👤 Kanchan Bhatia

Major Depressive Disorder (MDD) is a debilitating and multifactorial neuropsychiatric condition that significantly contributes to the global burden of disease. Its clinical spectrum encompasses persistent low mood, anhedonia, cognitive decline, neurovegetative disturbances, and suicidality. This review synthesizes current evidence on the neurovascular, neurochemical, genetic, and psychosocial mechanisms underlying MDD. A narrative review approach was employed, incorporating data from peer-reviewed publications retrieved through systematic searches in biomedical databases. Emphasis was placed on recent findings that elucidate the interplay between neurobiological dysfunction and systemic influences in MDD pathogenesis. MDD pathophysiology is intricately linked to dysregulation of monoaminergic neurotransmission, aberrant hypothalamic-pituitary-adrenal (HPA) axis activity, and chronic neuroinflammation. Glial cell impairment, particularly involving astrocytes and microglia, disrupts synaptic homeostasis and neurovascular integrity. Genetic analyses estimate a heritability range of 30-50%, with genome-wide association studies identifying susceptibility loci in synaptic and immune pathways. Epigenetic modifications and perturbations of the gut- brain axis modulate vulnerability and progression. Oxidative stress and attenuated neurotrophic signalling, especially involving brain-derived neurotrophic factor (BDNF), further exacerbate neural circuit dysfunction. Sociodemographic determinants, including sex, psychosocial stressors, and socioeconomic adversity, also shape disease onset and trajectory. Although therapeutic modalities exist, limitations in early detection, treatment response, and long-term remission underscore the need for individualized strategies. Emerging approaches integrating epigenetic biomarkers and systems biology hold potential for precision psychiatry. A systems-level, biopsychosocial understanding of MDD is essential to advance targeted, personalized interventions, ultimately improving clinical outcomes in this complex disorder. Show less

Multiple studies show conflicting association between APOE polymorphisms and the risk of PDD, yielding inconsistent results. To elucidate, a meta-analysis was conducted using existing articles from Web of Science, PubMed, Cochrane, Google Scholar, Embase, WanFang, and CNKI databases, including case-control studies published up to January 31, 2025. A total of 27 studies (3,115 PD controls and 1,338 PDD cases) were included, with pooled Odds Ratio (ORs) and 95% confidence intervals (CIs) calculated using CMA, Biostat, United States. To assess APOE genotypes and PDD risk, three comparisons were examined: 5 genotypes vs. ε3/3, ε2+/ε4 + vs. ε3/3, and ε4 + vs. ε4-. The ε3/4 (OR = 1.56, 95% CI: 1.25-1.95); ε4 + vs. ε3/3 (OR = 1.52, 95% CI: 1.20-1.93) and ε4 + vs. ε4- (OR = 1.62, 95% CI: 1.39-1.90) genotypes were associated with an increased PDD risk, while ε2 + showed no significant effect (OR = 1.21, 95% CI: 0.88-1.65, Show less

Lipoprotein(a) [Lp(a)] is a well-established, genetically determined risk factor for atherosclerotic cardiovascular disease, but its short-term response to aggressive lipid-lowering therapy after acute coronary syndrome (ACS) remains unclear. To evaluate 1-month changes in Lp(a) and assess whether baseline Lp(a) levels are associated with low-density lipoprotein cholesterol (LDL-C) goal achievement in statin-naive ACS patients undergoing triple oral lipid-lowering therapy. We retrospectively analyzed 345 patients with ACS treated with rosuvastatin (20-40 mg), ezetimibe (10 mg), and bempedoic acid (180 mg) for 1 month after percutaneous coronary intervention. Lp(a) and LDL-C were measured at baseline and 1 month. Multivariable logistic regression identified predictors of achieving the LDL-C goal (<50 mg/dL). Despite a 59.1 ± 17.3% reduction in the mean LDL-C, the average Lp(a) increased by 91% (from 42.2 ± 39.2 mg/dL to 80.5 ± 66.3 mg/dL, P < .001). LDL-C targets of <50 mg/dL and <55 mg/dL were achieved in 68.9% and 78.6% patients, respectively. Baseline Lp(a) independently predicted failure to reach LDL-C goals (adjusted odds ratio [OR] 0.97; 95% CI 0.96-0.98; P < 0.001), while diabetes mellitus increased the likelihood of achieving targets (adjusted OR 2.69; 95% CI 1.36-5.61; P = .006). A strong inverse relationship was observed between Lp(a) change and LDL-C goal achievement (ρ = -0.38, P < 10⁻¹²). In Indian patients with ACS, aggressive triple oral lipid-lowering therapy quickly reduces LDL-C, while being accompanied by a substantial rise in Lp(a) levels, likely reflecting an acute-phase response. Baseline Lp(a) may independently limit LDL-C target attainment. Early Lp(a) testing may improve residual risk assessment and help guide the use of emerging Lp(a)-focused treatments. Show less

Lipoprotein(a) [Lp(a)] is a causal risk factor for cardiovascular disease, but its impact on long-term coronary plaque progression remains unclear. This study synthesizes evidence from CCTA, IVUS, and OCT to clarify the relationship between high-risk Lp(a) and coronary plaque burden and high-risk plaque features. We conducted a comprehensive search of multiple databases up to July 2025 for studies evaluating Lp(a) and atherosclerotic plaque progression. Statistical analysis was performed using a random-effects model in RevMan 5.4, reporting odds ratios (OR) and mean differences (MD) with 95% confidence intervals (CI). The protocol is registered in PROSPERO (CRD420251113955). Our final analysis included 16 studies comprising 19,822 participants with a mean age of 62 years and a median imaging follow-up ranging from 10 months to 10.2 years. On analysis, high-risk Lp(a) levels were significantly associated with the presence of coronary plaque (OR 1.53; 95% CI, 1.03-2.29; p = 0.04) compared with low Lp(a) levels. Additionally, patients with elevated Lp(a) exhibited significantly greater progression in percent atheroma volume (ΔPAV) than those with low levels (MD 4.31%; 95% CI, 1.08-7.53; p = 0.009). Subgroup analysis by plaque phenotype revealed a statistically significant increase in low-attenuation plaque (LAP) presence among individuals in the high-risk Lp(a) category (OR 1.92; 95% CI, 1.13-3.27; p = 0.02). High-risk Lp(a) is associated with greater coronary plaque prevalence, accelerated progression, and increased LAP. These findings underscore Lp(a) as a driver of high-risk, rupture-prone plaques and a critical biomarker and potential therapeutic target in cardiovascular risk management. Show less

The utility of coronary artery calcium (CAC) scoring in individuals with elevated lipoprotein(a) [Lp(a)] for atherosclerotic cardiovascular disease (ASCVD) risk assessment is currently unclear given the propensity of Lp(a) toward noncalcified plaque. The authors aimed to evaluate the interaction between elevated Lp(a) (>50 mg/dL) and CAC score, and the association of Lp(a) with ASCVD risk across strata of CAC. A pooled cohort of participants without known ASCVD from 4 U.S.-based prospective cohort studies with baseline Lp(a) and CAC measurements was used. The association between elevated Lp(a) across CAC strata and incident ASCVD (myocardial infarction, stroke, coronary revascularization) was evaluated in multivariable Cox regression models. The study included 11,319 participants (mean age 56 years, 54% women) with 1,569 incident ASCVD events over 14.8 year mean follow-up. Lp(a) >50 mg/dL (HR: 1.24; 95% CI: 1.09-1.41) and CAC >0 (HR: 2.44; 95% CI: 2.14-2.77) were independently associated with ASCVD risk (P interaction = 0.80). Among individuals with CAC = 0, ASCVD incidence rates were low overall, but higher with Lp(a) >50 mg/dL vs ≤50 mg/dL (4.9 vs 3.8/1,000 person-years, HR: 1.28; 95% CI: 1.01-1.60). Among those with CAC >0, increased risk was again noted with elevated Lp(a) (21.2 vs 18.2/1,000 person-years, HR: 3.03; 95% CI: 2.52-3.64). Similar results were observed when examining further CAC strata with the greatest risk noted with both CAC ≥300 and Lp(a) >50 mg/dL (HR: 6.12; 95% CI: 4.80-7.81). Consistent results were noted by age and sex with greater absolute risk in general among individuals >50 years of age and men. Elevated Lp(a) is associated with higher relative risk across CAC strata, including CAC of 0. Among individuals with CAC of 0, absolute event rates remain low even when Lp(a) is elevated. CAC scoring remains a powerful tool for risk assessment among individuals with elevated Lp(a). Show less

Lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C) are causally linked to aortic valve calcium (AVC) and aortic stenosis (AS). Lipoprotein(a) has anti-fibrinolytic properties; therefore, aspirin may reduce cardiovascular disease risk among individuals with high Lp(a). This analysis sought to determine the association of aspirin with incident AVC and AS across Lp(a) and LDL-C levels. This observational study included up to 6598 participants in the Multi-Ethnic Study of Atherosclerosis. Aortic valve calcium was measured on non-contrast cardiac computed tomography. Multivariable Cox hazards regression assessed the association of self-reported regular aspirin use (≥3 days/week) with incident AVC and severe AS, stratified by Lp(a) and LDL-C. Aortic valve calcium and Lp(a) values were not reported to participants. Mean age was 62 years, 53% were women, 23% reported regular aspirin use, 8% developed AVC (median 8.9 years), and 1% developed severe AS (median 16.7 years). Among individuals with elevated Lp(a), regular aspirin use was associated with a lower risk of incident AVC (Lp(a) ≥75 mg/dL: hazard ratio (HR) .42, 95% confidence interval (CI) .19-.93; Lp(a) ≥100 mg/dL: HR .17, 95% CI .04-.67) and severe AS (Lp(a) ≥50 mg/dL: HR .13, 95% CI: .04-.47; Lp(a) ≥75 mg/dL: HR .02, 95% CI .001-.29). For participants with elevated LDL-C, there was no association of regular aspirin use with incident AVC (LDL-C ≥130 mg/dL: HR 1.02, 95% CI .66-1.58; LDL-C ≥160 mg/dL: HR 1.51, 95% CI .53-4.28) or severe AS (LDL-C ≥100 mg/dL: HR .70, 95% CI .39-1.26; LDL-C ≥130 mg/dL: HR .46, 95% CI .14-1.47). In this exploratory analysis of prospective observational cohort data, regular aspirin use was associated with a lower risk of AVC and severe AS in persons with high Lp(a), but not high LDL-C. Confirmatory studies are required to determine the role of aspirin in the prevention of AVC and AS for persons with high Lp(a). Show less

Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting. Show less

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for myocardial infarction and stroke. Elevated Lp(a) >50 mg/dL (>125 nmol/L) is common and present in about 1 in 5 individuals. Although Lp(a) may be a cause of young ischemic stroke (age ≤60), limited data on national testing trends in this population are available, testing in the general population remains low overall, and different organizations have varying guidelines for testing. By determining the degree to which this population is tested, information on national testing trends of Lp(a) in young ischemic stroke patients may influence future guideline recommendations to increase Lp(a) testing. This study aims to use a large, real-world dataset to assess trends of Lp(a) testing in young ischemic stroke patients in the United States from 2015-2024. We performed a retrospective analysis of Lp(a) testing in young ischemic stroke patients across the United States from January 1, 2015 to December 31, 2024 using Epic Cosmos, a nationwide, de-identified electronic health record (EHR) dataset comprising over 300 million patient records from over 1,715 hospitals and 41,000 clinics, including from all 50 states, Washington D.C., Lebanon, and Saudi Arabia. The current count values for patients, hospitals, and clinics are available on the Epic Cosmos website. Although the Epic Cosmos data dictionary includes Lebanon and Saudi Arabia as standardized site locations, no patients from these countries were present in our analytic cohort; thus, all analyses were restricted to individuals within the United States. We evaluated the number of young ischemic stroke patients, defined as age ≤60 with history of an ischemic cerebrovascular accident (CVA), who had ever undergone Lp(a) testing, the testing rate per annual young ischemic stroke patients, geographical variation, and percentages of patients tested stratified by age, sex, ethnicity, race, and diagnosis of coronary artery disease (CAD). Testing rates were calculated as the number of distinct patients tested per year and as the testing rate per annual patient population. For each stratum we calculated the proportion tested with Wilson 95 % confidence intervals and assessed between-group differences using chi square or Fisher exact tests as appropriate. Annual trends in the testing proportion were modeled using a binomial generalized linear model with a logit link, treating the annual number tested as the numerator and the annual young ischemic stroke population as the denominator, and we report the odds ratio per calendar year with robust standard errors. Geographical variation was visualized using a heat map of testing by state. All analyses were descriptive and intended to characterize population-level patterns of ischemic stroke within the Cosmos network rather than infer causal associations. Given the exploratory design, no additional model-based adjustment for confounding was performed. All data are de-identified in compliance with HIPAA standards and governed under Epic's "Rules of the Road" for institutional data use. From 2015 to 2024, out of a total of 188,305 distinct young ischemic stroke patients, 9,226 (4.9 %) underwent Lp(a) testing. Additionally, the annual number of tested patients increased significantly from 179 in 2015 to 1,992 in 2024 (p<0.001), and the annual percentage of patients undergoing Lp(a) testing increased from 4.3 % in 2015 to 9.3 % in 2024. The states with the largest number of tested patients were Ohio (10.4 %), Texas (7.4 %), and Pennsylvania (5.5 %). The rates of testing were significantly different between sexes, with a larger percentage of young women with ischemic strokes tested compared to young men. Analyzing patients with reported racial data, patients who identified as Black or African American underwent testing for Lp(a) at the highest rate, compared with patients who identified as Asian, "None of the above", White, or Other Race. Among patients undergoing testing with reported ethnic identity, a higher percentage of patients who identified as Hispanic or Latino were tested compared to those who identified as non-Hispanic. Stratifying the total tested patients by age, adults between the ages of 50-60 years made up the largest percentage of patients (4,460; 48.3 %); however, the highest rate of testing occurred in patients aged 5-18. In addition, a higher rate of the young ischemic stroke patients who had ever had a diagnosis of CAD underwent testing compared to patients without CAD. Lp(a) testing among young ischemic stroke patients has increased significantly over the past decade, likely reflecting growing clinical recognition of its causal role in atherosclerotic disease. The rise parallels key updates in lipid management and stroke prevention guidelines, including the 2019 European Society of Cardiology and 2024 National Lipid Association recommendations advocating at least once-in-a-lifetime Lp(a) measurement. Increasing assay availability and heightened awareness of the causal relationship of Lp(a) with atherosclerotic disease may also have contributed to the observed upward trend. Despite this, only about one in twenty young ischemic stroke patients had ever been tested, underscoring a substantial implementation gap between evidence and clinical practice. Show less

Lipoprotein(a) (Lp[a]) is an apolipoprotein B100 (apoB)-containing lipoprotein with a single apolipoprotein(a) (apo[a]) covalently bound to apoB via a disulfide bond and oxidized phospholipids linked to apoB and apo(a), which is associated with proinflammatory, prothrombotic, and proatherogenic mechanisms. Elevated Lp(a) (≥125 nmol/L [≥50 mg/dL]) is an independent, causal, genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD), affecting >1.4 billion individuals worldwide. There are no pharmacological Lp(a)-lowering therapies approved in the United States; however, lipoprotein apheresis may be considered under certain circumstances. Germany is the only country where apheresis is approved for patients with elevated Lp(a) and progressing ASCVD. Existing lipid-lowering therapies including proprotein convertase subtilisin/kexin type 9 inhibitors have shown modest effects on Lp(a) levels but fallen short of clinically meaningful reductions of >50 to 100 mg/dL. Several Lp(a)-lowering, RNA-targeted agents are in development, including antisense oligonucleotides (ASOs) and small interfering RNAs. Pelacarsen is a second-generation ASO that targets the production of apo(a) and includes chemical modifications such as triantennary N-acetylgalactosamine that improve biostability, decrease off-target toxicity compared with unmodified ASOs, and allow rapid, specific uptake by hepatocytes, the site of apo(a) synthesis. A phase 2b study of pelacarsen showed ≥80% reduction in Lp(a) concentration with a favorable safety profile in patients with established ASCVD. The ongoing phase 3 Lp(a)HORIZON study is evaluating whether the Lp(a)-lowering effects of pelacarsen translate into reductions in the incidence of major cardiovascular events, also in patients with established ASCVD. Herein, we review the mechanism of action of pelacarsen and evidence for its Lp(a)-lowering effects. Show less

With no currently available targeted therapies for lipoprotein(a) [Lp(a)] lowering, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) may be an option for management of increased cardiovascular risk in individuals with elevated Lp(a). However, Lp(a) lowering with PCSK9i is variable. We aimed to evaluate the real-world change in Lp(a) and predictors of response. Using data from the University of California Health Data Warehouse, we conducted a multi-center retrospective study among adults prescribed PCSK9i therapy with available Lp(a) measurement before and after prescription. We evaluated change in Lp(a) compared to baseline and evaluated potential predictors of Lp(a) reduction using multivariable linear regression, including among patients with multiple serial Lp(a) measurements. Among 453 included individuals, PCSK9i use was associated with a median 17.3 [IQR 35.3, 0.0]% and 11.3 [31.7, 0.0] mg/dL reduction in Lp(a) overall. Among those with Lp(a) >50 mg/dL, a 17.7 [33.6, 0.0]% and 19.2 [42.0, 0.0] mg/dL reduction was observed. Higher baseline Lp(a) level (β -0.31, p<0.001) was a significant predictor of greater Lp(a) reduction, while female sex was associated with less reduction (β 9.28, p=0.02). Results were consistent across Lp(a) assay types and by PCSK9i type and sustained in those with serial Lp(a) measurements (n=274). In contrast, in a control group of 6750 individuals, a median change of 0.00 [-2.00, 3.00] mg/dL in Lp(a) was noted in serial measurements. PCSK9i are associated with modest Lp(a) lowering of approximately 17% in real-world clinical practice, with a consistent percent reduction by baseline Lp(a) level, PCSK9i type and Lp(a) assay type. Predictors of Lp(a) reduction include baseline Lp(a) level and sex without significant variation by age, race/ethnicity or other evaluated comorbidities. Show less

Elevated lipoprotein(a) [Lp(a)] is associated with atherosclerotic cardiovascular disease (ASCVD) risk, and vascular inflammation is one mechanism through which Lp(a) causes ASCVD. The authors aimed to evaluate whether interleukin-6 (IL-6), a biomarker associated with inflammation and cardiovascular disease, helps risk-stratify individuals with elevated Lp(a). Data from participants in the MESA (Multi-Ethnic Study of Atherosclerosis) (n = 6,514) and the UK Biobank (UKB) (n = 26,574) were used for this analysis. The associations between Lp(a) and IL-6 with coronary heart disease (CHD) (defined as myocardial infarction or resuscitated cardiac arrest), ASCVD (CHD and ischemic stroke), and peripheral vascular disease (PVD) were evaluated separately and with mutual adjustment in Cox proportional hazard models adjusted for traditional cardiovascular risk factors and high-sensitivity C-reactive protein (hsCRP). HRs were presented per standard deviation. Participants were also grouped by Lp(a) level (≤50 or >50 mg/dL [125 nmol/L]) and IL-6 level (≤ median or > median) in similar models. Participants with higher IL-6 levels were more likely to have higher body mass index, systolic blood pressure, triglycerides, and hsCRP with lower high-density lipoprotein cholesterol. Lp(a) (HR: 1.13; 95% CI: 1.04-1.23 in MESA; HR: 1.11; 95% CI: 1.09-1.13 in UKB) and IL-6 (HR: 1.22; 95% CI: 1.10-1.35 in MESA; HR: 1.19; 95% CI: 1.15-1.24 in UKB) were both independently associated with CHD events when evaluated separately. When evaluated together, no significant change was noted, and interaction testing was not significant. Similar results were seen for ASCVD and PVD. When participants were categorized by both Lp(a) and IL-6 levels, the strongest association for each outcome was noted when both levels were high (for CHD: HR: 1.72; 95% CI: 1.25-2.36 in MESA; HR: 1.39; 95% CI: 1.12-1.72 in UKB). In 2 independent primary prevention cohorts, Lp(a) and IL-6 were independent predictors of ASCVD risk, and their combination identified individuals at highest risk. Show less

Oxidized phospholipids (OxPLs) are carried by apolipoprotein B-100-containing lipoproteins (OxPL-apoB) including lipoprotein(a) (Lp[a]). Both OxPL-apoB and Lp(a) have been associated with calcific aortic valve disease (CAVD). This study aimed to evaluate the associations between OxPL-apoB, Lp(a) and the prevalence, incidence, and progression of CAVD. OxPL-apoB and Lp(a) were evaluated in MESA (Multi-Ethnic Study of Atherosclerosis) and a participant-level meta-analysis of 4 randomized trials of participants with established aortic stenosis (AS). In MESA, the association of OxPL-apoB and Lp(a) with aortic valve calcium (AVC) at baseline and 9.5 years was evaluated using multivariable ordinal regression models. In the meta-analysis, the association between OxPL-apoB and Lp(a) with AS progression (annualized change in peak aortic valve jet velocity) was evaluated using multivariable linear regression models. In MESA, both OxPL-apoB and Lp(a) were associated with prevalent AVC (OR per SD: 1.19 [95% CI: 1.07-1.32] and 1.13 [95% CI: 1.01-1.27], respectively) with a significant interaction between the two (P < 0.01). Both OxPL-apoB and Lp(a) were associated with incident AVC at 9.5 years when evaluated individually (interaction P < 0.01). The OxPL-apoB∗Lp(a) interaction demonstrated higher odds of prevalent and incident AVC for OxPL-apoB with increasing Lp(a) levels. In the meta-analysis, when analyzed separately, both OxPL-apoB and Lp(a) were associated with faster increase in peak aortic valve jet velocity, but when evaluated together, only OxPL-apoB remained significant (ß: 0.07; 95% CI: 0.01-0.12). OxPL-apoB is a predictor of the presence, incidence, and progression of AVC and established AS, particularly in the setting of elevated Lp(a) levels, and may represent a novel therapeutic target for CAVD. Show less

Alzheimer's disease (AD) is the prime cause of 65-80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1. Show less

The association of melanocortin receptor 4 (MC4R) gene with adiposity measures is widely studied in European populations. Only six studies have investigated the role of MC4R gene with adiposity measures among Indian populations. We have evaluated the role of MC4R (rs17782313) gene polymorphism in influencing adiposity measures in India among children and adults. The present population based cross sectional study was conducted among 303 individuals (208 children and 95 adults) of age group 10-30 years, belonging to Rajasthan. Somatometric measurements (standing height, weight, and waist and hip girths) and blood samples were taken after obtaining written informed consent. Genotyping of MC4R rs17782313 single nucleotide polymorphism was done using restriction fragment length polymorphism method for polymerase chain reaction amplified fragments. We examined association between rs17782313 and different adiposity measures (height, weight, BMI, WHR, and waist and hip girths) using linear regression models. The MC4R variant (rs17782313) predicted increased body weight (0.15 kg, S.E ± 0.076, P = 0.043) among children. In combined population, the rs17782313 variant was moderately associated with body weight (0.13 kg, S.E ± 0.070, P = 0.057). This variant was not found to be associated with any other adiposity measure. Further studies are needed to evaluate the association of MC4R variants through sequencing and functional genomics with different adiposity measures in Indian populations for understanding the genetic underpinnings of adiposity in India. Show less

Spinal muscular atrophy (SMA) is caused by the low levels of survival motor neuron (SMN) protein and is characterized by motor neuron degeneration and muscle atrophy. Respiratory failure causes death in SMA but the underlying molecular mechanism is unknown. The zinc finger protein ZPR1 interacts with SMN. ZPR1 is down regulated in SMA patients. We report that ZPR1 functions downstream of SMN to regulate HoxA5 levels in phrenic motor neurons that control respiration. Spatiotemporal inactivation of Zpr1 gene in motor neurons down-regulates HoxA5 and causes defects in the function of phrenic motor neurons that results in respiratory failure and perinatal lethality in mice. Modulation in ZPR1 levels directly correlates and influences levels of HoxA5 transcription. In SMA mice, SMN-deficiency causes down-regulation of ZPR1 and HoxA5 that result in degeneration of phrenic motor neurons. Identification of ZPR1 and HoxA5 as potential targets provides a paradigm for developing strategies to treat respiratory distress in SMA. Show less

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. Show less

The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating the oxysterol 7alpha-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the RORalpha null (RORalpha(sg/sg)) mice, suggesting RORalpha as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of RORalpha, and transfection of RORalpha induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be RORalpha-specific, because RORgamma had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by RORalpha was suppressed by LXRalpha (NR1H3), whereas RORalpha inhibited both the constitutive and ligand-dependent activities of LXRalpha. The mutual suppression between RORalpha and LXR was supported by the in vivo observation that loss of RORalpha increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR alpha and beta isoforms showed activation of selected RORalpha target genes. Our results have revealed a novel role for RORalpha and a functional interplay between RORalpha and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis. Show less

Osteochondroma most frequently arises sporadically and as a solitary lesion, but also may arise as multiple lesions characterizing the autosomal dominant disorder hereditary multiple exostoses (HME) and the contiguous gene syndromes Langer-Giedion and DEFECT-11 syndromes. HME is genetically heterogeneous with association of three loci including 8q24.1 (EXT1), 11p11-12 (EXT2), and 19p (EXT3). Constitutional chromosomal microdeletions of 8q24.1 and 11p11-12 are features of the Langer-Giedion and DEFECT-11 syndromes, respectively. Cytogenetic studies of osteochondroma are rare. Cytogenetic analysis was performed on 34 osteochondroma specimens from 22 patients with sporadic lesions and 4 patients with HME utilizing standard methodologies. Fluorescence in situ hybridization with chromosome specific probes was performed on three cases to define structural rearrangements further. Clonal abnormalities were detected in ten cases. Notably, deletion of 11p11-13 was observed in one case (a sporadic tumor) and loss or rearrangement of 8q22-24.1 in eight cases (seven sporadic and one hereditary tumor). These findings: 1) confirm previous observations of 8q24.1 karyotypic anomalies in sporadic osteochondroma, 2) reveal the presence of somatic chromosomal anomalies in hereditary osteochondromata, 3) suggest that similar to hereditary lesions, sporadic osteochondromas also are genetically heterogeneic (involvement of both 8q24.1 and 11p11-12), and 4) support the hypothesis that loss or mutation of EXT1 and EXT2, two putative tumor suppressor genes, may be important in the pathogenesis of sporadic as well as hereditary osteochondromata. Show less