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Rheumatoid arthritis is categorized as a systematic autoimmune disease which causes chronic disabilities exclusively in bones that are aligned with synovium. RA aetiology is still unknown but previous studies have coined that several number of factors play a significant role e.g. environmental and genetic factors. Cellular signalling pathways orchestrate the inflammatory response that regulates various cellular functions like cellular progression, proliferation, death and secretion of signalling molecules (pro and anti-inflammatory cytokines) in response to genetic and environmental stimuli. These regulatory pathways are tightly controlled Rheumatoid arthritis is categorized as a systematic autoimmune disease which causes chronic disabilities exclusively in bones that are aligned with synovium. RA aetiology is still unknown but previous studies have coined that several number of factors play a significant role e.g. environmental and genetic factors. Cellular signalling pathways orchestrate the inflammatory response that regulates various cellular functions like cellular progression, proliferation, death and secretion of signalling molecules (pro and anti-inflammatory cytokines) in response to genetic and environmental stimuli. These regulatory pathways are tightly controlled and naturally activated by ligands that attach to their respective receptors on the cell surface. In diseased state, these signalling pathways escape the normal control mechanisms, resulting in intensification of cytokines and chemokines, transcription factors and mediatory proteins that disrupt normal cell processes and might bring about auto-destructive consequences such as in the case of rheumatoid arthritis. The review highlights multiple levels of targeting molecules in signalling pathways that may be potential diagnostic markers and also attempts to underline potential therapeutic targets.and naturally activated by ligands that attach to their respective receptors on the cell surface. In diseased state, these signalling pathways escape the normal control mechanisms, resulting in intensification of cytokines and chemokines, transcription factors and mediatory proteins that disrupt normal cell processes and might bring about auto-destructive consequences such as in the case of rheumatoid arthritis. The review highlights multiple levels of targeting molecules in signalling pathways that may be potential diagnostic markers and also attempts to underline potential therapeutic targets.

The spectrum of rheumatic disease is wide and includes conditions with diverse pathology, although most have in common a heritable risk with a complex genetic basis. Over the past decade intense efforts have been done to understand the contribution of genotype to the expression of disease in terms of both basic pathogenesis and clinical characteristics. The dramatic improvement in technology and methodology has accelerated the pace of gene discovery in complex disorders in an exponential fashion. This review focuses on rheumatoid arthritis and describes some of the recently described genes that underlie this condition and the extent to which they overlap.

Rheumatoid arthritis (RA) is a chronic polyarthritic autoimmune condition characterized by severe bone erosion. Osteoclasts, the bone resorbing cells, Rheumatoid arthritis (RA) is a chronic polyarthritic autoimmune condition characterized by severe bone erosion. Osteoclasts, the bone resorbing cells, are overly produced from the synovial inflammatory tissues in RA leading to excessive bone loss. RANKL-signaling pathway has been established to be the major pathway involved in osteoclastogenesis. This review highlights the role of around 40 osteoclastogenic factors involved in RANKL signaling and their potential to be targeted for antiresorptive therapy in RA. Furthermore, inhibitors of these proteins, which are already known to exhibit antiresorptive potential, have been reviewed. Elucidating new potential candidate therapeutic targets in the osteoclastogenesis pathway will open new avenues into the treatment and diagnosis of the arthritic conditionsare overly produced from the synovial inflammatory tissues in RA leading to excessive bone loss. RANKL-signaling pathway has been established to be the major pathway involved in osteoclastogenesis. This review highlights the role of around 40 osteoclastogenic factors involved in RANKL signaling and their potential to be targeted for antiresorptive therapy in RA. Furthermore, inhibitors of these proteins, which are already known to exhibit antiresorptive potential, have been reviewed. Elucidating new potential candidate therapeutic targets in the osteoclastogenesis pathway will open new avenues into the treatment and diagnosis of the arthritic conditions.

Type 2 diabetes is a complex multifactorial disease characterized by insufficient insulin secretion and insulin resistance. Global prevalence of diabetes is increasing day by day making diabetes a global epidemic. Various factors increase risk of diabetes and genetic predisposition is one of very important factor. Many anti-diabetic treatments are available to control blood glucose level in diabetic patients now-a-days. Initially, oral anti-diabetic treatment is successful but it fails later on and requires insulin administration and there are large numbers of non-responders also. Even patients that do respond show variability in drug response and tolerance. PharmType 2 diabetes is a complex multifactorial disease characterized by insufficient insulin secretion and insulin resistance. Global prevalence of diabetes is increasing day by day making diabetes a global epidemic. Various factors increase risk of diabetes and genetic predisposition is one of very important factor. Many anti-diabetic treatments are available to control blood glucose level in diabetic patients now-a-days. Initially, oral anti-diabetic treatment is successful but it fails later on and requires insulin administration and there are large numbers of non-responders also. Even patients that do respond show variability in drug response and tolerance. Pharmacogenomics is the study to determine the inter- individual differences that contribute toward drug response. Many studies have shown positive contribution of different polymorphism in alteration of drug response in various ethnicities. But still data related to pharmacogenomics of Asian population is limited. In this review, we have tried to summarize the genetic variations and their effect on three major classes of oral anti-diabetic medication that include thiazolidinediones, metformin and sulfonylureas.acogenomics is the study to determine the inter- individual differences that contribute toward drug response. Many studies have shown positive contribution of different polymorphism in alteration of drug response in various ethnicities. But still data related to pharmacogenomics of Asian population is limited. In this review, we have tried to summarize the genetic variations and their effect on three major classes of oral anti-diabetic medication that include thiazolidinediones, metformin and sulfonylureas.

Purpose The existing treatment modalities for rheumatoid arthritis are less effective and safe, therefore it is essential to develop new treatments that particularly target the inflamed joints with decreased off-target side-effects. The current study proposes a nanoparticle-based therapeutic approach to target the anti-oxidant defense system of arthritic Balb/c mice. Methods Biogenic selenium nanoparticles (SeNPs) were synthesized by using Trachyspermum ammi seed extract and were evaluated for their toxicological, as well as their therapeutic potential in collagen-induced arthritic mice. Results The tested doses of SeNPs had no significant toxic effects on liver, kidney, spleen, and serum biochemical parameters in comparison to healthy mice. The SeNPs treatment reduced the disease severity, as demonstrated by decreased paw edema along with reduced lymphocytic cellular infiltration in the histopathological findings. SeNPs also revealed dose-independent improvement in the redox state of inflamed synovium by significantly improving the activity of antioxidant enzymes in comparison to the arthritic controls. Conclusion It is therefore concluded that nano-selenium in combination with TAE extract showed enhanced therapeutic efficacy as compared to their individual effects.

Type 2 diabetes mellitus and breast cancer are complex, chronic, heterogeneous, and multi-factorial diseases; with common risk factors including but not limited to diet, obesity, and age. They also share mutually inclusive phenotypic features such as the metabolic deregulations resulting from hyperglycemia, hypoxic conditions and hormonal imbalances. Although, the association between diabetes and cancer has long been speculated; however, the exact molecular nature of this link remains to be fully elucidated. Both the diseases are leading causes of death worldwide and a causal relationship between the two if not addressed, may translate into a major global health concern. Previous studies have hypothesized hyperglycemia, hyperinsulinemia, hormonal imbalances and chronic inflammation, as some of the possible grounds for explaining how diabetes may lead to cancer initiation, yet further research still needs to be done to validate these proposed mechanisms. At the crux of this dilemma, hyperglycemia and hypoxia are two intimately related states involving an intricate level of crosstalk and hypoxia inducible factor 1, at the center of this, plays a key role in mediating an aggressive disease state, particularly in solid tumors such as breast cancer. Subsequently, elucidating the role of HIF1 in establishing the diabetes-breast cancer link on hypoxia-hyperglycemia axis may not only provide an insight into the molecular mechanisms underlying the association but also, illuminate on the prognostic outcome of the therapeutic targeting of HIF1 signaling in diabetic patients with breast cancer or vice versa. Hence, this review highlights the critical role of HIF1 signaling in patients with both T2DM and breast cancer, potentiates its significance as a prognostic marker in comorbid patients, and further discusses the potential prognostic outcome of targeting HIF1, subsequently establishing the pressing need for HIF1 molecular profiling-based patient selection leading to more effective therapeutic strategies emerging from personalized medicine.

MicroRNAs orchestrate the tight regulation of numerous cellular processes and the deregulation in their activities has been implicated in many diseases, including diabetes and cancer. There is an increasing amount of epidemiological evidence associating diabetes, particularly type 2 diabetes mellitus, to an elevated risk of various cancer types, including breast cancer. However, little is yet known about the underlying molecular mechanisms and even less about the role miRNAs play in driving the tumorigenic potential of the cell signaling underlying diabetes pathogenesis. This article reviews the role of miRNA in bridging the diabetes–breast cancer association by discussing specific miRNAs that are implicated in diabetes and breast cancer and highlighting the overlap between the disease-specific regulatory miRNA networks to identify a 20-miRNA signature that is common to both diseases. Potential therapeutic targeting of these molecular players may help to alleviate the socioeconomic burden on public health that is imposed by the type 2 diabetes mellitus (T2DM)–breast cancer association.

Rheumatoid arthritis (RA) is a systemic multifactorial autoimmune disorder. The interactions between diverse environmental and genetic factors lead to the onset of this complex autoimmune disorder. Serum levels of vitamin D (VD) are involved in the regulation of various immune responses. Vitamin D is a key signaling molecule in the human body that maintains calcium as well as phosphate homeostasis. It also regulates the functions of the immune system and, thus, can play a substantial role in the etiology of various autoimmune disorders, including RA. Low serum VD levels have been found to be associated with a higher risk of RA, although this finding has not been replicated consistently. The molecular mechanisms by which VD influences autoimmunity need to be further explored to understand how variation in plasma VD levels could affect the pathogenesis of RA. This mini-review focuses on the influence of VD and its serum levels on RA susceptibility, RA-associated complexities, treatment, and transcriptome products of key proinflammatory cytokines, along with other cytokines that are key regulators of inflammation in rheumatoid joints.

Introduction Multifunctional pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) has been implicated in a variety of inflammatory diseases including rheumatoid arthritis (RA). TNF-α polymorphisms are mostly located in its promoter region and play a significant role in disease susceptibility and severity. We therefore sought to investigate TNFA -863C/A (rs1800630) polymorphism association with RA activity in our Pakistani study group. Material and methods A total of 268 human subjects were enrolled. Among them, 134 were RA patients and 134 were controls. In this study the physical parameters of RA patients were collected, and the disease activity was measured by DAS28. The genotypes were determined following the allele-specific PCR along with the pre-requisite internal amplification controls. Subsequently, data were analyzed statistically for any significant association including χ2/Fisher's exact test using GraphPad prism 6 software. Results We found that the TNF-α -863 C/A (rs1800630) variant was not differentially segregated between cases and controls in either genotype frequency, with χ2 of 2.771 and a p-value of 0.2502, or allele frequency, with χ2 of 2.741 and a p-value of 0.0978, with an odds ratio (95% CI) of 0.7490 (0.5317-1.055). Conclusions The lack of positive association of TNF-α -863(rs1800630) polymorphism in our study group implies that TNF-α -863 polymorphism is not a susceptible marker to RA and cannot serve as a genetic factor for screening RA patients in Pakistan. There might be other factors that may influence disease susceptibility. However, further investigations on additional larger and multi-regional population samples are required to determine the consequences of genetic variations for disease prognosis.

Objective. Copy number variation (CNV) is a structural variation in the human genome that has been associated with multiple clinical phenotypes. B cells are important components of rheumatoid arthritis- (RA-) mediated immune response; hence, CNV in the regulators of B cells (such as VPREB1) can influence RA susceptibility. In this study, we aimed to explore the association of CNV in the VPREB1 gene with RA susceptibility in the Pakistani population. Methods. A total of 1,106 subjects (616 RA cases, 490 healthy controls) were selected from three rheumatology centers in Pakistan. VPREB1 CNV was determined using the TaqMan® CN assay (Hs02879734_cn, Applied Biosystems, Foster City, CA, USA), and CNV was estimated by using CopyCaller® (version 2.1; Applied Biosystems, USA) software. Odds ratio (OR) was calculated by logistic regression with sex and age as covariates in R. Results. A significant association between >2 VPREB1 CNV and RA risk was observed with an OR of 3.92 (95% CI: 1.27 - 12.12; p=0.01746) in the total sample. Whereas p=0.00381). Conclusion. CNV>2 of VPREB1 is a risk factor for RA in the total Pakistani population, while CNV<2 is protective in women.

Genome-wide association studies (GWAS) of coronary artery disease (CAD) have revealed multiple genetic risk loci. We assessed the association of 47 genome-wide significant single-nucleotide polymorphisms (SNPs) at 43 CAD loci with coronary stenosis in a Pakistani sample comprising 663 clinically ascertained and angiographically confirmed cases. Genotypes were determined using the iPLEX Gold technology. All statistical analyses were performed using R software. Linkage disequilibrium (LD) between significant SNPs was determined using SNAP web portal, and functional annotation of SNPs was performed using the RegulomeDB and Genotype-Tissue Expression (GTEx) databases. Genotyping comparison was made between cases with severe stenosis (≥70%) and mild/minimal stenosis (PLG/rs4252120 (p=0.0078), KIAA1462/rs2505083 (p=0.005), and SLC22A3/rs2048327 (p=0.045) and two with recessive models SORT1/rs602633 (p=0.005) and UBE2Z/rs46522 (p=0.03). PLG/rs4252120 was in LD with two functional PLG variants (rs4252126 and rs4252135), each with a RegulomeDB score of 1f. Likewise, KIAA1462/rs2505083 was in LD with a functional SNP, KIAA1462/rs3739998, having a RegulomeDB score of 2b. In the GTEx database, KIAA1462/rs2505083, SLC22A3/rs2048327, SORT1/rs602633, and UBE2Z/rs46522 SNPs were found to be expression quantitative trait loci (eQTLs) in CAD-associated tissues. In conclusion, five genome-wide significant SNPs previously reported in European GWAS were replicated in the Pakistani sample. Further association studies on larger non-European populations are needed to understand the worldwide genetic architecture of CAD.

Rheumatoid arthritis (RA) is a common chronic inflammation-mediated disorder having systematic complications. RA triggers a self-directed inflammatory and immunological cascade that culminates in joint destruction. Though a range of treatment options are available, none of them are without adverse effects and this has led researchers to search for alternative solutions. Nanomedicine has emerged as a powerful therapeutic alternative, and selenium (Se) is an essential micronutrient trace element that has a crucial role in human health and disease. Selenium nanoparticles (SeNPs) derived from biological sources, such as plants, bacteria, fungi, and proteins, have exhibited remarkable candidate properties and toxicological profiles, and hence have shown potential to be used as antirheumatic agents. The potential of SeNPs can be attributed to the effect of functional groups bound to them, concentration, and most importantly to their nano range size. The antirheumatic effect of SeNPs is considerable due to its potential in amelioration of oxidative stress-mediated inflammation via downregulation of radical and nonradical species, markers of inflammation, and upregulation of inherent antioxidant defenses. The size and concentration impact of SeNPs has been shown in the subsequent antioxidant and anti-inflammatory properties. Moreover, the article emphasizes the role of these biogenic SeNPs as a notable option in the nanomedicine arena that needs to be further studied as a prospective remedial alternative to cure RA and medication-related adverse events.

Rheumatoid Arthritis is an inflammatory disease primarily involves the inflamed synovium, affecting about 0.5-1 % population worldwide. It is the assumption from many years that oxidative stress is involved in the pathophysiology of inflammatory disorders like RA and many others. The significance of micronutrients in arthritis is linked to their role as a cofactor for the activation of selenoenzymes. Dietary interventions can manage the clinical symptoms of RA like pain, swelling and tenderness of joints and their associated disability along the progression of disease. This review highlights the antioxidant potential of selenium in treatment of RA along with the scientific evidence that Se supplementation can reduce disease progression by managing its clinical symptoms.

Cinnamomum verum (CV), also known as ‘Dalchini’, is the dry bark of the Cinnamomum verum (L.) plant, and has been used as a traditional Pakistani medicine to alleviate pain and inflammation in patients suffering from arthritic rheumatism. It contains alkaloids, triterpenes, Cinnamaldehyde and other volatile oils. The aim of the present study was to investigate the underlying biological effect of ethyl alcohol (EtOH) and methyl alcohol (MeOH) extracts from CV on collagen type-II induced arthritic (CIA) mice. Gas chromatography mass spectrophotometry was used to perform fingerprinting identification of the EtOH and MeOH extracts. CIA mice model was established by subdermal injections of type-II bovine collagen (CII) on the 1st, 8th and 14th day of the experiment. Ethyl alcohol extract and methyl alcohol extract (1 mg/KgBW, 2 mg/KgBW and 4 mg/KgBW), was orally administered from the 15th day onwards for 2 weeks. Progression of oedema and joint inflammation was measured in the paws using a digital Vernier calliper every 3 days from day 1 till the end of the experiment. The oxidative scavenging ability of cinnamaldehyde was evaluated using a DPPH assay. Similarly, the nitrogen free radical (NOS) production of isolated lymphocytes was evaluated using Greiss’s method. The spleen index was calculated and knee joint changes were observed by histopathological sectioning. Western blot analysis was performed on peripheral blood derived serum for CII, CAPN1, TNFα and NFATc3. Extracts were shown to be enriched in trans-cinnamaldehyde and its analogues. Extracts showed good ameliorative effects (p

Objective Type 1 diabetes (T1D) and rheumatoid arthritis (RA) are autoimmune diseases. It is known that certain genetic loci and factors that increase the overall autoimmunity risk can be shared among different autoimmune diseases. We sought to replicate seven T1D-related SNPs that have been previously reported to be associated with RA susceptibility in a small set of mixed family-based and case-control Pakistani sample in a relatively large and independent RA case-control sample from the same population. Seven T1D-associted SNPs (GLIS3/rs7020673, BACH2/rs11755527, SKAP2/rs7804356, GDSMB/rs2290400, C6orf173/rs9388489, LOC399716/rs947474 and DLK1-MEG2/rs941576) were genotyped in a large Pakistani RA case-control sample (n=1,959) using TaqMan® SNP genotyping assays. Results None of the tested SNPs showed statistically significant association with RA susceptibility; however, one SNP (GLIS3/rs7020673) showed a trend for association (OR= 0.88, p=7.99E-02). Our study has failed to replicate the previously reported association of seven T1D-associted SNPs with RA risk in a large sample from the same population. Thus, our results do not support a major role of these T1D SNPs in affecting RA susceptibility in the Pakistani population.

RA is a multifactorial autoimmune inflammatory disease characterized by synovitis, bone destruction and joint dysfunction that leads to shortening of lifespan and increased mortality rates. Currently available treatments of RA, by controlling various symptoms, only delay disease progression and have their own side effects. Consequently, there is the need for a novel therapeutic strategy that offers a more sustainable and biocompatible solution. Nanomedicine is a modern branch of nanobiotechnology that provides targeted therapy to inflamed rheumatic joints and thus prevents unwanted off-target side effects. This review highlights various nanotheranostic and nanotherapeutic strategies that are currently being used for the treatment of RA.

Background Rheumatoid arthritis (RA) is a common systemic autoimmune disease, influenced greatly by the pro-inflammatory cytokine tumor necrosis factor- alpha (TNF-α). Single nucleotide polymorphisms (SNPs) in regulatory regions of the TNF-α gene play a significant role in disease development and pathogenesis. The aim of this study was to investigate the association of TNF-α -857C/T (rs1799724) SNP with RA activity or severity in our Pakistani study group. Methods The study included 134 (116 women, 18 men) patients with RA and 134 ethnically matched healthy controls (108 women, 26 men). Each patient's disease activity was measured by Disease Activity Score of 28 joints. The genotypes were determined in all included individuals following allele-specific polymerase chain reaction along with the prerequisite internal amplification controls. Statistical analysis including chi-square/Fischer exact test and one-way analysis of variance; nonparametric Kruskal–Wallis test was employed using Graphpad Prism 6 software for association study. Results The prevalence of TNF-α -857C/T (rs1799724) polymorphism was not differentially distributed between RA patients and controls in either allele frequency, with odds ratio (95% CI) of 0.9661 (0.6714–1.390) and P-value of 0.8527, or genotype frequency with χ2 of 0.5015 and P-value of 0.7782. Moreover, no correlation was found when genotype frequency distribution was analyzed with disease severity (P = 0.6321 and Kruskal–Wallis statistics of 1.098). Conclusion The study demonstrated -857C/T (rs1799724) polymorphism may not have influenced RA susceptibility in our study group. However, investigations of genetic variability influence on disease outcome in large prospective cohorts are required, so the complicated interconnection of genetic and environmental elements can be emulated for better understanding.

AIM The burden of Type 2 diabetes is alarmingly high in South Asia, a region that has many genetically diverse ethnic populations. Genome-wide association studies (GWAS) conducted largely in European populations have identified a number of loci predisposing to Type 2 diabetes risk, however, the relevance of such genetic loci in many South Asian sub-ethnicities remains elusive. The aim of this study was to replicate 49 single nucleotide polymorphisms (SNPs) previously identified through GWAS in Punjabis living in Pakistan. METHODS We examined the association of 49 SNPs in 853 Type 2 diabetes cases and 1945 controls using additive logistic regression models after adjusting for age and gender. RESULTS Of the 49 SNPs investigated, eight showed a nominal association (P < 0.05) that also remained significant after controlling for the false discovery rate. The most significant association was found for rs7903146 at the TCF7L2 locus. For a per unit increase in the risk score comprising of all the 49 SNPs, the odds ratio in association with Type 2 diabetes risk was 1.16 (95% CI 1.13-1.19, P < 2.0E-16). CONCLUSION These results suggest that some Type 2 diabetes susceptibility loci are shared between Europeans and Punjabis living in Pakistan.

The epidemic of type 2 diabetes mellitus (T2DM) and the possibility of it contributing to the risk of Alzheimer&rsquo, s disease (AD) have become important health concerns worldwide and in Pakistan, where the co-occurrence of T2DM and AD is becoming more frequent. To gain insights on this phenomenon, a cross-sectional study was initiated. We recruited and interviewed 820 research participants from four cities in Pakistan: 250 controls, 450 T2DM, 100 AD, and 20 with both diseases. Significant differences between groups were observed for age (p &lt, 0.0001), urban vs. rural locality (p = 0.0472) and residing near industrial areas. The average HbA1c (%) level was 10.68 &plusmn, 2.34 in the T2DM group, and females had a lower level than males (p = 0.003). In the AD group, significant relationships existed between education and family history. Overall, the results suggest that T2DM and AD were associated with both socio-demographic and environmental factors in Pakistani participants. Detailed molecular investigations are underway in our laboratory to decipher the differential genetic pathways of the two diseases to address their increasing prevalence in this developing nation.

Commonly described as the reversal of the traditional approach of product development, reverse engineering is a putative concept of the field of engineering that has found numerous applications in diverse fields. Reverse engineering can be used to capture a three-dimensional product or model in digital form, remodeled, and exported for rapid prototyping/tooling or rapid manufacturing. A salient feature of reverse engineering approach is the ability to speed up the manufacturing process, as the production is typically based on prototypes that have already been manufactured and undergo desired modifications. This chapter gives an account of the application of reverse engineering in diverse fields of biological sciences such as bioinformatics, biosystems, human regulatory networks, medical device design, software design, pharmaceutical product design, and therapeutic protein production. From a legal and economic standpoint, reverse engineering has a long-standing history of being an acceptable practice, as it often endorsed as an appropriate way of obtaining information about another product and utilizing this information to develop another product that is directly in competition to the existing product. However, with an increase in the number of products being reverse engineered, several conflicts of legal origin have arisen, which highlight the need for the development of specific legislature governing the practices of reverse engineering that serve a regulatory purpose.

Genome-wide association studies have identified various susceptibility variants and loci associated with incidence of rheumatoid arthritis (RA) in different populations. One of these is T cell activation Rho GTPase activating protein (TAGAP). The present study sought to measure the expression of TAGAP in RA patients, CD4+ T cells subsets from healthy humans and in mice with collagen-induced arthritis. Peripheral blood mononuclear cells (PBMC) from RA patients and tissues of arthritic mice at different stages of the disease were used for the evaluation of TAGAP mRNA expression. Increased TAGAP expression was observed in RA patients compared to healthy controls, and there were differences in the expression level of TAGAP in the tissues of mice with experimental arthritis. Gene expression in CD4+ T cells from healthy humans was greatest 4 h after activation and protein expression was greatest after 24 h. The expression of TAGAP was not correlated with CD4+ lymphocyte subsets which were enriched for functionally defined subsets (Th17, Treg, Th1), further indicating its utility as an indicator of lymphocyte activation. These findings indicate that increased TAGAP expression is a distinguishing feature of inflammatory disease and further highlight the role of TAGAP in RA susceptibility.

The prevalence of type 2 diabetes (T2DM) is rapidly increasing in Pakistan. Various micro- and macro-vascular complications are associated with disease progression which increases the economic burden not only on patients but also on country. The aim of the present study was to determine the prevalence of micro- and macro-vascular complications among T2DM patients in Pakistan. A cross-sectional study was carried out on 692 T2DM patients during July 2011 to December 2012. The participants recruited in this study were clinically diagnosed by certified diabetologist and endocrinologists in the Pakistan Institute of Medical Sciences (PIMS) and Kahuta Research Laboratory (KRL) hospital of Islamabad. Demographic and clinical data was collected under supervision of a diabetologist and endocrinologist using a specially designed questionnaire. Clinical variables were statistically analyzed using SPSS version 16.0 and Graphpad prism 5 version 5.01. Of the 678 T2DM patients, 432 (63.62 %) were females with mean age of 51.81 ± 11.43. Out of total patients, 0.56 % were diagnosed with retinopathy, 0.84 % with nephropathy, 0.28 % with neuropathy, 28.17 % with ischemic heart diseases, 8.45 % with stroke, and 5.35 % with peripheral vascular disease. Overall, 55.77 % of T2DM patients were hypertensive and 0.56 % experienced impotence. Significant association of hypertension (P = 0.0072), ischemic heart disease (IHD; P = 0.0001), and peripheral vascular disease (PVD; P = 0.014) was observed at gender level in the study subjects. This study indicates high prevalence of macro-vascular complications along with high triglyceride level and hypertension among T2DM patients. A study with larger sample set is suggested to explore the relation of genetic and environmental factors on disease progression and sub-population variations.

Aim To identify risk alleles contributing towards type 1 diabetes in Pakistani patients. Introduction Type 1 diabetes (T1D) is an autoimmune disease which is caused by destruction of insulin producing β cells by immune system. Genetic predisposition as well as environmental factors contribute to its etiology. To date more than 40 risk loci have been identified for T1D. Methodology A total of 191 family-based and unrelated T1D cases and controls were recruited. DNA was extracted and 32 genome-wide significant single nucleotide polymorphisms (SNPs) previously reported in Europeans were genotyped. Genotyping was performed using TaqMan SNP genotyping assays and the data was analyzed using FamCC software. Results Our results showed significant association of 10 single nucleotide polymorphisms (SNPs) with T1D at p HLA -DQA 1 /rs9272346, ERBB3 /rs2292239, SIRPG /rs2281808, IL2-KIAA1109 /rs4505848, GLIS3 /rs7020673, CD226 /rs763361, PTPN2 /rs478582, IKZF1 /rs10272724, BACH2 /rs11755527, C6orf173 /rs9388489, whereas 5 more SNPs showed their association at 0.01 p Conclusion We have replicated many of the T1D loci established among Europeans in a Pakistani population.

Variations in T-cell activation Rho-GTPase activating protein (TAGAP) have been associated with various autoimmune diseases including Rheumatoid Arthritis (RA). The gene is involved in T cell activation and is therefore of particular interest in context of T cell-driven autoimmune diseases. Genome-wide association studies suggest association between TAGAP and RA in various populations. This study sought to investigate any association of TAGAP with RA in Pakistani population. For this, two variants in TAGAP ( rs182429 A/G and rs212389 A/G) were investigated because of their high implication in RA liability of European patients. The variants were genotyped in 186 Pakistani RA patients and 185 controls. No significant difference was observed in distribution of rs212389 between patients and controls ( P = 0.87 for genotypic frequency and P = 1.000 for allelic frequency) which differs from findings in European subjects. Conversely, statistically significant difference was observed in rs182429 ( P = 0.0026 for genotypic frequency and P = 0.0373 for allelic frequency). Heterozygous genotype AG and allele A were found to be disease susceptible genotype and allele respectively, because of their higher frequency in patients. While higher frequency of genotype GG and allele G in healthy controls suggests them as protective genotype and allele, respectively, in Pakistani population. This is the first TAGAP association study with RA in Pakistani cohort and its results suggest that the distribution of alleles regarding contribution to RA is actually population specific. In future, novel therapeutic targets for RA can be identified by exploring functional significance of these SNPs.

The hypoxic tumor microenvironment is the major contributor of chemotherapy resistance in solid tumors. One of the key regulators of hypoxic responses within the cell is the hypoxia inducible factor-1α (HIF-1α) that is involved in transcription of genes promoting cell survival and chemotherapy resistance. Multidrug resistance gene-1 (MDR1) and Lysosome-associated protein transmembrane 4B-35 (LAPTM4B-35) are among those notable players which augment their responses to cellular hypoxia. MDR1 is the hypoxia responsive gene involved in multidrug resistance phenotype while LAPTM4B-35 is involved in chemotherapy resistance by stabilizing HIF-1α and overexpressing MDR1. Overexpression of HIF-1α, MDR1 and LAPTM4B has been associated with poor disease outcome in many cancers when studied individually at tissue level. However, accessibility of the tissues following the course of chemotherapy for ascertaining chemotherapy resistance is difficult and sometimes not clinically feasible. Therefore, indication of hypoxic biomarkers in patient’s blood can significantly alter the clinical outcome. Hence there is a need to identify a blood based marker to understand the disease progression. In the current study the expression of hypoxia associated chemotherapy resistance genes were studied in the peripheral blood lymphocytes of solid tumor patients and any potential correlation with disease progression were explored. The expression of HIF-1α, MDR1 and LAPTM4B was studied in blood of 72 breast, 42 ovarian, 32 colon and 21 prostate cancer patients through real time PCR analysis using delta cycle threshold method. The statistical scrutiny was executed through Fisher’s Exact test and the Spearman correlation method. There was 12–13 fold increased in expression of HIF-1α, two fold increased in MDR1 and 13–14 fold increased in LAPTM4B mRNA level in peripheral blood of breast, ovarian, prostate and colon cancer patients. In the current study there was an association of HIF-1α, MDR1 and LAPTM4B expression with advanced tumor stage, metastasis and chemotherapy treated group in breast, ovarian, prostate and colon cancer patients. The Spearman analysis also revealed a positive linear association among HIF-1α, MDR1 and LAPTM4B in all the studied cancer patients. The elevated expression of HIF-1α, MDR1 and LAPTM4B in peripheral blood of solid tumor patients can be a predictor of metastasis, disease progression and treatment response in these cancers. However, larger studies are needed to further strengthen their role as a potential biomarker for cancer prognosis.

Rheumatoid arthritis is an autoimmune disorder which involves inflammation of the synovial tissue, leading to synovial proliferation, bone erosion and ultimately joint disability. It is a complex disorder, and the proper etiology is still unknown. Both environmental and genetic factors are responsible for the development of rheumatoid arthritis. Clinically, the disease is generally diagnosed by the presence of auto-antibodies like rheumatoid factor. But these are not specifically associated with rheumatoid arthritis. These are also present in patients with other autoimmune disorders and also in healthy persons. Citrullinated epitopes are shown to be more specific for rheumatoid arthritis. Citrullination normally occurs in cells undergoing apoptosis, and hence, citrullinated proteins are cleared from body and not encountered by immune system. However, in rheumatoid arthritis patients, these are not cleared. Anti-citrullinated protein antibodies are detectable in patients at risk of rheumatoid arthritis long before the onset of the disease. The concentration of which normally increases as the disease progress. Hence, these are important for diagnosis of rheumatoid arthritis. This review is focused on the importance of anti-citrullinated protein antibodies in disease pathogenesis and its importance in the diagnosis of rheumatoid arthritis.

MicroRNAs are short non-coding molecules expressed in different tissues and regulate the transcription of different genes. They are highly specific in their action. Upregulation or downregulation of specific microRNAs has been observed during different diseases like cancers, embryogenesis, organogenesis, apoptosis and arthritis. They are also known to be involved in autoimmune diseases. MicroRNAs are also found to be stable and easy to validate. Differential expression of microRNA-155 has been studied by different groups in inflammatory diseases including arthritis along with other miRNAs. This suggests that it can be used as a potential biomarker or therapeutic in the autoimmune diseases, especially rheumatoid arthritis. Experimental studies are needed to explore their role as biomarker or therapeutic.

Genetic variation in lipid regulatory genes, particularlyAPOE, significantly influences the risk of coronary artery disease (CAD). This study aimed to assess the association betweenAPOEpolymorphism and angiographically assessed coronary stenosis in Pakistani population. A total of 695 subjects (22.3% female, mean age =54±11years) presenting with chest pain were enrolled after obtaining written informed consent. CAD stenosis/extent was assessed by angiography. Patients were classified as having severe stenosis (≥70%), moderate stenosis (30–69%), and mild stenosis (n=491) were further categorized based on possessing one, two, or three vessel diseases to assess the disease extent. Genomic DNA from leukocytes was isolated with DNA purification kit (Qiagen) andAPOEpolymorphisms (E2/E3/E4) were determined using TaqMan assays. Six hundred and seventy-two of 695 subjects were successfully genotyped. The frequency ofAPOE∗4carriers (3/4 and 4/4 genotypes) was significantly higher in severe stenosis group (≥70%) as compared to mild group (P=0.01). In multiple regression, the odds ratio forAPOE∗4carriers to develop ≥70% stenosis was 2.16 (95% CI: 1.29–3.79;P<0.005). In conclusion, the presence ofAPOE∗4allele is a significant risk factor to develop severe coronary stenosis (>70%) among Pakistanis.

It has been the requirement of the human population to obtain greater supplies of food items for consumption.

Prevalence of type 2 diabetes is increasing rapidly around globe and effecting not only health of individuals but also socially and economically. It is a multi-factorial, polygenic metabolic disorder involving complex interaction of both genetic and environmental factors and it is characterized by increased glucose level in blood due to deficiency in insulin secretion. Recent advent of genome-wide association studies has improved the knowledge of genetic factors involved in disease progression, pathogenesis and paving way to better understand the complex pathways. These genetic variants change the drug response in patients thus making it difficult to maintain optimal glycemic levels. The genome-wide association studies are providing great insight into pharmacogenomics by revealing various new variants that effect drug response and development of personalized medication in future.