RPTOR Is an Alzheimer's Disease Susceptibility Gene Associated with the Risk Factors Body Mass Index and Infectious Encephalitis.

Background: In comparison to persons who did not have viral encephalitis, people with viral encephalitis had a later-life risk of Alzheimer's disease (AD) that was 31 times higher. In a previous study, we were able to confirm the association of viral encephalitis with AD and suggest that West Nile Virus infection is a significant AD risk factor. A genome wide association study (GWAS) with UK Biobank data revealed that the gene RAR Related Orphan Receptor B (RORB) is significantly associated with viral encephalitis. Objective: To use data from the 8 PheWeb datasets to try to identify genes other than RORB that might be involved in both infectious encephalitis and AD. Methods: PheWeb includes data from UKBB and 5 other databanks. We used UK Biobank data to examine gene expression and phenotypic expression. Results: PheWeb identified additional genes associated with both infectious encephalitis and AD. RPTOR, a gene associated with the mTOR pathway, emerges as significant. Analyses of UK Biobank data reveal the impact of RPTOR on AD risk, with carriers of the minor allele A exhibiting decreased prevalence in subjects under age 55. Further analysis demonstrates that RPTOR genotypes influence body mass index (BMI) in subjects of all ages, with carriers of the minor allele A having lower BMI. Logistic regression analyses confirm the association between reduced BMI and increased AD risk, along with the established factor of age. Conclusions: RPTOR may represent an AD gene, though mTOR's role in AD and BMI is complex. Nevertheless, RPTOR and mTOR could represent potential therapeutic targets for AD.

Long-lasting cigarette smoking alterations in immune function occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.

Background: Active cigarette smoking leads to increased CXCL5 production. CXCL5 mediates the immune response by attracting immune cells to areas of inflammation. Elevated CXCL5 levels are associated with various inflammatory diseases and tumorigenesis. In addition, smoking is linked to an increase in the level of the cytokine CEACAM6 in the bloodstream of smokers. CEACAM6 is increased in pancreatic adenocarcinoma, breast cancer, non small cell lung cancer, gastric cancer, colon cancer and other cancers and promotes tumor progression, invasion, and metastasis. Although cytokine secretion in the innate immune response returns to nonsmoker levels after quitting smoking, the effects on the adaptive response appear to persist for years or decades due to epigenetic memory. As a result, epigenetic changes induced by smoking may contribute to long-lasting alterations in immune function, including elevated CXCL5 and CEACAM6. The effects of cannabis smoking might be similar. Methods: In the current study we used UK Biobank (UKB) data to assess the relationship of CXCL5, CEACAM6, and pulmonary function to cigarette and cannabis smoking. Our UK Biobank application was approved as UKB project 57245 (S.L., P.H.R.). Our analysis included all subjects with smoking and/or marijuana use data in the UK Biobank database. Circulating levels of CXCL5 and CEACAM6 were from UKB Olink data. Individual CXCL5 and CEACAM6 levels are NPX, Normalized Protein expression, Olink arbitrary unit in Log2 scale (Olink Proteomics AB, Uppsala, Sweden; http://www.olink.com). Results: Current smokers and past smokers had elevated circulating levels of CXCL5 and CECAM6. In multivariate analysis, current, past, or no smoking history was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex. Frequency of cannabis use had a similar effect. In multivariate analysis, frequency of cannabis use was significantly related to CXCL5 level and CECAM6 levels, independent of the effects of age, sex, and years between last cannabis use and enrollment in study. Conclusion: we can confirm a previous report of epigenetic changes induced by cigarette smoking that may contribute to long-lasting alterations in immune function related to CXCL5 and CEACAM6. In addition, we have found that these same long-lasting smoking alterations in immune function related to CXCL5 and CEACAM6 occur in cannabis smokers, possibly rendering them vulnerable to smoking-related tumors in later life.

Effect of Glucosamine on Intraocular Pressure and Risk of Developing Glaucoma.

PRCIS: Glucosamine supplementation is common but can be associated with increased intraocular pressure (IOP) and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted. BACKGROUND: The most frequently recommended slow-acting medication for osteoarthritis symptoms is glucosamine, although its effectiveness is questionable. Widely used glucosamine sulfate supplements may increase IOP. METHODS: In the current study, we analyzed online databases such as UK Biobank, MedWatch, and FinnGen to evaluate the relationship between glucosamine and IOP and glaucoma. We included budesonide and fluticasone in the analysis for comparison since these drugs are associated with increased IOP. RESULTS: In UK Biobank subjects, glucosamine use was associated with increased corneal compensated IOP ( P =0.002, 2-tailed t test). This was also true in subjects without glaucoma ( P =0.002, 2-tailed t test). However, no significant association between glucosamine and IOP was detected in subjects with a diagnosis of glaucoma. In MedWatch, 0.21% of subjects taking glucosamine reported glaucoma, 0.29% of subjects using budesonide reported glaucoma, and 0.22% of subjects using fluticasone reported glaucoma. In contrast, 0.08% of subjects using any other drug reported glaucoma. This variability is significant ( P <0.001, 2-tailed Fisher exact test). Data from FinnGen on the risk of primary open angle glaucoma or glaucoma in subjects using glucosamine before the diagnosis of the disease revealed a significantly increased risk for both primary open angle glaucoma (hazard ratio: 2.35) and glaucoma (hazard ratio: 1.95). CONCLUSION: Glucosamine supplementation is common but can be associated with increased IOP and could contribute to the pathogenesis of glaucoma. It may be prudent for ophthalmologists to elicit any history of glucosamine use from their patients and advise them accordingly. Further studies on the role of glucosamine in glaucoma are warranted.

Increased Maternal Compared to Paternal Transmission of Alzheimer's Disease May Be Due to Increased Incidence of Depression in Women.

BACKGROUND: Mothers transmit Alzheimer's disease (AD) more frequently than fathers. Factors other than female longevity may be at work to promote maternal transmission of AD. Among these are the X chromosome, mitochondrial DNA, and AD comorbidities, especially depression. A recent study associated mitochondrial SNP rs2853499 with AD. MATERIALS AND METHODS: We used UK Biobank (UKBB) data to investigate the relation of mitochondrial SNP rs2853499, with AD. To identify cases of AD we used ICD10 code G30.9. Data processing was performed on Minerva, a Linux mainframe with Centos 7.6, at the Icahn School of Medicine at Mount Sinai. We used PLINK, a whole-genome association analysis toolset, to analyze the UKB22418 mitochondrial hard-called chromosome file. RESULTS: Of 953 AD cases, 493 were male (51.7%) and 460 were female (48.3%). Mothers were twice as likely to transmit AD compared to fathers. We found that in individuals with AD, 22.3% (n=201) carried the A allele of SNP rs2853499, 77.7% (n=700) carried the G allele. In individuals without AD, 22.2% (n=10,7726) carried the A allele of SNP rs2853499, 77.8% (n=378,535) carried the G allele. This difference was not significant (p=0.91, two-tailed Fisher exact test). Therefore, factors other than mitochondrial SNP rs2853499 may be at work to promote maternal transmission of AD. CONCLUSION: We conclude that depression, a multigenic illness, in the mother is most likely the basis for the fact that mothers transmit AD twice as often as fathers.

RORB, an Alzheimer's disease susceptibility gene, is associated with viral encephalitis, an Alzheimer's disease risk factor.

BACKGROUND: Viral encephalitis increases later-life risk of Alzheimer's disease (AD) by a factor of 31. METHODS: To further evaluate this finding, we examined the relationship of West Nile virus (WNV) to Alzheimer's disease in 50 US states. In addition, we performed a genome wide association study (GWAS) of viral encephalitis cases in UK Biobank (UKBB) to see if encephalitis genes might be related to AD. RESULTS: WNV was significantly associated with deaths from Alzheimer's disease in 50 US states (r = 0.806, p < 0.001). One gene, RORB-AS1, was most significantly related on GWAS to viral encephalitis. RORB-AS1 (RORB Antisense RNA 1) is an RNA gene. Diseases associated with RORB-AS1 include childhood epilepsy and idiopathic generalized epilepsy. The closely related RORB (Related Orphan Receptor B) is a marker of selectively AD vulnerable excitatory neurons in the entorhinal cortex; these neurons are depleted and susceptible to neurofibrillary inclusions during AD progression. RORB variants significantly decreased the risk of AD, independent of the significant effects of epilepsy, age, and years of education. The total effect size of variant RORB on AD prevalence is small, 0.19%, probably the reason RORB has not turned up on genome wide association studies of AD. But the decrease in effect size on AD, no variant versus varian is larger 0.20-0.16%. To produce the 31-fold increase in AD risk associated with viral encephalitis, non-variant RORB may need to interact with encephalitis virus. LIMITATIONS: A weakness in our correlative analysis is possible confounding by the ecological fallacy (or ecological inference fallacy), a logical fallacy in the interpretation of statistical data where inferences about the nature of individuals are derived from inference for the group to which those individuals belong. In this case, inferences about individuals are being drawn from the characteristics of U.S. states where they reside, rather than from the individuals themselves. A weakness in our GWAS is that UK Biobank had only 18 cases of viral encephalitis and none of these had AD. CONCLUSION: data presented here confirm the association of viral encephalitis with AD and suggest that WNV infection is a significant AD risk factor. In addition, GWAS suggests that the gene RORB, an AD vulnerability factor, is significantly related to viral encephalitis. FUTURE PROSPECTS: A human WNV vaccine could reduce Alzheimer's disease morbidity and mortality.

Association of Kallikrein Related Peptidase 3 (KLK3) gene with dermatophytosis in the UK biobank cohort.

BACKGROUND: In a previous genome wide association study (GWAS) of UK Biobank (UKB) data, we identified one susceptibility locus, tubulointerstitial nephritis antigen (TINAG), with genome wide significance for dermatophytosis. We used genotype calls from file UKB22418. These data are derived directly from Affymetrix DNA microarrays but are missing many genotype calls. Using computationally efficient approaches, UKB has entered imputed genotypes into a second dataset, UKB22828, increasing the number of testable variants by over 100-fold to 96 million variants. METHODS: In the current study, we used UKB imputed genotypes in UKB22828 to identify dermatophytosis susceptibility loci. To identify cases of dermatophytosis, we used ICD10 code B35, which covers tinea barbae, tinea capitis, tinea unguium, tinea manuum, tinea pedis, tinea corporis, tinea imbricata, tinea cruris, other dermatophytoses and dermatophytosis, unspecified. We used PLINK, a whole-genome association analysis toolset, to analyse the UKB22828 chromosome files. RESULTS: GWAS summary (Manhattan) plot of the meta-analysis association statistics highlighted two susceptibility loci, TINAG and Kallikrein Related Peptidase 3 (KLK3), with genome wide significance for dermatophytosis. KLK3, also known as prostate specific antigen (PSA), belongs to a subclass of serine proteases with a variety of physiological functions. CONCLUSION: KLK3 may be a dermatophytosis susceptibility gene. KLK3 could affect risk of dermatophytosis, since kallikreins are necessary for normal homeostasis of the skin.

Increased KCNN4 Expression Is Correlated With Poor Survival in Lower Grade Glioma.

BACKGROUND/AIM: Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of the Ca2+ activated potassium-channel protein KCa3.1 in in vitro models and mice, preventing the proliferation of glioma cells and tumor expansion. Marked reduction of tumor cell viability occurred within the entire network, as well as reduced tumor growth in mice and extended animal survival. MATERIALS AND METHODS: KCa3.1 is encoded by the gene potassium calcium-activated channel subfamily N member 4 (KCNN4) on the chromosomal location 19q13.31. We used the Cancer Genome Atlas (TCGA) to evaluate the effect of KCNN4 on human glioma survival in the TCGA Lower Grade Glioma (LGG) dataset. RESULTS: In humans, KCNN4 is prognostic in glioma; high expression is unfavorable. In addition, KCNN4 copy number variations are prognostic. Increased masked copy number segments are unfavorable in lower grade glioma. KCNN4 is lost in gliomas with the 1p 19q co-deletion, which may explain in part the comparatively favorable prognosis of 1p 19q co-deletion tumors. CONCLUSION: Our finding of increased KCNN4 expression related to poor survival in human lower grade glioma suggests that developing novel therapies, such as KCa3.1-inhibiting drugs, might be worthwhile.

Predicted Configuration and Stability of the ATAD2/SOX10 Complex Using Molecular Dynamics Simulations.

BACKGROUND/AIM: ATAD2, a melanoma competence factor, forms a protein complex with SOX10 that facilitates expression of SOX10 developmental target genes. The complex enables a strong transcriptional response to oncogenes such as BRAFV600E and is sufficient to endow oncogenic competence to melanocytes. The elucidation of the ADAT2/SOX10 complex structure may facilitate the development of drugs that can block formation of the complex. MATERIALS AND METHODS: We used the ClusPro web server for protein-protein docking to visualize and analyze the complex and GROMACS to perform molecular dynamics simulations. RESULTS: ClusPro protein docking analysis demonstrated the central position of ADAT2 in the ADAT2/SOX10 complex. Molecular dynamics simulations of ATAD2 docked to SOX10 suggest that ATAD2/SOX10 is not a stable structure. CONCLUSION: The central position of ADAT2 in the complex suggested that ADAT2 complexed to SOX10 may have the capability to modify multiple functions of the latter, one of which allows BRAFV600E to impart increased oncogenic function to melanocytes. The results of the molecular dynamics simulations imply that the ADAT2/SOX10 complex is not stable and might be disrupted by a therapeutic molecule, reducing the risk of melanoma. Knowledge of the ADAT2/SOX10 complex structure may facilitate the development of drugs that can block complex formation.

Insulin Docking Within the Open Hemichannel of Connexin 43 May Reduce Risk of Amyotrophic Lateral Sclerosis.

BACKGROUND/AIM: Type 2 diabetes (T2D), characterized by hyperinsulinemia, protects motor neurons against amyotrophic lateral sclerosis (ALS). Type 1 diabetes and a total lack of insulin are associated with increased risk of ALS. Connexin 43 (Cx43), an astrocyte protein, operates as an open pore via which toxic substances from the astrocytes reach motor neurons. MATERIALS AND METHODS: In the current study, we performed molecular docking of insulin with monomeric Cx31, monomeric Cx43, and hexameric Cx31 to assess whether insulin might affect the pore. Hexameric Cx31 and hexameric Cx43 are transmembrane hemichannels composed of 6 subunits; they bind together to form gap junction intercellular channels. We used the program AutoDock Vina Extended for the molecular docking study. RESULTS: Cx31 shares amino acid and structural similarity to Cx43, and insulin docks to the same position at the N-terminal domain of monomeric Cx31 and monomeric Cx43. Insulin docks within the open hemichannel of hexameric Cx31, potentially blocking it. Molecular dynamics simulation shows that the block is highly stable and may be responsible for the protective effect of T2D on ALS. CONCLUSION: Insulin, especially intranasal insulin, might be a treatment for ALS. An insulin secretogogue such as oral sulfonylurea or meglitinide might also be of value.

Androgen Deprivation Therapy Unrelated to Alzheimer's Disease in the UK Biobank Cohort.

BACKGROUND/AIM: In a meta-analysis of 14 studies, men who received androgen deprivation therapy (ADT) for prostate cancer had a higher risk of dementia and/or Alzheimer disease (AD) than men who did not receive ADT. The effect was more pronounced when ADT was given for more than 12 months. However, in all these analyses, two of the strongest AD risk factors after age, family history of AD and the apolipoprotein e4 allele, were not included. In the current study, we have used data from the UK Biobank (UKB) that incorporates these two factors. PATIENTS AND METHODS: Our analysis included all subjects with prostate cancer and AD. Prostate cancer diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10), C61. AD diagnosis was ascertained using the 10th Revision of the International Classification of Diseases (ICD10) G30. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to determine ApoE genotypes. ADT was in UKB field 20003, Treatment/medication code, Medications. Family history of AD was in UKB data fields 20107, Illnesses of father; 20110, Illnesses of mother; 20111, Illnesses of siblings. RESULTS: We studied 13,203 men with prostate cancer. The age of 132 subjects that received ADT was 64±5.6 (mean±standard deviation), and the age of 13,071 subjects that did not receive ADT was 62±5.6 (p<0.001). ADT was not associated with AD, but Apoe3e3 was significantly associated with diminished risk of AD when compared to e4e4. Moreover, every year of age was associated with increased risk of AD. ADT was unrelated to AD (p=0.997). CONCLUSION: Our UK Biobank data analysis does not confirm that ADT causes AD in men with prostate cancer. Large studies that include family history of AD and ApoeE genotype are needed. Mendelian randomization would also be desirable for a more definitive result.

Chromosome 1p deletion in colorectal cancer and lower grade glioma: possible relationship with the enteric nervous system.

Background: Enteric neurons and enteric glial cells are a part of the enteric nervous system, which is sometimes referred to as the "second brain" of the body. This complex network of neurons controls various functions of the gastrointestinal tract, including motility, secretion, and blood flow. Research has shown that there is a connection between enteric neurons and the development of colorectal cancer, although the exact mechanisms are still being studied. Methods: Because of the potential influence of chromosome mutations that may be common to both gliomas and colorectal cancer, we used the Cancer Genome Atlas (TCGA) to examine these mutations. Results: 166 of 506 lower grade gliomas had the 1p 19q co-deletion. 150 of 616 colorectal cancers had a 1p deletion but no 19q deletion. Conclusion: Colorectal cancer cells adhere to and migrate along the neurons of the enteric nervous system. Therefore, cancer cells might be expected to pick up mutations from neurons and enteric glial cells during recombination events. We hypothesize that the chromosome 1p deletion in colorectal cancer above is not a chance event and instead was acquired from adjacent enteric glial cells. Chromosome 1p co-deletion may confer better survival in patients with lower grade glioma in part because of loss of the MycBP oncogene, which is important in glioma development. Enteric glia might have the chromosome 1p deletion but lack the chromosome 19q deletion of CNS gliomas, making them much less vulnerable to malignant transformation than CNS gliomas. Indeed, evidence exists for a tumor suppressor gene on chromosome 19q associated with human astrocytomas, oligodendrogliomas, and mixed gliomas.

α-synuclein enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis.

Background: Parkinson's disease (PD) results from degeneration of dopamine and norepinephrine neurons due to α-synuclein aggregates that likely have their origin in the gut. Tyrosine hydroxylase (TH) catalyses the formation of L-DOPA, the rate-limiting step in the biosynthesis of dopamine. A second enzyme, DOPA decarboxylase (DDC), catalyzes the conversion of L-DOPA to dopamine. A third enzyme, dopamine ß-hydroxylase (DBH), catalyzes the conversion of dopamine to norepinephrine. To analyze possible interactions of α-synuclein with TH, DDC and DBH, we performed in silico protein-protein docking. Methods: Protein data bank (pdb) entries were searched on the RCSB Protein Data Bank. We identified four structures that allowed us to examine the relationship of α-synuclein with TH, DDC, and DBH: (1) Human micelle-bound alpha-synuclein, (2) solution structure of the regulatory domain of tyrosine hydroxylase (Rattus norvegicus), (3) crystal structure of human aromatic L-amino acid decarboxylase (DOPA decarboxylase) in the apo form and (4) crystal structure of human dopamine ß-hydroxylase at 2.9 angstrom resolution. We used the ClusPro server (https://cluspro.org) for protein-protein docking. The protein structures were visualized with PyMOL v 2.3.4. Results: α-synuclein partially enfolds tyrosine hydroxylase and dopamine ß-hydroxylase, potentially reducing dopamine and norepinephrine synthesis. α-synuclein may dock too far away from DOPA decarboxylase to affect its function directly. Conclusions: Our in silico finding of α-synuclein partly enfolding tyrosine hydroxylase and dopamine ß-hydroxylase suggests that α-synuclein docking inhibition could increase dopamine and norepinephrine biosynthesis, ameliorating PD symptoms. Small molecules that bind to α-synuclein have already been identified. Further studies may lead to new small molecule drugs that block α-synuclein enfolding of tyrosine hydroxylase and dopamine ß-hydroxylase.

Vaccination Reduces Risk of Alzheimer's Disease, Parkinson's Disease and Other Neurodegenerative Disorders.

Neurodegeneration is an increasing problem of aging. Alzheimer's Disease (AD) and Parkinson's Disease (PD) are the most frequent forms of age-related neurodegeneration. Infectious diseases, in general, confer a risk of AD. Influenza and pneumonia vaccinations reduce risk of AD. Being vaccinated against pneumonia between ages 65-75 is associated with a reduction in the risk of AD afterwards. Protection against bacterial and viral infection is beneficial to the brain since these infections may activate dormant herpes simplex type 1 (HSV-1) and herpes zoster virus (HZV). HSV-1 and HZV may interact to trigger AD. Shingles (HZV) vaccine Zostavax reduces risk of AD and PD. This finding is consistent with the link between viruses and neurodegeneration. Herpes virus-induced reactivation of embryologic pathways silenced at birth could be one of the pathologic processes in AD and PD. Once embryologic reactivation has occurred in the brain of an older person and AD or PD develops, this complex process relentlessly destroys the protective mechanism it created in utero. Unanswered question: Are the AD-risk-reducing effects of flu, pneumonia, and shingles vaccinations cumulative?

Circulating Chlamydia Trachomatis Antigens in Subjects With Alzheimer's Disease.

BACKGROUND/AIM: Chlamydia pneumoniae (C. pneumoniae) is implicated in the pathogenesis of Alzheimer's disease (AD). Chlamydial elementary and reticulate bodies have been identified in tissues from afflicted AD brain regions by electron and immunoelectron microscopy, whereas similar tests of non-AD brains were negative for the bacterium. Studies in mice have shown that C. pneumoniae can rapidly penetrate the central nervous system by entering glia and causing beta amyloid deposition via the nerves between the nasal cavity and the brain, which serve as invasion pathways. MATERIALS AND METHODS: We used data from the UK Biobank (UKBB) to assess the relationship of chlamydia and AD. Circulating C. pneumoniae antigen measurements were not available, but UKBB data field 23037 held measurements of PorB antigen for Chlamydia trachomatis (C. trachomatis). We used C. trachomatis as a surrogate for C. pneumoniae since serum cross-reactivity to C. trachomatis and C. pneumoniae antigens occurs in patients with documented infection and in healthy children as revealed by microimmunofluorescence and immunoblotting techniques. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to impute ApoE genotypes. RESULTS: PorB antigen levels for C. trachomatis were significantly higher in subjects with AD (p=0.007). PorB antigen levels were not related to ApoE genotype (e3e3, e3e4, e4e4) p=0.783. To control for the effects of age, sex, educational level, and apoE genotype, logistic regression analysis was performed. AD was the dependent variable. Independent variables were sqrt PorB antigen for C. trachomatis, age, sex, educational level, apoE genotype. AD odds ratio (OR) increased 1.156 for each unit increase of sqrt PorB antigen for C. trachomatis and the effect was significant (p=0.004). CONCLUSION: PorB antigens for C. trachomatis being significantly higher in subjects with AD, corroborates previous studies demonstrating that C. pneumoniae inflammation appears to play a role in AD development. AD may result from the reactivation of embryologic processes and pathways silenced at birth. A trigger for the reactivation may be bacterial or viral infections. Further studies are warranted.