MicroRNAs: Micromanagers for the pathology of age related macular degeneration

Inflammation, oxidative stress, apoptosis and neovascularization are risky parameters which influence different phases in the pathogenesis of age related macular degeneration (AMD). Beside other mediators, this multitiered and complex event of retinal worsening has been exposed to be orchestrated by small non coding RNA fragments that bind to specific mRNAs and modulate their post transcriptional regulation and gene expression in retina. Several microRNAs (miRNAs) have been revealed which are expressed in retina and influence its functionality. These miRNA fragments play significant role in the development and maintenance of photoreceptors hence, dysregulation of them may augment severe retinal etiopathology. This comprehensive review summarizes the role and relevance of several known miRNAs along with their potential utilities as therapeutic targets in AMD pathogenesis

Prevalence and predictors of age related macular degeneration in the population of Punjab: North Indian age related macular degeneration epidemiology and molecular genetic study (NI-ARMEMS)

Background: Age related macular degeneration (AMD) is an ocular disease that is threatening elderly population of Punjab for vision impairment and blindness. Comprehensive understanding of the susceptible factors still remains to be explored in this region. Objective: To examine the risk variables which are independently associated with the risk of AMD along with the investigation of its prevalence in the population of Punjab. Methods: A case-control study by design involved 416 subjects (cases; 219, controls; 197) of age ranging from 45 to 75 years. Various risk factors were investigated for their role in consenting and confirmed AMD subjects along with controls. Results: In the univariate full factorial regression analysis, advancing age (≥66years), being a woman, diastolic blood pressure (DBP) (>80mmHg), cigarette smoking, alcohol drinking, body mass index (BMI) (23-29.9Kgm-2 and ≥30Kgm-2 ), sedentary life style, total cholesterol (>200mg/dl), low density lipoproteins (>100mg/dl), high density lipoproteins (≥40mg/dl), non-vegetarian diet and positive family history were found to be risky determinants. Multivariable stepwise regression analysis revealed age ≥66 years, DBP > 80mmHg, alcohol drinking and smoking as independent predictors for the risk of AMD. Conclusion: Considerable prevalence of dry AMD (20.5%) is evident in the population of Punjab which is mediated independently by age (≥66 years), DBP (>80 mmHg), alcohol drinking and smoking

Risk of depression in subjects with type 2 diabetes Is modulated by a genetic variant within DRD4 gene: North Indian diabetes-depression link exploration study (NIDDLES)

The role and relevance of DRD4 gene SNPs for the risk of depression in type 2 diabetes remains to be clarified. To investigate its association, present cross sectional study was conducted on 399 type 2 diabetics who were diagnosed for depression using primary health care questionnaire-9 (PHQ-9) > 10 criteria. 191 subjects were depressed whereas, 208 subjects were found to be clinically non-depressed. Minor allele frequencies of two DRD4 SNPs rs1800955 and rs747302 were 0.45, 0.42 and 0.42, 0.34 in depressed and non depressed subjects respectively. C allele of rs747302 showed risk of depression (OR 1.41 95% CI 1.05- 1.87, P= 0.024) in comparison to G allele. It has been observed that carriers of CC genotype had approximately double the risk of depression (OR 1.96 95% CI 1.08- 3.56, P= 0.03) than GG carriers and this risk manifests in recessive mode

Promoter polymorphisms in IL-6 gene influence pro-inflammatory cytokines for the risk of osteoarthritis

BackgroundInterleukin-6 (IL-6) gene regulates IL-6 levels, interplay of which has been found to influence pathophysiology of osteoarthritis (OA). Polymorphism within promoter region of IL-6 gene and its association with plasma levels of pro-inflammatory cytokines; IL-6, interleukin 1-beta (IL-1β) and tumor necrosis factor–alpha (TNF-α) remained to be investigated in Punjab region of India, where OA is highly prevalent.MethodsSix single nucleotide polymorphisms (SNPs) in the promoter region of IL-6 gene; rs1800795 (−174G/C), rs1800796 (−572G/C), rs1800797 (−597G/A), rs2069827 (−1363G/T), rs12700386 (−2954G/C) and rs10499563 (−6331G/T) were investigated by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 279 confirmed osteoarthritis patients and 287 controls. Plasma levels of pro-inflammatory cytokines; IL-6, IL-1β and TNF-α were measured by sandwich Enzyme Linked Immunosorbent Assay (ELISA).ResultsAllele frequency spectrum after adjusting the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), total cholesterol (TC), low density lipoprotein (LDL), triglycerides (TG) and body mass index (BMI) revealed that major allele G of rs1800795 and T of rs10499563 were significantly associated with increased risk of OA (P ConclusionThe present study discovered susceptibility (GGGGCT) and protective (CGAGGC) haplotypes within promoter region of IL-6 gene which influenced the plasma levels of IL-6 and IL-1β for the risk of osteoarthritis in the population of Punjab, India.</div

Implications of siRNA therapy in bone health: silencing communicates

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its ‘bench-to-bedside’ usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures.</p

A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India

Despite strong genetic implications of NLRP3 inflammasome, its examination as genetic determinant of ischaemic stroke (IS) remains to be done in Punjab, which has been investigated in this study. In this case control study, 400 subjects (200 IS patients, 200 stroke free controls) were included. Contributions of 5 single nucleotide polymorphisms (SNPs) including a functional SNP within NLRP3 gene (rs10754558, rs4612666, rs2027432, rs3738488 and rs1539019) for the risk of IS were investigated through genetic models after correcting the effect of significant variables. Plasma levels of three pro-inflammatory markers, that is, C-reactive protein (CRP), interleukin-1beta (IL-1β) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assays (ELISA). Minor alleles of 3 out of 5 SNPs (rs10754558, rs4612666 and rs1539019) exhibited association with IS risk in additive, recessive and multiplicative models. Multivariable regression analysis confirmed that higher levels of systolic blood pressure (β ± SE: 1.42 ± 0.57, p = .013), CRP (β ± SE: 1.22 ± 0.41, p = .003), IL-1β (β ± SE: 1.78 ± 0.88, p = .043) and IL-18 (β ± SE: 1.13 ± 0.49, p = .021) were independent risk predictors for IS. Haplotype analysis revealed a susceptibility putative haplotype GTGTA, which approximately doubled the IS risk (OR: 1.98, 95% CI: 1.12–3.78, p = .04) in dominant mode after adjusting the effect with confounding variables. This susceptibility putative haplotype GTGTA was significantly associated with increased concentrations of CRP (β = 1.21, p = .014) and IL-1β (β = 1.53, p = .034) in dose-dependent manner (less in carriers of 1 copy than those who had 2 copies of GTGTA). The present study has revealed a susceptibility putative haplotype GTGTA within NLRP3 gene, carriers of which have double the risk of IS by having increased plasma levels of CRP and IL-1β in a dose-dependent manner

Higher C-reactive protein levels as biochemical determinant of osteoporosis in Punjab

The present cross-sectional study involved 300 postmenopausal women to examine the role and relevance of C-reactive protein (CRP) and nitric oxide (NO) as the biochemical determinants of osteoporosis in the population of Punjab, India. Subjects were verified having osteoporosis on the basis of dual energy x-ray absorptiometry (DEXA) testing at hip (femoral neck) and lumbar spine (L1-L4 vertebrae). Enzyme linked immunosorbent assays (ELISA) were conducted for the quantitative analysis of CRP and NO. It was observed that women having higher levels of CRP (>3mg/L) were at substantially higher risk of osteoporosis (OR 2.29 95%CI: 1.44 – 3.87, P<0.001) than women having lower levels of CRP (<3mg/L). Present study could not find any association of NO levels with the risk of osteoporosis. Linear regression analysis confirmed that higher the CRP levels, higher was the risk of low BMD at both lumbar spine (P<0.001) and femoral neck (P<0.001). In conclusion, present study has revealed that higher serum CRP levels are associated with the risk of osteoporosis, whereas, NO does not participate in it.</div

Supplementary information files for A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India

Supplementary information files for article A susceptibility putative haplotype within NLRP3 inflammasome gene influences ischaemic stroke risk in the population of Punjab, India   Despite strong genetic implications of NLRP3 inflammasome, its examination as genetic determinant of ischaemic stroke (IS) remains to be done in Punjab, which has been investigated in this study. In this case control study, 400 subjects (200 IS patients, 200 stroke free controls) were included. Contributions of 5 single nucleotide polymorphisms (SNPs) including a functional SNP within NLRP3 gene (rs10754558, rs4612666, rs2027432, rs3738488 and rs1539019) for the risk of IS were investigated through genetic models after correcting the effect of significant variables. Plasma levels of three pro-inflammatory markers, that is, C-reactive protein (CRP), interleukin-1beta (IL-1β) and interleukin-18 (IL-18) were measured by enzyme-linked immunosorbent assays (ELISA). Minor alleles of 3 out of 5 SNPs (rs10754558, rs4612666 and rs1539019) exhibited association with IS risk in additive, recessive and multiplicative models. Multivariable regression analysis confirmed that higher levels of systolic blood pressure (β ± SE: 1.42 ± 0.57, p = .013), CRP (β ± SE: 1.22 ± 0.41, p = .003), IL-1β (β ± SE: 1.78 ± 0.88, p = .043) and IL-18 (β ± SE: 1.13 ± 0.49, p = .021) were independent risk predictors for IS. Haplotype analysis revealed a susceptibility putative haplotype GTGTA, which approximately doubled the IS risk (OR: 1.98, 95% CI: 1.12–3.78, p = .04) in dominant mode after adjusting the effect with confounding variables. This susceptibility putative haplotype GTGTA was significantly associated with increased concentrations of CRP (β = 1.21, p = .014) and IL-1β (β = 1.53, p = .034) in dose-dependent manner (less in carriers of 1 copy than those who had 2 copies of GTGTA). The present study has revealed a susceptibility putative haplotype GTGTA within NLRP3 gene, carriers of which have double the risk of IS by having increased plasma levels of CRP and IL-1β in a dose-dependent manner.</p

Investigation of eNOS gene polymorphism exposes a genetic association between endothelial dysfunction and osteoporosis in postmenopausal women

Objectives:To investigate the association of genetic polymorphisms of endothelial nitric oxide synthase (eNOS) gene with endothelial dysfunction associated osteoporosis in postmenopausal women of Punjab, India.Methods:The study involved 456 postmenopausal women having endothelial dysfunction categorized according to women with (n=236) and without osteoporosis (n=220). Bone mineral density (BMD) and reactive hyperemia index (RHI) were evaluated together with six SNPs within the eNOS gene (rs2070744, rs1799983, rs1800780, rs3918181, rs891512 and rs1808593).Results:A moderate association between RHI and BMD at femoral neck (r2=0.213, P=0.002) and lumbar spine (r2=0.267, PConclusion:A susceptibility haplotype CTAAAT within eNOS gene is associated with double the possibility of endothelial dysfunction affiliated osteoporosis in postmenopausal women of Punjab, India.</div

Genetic scores of ENOS, ACE and VEGFA genes are predictive of endothelial dysfunction associated osteoporosis in postmenopausal women

© 2021 by the authors. Licensee MDPI, Basel, Switzerland. The present study aimed to examine the participation and contribution of endothelial nitric oxide synthase (eNOS), angiotensin converting enzyme (ACE) and vascular endothelial growth factor (VEGFA) genes for the risk of endothelial dysfunction (ED)-associated osteoporosis risk in postmenopausal women of Punjab, India. Women with ED were categorized into women with osteoporosis (n = 346) and women without osteoporosis (n = 330). They were examined for selected SNPs within eNOS, ACE and VEGFA genes. Linear regression analysis revealed a positive association of ED with bone mineral densities (BMDs) at femoral neck (r2 = 0.78, p < 0.001) and lumbar spine (r2 = 0.24, p = 0.001) after Bonferroni correction. Three susceptibility haplotypes were exposed within eNOS (CTAAAT), ACE (ACDG) and VEGFA (GATA) genes. Bearers of CTAAAT (OR 2.43, p = 0.007), ACDG (OR 2.50, p = 0.002) and GATA (OR 2.10, p = 0.009) had substantial impact for osteoporosis after correcting the effects with traditional risk factors (TRD).With uncertainty measure (R2h) and Akaike information criterion (AIC), best fit models showed that CTAAAT manifested in multiplicative mode (β ± SE: 2.19 ± 0.86, p < 0.001), whereas ACDG (β ± SE: 1.73 ± 0.54, p = 0.001) and GATA (β ± SE: 3.07 ± 0.81, p < 0.001) expressed in dominant modes. Area under receiver operating characteristic curve using weighted risk scores (effect estimates) showed substantial strength for model comprising TRD + GATA (AUC = 0.8, p < 0.001) whereas, model comprising TRD + GATA + CTAAAT exhibited excellent ability to predict osteoporosis (AUC = 0.824, p < 0.001)