Human Epistatic Interaction Controls IL7R Splicing and Increases Multiple Sclerosis Risk.

Multiple sclerosis (MS) is an autoimmune disorder where T cells attack neurons in the central nervous system (CNS) leading to demyelination and neurological deficits. A driver of increased MS risk is the soluble form of the interleukin-7 receptor alpha chain gene (sIL7R) produced by alternative splicing of IL7R exon 6. Here, we identified the RNA helicase DDX39B as a potent activator of this exon and consequently a repressor of sIL7R, and we found strong genetic association of DDX39B with MS risk. Indeed, we showed that a genetic variant in the 5' UTR of DDX39B reduces translation of DDX39B mRNAs and increases MS risk. Importantly, this DDX39B variant showed strong genetic and functional epistasis with allelic variants in IL7R exon 6. This study establishes the occurrence of biological epistasis in humans and provides mechanistic insight into the regulation of IL7R exon 6 splicing and its impact on MS risk.

Sex Differences Among Older Adults With Bipolar Disorder: Results From the Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) Project.

OBJECTIVE: Sex-specific research in adult bipolar disorder (BD) is sparse and even more so among those with older age bipolar disorder (OABD). Knowledge about sex differences across the bipolar lifespan is urgently needed to target and improve treatment. To address this gap, the current study examined sex differences in the domains of clinical presentation, general functioning, and mood symptoms among individuals with OABD. METHODS: This Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) study used data from 19 international studies including BD patients aged ≥50 years (N = 1,185: 645 women, 540 men).A comparison of mood symptoms between women and men was conducted initially using two-tailed t tests and then accounting for systematic differences between the contributing cohorts by performing generalized linear mixed models (GLMMs). Associations between sex and other clinical characteristics were examined using GLMM including: age, BD subtype, rapid cycling, psychiatric hospitalization, lifetime psychiatric comorbidity, and physical health comorbidity, with study cohort as a random intercept. RESULTS: Regarding depressive mood symptoms, women had higher scores on anxiety and hypochondriasis items. Female sex was associated with more psychiatric hospitalizations and male sex with lifetime substance abuse disorders. CONCLUSION: Our findings show important clinical sex differences and provide support that older age women experience a more severe course of BD, with higher rates of psychiatric hospitalization. The reasons for this may be biological, psychological, or social. These differences as well as underlying mechanisms should be a focus for healthcare professionals and need to be studied further.

Sociodemographic and clinical characteristics of people with oldest older age bipolar disorder in a global sample: Results from the global aging and geriatric experiments in bipolar disorder project.

OBJECTS: Studies of older age bipolar disorder (OABD) have mostly focused on "younger old" individuals. Little is known about the oldest OABD (OOABD) individuals aged ≥70 years old. The Global Aging and Geriatric Experiments in Bipolar Disorder (GAGE-BD) project provides an opportunity to evaluate the OOABD group to understand their characteristics compared to younger groups. METHODS: We conducted cross-sectional analyses of the GAGE-BD database, an integrated, harmonized dataset from 19 international studies. We compared the sociodemographic and clinical characteristics of those aged <50 (YABD, n = 184), 50-69 (OABD, n = 881), and ≥70 (OOABD, n = 304). To standardize the comparisons between age categories and all characteristics, we used multinomial logistic regression models with age category as the dependent variable, with each characteristic as the independent variable, and clustering of standard errors to account for the correlation between observations from each of the studies. RESULTS: OOABD and OABD had lower severity of manic symptoms (Mean YMRS = 3.3, 3.8 respectively) than YABD (YMRS = 7.6), and lower depressive symptoms (% of absent = 65.4%, and 59.5% respectively) than YABD (18.3%). OOABD and OABD had higher physical burden than YABD, especially in the cardiovascular domain (prevalence = 65% in OOABD, 41% in OABD and 17% in YABD); OOABD had the highest prevalence (56%) in the musculoskeletal domain (significantly differed from 39% in OABD and 31% in YABD which didn't differ from each other). Overall, OOABD had significant cumulative physical burden in numbers of domains (mean = 4) compared to both OABD (mean = 2) and YABD (mean = 1). OOABD had the lowest rates of suicidal thoughts (10%), which significantly differed from YABD (26%) though didn't differ from OABD (21%). Functional status was higher in both OOABD (GAF = 63) and OABD (GAF = 64), though only OABD had significantly higher function than YABD (GAF = 59). CONCLUSIONS: OOABD have unique features, suggesting that (1) OOABD individuals may be easier to manage psychiatrically, but require more attention to comorbid physical conditions; (2) OOABD is a survivor cohort associated with resilience despite high medical burden, warranting both qualitative and quantitative methods to better understand how to advance clinical care and ways to age successfully with BD.

Bipolar symptoms, somatic burden and functioning in older-age bipolar disorder: A replication study from the global aging & geriatric experiments in bipolar disorder database (GAGE-BD) project.

OBJECTIVES: The Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) project pools archival datasets on older age bipolar disorder (OABD). An initial Wave 1 (W1; n = 1369) analysis found both manic and depressive symptoms reduced among older patients. To replicate this finding, we gathered an independent Wave 2 (W2; n = 1232, mean ± standard deviation age 47.2 ± 13.5, 65% women, 49% aged over 50) dataset. DESIGN/METHODS: Using mixed models with random effects for cohort, we examined associations between BD symptoms, somatic burden and age and the contribution of these to functioning in W2 and the combined W1 + W2 sample (n = 2601). RESULTS: Compared to W1, the W2 sample was younger (p < 0.001), less educated (p < 0.001), more symptomatic (p < 0.001), lower functioning (p < 0.001) and had fewer somatic conditions (p < 0.001). In the full W2, older individuals had reduced manic symptom severity, but age was not associated with depression severity. Age was not associated with functioning in W2. More severe BD symptoms (mania p ≤ 0.001, depression p ≤ 0.001) were associated with worse functioning. Older age was significantly associated with higher somatic burden in the W2 and the W1 + W2 samples, but this burden was not associated with poorer functioning. CONCLUSIONS: In a large, independent sample, older age was associated with less severe mania and more somatic burden (consistent with previous findings), but there was no association of depression with age (different from previous findings). Similar to previous findings, worse BD symptom severity was associated with worse functioning, emphasizing the need for symptom relief in OABD to promote better functioning.

Demographic and clinical associations to employment status in older-age bipolar disorder: Analysis from the GAGE-BD database project.

OBJECTIVE: The current literature on employment in older adults with bipolar disorder (OABD) is limited. Using the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD), we examined the relationship of occupational status in OABD to other demographic and clinical characteristics. METHODS: Seven hundred and thirty-eight participants from 11 international samples with data on educational level and occupational status were included. Employment status was dichotomized as employed versus unemployed. Generalized linear mixed models with random intercepts for the study cohort were used to examine the relationship between baseline characteristics and employment. Predictors in the models included baseline demographics, education, psychiatric symptom severity, psychiatric comorbidity, somatic comorbidity, and prior psychiatric hospitalizations. RESULTS: In the sample, 23.6% (n = 174) were employed, while 76.4% were unemployed (n = 564). In multivariable logistic regression models, less education, older age, a history of both anxiety and substance/alcohol use disorders, more prior psychiatric hospitalizations, and higher levels of BD depression severity were associated with greater odds of unemployment. In the subsample of individuals less than 65 years of age, findings were similar. No significant association between manic symptoms, gender, age of onset, or employment status was observed. CONCLUSION: Results suggest an association between educational level, age, psychiatric severity and comorbidity in relation to employment in OABD. Implications include the need for management of psychiatric symptoms and comorbidity across the lifespan, as well as improving educational access for people with BD and skills training or other support for those with work-life breaks to re-enter employment and optimize the overall outcome.

Bipolar symptoms, somatic burden, and functioning in older-age bipolar disorder: Analyses from the Global Aging & Geriatric Experiments in Bipolar Disorder Database project.

OBJECTIVE: Literature on older-age bipolar disorder (OABD) is limited. This first-ever analysis of the Global Aging & Geriatric Experiments in Bipolar Disorder Database (GAGE-BD) investigated associations among age, BD symptoms, comorbidity, and functioning. METHODS: This analysis used harmonized, baseline, cross-sectional data from 19 international studies (N = 1377). Standardized measures included the Young Mania Rating Scale (YMRS), Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Global Assessment of Functioning (GAF). RESULTS: Mean sample age was 60.8 years (standard deviation [SD] 12.2 years), 55% female, 72% BD I. Mood symptom severity was low: mean total YMRS score of 4.3 (SD 5.4) and moderate-to-severe depression in only 22%. Controlled for sample effects, both manic and depressive symptom severity appeared lower among older individuals (p's < 0.0001). The negative relationship between older age and symptom severity was similar across sexes, but was stronger among those with lower education levels. GAF was mildly impaired (mean =62.0, SD = 13.3) and somatic burden was high (mean =2.42, SD = 1.97). Comorbidity burden was not associated with GAF. However, higher depressive (p < 0.0001) and manic (p < 0.0001) symptoms were associated with lower GAF, most strongly among older individuals. CONCLUSIONS: Findings suggest an attenuation of BD symptoms in OABD, despite extensive somatic burden. Depressive symptom severity was strongly associated with worse functioning in older individuals, underscoring the need for effective treatments of BD depression in older people. This international collaboration lays a path for the development of a better understanding of aging in BD.

Physical Health Burden Among Older Men and Women With Bipolar Disorder: Results From the Gage-Bd Collaboration.

OBJECTIVES: To compare the prevalence of physical morbidities among men and women with older adult bipolar disorder (OABD), and men with and without OABD. METHODS: Cross-sectional analysis of the collaborative Global Aging & Geriatric Experiments in Bipolar Disorder (GAGE-BD) database and non-OABD data from the Health in Men Study. OABD defined as bipolar disorder among adults aged greater than or equal to 50 years. Outcomes of interest were diseases affecting the cardiovascular, respiratory, gastrointestinal, renal, musculoskeletal and endocrinological systems. RESULTS: We examined 1407 participants with OABD aged 50-95 years, of whom 787 were women. More women than men showed evidence of morbidities affecting the respiratory, gastrointestinal, musculoskeletal and endocrinological systems. More men with than without OABD showed evidence of cardiovascular, renal and endocrinological diseases. CONCLUSION: GAGE-BD data showed that physical morbidities affect more women than men with OABD, and more men with than without OABD. The underlying reasons for these differences require clarification.

Symptom Severity Mixity in Older-Age Bipolar Disorder: Analyses From the Global Aging and Geriatric Experiments in Bipolar Disorder Database (GAGE-BD).

OBJECTIVE: Some individuals with bipolar disorder (BD) experience manic and depressive symptoms concurrently, but data are limited on symptom mixity in older age bipolar disorder (OABD). Using the Global Aging & Geriatric Experiments in Bipolar Disorder Database, we characterized mixity in OABD and associations with everyday function. METHODS: The sample (n = 805), from 12 international studies, included cases with both mania and depression severity ratings at a single timepoint. Four mixity groups were created: asymptomatic (A), mixed (Mix), depressed only (Dep), and manic only (Man). Generalized linear mixed models used mixity group as the predictor variable; cohort was included as a random intercept. Everyday function was assessed with the Global Assessment of Functioning score. RESULTS: Group proportions were Mix (69.6%; n = 560), followed by Dep (18.4%; n = 148), then A (7.8%; n = 63), then Man (4.2%; n= 34); levels of depression and mania were similar in Mix compared to Dep and Man, respectively. Everyday function was lowest in Mix, highest in A, and intermediate in Man and Dep. Within Mix, severity of depression was the main driver of worse functioning. Groups differed in years of education, with A higher than all others, but did not differ by age, gender, employment status, BD subtype, or age of onset. CONCLUSIONS: Mixed features predominate in a cross-sectional, global OABD sample and are associated with worse everyday function. Among those with mixed symptoms, functional status relates strongly to current depression severity. Future studies should include cognitive and other biological variables as well as longitudinal designs to allow for evaluation of causal effects.

Demographic and clinical characteristics of lithium-treated older adults with bipolar disorder.

OBJECTIVES: There is limited information on the characteristics of older adults with bipolar disorder (OABD) treated with lithium, along with safety concerns about its use by older adults. The aim of the present study is to describe the demographic and clinical characteristics of OABD receiving lithium therapy, using data from the Global Ageing & Geriatric Experiments in Bipolar Disorder (GAGE-BD). EXPERIMENTAL PROCEDURES: Cross-sectional analysis of the GAGE-BD dataset to determine differences and similarities between lithium users and non-users. We analysed data from 986 participants aged 50 years or older (mean age 63.5 years; 57.5% females) from 12 study sites. Two subgroups ('Lithium'; 'Non-lithium') were defined according to the current prescription of lithium. We compared several outcomes between these groups, controlling for age, gender, and study site. RESULTS: OABD treated with lithium had lower scores on depression rating scales and were less likely to be categorised as with moderate or severe depression. There was a lower proportion of lithium users than non-users among those with evidence of rapid cycling and non-bipolar psychiatric diagnoses. Assessment of global cognitive state and functionality indicated better performance among lithium users. The current use of antipsychotics was less frequent among lithium users, who also reported fewer cardiovascular comorbidities than non-users. CONCLUSION: We found several potentially relevant differences in the clinical profile of OABD treated with lithium compared with those treated with other mood stabilisers. However, the interpretation of the present results must take into account the methodological limitations inherent to the cross-sectional approach and data harmonisation.

A community-targeted implementation of self-management for people with epilepsy and a history of negative health events (SMART): A research and community partnership to reduce epilepsy burden.

AIMS: Self-management for people with epilepsy and a history of negative health events (SMART) is a behavioral intervention that has been demonstrated to reduce epilepsy-related complications and improve physical and mental health functioning among people with epilepsy (PWE) [1]. The Community-SMART (C-SMART) initiative was a 4-month prospective implementation of feasibility and pre/post outcomes of SMART in a community setting and in collaboration with key epilepsy service stakeholders. METHODS: Self-management for people with epilepsy and a history of negative health events is a group-format, entirely virtual intervention delivered in eight 60-90 sessions over the course of 8-10 weeks. The C-SMART initiative used research staff to guide intervention performance evaluation and staff of a regional epilepsy advocacy agency to assist with community engagement. Process evaluations included outreach and engagement efforts needed to reach PWE, the barriers and facilitators to roll-out, and participant retention and satisfaction. Outcomes included depressive symptoms and epilepsy self-management competency. RESULTS: Thirty individuals were enrolled in 3 "cohorts" of approximately 10 PWE per cohort. Mean age of participants was 48.50 (standard deviation 16.15) years, 60% were female and 53.3% were African-American. Individuals had epilepsy, on average, for over 2 decades, were on approximately 2 prescribed antiepileptic drugs (AEDs) and had an average of just over 6 seizures in the last 30 days. Over 63% had a comorbid mental health condition. There were 23 individuals (76.7%) who were retained at the 4-month follow-up. Baseline to 4-month outcomes for depression and epilepsy self-management were significantly improved. Most (90%) of participants reported high levels of satisfaction with the program. CONCLUSIONS: The SMART epilepsy self-management program can be successfully implemented in partnership with epilepsy-focused community partners, is acceptable to participants and associated with improved outcomes. Future work might consider how to make virtual epilepsy self-management available to the full spectrum of PWE.

Clinical correlates of late-onset versus early-onset bipolar disorder in a global sample of older adults.

OBJECTIVES: Late-onset bipolar disorder (LOBD) represents a significant subgroup of bipolar disorder (BD). However, knowledge for this group is mostly extrapolated from small studies in subjects with early/mixed age of illness onset. In this global sample of older adults with BD (OABD: ≥50 years old) we aim to characterize the sociodemographic and clinical presentation of LOBD (≥40 years at BD onset) compared to early-onset BD (EOBD: <40 years at BD onset). METHODS: The Global Aging and Geriatric Experiments in Bipolar Disorder consortium provided international data on 437 older age bipolar disorder participants. We compared LOBD versus EOBD on depression, mania, functionality, and physical comorbidities. Exploratory analyses were performed on participants with BD onset ≥50 years old. RESULTS: LOBD (n = 105) did not differ from EOBD (n = 332) on depression, mania, global functioning, nor employment status (p > 0.05). Late-onset bipolar disorder was associated with higher endocrine comorbidities (odds ratio = 1.48, [95%CI = 1.0,12.1], p = 0.03). This difference did not remain significant when subjects with BD onset ≥50 years old were analyzed. LIMITATIONS: This study is limited by the retrospective nature of the variable age of onset and the differences in evaluation methods across studies (partially overcame by harmonization processes). CONCLUSION: The present analysis is in favor of the hypothesis that LOBD might represent a similar clinical phenotype as classic EOBD with respect to core BD symptomatology, functionality, and comorbid physical conditions. Large-scale global collaboration to improve our understanding of BD across the lifespan is needed.

Depression and suicidality among Hispanics with epilepsy: Findings from the Managing Epilepsy Well (MEW) Network integrated database.

OBJECTIVE: Although psychiatric disorders are more common among people with epilepsy,2 depression and suicidal ideation among Hispanics with epilepsy remain understudied. We examined the prevalence and correlates of depression and suicidal ideation among Hispanic adults with epilepsy who participated in self-management studies in the Managing Epilepsy Well3 Network. METHODS: This cross-sectional analysis of pooled data from ten studies used the Patient Health Questionnaire-94 or Neurological Disease Depression Inventory-Epilepsy5 to examine the prevalence of elevated depressive symptoms (PHQ ≥ 10, NDDI-E ≥ 15) and suicidal ideation (PHQ-9 item 9 ≥ 1, NDDI-E item 4 ≥ 2). Multilevel mixed-effects logistic regression models examined associations between ethnicity, elevated depressive symptoms, and suicidal ideation among PWE. Secondary analyses examined correlates of elevated depressive symptoms and suicidal ideation among Hispanic PWE. RESULTS: Of 559 participants, 49.6% (n = 277) were Hispanic. Elevated depressive symptoms were endorsed by 38.1% (n = 213) of all participants (32.5% of Hispanics); suicidal ideation was endorsed by 18.4% (n = 103) of all participants (16.3% of Hispanics). After adjustment for sociodemographic and health attributes, Hispanic PWE had a 44% lower prevalence of elevated depressive symptoms (OR = 0.56, CI 0.37-0.84, p = 0.0056) compared to non-Hispanics but similar rates of suicidal ideation (OR = 0.84, CI 0.45-1.58, p = 0.59). Acculturation measures were available for 256 (92.4%) of Hispanic PWE: language preference was Spanish for 62.9%, 46.1% were foreign-born. Spanish-speaking Hispanics were less likely than English-speaking Hispanics to report elevated depressive symptoms (OR = 0.43, CI 0.19-0.97, p = 0.041); however, Hispanics who reported fair or poor health status had a four-fold higher depression prevalence compared to those who reported excellent or very good health status [reference group] (OR = 4.44, CI 1.50-13.18, p = 0.0071). Of the Hispanics who provided prior 30-day seizure data, ≥1 monthly seizure was independently associated with higher depression prevalence (OR = 3.11, CI 1.29-7.45, p = 0.01). Being foreign-born was not associated with elevated depressive symptoms or suicidal ideation prevalence. CONCLUSIONS: In a large, geographically diverse sample of PWE, elevated depressive symptoms were significantly lower in Hispanics compared to non-Hispanics. Spanish language preference was associated with a lower prevalence of elevated depressive symptoms among Hispanic PWE. Future studies should include acculturation data to better screen for depression and suicidal ideation risk and optimize interventions for Hispanic PWE.

Health literacy and education level correlates of participation and outcome in a remotely delivered epilepsy self-management program.

SIGNIFICANCE: Health literacy, the ability to understand necessary health information to make proper health decisions, has been linked to greater frequency of hospitalizations. However, there is limited literature on the associations between health literacy and outcomes in patients with epilepsy, and thus, this secondary analysis investigates the associations between health literacy and outcomes in patients with epilepsy enrolled in the self-management intervention "Self-management for people with epilepsy and a history of negative events" (SMART). We examined the associations between higher health literacy and higher education level and outcomes of the SMART trial. METHODS: This is a secondary analysis of data from the SMART self-management intervention, where individuals were randomized to the SMART intervention or a 6-month waitlist (WL) control. Health literacy was assessed at baseline before randomization using the Rapid Estimate of Adult Literacy in Medicine (REALM-R). Education level was self-reported by participants at baseline. Pearson correlations between REALM-R scores and continuous demographic and clinical variables were conducted. Point-biserial Pearson correlations were computed for REALM-R and dichotomous variables. The effect of education on change in negative health events (NHEs) counts from baseline to six months was conducted using a linear regression. A logistic regression with health literacy and randomization arm as predictors and improvement in NHE (1 = improvement, 0 = no change or increased NHEs at 6 months) as the outcome was conducted. RESULTS: Lower education and lower income were significantly correlated with lower health literacy (p < 0.001 and p = 0.03). Higher education level was associated with a greater improvement in 6-month seizure counts (rs(105) = 0.29, p = 0.002), and a greater improvement in total 6-month NHEs (rs(95) = 0.20, p = 0.045). Health literacy was not associated with change in NHEs or with study retention. CONCLUSIONS: The SMART intervention appears effective for individuals regardless of health literacy competency. Nevertheless, individuals with higher levels of education have fewer epilepsy complications, and thus, those with limited education may still require additional support while participating in epilepsy self-management programs.

Mind the gap: resources required to receive, process and interpret research-returned whole genome data.

Most genotype-phenotype studies have historically lacked population diversity, impacting the generalizability of findings and thereby limiting the ability to equitably implement precision medicine. This well-documented problem has generated much interest in the ascertainment of new cohorts with an emphasis on multiple dimensions of diversity, including race/ethnicity, gender, age, socioeconomic status, disability, and geography. The most well known of these new cohort efforts is arguably All of Us, formerly known as the Precision Medicine Cohort Initiative Program. All of Us intends to ascertain at least one million participants in the United States representative of the multiple dimensions of diversity. As an incentive to participate, All of Us is offering the return of research results, including whole genome sequencing data, as well as the opportunity to contribute to the scientific process as non-scientists. The scale and scope of the proposed return of research results are unprecedented. Here, we briefly review possible return of genetic data models, including the likely data file formats and modes of data transfer or access. We also review the resources required to access and interpret the genetic or genomic data once received by the average participant, highlighting the nuanced anticipated barriers that will challenge both the digitally, computationally literate and illiterate participant alike. This inventory of resources required to receive, process, and interpret return of research results exposes the potential for access disparities and warns the scientific community to mind the gap so that all participants have equal access and understanding of the benefits of human genetic research.

Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.

Genetic susceptibility to type 1 diabetes (T1D) is well supported by epidemiologic evidence; however, disease risk cannot be entirely explained by established genetic variants identified so far. This study addresses the question of whether epigenetic modification of the inherited DNA sequence may contribute to T1D susceptibility. Using the Infinium HumanMethylation450 BeadChip array (450k), a total of seven long-term disease-discordant monozygotic (MZ) twin pairs and five pairs of HLA-identical, disease-discordant non-twin siblings (NTS) were examined for associations between DNA methylation (DNAm) and T1D. Strong evidence for global hypomethylation of CpG sites within promoter regions in MZ twins with TID compared to twins without T1D was observed. DNA methylation data were then grouped into three categories of CpG sites for further analysis, including those within: 1) the major histocompatibility complex (MHC) region, 2) non-MHC genes with reported T1D association through genome wide association studies (GWAS), and 3) the epigenome, or remainder of sites that did not include MHC and T1D associated genes. Initial results showed modest methylation differences between discordant MZ twins for the MHC region and T1D-associated CpG sites, BACH2, INS-IGF2, and CLEC16A (DNAm difference range: 2.2%-5.0%). In the epigenome CpG set, the greatest methylation differences were observed in MAGI2, FANCC, and PCDHB16, (DNAm difference range: 6.9%-16.1%). These findings were not observed in the HLA-identical NTS pairs. Targeted pyrosequencing of five candidate CpG loci identified using the 450k array in the original discordant MZ twins produced similar results using control DNA samples, indicating strong agreement between the two DNA methylation profiling platforms. However, findings for the top five candidate CpG loci were not replicated in six additional T1D-discordant MZ twin pairs. Our results indicate global DNA hypomethylation within gene promoter regions may contribute to T1D; however, findings do not support the involvement of large DNAm differences at single CpG sites alone in T1D.

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children.

BACKGROUND: Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections). METHODS: Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term. RESULTS: Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed. CONCLUSIONS: Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.

Smoking and risk of multiple sclerosis: evidence of modification by NAT1 variants.

BACKGROUND: Tobacco smoke is an established risk factor for multiple sclerosis (MS). We hypothesized that variation in genes involved in metabolism of tobacco smoke constituents may modify MS risk in smokers. METHODS: A three-stage gene-environment investigation was conducted for NAT1, NAT2, and GSTP1 variants. The discovery analysis was conducted among 1588 white MS cases and controls from the Kaiser Permanente Northern California Region HealthPlan (Kaiser). The replication analysis was carried out in 988 white MS cases and controls from Sweden. RESULTS: Tobacco smoke exposure at the age of 20 years was associated with greater MS risk in both data sets (in Kaiser, odds ratio [OR] = 1.51 [95% confidence interval (CI) = 1.17-1.93]; in Sweden, OR = 1.35 [1.04-1.74]). A total of 42 NAT1 variants showed evidence for interaction with tobacco smoke exposure (P(corrected) < 0.05). Genotypes for 41 NAT1 single nucleotide polymorphisms (SNPs) were studied in the replication data set. A variant (rs7388368C>A) within a dense transcription factor-binding region showed evidence for interaction (Kaiser, OR for interaction = 1.75 [95% CI = 1.19-2.56]; Sweden, OR = 1.62 [1.05-2.49]). Tobacco smoke exposure was associated with MS risk among rs7388368A carriers only; homozygote individuals had the highest risk (A/A, OR = 5.17 [95% CI = 2.17-12.33]). CONCLUSIONS: We conducted a three-stage analysis using two population-based case-control datasets that consisted of a discovery population, a replication population, and a pooled analysis. NAT1 emerged as a genetic effect modifier of tobacco smoke exposure in MS susceptibility.

Male sexual and reproductive health in multiple sclerosis: a scoping review.

BACKGROUND: Multiple sclerosis (MS) is a chronic neuroinflammatory disease with highest incidence during the period of optimal reproductive health. This scoping review aimed to identify and summarize available data on sexual/reproductive health in males with MS (MwMS). METHODS: This review was based on PRISMA extension for Scoping Review. PubMed database was searched for keyword "multiple sclerosis" alongside keywords "sexual health", "reproductive health", "family planning", "male fertility", "male infertility", "sexual dysfunction", and "erectile dysfunction", iteratively using the "AND" logical operator. Descriptive analysis was performed on the included articles. RESULTS: Thirty-four studies were included, and four topics emerged: sexual dysfunction, erectile dysfunction, fertility, and family planning. Sexual dysfunction is common in MwMS (35-72%), yet only a minority of MwMS discuss their sexual health with their treatment teams. Both MS disability and depression were associated with sexual dysfunction in MwMS, with erectile dysfunction and decreased libido as the most prevalent aspects of sexual dysfunction. Positively, phosphodiesterase-5 inhibitors appear effective for treating erectile dysfunction and improving sexual quality of life in MwMS. There may also be a relationship between MS and male infertility, though changes in sexual behavior may underlie this association. Finally, a prominent knowledge gap was observed for disease-modifying therapy use and family planning in MwMS. CONCLUSION: Sexual dysfunction is common, impacted by MS severity, and associates with decreased quality of life in MwMS. Communication barriers regarding sexual and reproductive health appear to exist between MwMS and providers, as do literature gaps related to MS therapeutics and sexual/reproductive health.