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Background: Obesity and related metabolic disturbances including diabetes, hypertension and hyperlipidemia predict future cognitive decline. Asia has a high prevalence of both obesity and metabolic disease, potentially amplifying the future burden of dementia in the region. We aimed to investigate the impact of adiposity and metabolic risk on cognitive function in Asian populations, using an epidemiological analysis and a two-sample Mendelian Randomization (MR) study. Methods: The Health for Life in Singapore (HELIOS) Study is a population-based cohort of South-East-Asian men and women in Singapore, aged 30–84 years. We analyzed 8769 participants with metabolic and cognitive data collected between 2018 and 2021. Whole-body fat mass was quantified with Dual X-Ray Absorptiometry (DEXA). Cognition was assessed using a computerized cognitive battery. An index of general cognition ‘g’ was derived through factor analysis. We tested the relationship of fat mass indices and metabolic measures with ‘g’ using regression approaches. We then performed inverse-variance-weighted MR of adiposity and metabolic risk factors on ‘g’, using summary statistics for genome-wide association studies of BMI, visceral adipose tissue (VAT), waist-hip-ratio (WHR), blood pressure, HDL cholesterol, triglycerides, fasting glucose, HbA1c, and general cognition. Findings: Participants were 58.9% female, and aged 51.4 (11.3) years. In univariate analysis, all 29 adiposity and metabolic measures assessed were associated with ‘g’ at P < 0.05. In multivariable analyses, reduced ‘g’ was consistently associated with increased visceral fat mass index and lower HDL cholesterol (P < 0.001), but not with blood pressure, triglycerides, or glycemic indices. The reduction in ‘g’ associated with 1SD higher visceral fat, or 1SD lower HDL cholesterol, was equivalent to a 0.7 and 0.9-year increase in chronological age respectively (P < 0.001). Inverse variance MR analyses showed that reduced ‘g’ is associated with genetically determined elevation of VAT, BMI and WHR (all P < 0.001). In contrast, MR did not support a causal role for blood pressure, lipid, or glycemic indices on cognition. Interpretation: We show an independent relationship between adiposity and cognition in a multi-ethnic Asian population. MR analyses suggest that both visceral adiposity and raised BMI are likely to be causally linked to cognition. Our findings have important implications for preservation of cognitive health, including further motivation for action to reverse the rising burden of obesity in the Asia–Pacific region. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Ministry of Health (MOH) Nanyang Technological University National Medical Research Council (NMRC) Published version This work was supported by intramural funding from Nanyang Technological University, Lee Kong Chian School of Medicine, and the National Healthcare Group. J.C. is supported by: the Singapore Ministry of Health and National Medical Research Council STaR funding scheme [NMRC/StaR/0028/2017], LCG funding [MOH-000271], and Phase 2 National Precision Medicine Programme (Research Platform and Data Enablers) [NMRC/PRECISE/2020]; and the Singapore Agency for Science Technology and Research IAF-PP National Precision Medicine Program Phase 1A (A Population Level Genomic Infrastructure) [H17/ 01/a0/007] and IAF-PP Asian Skin Microbiome Programme [H18/01/ a0/016]. T.M. received postdoctoral fellowship from the Singapore Ministry of Education – Research Scholarship Block and Lee Kong Chian School of Medicine.

Aim: Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of sympathetic neurotransmitter norepinephrine to epinephrine. We examined the association of PNMT polymorphisms with acute and chronic pain in sickle cell disease (SCD). Methods: Utilization of emergency care owing to painful crisis was used as a marker for acute pain in 131 patients with SCD. Results: rs876493 A allele, rs2934965 T allele and rs2941523 G allele were significantly associated with decreased utilization (p ≤ 0.05). rs876493 A allele showed association with utilization in females (p = 0.003), not males (p = 0.803). rs2934965 T allele and rs2941523 G allele were predicted to cause loss of putative transcription factor binding sites. This is the first report of the association of PNMT polymorphisms with acute crisis pain in SCD. Together with our previous findings in catechol-o-methyltransferase, polymorphisms in catecholamine metabolizing enzymes appear to primarily influence acute pain in SCD.

Background Pain in sickle cell disease (SCD) is severe and multifaceted resulting in significant differences in its frequency and intensity among individuals. In this study, we examined the influence of S100B gene single nucleotide polymorphisms (SNP) on acute and chronic pain variability in SCD. Methods Composite pain index (CPI) scores captured chronic pain. Painful crisis related emergency care utilization recorded acute pain incidence. Genotyping was performed using MassARRAY iPLEX platform. Results Regression analysis revealed associations of increased CPI with rs9722 A allele in additive (p = 0.005) and dominant (p = 0.005) models. Rs1051169 G allele on the other hand was associated with decreased CPI in additive (p = 0.001), and dominant (p = 0.005) models. Sex-specific analysis found that these associations were significant in females but not males in this cohort. Linkage analysis identified two haploblocks. Block 1 (rs9983698-rs9722) haplotype T-A was associated with increased CPI (p = 0.002) while block 2 (rs1051169-rs11911834) haplotype G-G was associated with decreased CPI (p = 0.001). Both haplotypic associations were only significant in females. No association of S100B SNPs with utilization reached statistical significance. Conclusions S100B SNPs and haplotypes are associated with chronic pain in female, but not male, patients with SCD, implicating a potential role of S100B polymorphism in SCD pain heterogeneity in a sex-dependent manner.

Sickle cell disease (SCD) is a genetic blood disorder characterized by debilitating episodes of acute pain along with lifelong chronic pain. Pain is not only the major reason for high healthcare costs and poor quality of life but has also been reported as a predictor of mortality among SCD patients. Yet pain management in SCD remains a challenging task owing to the high inter-individual variability in the manifestation of pain. Research in the field of pain genetics, including some of our preliminary work, suggests that pain variability can be explained, to some extent, by genetic factors such as single nucleotide polymorphisms (SNPs). However, comprehensive candidate gene studies and polygenic modeling of the different SCD pain phenotypes are still largely missing. In this dissertation, I investigated the role of numerous SNPs in acute and chronic pain variability in SCD. First, I examined the effect of SNPs in four candidate genes: phenylethanolamine N-methyltransferase (PNMT), serotonin 1A receptor (HTR1A), dopamine beta-hydroxylase (DBH), and S100 calcium-binding protein B (S100B). DBH SNPs associated with both acute and chronic pain, PNMT and HTR1A SNPs associated with acute pain only, and S100B SNPs associated with chronic pain only. Several SNPs exhibited sex-specific associations. Functional analyses revealed that some SNPs may be altering tissue-specific gene expression, and/or potentially interfering with transcription factor binding. Pain being a complex phenotype, I also performed polygenic analyses by applying machine-learning and statistical methods to capture the collective effect of SNPs across several interacting genes on the chronic pain variability in SCD. Using a network-assisted analysis approach, I built a 12-SNP polygenic model for prediction of chronic pain severity among SCD patients. I also evaluated the contribution of SNPs in different nervous-system signaling pathways using pathway-based analysis. I found that SNPs in monoamine signaling genes accounted for ~ 30% of the variability in chronic pain. Findings from this research not only expand our understanding of the genetic factors involved in modulating pain in SCD, but also offer a platform for the development of polygenic pain prediction models for a more comprehensive and personalized approach towards pain diagnosis, classification, and management.

Aim: Pain in sickle cell disease patients is heterogeneous and genetic polymorphisms may predispose an individual to varied vulnerability to painful events. We studied the association of SNPs in the glucocorticoid receptor gene (NR3C1) with pain in sickle cell disease. Method: Acute pain was scored as the number of utilizations due to crisis pain in a 12-month period. Chronic pain was calculated as the Composite Pain Index score. Results & conclusion: rs33389 T allele (IRR = 1.53, p = 0.014 additive; IRR = 1.64, p = 0.011 recessive), rs2963155 G allele (IRR = 1.80, p

Aim: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. Methods: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. Results & conclusion: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD.

The multidimensional nature of pain in sickle cell disease (SCD) has rendered its therapeutic management extremely challenging. In this study, we explored the role of five single nucleotide polymorphisms (SNPs) of candidate gene GCH1 in SCD pain. Composite pain index (CPI) scores and acute care utilization rates were used as phenotype markers. Rs8007267 was associated with chronic pain (additive model: B = −3.76, p = 0.037; dominant model: B = −5.61, p = 0.021) and rs3783641 (additive model: incident rate ratio [IRR] = 1.37, p = 0.024; recessive model: IRR = 1.81, p = 0.018) with utilization rate. These associations persisted when subjects with HbSS and HbS(−)β genotype only were analyzed. We also identified two haploblocks (rs10483639[G>C]-rs752688 [C>T]-rs4411417[T>C] and rs3783641[T>A]-rs8007267[T>C]) with SNPs in high linkage disequilibrium. Of these, haplotype T-C of haploblock rs3783641-rs8007267 showed significant association with rate of utilization (odds ratio [OR] = 0.31, p = 0.001). Our study indicates potential contribution of GCH1 polymorphisms to the variability of pain in African Americans with SCD.

Pain in sickle cell disease (SCD) is complex and heterogeneous. In this study, we examine the influence of single nucleotide polymorphisms (SNP) in the S100B gene on acute and chronic pain variation in SCD. 136 subjects with SCD recorded their baseline, non-crisis pain experience on a digital version of the McGill Pain Questionnaire, from which we obtained composite pain index (CPI) scores as a measurement for chronic pain. Utilization of emergency or urgent care owing to painful crisis was recorded as a marker for acute pain. Blood/buccal swab samples were collected and genotyped using MassARRAY iPLEX platform. Multiple linear regression analyses revealed association with higher CPI scores for rs9983698 T allele (additive: B= 4.91, p= 0.014; dominant: B= 6.43, p= 0.009), rs9722 A allele (additive: B= 4.81, p= 0.005; dominant: B= 7.80, p= 0.003), and rs11911834 T allele (additive: B= 4.75, p= 0.016; dominant: B= 6.13, p= 0.011). On the other hand, the G allele of rs1051169 associated with decreased CPI (additive: B= -6.14, p= 0.001; dominant: B= -6.56, p= 0.009; recessive: B= -9.78, p= 0.005). Further, ordinal logistic regression of utilization groups showed that the G allele of rs1051169 also associated with lower utilization (additive: B= -1.02, p= 0.0003; dominant: B= -1.20, p= 0.002; recessive: B= -1.26, p= 0.015). Employing linkage disequilibrium plot, we identified two haploblocks for these 4 SNPs. In block 1 (rs9983698-rs9722), haplotypes T-A and C-G significantly associated with CPI (B= 5.63, -4.81; p= 0.007, 0.005, respectively). In block 2 (rs1051169-rs11911834), C-T and G-G haplotypes showed significant association with CPI (B= 4.52, -6.02; p= 0.024, 0.001, respectively). S100B SNPs and haplotypes were found to associate with acute and chronic pain in SCD indicating the potential role of S100B in sickle cell pain heterogeneity. Supported by grants from the NIH (R01HL124945, R01HL098141, T32DE018381) and IDPH.

In the present study controlled release effervescent buccal discs of buspirone hydrochloride (BS) were designed using HPMC as rate controlling and bioadhesive polymer by direct compression method. Sodium bicarbonate and citric acid were used in varying amounts as effervescence forming agents. Carbon dioxide evolved due to reaction of sodium bicarbonate and citric acid was explored for its potential as buccal permeation enhancer. The designed buccal discs were evaluated for physical characteristics and in vitro drug release studies. Bioadhesive behavior of designed buccal discs was assessed using texture analyzer. In vivo animal studies were performed in rabbits to study bioavailability of BS in the designed buccal discs and to establish permeation enhancement ability of carbon dioxide. It was observed that effervescent buccal discs have faster drug release compared to non-effervescent buccal discs in vitro and effervescent buccal discs demonstrated significant increase in bioavailability of drug when compared to non-effervescent formulation. Hence, effervescent buccal discs can be used as an alternative to improve the drug permeation resulting in better bioavailability. However, the amount of acid and base used for generation of carbon dioxide should be selected with care as this may damage the integrity of bioadhesive dosage form.