic effects, the T allele carriers of the CNR1 rs1049353 presented higher PANSS disorganization scores than CC homozygotes (p = 0.014). Third, we detected that the observed association between cannabis and manipulative abilities is modified by the CNR2 polymorphism (p = 0.022): cannabis users carrying the G allele displayed better manipulative abilities than AA genotype carriers, while the cannabis non-users presented the opposite genotype-performance pattern. Such gene-environment interaction significantly improved the overall fit of the cannabis-only model (Δ-R2 = 8.4%, p = 0.019). Despite the preliminary nature of the sample, our findings point towards the role of genetic variants at CNR1 and CNR2 genes in the severity of the disorganized symptoms of first-episode psychosis and modulating cognitive performance conditional to cannabis use. This highlights the need for further characterization of the combined role of endocannabinoid system genetic variability and cannabis use in the understanding of the pathophysiology of psychosis.

Coffee, Phosphoinositide 3-Kinase Signaling Pathway, and Prostate Cancer: A Prospective Study in the Health Professionals Follow-Up Study

BackgroundHigher coffee intake has been associated with reduced risk of prostate cancer, particularly aggressive forms. The activation of the phosphoinositide 3-kinase (PI3K) signaling pathway plays an important role in prostate carcinogenesis. ObjectiveTo evaluate associations between prediagnostic coffee intake and a PI3K activation score, the expression/presence of PI3K regulators, and downstream effectors in tumor tissue from men with prostate cancer in the Health Professionals Follow-Up Study, a prospective cohort study conducted in the United States. DesignA case-only study design was applied. Coffee intake was assessed using validated food frequency questionnaires completed in 1986 and every 4 years thereafter until prostate cancer diagnosis. Participants settingStudy participants comprised 1242 men diagnosed with prostate cancer from 1986 to 2009 and with tumor markers assessed from tissue microarrays constructed from tumor specimens. Main outcome measuresThe outcomes include the PI3K activation score; expression of insulin receptor and insulin-like growth factor 1 receptor; angiogenesis markers; and presence of the tumor suppressor phosphatase and tensin homolog, chronic and acute inflammation, simple atrophy, and post-atrophic hyperplasia. Statistical analyses performedMultivariable linear or logistic regression was conducted to estimate associations between coffee intake and tumor marker expression/presence. ResultsAmong coffee drinkers (86.6% of the population), median (25th, 75th percentile) coffee intake was 2 c/day (1, 3 c/day). The associations between coffee consumption and the tumor markers of interest were generally weak with modest precision. When comparing men who drank >3 c/day coffee with nondrinkers, the absolute percent difference in the PI3K activation score and angiogenesis markers ranged from 0.6% to 3.6%. The odds ratios for phosphatase and tensin homolog loss, insulin-like growth factor 1 receptor and insulin receptor expression, and presence of chronic and acute inflammation, simple atrophy, and postatrophic hyperplasia also were not statistically significant, were imprecise, and ranged from 0.82 to 1.58. ConclusionsCoffee intake was not observed to be associated with PI3K activation, related regulators, and several effectors in prostate tumor tissue. Studies exploring alternative pathways or earlier steps in carcinogenesis are needed to investigate the underlying mechanisms of the coffee and prostate cancer association.

Genetic Associations of Primary Angle-Closure Disease

Effects of genetic variants on primary angle-closure disease remained uncertain. To systematically review the associations of common single-nucleotide variants (SNVs) and rare coding variants with primary angle-closure disease, its subtypes (including primary angle-closure glaucoma, primary angle-closure suspect, and primary angle-closure) and progression. Eligible studies from PubMed, Embase, and Web of Science were retrieved up to April 3, 2023. SNV information was extracted from eligible reports and 2 genome-wide association studies summary statistics, UK BioBank and FinnGen. Studies providing analyzable genotype or allele data in a case-control design for primary angle-closure disease association and longitudinal case-only design for primary angle-closure disease progression. PRISMA guidelines were used for literature screening and the Newcastle Ottawa Scale for data quality assessment. Pooled effect size with 95% CIs of SNV associations were calculated using fixed- or random-effect models according to I2 statistics. SNVs reported in 2 or more studies were meta-analyzed to generate pooled odds ratios and P values. Common and rare coding variants from single reports were summarized. Sixty-nine citations were eligible for meta-analysis on overall primary angle-closure disease, involving 206 SNVs in 64 genes or loci. Seventeen SNVs in 15 genes or loci showed associations with primary angle-closure disease, and 15 SNVs in 13 genes or loci showed associations with primary angle-closure glaucoma. Two SNVs, ABCA1 rs2422493 and ZNRF3 rs3178915, were associated only with primary angle-closure disease. Two SNVs, PCMTD1-ST18 rs1015213 and COL11A1 rs3753841, were associated with primary angle-closure suspect, and 1 SNV, MMP9 rs3918249, was associated with primary angle-closure. This systematic review and meta-analysis newly confirmed 7 genes or loci associated with primary angle-closure glaucoma: ATOH7, CALCRL, FBN1, IL6, LOXL1, MMP19, and VAV3. Common and rare coding variants in 16 genes or loci that have been associated with primary angle-closure disease were cataloged. Stratification analysis revealed different primary angle-closure disease-associated genes in different ethnic populations. Only 1 study regarding the genetic association of primary angle-closure glaucoma progression was identified. This study revealed the genetic complexity of primary angle-closure disease, involving common SNVs and rare coding variants in more than 30 genes or loci, with ethnic and phenotypic diversities. Further replication, genotype-phenotype correlation, and pathway analyses are warranted.

Structural models of genome-wide covariance identify multiple common dimensions in autism.

Common genetic variation has been associated with multiple phenotypic features in Autism Spectrum Disorder (ASD). However, our knowledge of shared genetic factor structures contributing to this highly heterogeneous phenotypic spectrum is limited. Here, we developed and implemented a structural equation modelling framework to directly model genomic covariance across core and non-core ASD phenotypes, studying autistic individuals of European descent with a case-only design. We identified three independent genetic factors most strongly linked to language performance, behaviour and developmental motor delay, respectively, studying an autism community sample (N = 5331). The three-factorial structure was largely confirmed in independent ASD-simplex families (N = 1946), although we uncovered, in addition, simplex-specific genetic overlap between behaviour and language phenotypes. Multivariate models across cohorts revealed novel associations, including links between language and early mastering of self-feeding. Thus, the common genetic architecture in ASD is multi-dimensional with overarching genetic factors contributing, in combination with ascertainment-specific patterns, to phenotypic heterogeneity.

Risk Factors for Ovarian Cancer by BRCA Status: A Collaborative Case-Only Analysis.

Women with an inherited pathogenic variant in BRCA1 or BRCA2 have a greatly increased risk of developing ovarian cancer, but the importance of behavioral factors is less clear. We used a case-only design to compare the magnitude of associations with established reproductive, hormonal, and lifestyle risk factors between BRCA mutation carriers and noncarriers. We pooled data from five studies from the Ovarian Cancer Association Consortium including 637 BRCA carriers and 4,289 noncarriers. Covariate-adjusted generalized linear mixed models were used to estimate interaction risk ratios (IRR) and 95% confidence intervals (CI), with BRCA (carrier vs. noncarrier) as the response variable. IRRs were above 1.0 for known protective factors including ever being pregnant (IRR = 1.29, 95% CI; 1.00-1.67) and ever using the oral contraceptive pill (1.30, 95% CI; 1.07-1.60), suggesting the protective effects of these factors may be reduced in carriers compared with noncarriers. Conversely, the IRRs for risk factors including endometriosis and menopausal hormone therapy were below 1.0, suggesting weaker positive associations among BRCA carriers. In contrast, associations with lifestyle factors including smoking, physical inactivity, body mass index, and aspirin use did not appear to differ by BRCA status. Our results suggest that associations with hormonal and reproductive factors are generally weaker for those with a pathogenic BRCA variant than those without, while associations with modifiable lifestyle factors are similar for carriers and noncarriers. Advice to maintain a healthy weight, be physically active, and refrain from smoking will therefore benefit BRCA carriers as well as noncarriers.

Assessing Vulnerability to Surges in Suicide-Related Tweets Using Japan Census Data: Case-Only Study.

As the use of social media becomes more widespread, its impact on health cannot be ignored. However, limited research has been conducted on the relationship between social media and suicide. Little is known about individuals' vulnerable to suicide, especially when social media suicide information is extremely prevalent. This study aims to identify the characteristics underlying individuals' vulnerability to suicide brought about by an increase in suicide-related tweets, thereby contributing to public health. A case-only design was used to investigate vulnerability to suicide using individual data of people who died by suicide and tweet data from January 1, 2011, through December 31, 2014. Mortality data were obtained from Japanese government statistics, and tweet data were provided by a commercial service. Tweet data identified the days when suicide-related tweets surged, and the date-keyed merging was performed by considering 3 and 7 lag days. For the merged data set for analysis, the logistic regression model was fitted with one of the personal characteristics of interest as a dependent variable and the dichotomous exposure variable. This analysis was performed to estimate the interaction between the surges in suicide-related tweets and personal characteristics of the suicide victims as case-only odds ratios (ORs) with 95% CIs. For the sensitivity analysis, unexpected deaths other than suicide were considered. During the study period, there were 159,490 suicides and 115,072 unexpected deaths, and the number of suicide-related tweets was 2,804,999. Following the 3-day lag of a highly tweeted day, there were significant interactions for those who were aged 40 years or younger (OR 1.09, 95% CI 1.03-1.15), male (OR 1.12, 95% CI 1.07-1.18), divorced (OR 1.11, 95% CI 1.03 1.19), unemployed (OR 1.12, 95% CI 1.02-1.22), and living in urban areas (OR 1.26, 95% CI 1.17 1.35). By contrast, widowed individuals had significantly lower interactions (OR 0.83, 95% CI 0.77-0.89). Except for unemployment, significant relationships were also observed for the 7-day lag. For the sensitivity analysis, no significant interactions were observed for other unexpected deaths in the 3-day lag, and only the widowed had a significantly larger interaction than those who were married (OR 1.08, 95% CI 1.02-1.15) in the 7-day lag. This study revealed the interactions of personal characteristics associated with susceptibility to suicide-related tweets. In addition, a few significant relationships were observed in the sensitivity analysis, suggesting that such an interaction is specific to suicide deaths. In other words, individuals with these characteristics, such as being young, male, unemployed, and divorced, may be vulnerable to surges in suicide-related tweets. Thus, minimizing public health strain by identifying people who are vulnerable and susceptible to a surge in suicide-related information on the internet is necessary.

Genome-wide case-only analysis of gene-gene interactions with known Parkinson’s disease risk variants reveals link between LRRK2 and SYT10

The effects of one genetic factor upon Parkinson’s disease (PD) risk may be modified by other genetic factors. Such gene-gene interaction (G×G) could explain some of the ‘missing heritability’ of PD and the reduced penetrance of known PD risk variants. Using the largest single nucleotide polymorphism (SNP) genotype data set currently available for PD (18,688 patients), provided by the International Parkinson’s Disease Genomics Consortium, we studied G×G with a case-only (CO) design. To this end, we paired each of 90 SNPs previously reported to be associated with PD with one of 7.8 million quality-controlled SNPs from a genome-wide panel. Support of any putative G×G interactions found was sought by the analysis of independent genotype-phenotype and experimental data. A total of 116 significant pairwise SNP genotype associations were identified in PD cases, pointing towards G×G. The most prominent associations involved a region on chromosome 12q containing SNP rs76904798, which is a non-coding variant of the LRRK2 gene. It yielded the lowest interaction p-value overall with SNP rs1007709 in the promoter region of the SYT10 gene (interaction OR = 1.80, 95% CI: 1.65–1.95, p = 2.7 × 10−43). SNPs around SYT10 were also associated with the age-at-onset of PD in an independent cohort of carriers of LRRK2 mutation p.G2019S. Moreover, SYT10 gene expression during neuronal development was found to differ between cells from affected and non-affected p.G2019S carriers. G×G interaction on PD risk, involving the LRRK2 and SYT10 gene regions, is biologically plausible owing to the known link between PD and LRRK2, its involvement in neural plasticity, and the contribution of SYT10 to the exocytosis of secretory vesicles in neurons.

Risk of estrogen receptor-specific breast cancer by family history of estrogen receptor subtypes and other cancers.

The extent to which the risk of estrogen receptor (ER)-specific breast cancer is associated with ER status of breast cancer and other cancers among first-degree relatives is unclear. This population-based cohort included 464 707 cancer-free women in Stockholm, Sweden, during 1978-2019. For ER-negative and ER-positive breast cancers, we estimated hazard ratios (HRs) associated with ER status of female first-degree relatives with breast cancer and of other cancers in all first-degree relatives. Associations between ER-negative and ER-positive status by family cancer history were estimated using logistic regression in a case-only design. Women with familial ER-positive breast cancer had 1.87 times (95% confidence interval [CI] = 1.77 to 1.97) higher risk of ER-positive subtype, whereas the corresponding hazard ratio for ER-negative was 2.54 (95% CI = 2.08 to 3.10) when having familial ER-negative breast cancer. The risk increased with an increasing number of female first-degree relatives having concordant subtypes and younger age at diagnosis (Ptrend <.001 for both). Nonbreast cancers among first-degree relatives were associated with both ER-positive (HR = 1.14, 95% CI = 1.10 to 1.17) and ER-negative (HR = 1.08, 95% CI = 1.01 to 1.16) breast cancers. Compared with women with ER-positive breast cancer, women with ER-negative breast cancer were more likely to have family history of liver (odds ratio [OR] = 1.33, 95% CI = 1.05 to 1.67), ovary (OR = 1.28, 95% CI = 1.01 to 1.61), and testicle cancer (OR = 1.79, 95% CI = 1.01 to 3.16) but less likely to have family history of endometrial cancer (OR = 0.77, 95% CI = 0.60 to 1.00) and leukemia (OR = 0.72, 95% CI = 0.56 to 0.91). Risk of ER-specific breast cancer differs according to ER status of female first-degree relatives with breast cancer and some other cancers of first-degree relatives. This family history information should be considered in the individual risk prediction for ER subtypes.

Cannabis Use and Endocannabinoid Receptor Genes: A Pilot Study on Their Interaction on Brain Activity in First-Episode Psychosis.

The role of both cannabis use and genetic background has been shown in the risk for psychosis. However, the effect of the interplay between cannabis and variability at the endocannabinoid receptor genes on the neurobiological underpinnings of psychosis remains inconclusive. Through a case-only design, including patients with a first-episode of psychosis (n = 40) classified as cannabis users (50%) and non-users (50%), we aimed to evaluate the interaction between cannabis use and common genetic variants at the endocannabinoid receptor genes on brain activity. Genetic variability was assessed by genotyping two Single Nucleotide Polymorphisms (SNP) at the cannabinoid receptor type 1 gene (CNR1; rs1049353) and cannabinoid receptor type 2 gene (CNR2; rs2501431). Functional Magnetic Resonance Imaging (fMRI) data were obtained while performing the n-back task. Gene × cannabis interaction models evidenced a combined effect of CNR1 and CNR2 genotypes and cannabis use on brain activity in different brain areas, such as the caudate nucleus, the cingulate cortex and the orbitofrontal cortex. These findings suggest a joint role of cannabis use and cannabinoid receptor genetic background on brain function in first-episode psychosis, possibly through the impact on brain areas relevant to the reward circuit.

Abstract 5757: Breast cancer diagnosis and treatment associated with acceleration of biological aging over time in a racially diverse cohort of women

Abstract Leukocyte DNA methylation (DNAm) at individual sites across the genome can be used to construct measures of biological age. Positive age acceleration—when biological age is older than chronological age—is associated with higher risk of age-associated diseases. Recent adjuvant therapy is reported to increase age acceleration, but the longer-term effects of a breast cancer diagnosis and treatment on age acceleration remain unknown. Here, we use blood samples collected at two timepoints to examine changes in age acceleration over time comparing women who did and did not develop breast cancer. Paired whole blood samples were drawn an average of 8 years apart (range: 5-11 years) in a sample of non-Hispanic White and Black (Hispanic and non-Hispanic) women. DNAm was profiled using Infinium MethylationEPIC BeadChips. Approximately half the women were diagnosed and treated for breast cancer between blood draws (cases; n= 190, baseline mean age= 57) whereas the other half remained breast cancer-free (controls; n= 227, baseline mean age= 56). Longitudinal changes in three age acceleration metrics were compared to determine whether an intervening breast cancer diagnosis and treatment was associated with trajectories in biological aging. On average, the cases were diagnosed with breast cancer 3.5 years after the initial blood draw and 4 years before the second blood draw. Among the cases, 36% were treated with chemotherapy, 65% with radiation therapy, and 70% with hormonal therapies; 45% of the cases received two types of therapy, and 13% received all three. Compared to women who remained cancer-free, women diagnosed and treated for breast cancer had increases in age acceleration over time as measured by PhenoAgeAccel (adjusted standardized mean difference (β)= 0.13, 95% CI: 0.00, 0.26), GrimAgeAccel (β= 0.13, 95% CI: 0.03, 0.24), and DunedinPACE (β= 0.35, 95% CI: 0.23, 0.48). The associations did not vary by timing of diagnosis between the blood draws or race; however, women diagnosed with estrogen receptor (ER) negative tumors appeared to experience faster increases in age acceleration than women diagnosed with ER positive tumors (GrimAgeAccel; ER negative β= 0.27, 95% CI: 0.07, 0.47; ER positive β= 0.10, 95% CI: -0.01, 0.21; P-interaction= 0.14). To investigate the impact of different types of breast cancer therapies, associations were examined using a case-only design. In models that simultaneously included chemotherapy, radiation therapy and hormone therapy, radiation therapy had the strongest associations with accelerated biological aging as measured by PhenoAgeAccel (β= 0.38, 95% CI: 0.18, 0.58), GrimAgeAccel (β= 0.27, 95% CI: 0.09, 0.45), and DunedinPACE (β= 0.25, 95% CI: 0.03, 0.47). We find that years after the initial diagnosis, breast cancer survivors have significantly accelerated biological aging; treatment modalities may differentially influence these rates. Citation Format: Jacob K. Kresovich, Katie M. O'Brien, Zongli Xu, Clarice R. Weinberg, Dale P. Sandler, Jack A. Taylor. Breast cancer diagnosis and treatment associated with acceleration of biological aging over time in a racially diverse cohort of women. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5757.

EPID-22. MATERNAL USE OF TOBACCO, ALCOHOL, AND ILLICIT DRUGS DURING PREGNANCY AND ASSOCIATION WITH CHILDHOOD CANCER SUBTYPES

Abstract OBJECTIVE To investigate the association between maternal prenatal substance use/abuse and diagnosis of childhood cancer subtypes, including childhood brain tumors. To minimize recall bias, we employed a case-only study design in which all respondents had a child diagnosed with cancer. STUDY DESIGN: We deployed a cross-sectional, case-only survey of parents of children diagnosed with cancer regarding prenatal smoking, drinking, and illicit drug use behaviors (scored on 1-7 Likert scale), demographic, gestational, and perinatal factors. Multivariable logistic regression assessed associations of gestational smoking, alcohol, and illicit drug use with childhood cancer subtypes, adjusting for child sex, race/ethnicity, birthweight, and household income. RESULTS 3145 families completed the survey, including 232 with astrocytoma (grades I-IV, including DIPG) and 210 with an embryonal CNS tumor (medulloblastoma, AT/RT, PNET). A minority reported ever smoking tobacco products during pregnancy (Likert score ≥ 2; 14%), ever consuming illicit drugs during pregnancy (Likert score ≥ 2; 4%), or drinking more than a moderate amount of alcohol during pregnancy (Likert score ≥ 5; 2%). Prenatal smoking was associated with lower odds of rhabdomyosarcoma (OR=0.48, P=0.023) and moderately elevated odds of non-Hodgkin lymphoma (OR = 1.52, P=0.098) and AML (OR = 1.52, P = 0.083). Moderate to heavy alcohol consumption was unassociated with cancer subtypes. Prenatal illicit drug use was associated with increased odds of retinoblastoma (OR = 5.03, 95% CI = 1.73-14.7, P = 0.003) and CNS embryonal tumors (OR = 2.56, 95% CI = 1.32-4.99, P = 0.006), with similar effects across subgroups of medulloblastoma, AT/RT, and supratentorial PNETs. CONCLUSIONS Associations between self-reported use of alcohol, tobacco, and illicit drugs during pregnancy and risk of childhood cancer is often biased by differential misreporting among parents of affected children. Consistent with prior reports, we observe elevated odds of hematologic malignancies in association with gestational tobacco smoke exposure and novel association between maternal illicit drug use during pregnancy and elevated odds of retinoblastoma and CNS embryonal tumors.

Case-only design identifies interactions of genetic risk variants at SIGLEC5 and PLG with the lncRNA CTD-2353F22.1 implying the importance of periodontal wound healing for disease aetiology.

The basis of phenotypic variation of periodontitis is genetic variability. Disease relevant effects of individual risk alleles are considered to result from genetic interactions. We investigated gene × gene (G×G) interactions of suggestive periodontitis susceptibility alleles. We used the case-only design and investigated single-nucleotide polymorphism (SNPs) that showed associations in our recent genome-wide association study (GWAS) and GWAS meta-analysis with p < 5 × 10-6 . CRISPR-dCas9 gene activation followed by RNA-sequencing and gene-set enrichment analyses elucidated differentially expressed genes and gene networks. With the databases of SNPInspector and Transfac professional, luciferase reporter gene assays and antibody electrophoretic mobility shift experiments, we analysed allele-specific effects on transcription factor binding. SNPs at the genes sialic acid binding Ig-like lectin 5 (SIGLEC5) and plasminogen (PLG) showed G×G interactions with rs1122900 at the long non-coding RNA (lncRNA) CTD-2353F22. Associated chromatin cis-activated CTD-2353F22.1 6.5-fold (p=.003), indicating CTD-2353F22.1 as target gene of this interaction. CTD-2353F22.1 regulated GADD45A (padj < 4.9 × 10-11 , log2 fold change (FC)=-0.55), THBS1, SERPINE1 and Tissue Factor F3 (padj < 5 × 10-7 , log2 FC ≥ -0.35) and the gene set "angiogenesis" (area under the curve=0.71, padj =8.2 × 10-5 ). rs1122900 effect C-allele decreased reporter gene activity (5.5-fold, p=.0003) and PRDM14 binding (76%). CTD-2353F22.1 mediates interaction of SIGLEC5 and PLG, together with genes that function in periodontal wound healing.

Proton Pump Inhibitors and Risk of Cardiovascular Disease: A Self-Controlled Case Series Study.

We investigated cardiovascular risk due to proton pump inhibitor (PPI) treatment using a self-controlled case series (SCCS) study design, a type of case-only design and an approach to overcome between-person confounding in which individuals act as their own control. We conducted an SCCS study using the National Health Insurance Service-Health Screening cohort in Korea (2002-2015). The cohort included 303,404 adult participants without prior cardiovascular events, who were followed up until December 2015. The primary outcome was a composite of stroke or myocardial infarction. The SCCS method estimated the age-adjusted incidence rate ratio between periods with and without exposure to PPI among patients with primary outcomes. As sensitivity analysis, conventional multivariable Cox proportional regression analyses were performed, which treated the exposure to PPI and H2 blocker during follow-up as time-dependent variables. In the SCCS design, 10,952 (3.6%) patients with primary outcomes were included. There was no association between PPI exposure and primary outcome (incidence rate ratio 0.98, 95% confidence interval [CI] 0.89-1.09). In the time-dependent Cox regression analyses, both PPI (adjusted hazard ratio 1.36, 95% CI 1.24-1.49) and H2 blocker (adjusted hazard ratio 1.46, 95% CI 1.38-1.55) were associated with an increased risk of the primary outcome. Negative findings in the SCCS design suggest that association between increased cardiovascular risk and PPI, frequently reported in prior observational studies, is likely due to residual confounding related to conditions with PPI treatment, rather than a true relationship.

Sex-specific genetic factors affect the risk of early-onset periodontitis in Europeans.

Various studies have reported that young European women are more likely to develop early-onset periodontitis compared to men. A potential explanation for the observed variations in sex and age of disease onset is the natural genetic variation within the autosomal genomes. We hypothesized that genotype-by-sex (G × S) interactions contribute to the increased prevalence and severity. Using the case-only design, we tested for differences in genetic effects between men and women in 896 North-West European early-onset cases, using imputed genotypes from the OmniExpress genotyping array. Population-representative 6823 controls were used to verify that the interacting variables G and S were uncorrelated in the general population. In total, 20 loci indicated G × S associations (P < 0.0005), 3 of which were previously suggested as risk genes for periodontitis (ABLIM2, CDH13, and NELL1). We also found independent G × S interactions of the related gene paralogs MACROD1/FLRT1 (chr11) and MACROD2/FLRT3 (chr20). G × S-associated SNPs at CPEB4, CDH13, MACROD1, and MECOM were genome-wide-associated with heel bone mineral density (CPEB4, MECOM), waist-to-hip ratio (CPEB4, MACROD1), and blood pressure (CPEB4, CDH13). Our results indicate that natural genetic variation affects the different heritability of periodontitis among sexes and suggest genes that contribute to inter-sex phenotypic variation in early-onset periodontitis.

Interaction between genetic variation and Helicobacter pylori infection in the occurrence of gastric cancer

Objective To investigate the interaction between known genetic variation of gastric cancer and Helicobacter pylori (H. pylori) in the occurrence of gastric cancer, and its effect on tumor site and the age at onset of gastric cancer. Methods With a case-only design, the interaction between genetic variation and H. pylori was analyzed by binary Logistic regression analysis in 2 426 patients with gastric cancer. Results After adjusting confounding factors, the interactions of genetic variation NSUN 3 rs7624041 and DEFB rs 2376549 with H. pylori infection in gastric cancer were statistically significant (OR=1.257, 95% CI: 1.006-1.571, P=0.044; OR=0.845, 95% CI: 0.715-0.999, P=0.048). Based on the hierarchical analysis of tumor location, there was no interaction between genetic variation and H. pylori infection. Hierarchical analysis based on tumor stage showed that the interaction between lnc-POLR3G-4 rs7712641 and H. pylori infection was statistically significant in patient with early gastric cancer (OR=1.757, 95% CI: 1.060-2.915, P=0.029). The age-based stratified analysis results showed that the interactions between ASHIL rs80142782, NSUN 3 rs7624041, DEFB rs2376549 and H. pylori infection were statistically significant in people aged Conclusions The occurrence and development of gastric cancer is complex. It is helpful to prevent the occurrence and development of gastric cancer by integrating genetic factors and environmental factors and taking targeted H. pylori eradication measures for susceptible and high-risk groups.

Differential Susceptibility to Aridity for Mortality Outcomes in South Africa: Application of Mixed-Effect Regression Tree Analysis to a Case-Only Design

BACKGROUND AND AIM: We investigated whether the relationship between recent aridity and mortality might be different according to demographic subgroups in South Africa over 1997-2013. METHODS: DESIGN: This study drew on a case-only sample comprised of recorded deaths (n=8,509,130) in South Africa over 1997-2013, using data from the country’s civil registration system. The dataset included race, sex, and age of the deceased, as well as the district municipality (52 clusters) of the deceased. We linked to each person the district-level 6-month Standardized Precipitation Index (6-month SPI) representing the relative aridity over the 6 months preceding their death. ANALYSIS: For this analysis we excluded participants with missing data (included n=6,139,287). We applied an algorithm for recursive partitioning based on linear mixed-effect models to distinguish demographic subgroups with high homogeneity in their 6-month SPI at time of death (conditional on partitioning variables), while accounting for the clustering of participants in districts. Our predictors were: recorded race (5 categories recorded in dataset: Black African, White, Indian or Asian, Coloured, or Other/Unknown/Unspecified), recorded sex (male or female), and age category (4 categories: 0-4 years, 5-14 years, 14-64 years, and 65+ years). RESULTS:The recursive partitioning algorithm indicated six demographic subgroups that appeared to have potentially differential vulnerability to 6-month SPI for mortality outcomes: [1] “Coloured” males ages 14-64; [2] “Black African or White or Indian or Asian or Other” males ages 14-64; [3] females of any race ages 14-64; [4] “White or Indian or Asian or Coloured” of any sex ages 0-4; [5] “Black or Other/Unknown/Unspecified race” of any sex not ages 14-64; and [6] “White or Indian or Asian or Coloured” of any sex ages 5-14 or 65+. CONCLUSIONS:This approach suggested several composite demographic groups that may be the focus of future research on aridity-demographic interactions for mortality rates, potentially simplifying from 40 strata to 6 priority groups. KEYWORDS: Climate, Methodological study design, Modeling, Environmental disparities, Environmental epidemiology, Socio-economic factors

Investigation of gene\u2013environment interactions in relation to tic severity

Tourette syndrome (TS) is a neuropsychiatric disorder with involvement of genetic and environmental factors. We investigated genetic loci previously implicated in Tourette syndrome and associated disorders in interaction with pre- and perinatal adversity in relation to tic severity using a case-only (N = 518) design. We assessed 98 single-nucleotide polymorphisms (SNPs) selected from (I) top SNPs from genome-wide association studies (GWASs) of TS; (II) top SNPs from GWASs of obsessive–compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD); (III) SNPs previously implicated in candidate-gene studies of TS; (IV) SNPs previously implicated in OCD or ASD; and (V) tagging SNPs in neurotransmitter-related candidate genes. Linear regression models were used to examine the main effects of the SNPs on tic severity, and the interaction effect of these SNPs with a cumulative pre- and perinatal adversity score. Replication was sought for SNPs that met the threshold of significance (after correcting for multiple testing) in a replication sample (N = 678). One SNP (rs7123010), previously implicated in a TS meta-analysis, was significantly related to higher tic severity. We found a gene–environment interaction for rs6539267, another top TS GWAS SNP. These findings were not independently replicated. Our study highlights the future potential of TS GWAS top hits in gene–environment studies.

A Decade of Pharmacogenetic Studies in Jordan: ASystemic Review.

The aim of this study was to perform a systematic overview of the pharmacogenetic studies conducted in Jordan. A structured search of Medline was conducted for articles over the last decade (January 2010-July 2020). Studies were classified by design, sample size, drug-gene combination, and the significance of the results. Thirty-two studies met the criteria for review. Most pharmacogenomic studies had a case-only design (n = 23). Only five studies included >500 participants. The total number of genetic variants in all studies was one hundred fifteen, which were found in forty genes, including dynamic (n = 27), and kinetic (n = 9) genes. The most commonly studied drugs were within the hematology and cardiology therapeutic areas and included statins, warfarin, aspirin, and clopidogrel. Most studies (n = 18) reported results with mixed p values [<0.05 and >0.05]. Pharmacogenomic research in Jordan is still in its infancy and is limited mainly to replication attempts. The need for standardization is imperative, especially in developing countries with scarce funding resources.

An updated meta-analysis showed smoking modify the association of GSTM1 null genotype on the risk of coronary heart disease.

Background Oxidative stress is considered to be involved in the pathogenesis of coronary heart disease (CHD). Glutathione-S-transferase (GST) enzymes play important roles in antioxidant defenses and may influence CHD risk. The present meta-analysis was performed to investigate the link between glutathione S-transferase M1 (GSTM1) null genotype and CHD and to get a precise evaluation of interaction between GSTM1 null genotype and smoking by the case-only design.Methods PubMed and EMBASE databases were searched through 15 December 2020 to retrieve articles. Odds ratios (ORs) were pooled using either fixed-effects or random-effects models.Results Thirty-seven studies showed that GSTM1 null genotype was associated with risk of CHD in total population, Caucasians and Asians (for total population, OR = 1.38, 95% confidence interval (CI): 1.15, 1.65; for Caucasians, OR = 1.34, 95% CI: 1.04, 1.72; for Asians, OR = 1.40, 95% CI: 1.11, 1.77). After adjustment for heterogeneity, these relationships were still significant. After adjustment for heterogeneity, case-only analysis of 11 studies showed a positive multiplicative interaction between GSTM1 null genotype and smoking (ever smoking vs. never smoking) (OR = 1.27, 95% CI: 1.08, 1.50; I2 = 0%, P=0.553).Conclusions The overall results indicated that GSTM1 null genotype was associated with a higher risk of CHD, and the association may be affected by smoking status. This is the first meta-analysis to prove a positive effect of the interaction between GSTM1 null genotype and smoking status on the risk of CHD. Well-designed studies are needed to investigate the possible gene–gene or gene–environment interactions.