Browsing by Subject "Genetic risk factors"
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Item Adverse Health Outcomes in Relationship to Hypogonadism After Chemotherapy: A Multicenter Study of Testicular Cancer Survivors(National Comprehensive Cancer Network, 2019-05-01) Abu Zaid, Mohammad; Dinh, Paul C., Jr.; Monahan, Patrick O.; Fung, Chunkit; El-Charif, Omar; Feldman, Darren R.; Hamilton, Robert J.; Vaughn, David J.; Beard, Clair J.; Cook, Ryan; Althouse, Sandra; Ardeshir-Rouhani-Fard, Shirin; Sesso, Howard D.; Huddart, Robert; Mushiroda, Taisei; Kubo, Michiaki; Dolan, M. Eileen; Einhorn, Lawrence H.; Fossa, Sophie D.; Travis, Lois B.; Platinum Study Group; Medicine, School of MedicineBackground: This study examined the prevalence of hypogonadism, its clinical and genetic risk factors, and its relationship to adverse health outcomes (AHOs) in North American testicular cancer survivors (TCS) after modern platinum-based chemotherapy. Patients and Methods: Eligible TCS were <55 years of age at diagnosis and treated with first-line platinum-based chemotherapy. Participants underwent physical examinations and completed questionnaires regarding 15 AHOs and health behaviors. Hypogonadism was defined as serum testosterone levels ≤3.0 ng/mL or use of testosterone replacement therapy. We investigated the role of 2 single nucleotide polymorphisms (rs6258 and rs12150660) in the sex hormone-binding globulin (SHBG) locus implicated in increased hypogonadism risk in the general population. Results: Of 491 TCS (median age at assessment, 38.2 years; range, 18.7–68.4 years), 38.5% had hypogonadism. Multivariable binary logistic regression analysis identified hypogonadism risk factors, including age at clinical evaluation (odds ratio [OR], 1.42 per 10-year increase; P=.006) and body mass index of 25 to <30 kg/m2 (OR, 2.08; P=.011) or ≥30 kg/m2 (OR, 2.36; P=.005) compared with <25 kg/m2. TCS with ≥2 risk alleles for the SHBG SNPs had a marginally significant increased hypogonadism risk (OR, 1.45; P=.09). Vigorous-intensity physical activity appeared protective (OR, 0.66; P=.07). Type of cisplatin-based chemotherapy regimen and socioeconomic factors did not correlate with hypogonadism. Compared with TCS without hypogonadism, those with hypogonadism were more likely to report ≥2 AHOs (65% vs 51%; P=.003), to take medications for hypercholesterolemia (20.1% vs 6.0%; P<.001) or hypertension (18.5% vs 10.6%; P=.013), and to report erectile dysfunction (19.6% vs 11.9%; P=.018) or peripheral neuropathy (30.7% vs 22.5%; P=.041). A marginally significant trend for increased use of prescription medications for either diabetes (5.8% vs 2.6%; P=.07) or anxiety/depression (14.8% vs 9.3%; P=.06) was observed. Conclusions: At a relatively young median age, more than one-third of TCS have hypogonadism, which is significantly associated with increased cardiovascular disease risk factors, and erectile dysfunction. Providers should screen TCS for hypogonadism and treat symptomatic patients.Item Contributions of heavy metal exposure to late‐onset Alzheimer’s disease(Wiley, 2025-01-03) Kotredes, Kevin P.; Minaeva, Olga; Pandey, Ravi S.; Moncaster, Juliet A.; Lamb, Bruce T.; Carter, Gregory W.; Goldstein, Lee E.; Howell, Gareth R.; Medical and Molecular Genetics, School of MedicineBackground: Late‐onset Alzheimer’s disease (LOAD) is the leading cause of dementia and a major contributor to increased mortality. Recent human datasets have revealed many LOAD genetic risk factors that are correlated with the degree of AD burden. Further, the complexity and heterogeneity of LOAD appears to be promoted by interactions between genetics and environmental factors such as diet, sedentary behavior, and exposure to toxicants, like lead (Pb), cadmium (Cd), and arsenic (As). While the neurotoxicants‐LOAD association is known, the molecular mechanisms modulated by these gene‐environmental interactions are unknown. Here we test the hypothesis that heavy metal exposure induces cerebrovascular deficits, neuroinflammation, and brain biometal dyshomeostasis which exacerbate AD‐associated brain pathologies in next‐generation mouse models of LOAD. Examination of these gene‐environmental (“exposome”) interactions provides essential insight into the heterogeneity observed in human disease and may uncover potentially modifiable mechanisms that mediate AD pathogenesis. Method: Young and aged mice from novel polygenic strains expressing LOAD risk alleles (APOE4, Trem2, APP, Mthfr, Abca7) were exposed to heavy metal toxicants in drinking water. Toxicants and endogenous biometals were assayed by ICP‐mass spectrometry in the brain, blood, and urine. Transcriptional profiling of brains revealed specific changes in human‐aligned, LOAD‐related gene expression networks indicating mechanisms of disease progression. Neuropathology was evaluated with LOAD‐relevant phenotypes, including amyloid burden, glial activity, and neuron loss. Result: Neurotoxicants were detected in all tissue samples collected. Pb, Cd, and As accumulated in the brain and altered expression of LOAD‐relevant genes in a toxicant‐specific manner, including a decrease in Vgf and an increase in App. Reduced VGF expression has been observed and reported in all four independent AMP‐AD studies and nominated as a key therapeutic target in each and APP encodes amyloid precursor protein (APP) from which the Aβ peptides are generated. Conclusion: Pb, Cd, and As exposure is common, especially in disadvantaged populations (urban, rural), raising concern about LOAD risk disparities, socioeconomic/racial inequities, and environmental justice. These experiments provide critical feedback related to the impact of the “exposome” in the aging, disease progression, and gene expression of novel preclinical LOAD models. Collectively these data suggest a direct effect of neurotoxicant exposure related to LOAD progression.Item Genetic architecture of age-related cognitive decline in African Americans(American Academy of Neurology, 2016-12-21) Raj, Towfique; Chibnik, Lori B.; McCabe, Cristin; Wong, Andus; Replogle, Joseph M.; Yu, Lei; Gao, Sujuan; Unverzagt, Frederick W.; Stranger, Barbara; Murrell, Jill; Barnes, Lisa; Hendrie, Hugh C.; Foroud, Tatiana; Krichevsky, Anna; Bennett, David A.; Hall, Kathleen S.; Evans, Denis A.; De Jager, Philip L.; Department of Biostatistics, Richard M. Fairbanks School of Public HealthOBJECTIVE: To identify genetic risk factors associated with susceptibility to age-related cognitive decline in African Americans (AAs). METHODS: We performed a genome-wide association study (GWAS) and an admixture-mapping scan in 3,964 older AAs from 5 longitudinal cohorts; for each participant, we calculated a slope of an individual's global cognitive change from neuropsychological evaluations. We also performed a pathway-based analysis of the age-related cognitive decline GWAS. RESULTS: We found no evidence to support the existence of a genomic region which has a strongly different contribution to age-related cognitive decline in African and European genomes. Known Alzheimer disease (AD) susceptibility variants in the ABCA7 and MS4A loci do influence this trait in AAs. Of interest, our pathway-based analyses returned statistically significant results highlighting a shared risk from lipid/metabolism and protein tyrosine signaling pathways between cognitive decline and AD, but the role of inflammatory pathways is polarized, being limited to AD susceptibility. CONCLUSIONS: The genetic architecture of aging-related cognitive in AA individuals is largely similar to that of individuals of European descent. In both populations, we note a surprising lack of enrichment for immune pathways in the genetic risk for cognitive decline, despite strong enrichment of these pathways among genetic risk factors for AD.Item miRNA, transcriptional regulation and cognitive decline(Wiley, 2025-01-03) Fischer, Andre; Sananbenesi, Farahnaz; Nho, Kwangsik; Manfred Krüger, Dennis; Shaw, Leslie M.; Saykin, Andrew J.; Delalle, Ivana; Radiology and Imaging Sciences, School of MedicineBackground: Despite significant advancements in the development of blood biomarkers for AD, challenges persist due to the complex interplay of genetic and environmental risk factors in AD pathogenesis. Epigenetic processes, including non‐coding RNAs and especially microRNAs (miRs), have emerged as important players in the molecular mechanisms underlying neurodegenerative diseases. MiRs have the ability to fine‐tune gene expression and proteostasis, and microRNAome profiling in liquid biopsies is gaining increasing interest since changes in miR levels can indicate the presence of multiple pathologies. We have profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE and 847 individuals of the ANDI cohort. Methods: We profiled blood samples via smallRNA sequencing for 1056 individuals of the DELCODE (German Longitudinal Cognitive Impairment and Dementia Study) and 847 individuals of the ANDI (Aging and Dementia in the Community) cohort, consisting of individuals diagnosed with SCD, MCI, AD, or control. Results: By applying differential expression, WGCNA, as well as linear and non‐linear machine learning approaches, we identify microRNA signatures that can help identify patients at distinct stages of disease progression, as well as signatures that can predict the course of the disease. These data are compared with phenotyping data, such as cognitive function and ATN biomarkers. We will also discuss the role of other non‐coding RNAs besides microRNAs and provide a framework for developing RNA‐based point‐of‐care assays.Item Molecular and Synaptic Signatures in Mouse Models of Late‐Onset Alzheimer’s Disease Independent of Amyloid and Tau Pathology(Wiley, 2025-01-03) Oblak, Adrian L.; Pharmacology and Toxicology, School of MedicineBackground: MODEL‐AD (Model Organism Development and Evaluation for Late‐onset AD) is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant genetic risk factors. Models expressing human‐relevant risk genetic risk factors are expected to better phenocopy LOAD than widely used transgenic models. Method: Here, two genetic risk factors APOE4 and Trem2*R47H, were incorporated into C57BL/6J (B6) mice along with humanized amyloid‐beta to produce the LOAD2 model. LOAD2 and control mice were aged up to 24 months with some being provided in the absence or presence of normal chow or a high fat/high sugar diet (LOAD2 HFD) from two months of age. A phenotyping pipeline was employed to evaluate disease outcomes observed in human patients, including in vivo imaging, brain and blood biomarker and cytokine analyses, multi‐omics (transcriptomics and proteomics), neuropathology and behavior. Result: By 18 months, unlike control mice (e.g., LOAD2 mice fed a control diet, CD), LOAD2 HFD mice presented subtle but significant loss of neurons in the cortex, elevated levels of insoluble AΒ42 in the brain, and increased plasma neurofilament light chain (NfL). Transcriptomics and proteomics showed changes in gene/proteins relating to a variety of disease‐relevant processes including lipid metabolism and synaptic function. In vivo imaging revealed an age‐dependent reduction in brain region volume (MRI) and neurovascular uncoupling (PET/CT). LOAD2 HFD mice also showed a learning deficit based on a Touchscreen cognitive assay. Conclusion: Despite the absence of hallmark amyloid and Tau pathologies, collectively these data support the use of LOAD2 HFD mice reveal this model as important for preclinical studies that target other features of LOAD independent of amyloid and tau.Item Novel HLA Class I Alleles Outside the Extended DR3 Haplotype Are Protective against Autoimmune Hepatitis(Wolters Kluwer, 2019-06) Lammert, Craig; McKinnon, Elizabeth J.; Chalasani, Naga; Phillips, Elizabeth J.; Gastroenterology & Hepatology, IU School of MedicineINTRODUCTION: HLA class II allele, DRB1*03:01, is the most common genetic risk factor for autoimmune hepatitis (AIH), but other unrecognized HLA related risks exist. METHODS: We compared the HLA class I (A, B, C) and class II (DR, DQ, DP) typing between patients with well-characterized AIH and healthy controls by high resolution sequencing of the HLA region. Seventy-three patients with AIH and 87 healthy controls were included. Association between HLA alleles and AIH was considered singly and in clusters and adjusted for age, gender, and DRB1*03:01. RESULTS: DRB1*03:01 was singly associated with AIH among whites (odds ratio [OR]: 3.09, P = 0.002) and carriers of DRB1*03:01 also carried DQA*05:01 and DQB1*02:01. Significant HLA class I alleles were associated with AIH including those belonging to the A03 (OR: 0.4, P = 0.01) and B44 supertype (OR: 0.44, P = 0.03). Further refinement of HLA-A by binding pocket structure revealed that the sequence Y(F/T)AVMENV(H/Q)Y, corresponding to HLA-A alleles A*03:01-02; *31:01; *32:02, was protective for AIH (OR: 0.3, P = 0.002). A protective association also existed for alleles belonging to the HLA-B binding pocket structure Y(H/Y)TVKEISNY (OR: 0.35, P = 0.01), corresponding to HLA-B alleles: B*40:01-02; *41:02; *44:02-03; *45:01; *49:01; *50:01-02. Associations with specific class I alleles belonging to the 8.1 ancestral haplotype (HLA-A*01:01, HLA-B*08:01, HLA-C*07:01) were not significant when considered jointly with DRB1*03:01 and reported protective class I alleles. DISCUSSION: Our study identified novel supertypes and HLA-A and B peptide binding structures protective against AIH. Further risk assessment of class I molecules remains important in AIH as they are key mediators of adaptive immunity.Item TREM2 in Neurodegenerative Diseases(BMC, 2017-08-02) Jay, Taylor R.; von Saucken, Victoria E.; Landreth, Gary E.; Neurology, School of MedicineTREM2 variants have been identified as risk factors for Alzheimer’s disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer’s disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.Item Type 2 Diabetes Genetic Risk Scores Are Associated With Increased Type 2 Diabetes Risk Among African Americans by Cardiometabolic Status(Sage, 2018-01-03) Layton, Jill; Li, Xiaochen; Shen, Changyu; de Groot, Mary; Lange, Leslie; Correa, Adolfo; Wessel, Jennifer; Epidemiology, School of Public HealthThe relationship between genetic risk variants associated with glucose homeostasis and type 2 diabetes risk has yet to be fully explored in African American populations. We pooled data from 4 prospective studies including 4622 African Americans to assess whether β-cell dysfunction (BCD) and/or insulin resistance (IR) genetic variants were associated with increased type 2 diabetes risk. The BCD genetic risk score (GRS) and combined BCD/IR GRS were significantly associated with increased type 2 diabetes risk. In cardiometabolic-stratified models, the BCD and IR GRS were associated with increased type 2 diabetes risk among 5 cardiometabolic strata: 3 clinically healthy strata and 2 clinically unhealthy strata. Genetic risk scores related to BCD and IR were associated with increased risk of type 2 diabetes in African Americans. Notably, the GRSs were significant predictors of type 2 diabetes among individuals in clinically normal ranges of cardiometabolic traits.