Fouzia Rashid

Pattern of urinary albumin excretion in normotensive young and adolescent Indian women with polycystic ovary syndrome

Objective: Polycystic ovarian syndrome (PCOS) is a clinically heterogeneous endocrine disorder affecting up to 4–8% of women of reproductive age. The aim of this study was to evaluate the presence of microalbuminuria in women with PCOS and study its correlation with the various metabolic, clinical, and hormonal parameters. Materials and Methods: A cross-sectional study involving 69 PCOS women was carried out in a tertiary care center hospital. The diagnosis of PCOS was made according to the Rotterdam criteria. Blood samples were collected in the follicular phase of the menstrual cycle and analyzed for fasting luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), 17-hydroxyprogesterone (17-OHP), total testosterone (T), glucose, insulin, and lipid profile. Urinary albumin was measured in the first void spot urine sample. Results: The mean age of the subjects was 22.0 ± 4.1 years and 21.8 ± 4.7 years in normoalbuminuric and microalbuminuric groups, respectively. Urinary albumin excretion (UAE) varied from 5 mg/l to 100 mg/ml, with a median of 5 mg/l. Microalbuminuria was observed in 17/69 (24.6%) of subjects. The mean UAE was 3.65 ± 4.44 mg/l in the normoalbuminuria group versus 45.29 ± 22.74 mg/l in the microalbuminuria group. Upon univariate analysis, hip circumference, diastolic blood pressure, and fasting blood glucose showed significant correlations with urinary albumin concentration (r = 0.264, 0.264, and 0.551, respectively; P = 0.028, 0.029, and 0.000, respectively). No association between UAE and the usual cardiovascular risk factors could be found upon regression analysis. Conclusion: About 24.6% of women with PCOS showed presence of microalbuminuria in the first void spot urine sample. Screening for the presence of microalbuminuria can help in early identification of a subset of PCOS women with a high risk for future CVD, who can be subjected to preventive strategies at the earliest. However, further studies are needed before recommending routine use of UAE in PCOS cases for the detection of CVD risk.

Polymorphism of the DNA Repair Gene XRCC1 (Arg194Trp) and its role in Colorectal Cancer in Kashmiri Population: a Case Control Study.

BACKGROUND Genetic polymorphisms in DNA repair genes may influence individual variation in DNA repair capacity, which may be associated with risk of developing cancer. For colorectal cancer the importance of mutations in mismatch repair genes has been extensively documented. MATERIALS AND METHODS In this study we focused on the Arg194Trp polymorphism of the DNA repair gene XRCC1, involved in base excision repair (BER) and its role in colorectal cancer in Kashmiri population. A case-control study was conducted including 100 cases of colorectal cancer, and 100 hospital-based age- and sex-matched healthy controls to examine the role of XRCC1 genetic polymorphisms in the context of colorectal cancer risk for the Kashmiri population. RESULTS Genotype analysis of XRCC1 Arg194Trp was conducted with a restriction fragment length polymorphism (RFLP) method. The overall association between the XRCC1 polymorphism and the CRC cases was found to be significant (p<0.05) with both the heterozygous genotype (Arg/Trp) as well as homozygous variant genotype (Trp/Trp) being moderately associated with the elevated risk for CRC [OR=2.01 (95% CI=1.03-3.94) and OR=5.2(95% CI=1.42-19.5)] respectively. CONCLUSIONS Our results suggest an increased risk for CRC in individuals with XRCC1 Arg194Trp polymorphism suggesting BER repair pathway modulates the risk of developing colorectal cancer in the Kashmiri population.

High-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of polycystic ovary syndrome in Indian adolescent women with polycystic ovary syndrome (PCOS).

Abstract C-reactive protein (CRP) is a risk marker for type 2 diabetes mellitus and cardiovascular diseases. In polycystic ovary syndrome (PCOS), limited data are available on high-sensitivity C-reactive protein (hs-CRP) levels and its relationship with components of PCOS especially in Indian women. The objective was to determine serum hs-CRP concentration in adolescent women with and without PCOS and to assess possible correlations of serum hs-CRP levels with components of PCOS in Indian women. One hundred and sixty women with PCOS and sixty non-PCOS women having normal menstrual cycles were included. Clinical assessment included anthropometry, Ferriman–Gallwey (FG) score and blood pressure (BP) measurement. Laboratory evaluation included estimation of T4, TSH, LH, FSH, total testosterone, prolactin, cortisol, 17OHP, hs-CRP, lipid profile, and insulin, and glucose after 2-h oral glucose tolerance test. Homeostasis Model Assessment Insulin resistance index (HOMA-IR) and Quantitative Insulin Sensitivity Check Index (QUICKI) and glucose intolerance was calculated. FG score, LH, FSH, total Testosterone, HOMA-IR and QUICKI were significantly different among women with or without PCOS (p < 0.01). Although hs-CRP levels showed a higher trend in women having PCOS, there was no significant difference between the groups (p > 0.05). A significant and positive correlation was found between hs-CRP and body mass index (BMI) (r = 0.308, p < 0.01) among PCOS group. The results in Indian adolescent women suggest that hs-CRP levels may not per se be associated with PCOS, rather can be related to fat mass in this subset of subjects. Chinese abstract C反应蛋白（CRP）是2型糖尿病和心血管疾病的危险因素。对于多囊卵巢综合征（PCOS），尤其是印度女性，在高敏C反应蛋白（hs-CRP）水平及其与PCOS的各项组分的关系方面，可查到的数据很有限。本研究的目的是监测患或不患PCOS的青春期女性的血清hs-CRP浓度，评估印度女性的血清hs-CRP浓度与PCOS指标间可能的相关性。160名PCOS患者和60名有正常月经周期的非PCOS女性参与了本试验。临床评价包括人体测量，Ferriman–Gallwey（FG）评分和血压（BP）测量。实验室测定指标包括T4，TSH， LH,，FSH，总睾酮，催乳素，皮质醇，17-OHP，hs-CRP，血脂，胰岛素的测量和2h口服葡萄糖耐量试验。同时测量稳态模式评估胰岛素抵抗指数（HOMA-IR），定量胰岛素敏感性检测指数（QUICKI）以及葡萄糖耐量。PCOS患者与正常女性的FG得分，LH,，FSH，HOMA-IR，QUICKI存在显著不同（p<0.01），尽管PCOS患者的hs-CRP水平有增高的趋势，但两组并无显著差别（p>0.05)。在PCOS组还发现hs-CRP与体重指数（BMI）有显著正相关（r=0.308, p<0.01）。该结果表明，hs-CRP水平与PCOS也许无关联性，而可能与该课题中的子项目即体重相关。

DNA Repair Gene - XRCC1 in Relation to Genome Instability and Role in Colorectal Carcinogenesis

Colorectal carcinogenesis is a multifactorial and multi-gene process, involving 3 major genetic instability pathways: chromosomal instability, microsatellite instability and CpG island methylator phenotype. Inefficient DNA repair is one of the causes of genetic instability leading to tumorigenesis. Defects in DNA repair genes are associated with cancer development. The XRCC1 gene is an important DNA repair genes and forms the component of several different damage recovery pathways, including base excision repair and single-strand breaks repair - the processes frequently involved in cancer transformation. In this review we have shed light on the structure and functioning of the XRCC1 gene and its protein, and the role played by XRCC1 in colorectal carcinogenesis.

Evaluation of deletion polymorphisms of glutathione S-transferase genes and colorectal cancer risk in ethnic Kashmiri population: A case–control study

AIM Glutathione S.transferases. (GSTs) are known to play a pivotal role in the detoxification of potential carcinogens, and their gene variation may alter susceptibility to colorectal cancer. (CRC). The aim of the study was to evaluate the genetic association of GSTM1 and GSTT1 gene deletion/null polymorphism with disease susceptibility and risk development in CRC patients of ethnic Kashmiri population. MATERIALS AND METHODS Genotype frequencies of GSTM1 and GSTT1 gene deletion/null polymorphism were compared between 160 CRC patients and 200 healthy controls using polymerase chain reaction multiplex. RESULTS The frequency of GSTM1-null was found to be 76.2% in cases and 81.5% in controls and odds ratio. (OR) = 1.37 (95% confidence interval. [CI]: 0.82-2.28). Likewise, the GSTT1-null genotype was found in 75.5% of cases and 77.5% of controls and the OR = 1.14 (95% CI: 0.76-1.8). The overall association between the GSTM1-null and GSTT1-null polymorphism and the CRC cases was found to be insignificant (P < 0.05). However, individuals with double-null genotype (GSTM1-/GSTT1-) were found to have 3.5-fold increased risk for the development of CRC. Further, the risk genotype (null) of GSTT1 was found to be associated with tumor grade (P = 0.001) and GSTM1 (null) genotype was significantly associated with smoking status (P = 0.004), when compared to the (present) genotype in CRC cases. CONCLUSION Our results suggest that GSTM1 and GSTT1 gene deletion/null gene polymorphisms are not a key modulators of the risk of developing CRC in Kashmiri population.

Glutathione S Transferases: Biochemistry, Polymorphism and Role in Colorectal Carcinogenesis

Glutathione S-transferases (GSTs) are enzymes detoxifying a wide range of hazardous substances both of endogenous or exogenous origin, such as reactive oxygen species (ROS) or xenobiotics and environmental carcinogens; thereby imparting protection to DNA against oxidative damage. GST gene polymorphisms on the other hand, exert an effect on the functioning of enzymes encoded by these genes at both gene expression level and the activity of the protein. In this way it may influence the possibility of detoxification of carcinogens, and consequently, the level of DNA damage; thus it may have an effect on the risk of development of cancer. In this review we aim to understand the function of GSTs in the xenobiotic metabolism and their role in modulation of colorectal cancer (CRC).

The Lys469glu/K469E Polymorphism of the Inflammatory Gene Intercellular Adhesion Molecule-1 Lacks any Apparent Role in the Polycystic Ovary Syndrome in Kashmiri Women: A Case Control Study

Background: Polycystic ovary syndrome (PCOS), associated with a state of low grade chronic inflammation, depends on multiple genetic and environmental factors. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) have been demonstrated in affected women. Recent evidence indicates a significant linkage between chromosome 19p13 loci and multifactorial diseases that have an inflammatory component. The aim of this study was to assess the possible association of the lys469glu (K469E) polymorphism of the ICAM-1 gene located on chromosome 19p13 with risk of PCOS in Kashmiri women. Material and Methods: The K469E single nucleotide polymorphism (SNP) was analysed with DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls using PCR-RFLP. Results: Genotypic frequencies in cases were found to be 32 (14.5%) for EE, 98 (44.5%) for KE, and 90 (40.9%) for KK, with 130 (59.1%) for the KE+EE genotypes compared to healthy control values of 29 (13.2%) for EE, 113 (51.4%) for KE, 78 (35. 5%) for KK and 142 (64.5%) for KE+EE combined. The odds ratios for the EE, KE and KE: EE genotypes were 0.95(95% CI= 0.53-1.71)[p= 0.88], 0.75(95% CI= 0.50-1.12)[p =0.168] and 0.79 (95% CI =0.53-1.16) [p = 0.23], no statistically significant differences being found between cases and controls (χ2 =2.07; p=0.35). Conclusion: In conclusion, there was no apparent significant influence of the K469E polymorphism on risk of PCOS, or any clinical or laboratory parameters.

The ICAM-1 Gly241Arg Polymorphism is Not Associated With Polycystic Ovary Syndrome - Results from a Case Control study in Kashmir, India.

BACKGROUND Polycystic ovary syndrome (PCOS) is considered to be a multifactorial disorder resulting from the interaction of several predisposing and protective genetic variants. PCOS is associated with low-grade chronic inflammation. Elevated levels of inflammatory markers including intercellular adhesion molecule-1 (ICAM-1) are demonstrated in women with PCOS. Recent evidence indicates a significant linkage between a locus on chromosome 19p13 and multifactorial diseases that have an inflammatory component. The aim of the study was to assess the possible association of Gly241Arg polymorphism of ICAM-1 gene located on chromosome 19p13 in determining risk of PCOS in Kashmiri women. MATERIALS AND METHODS Gly241Arg SNP in DNA from peripheral blood leukocytes of 220 PCOS cases and 220 age matched non-PCOS healthy controls was analysed using allel specific PCR. RESULTS The genotype and allele frequency distributions of Gly241Arg SNP showed insignificant difference between the PCOS cases and control women, indicating no role of this SNP in PCOS susceptibility. The odds ratio for Arg/Arg genotype was 0.87 (95% CI=0.32-2.3) [P=0.79], for Gly/Arg genotype was 0.98 (95% CI= 0.66-1.47) [P=1] and for Arg/Arg+Gly/Arg genotype was 0.97 (95% CI=0.65-1.45) [P=0.92]. The genotypic frequencies of ICAM-1codon 241 showed statistically insignificant difference between cases and controls (χ2=0.07; p=0.96) Nor the studied polymorphism was found to affect clinical and laboratory parameters significantly. CONCLUSIONS Although Gly241Arg polymorphism have not shown significant association with PCOS. Further, specifically designed studies on large cohorts are required to conclusively establish any role of ICAM-1 gene polymorphisms in PCOS in our study.

Protein Misfolding Diseases: In Perspective of Gain and Loss of Function

Misfolding of proteins is quite a familiar occurrence within the cell. The most common reason for this can be either genetic variations – acquired or inherited or some post-translational modifications of proteins. These if left unchecked may create havoc within the cells. Protein folding is guided by universal driving force for lower free energy state than the unfolded one. But there are several proteopathies – protein misfolding diseases as discussed below in detail that have changed the cellular functions tremendously leading to cell death. In some it is toxic gain of function that means the misfolded and aggregated protein although loses its native form or function but develops the tendency of turning other proteins into aggregates by means of intermolecular interaction as exampled best in well-known proteopathies like Parkinson’s disease, Alzheimer’s disease, etc. Another situation is where protein simply loses its natural role and keeps on getting accumulated inside cells as aggregates choking them of their normal routine processes, e.g. Alpha 1 antiproteinase deficiency. The story down from here will try to shed light on how a single mutation can influence protein structure, alter its folding pattern and functioning and how it turns into a disease. Further, this chapter will shed some light on what are the future prospects of going back to normal/native state.

Chromosome 18p11.2 harbors susceptibility marker: D18S452, for bipolar affective disorder.

Aim: The aim of our study was to investigate whether the tandem repeat polymorphism in D18S452 microsatellite marker at locus 18p11.2 is a risk factor of bipolar affective disorder (BPAD) in Kashmiri population. Materials and Methods: The repeat polymorphism in D18S452 was evaluated by polymerase chain reaction (PCR) analysis of in 74 diagnosed BPAD patients and 74 controls subjects. Results: Tandem repeat (300 bp*) allele frequency was found to be 1.35% in controls and 8.108% in cases. The tandem repeat (250 bp*) allele frequency was found to be in 91.89% in cases and 98.65% in controls. The 252 bp/252 bp genotype was found to be present in 89.18% of cases and 98.64% of controls, the 300 bp/300 bp genotype in 5.40% of cases and 1.35% of controls and the 252 bp/300 bp variant in 5.40% of cases and none among the controls. Although the proportion of patients homozygous for tandem repeat (300 bp/300 bp) was higher in cases than in controls, the difference was not statistically significant when 252 bp/252 bp genotype was taken as reference (odds ratio [OR]=4.4242; 95% confidence interval [CI] 0.4822-40.5924); P=0.1529). However, when the frequency of heterozygous genotype (252 bp/300 bp) was compared with 252 bp/252 bp statistical significance was observed (OR=8.0603; 95% CI 1.1112-58.4646; P=0.0383). Conclusion: This is the first study reporting a significant association between D18S452 maker with tandem repeat polymorphism in heterozygous condition (252 bp/300 bp) and the development of BPAD in Kashmiri population.