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BACKGROUND & OBJECTIVE: The most common risk factors for Obstructive Sleep Apnea includes: Obesity and increased neck circumference in male gender. The objective of the study was to compare the anthropometric parameters between obese male participants with and without obstructive sleep apnea (OSA). METHODOLOGY: Study was conducted at Department of Physiology,Post Graduate Medical Institute, Lahore during 24 August 2014 to 26 May 2015. Obese males (n=64)with body mass index (BMI)>25kg/m2 andaged 20-45 years were recruited by convenience sampling. Screening of OSA was made by two subjective tools: STOP BANG Questionnaire, and Berlin Questionnaire while final diagnosis was made by overnight portable pulse oximetry. Study population was divided into two groups. Group-I comprised of 32 obese males with OSA. Group II had 32 obese males without OSA. BMI, neck circumference, and waist circumference were measured by standard methods. Comparison of variables was done between the groups by Mann-Whitney Utest and t-test. RESULTS: BMI was higher in group-I than in group-II (p=0.004). Median BMI for group-I was 30.83 (28.16-32.80) and for group-II was 27.99 (26.59-30.08)Kg/m2. A significantly higher neck circumference (p<0.001) was present in group-I (41.95±2.40cm) than group-II (39.66±2.07cm). Moreover, significantly higher median waist circumference (p<0.001) was present in group I (107.5cm) as compared to group-II (98.5cm). CONCLUSION: Anthropometric parameters (BMI, neck circumference, and waist circumference) are higher in obese individuals with OSA as compared to obese males without OSA. [ABSTRACT FROM AUTHOR]

Highlights: [•] Renal cell carcinoma (RCC) is the most frequent form of kidney cancer in adults. [•] We report somatic mutations and promoter hypermethylation in 300 RCC patients. [•] Our data showed molecular alterations in the VHL gene in 163 (54%) RCC patients. [•] Somatic mutations were found in only 29% patients as compared to 40–70% worldwide. [•] We found a low frequency of somatic mutations and high frequency of hypermethylation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Mutations in the NPHS1 and NPHS2 genes are among the main causes of early-onset and familial steroid resistant nephrotic syndrome respectively. This study was carried out to assess the frequencies of mutations in these two genes in a cohort of Pakistani pediatric NS patients. Methods: Mutation analysis was carried out by direct sequencing of the NPHS1 and NPHS2 genes in 145 nephrotic syndrome (NS) patients. This cohort included 36 samples of congenital or infantile onset NS cases and 39 samples of familial cases obtained from 30 families. Results: A total of 7 homozygous (6 novel) mutations were found in the NPHS1 gene and 4 homozygous mutations in the NPHS2 gene. All mutations in the NPHS1 gene were found in the early onset cases. Of these, one patient has a family history of NS. Homozygous p.R229Q mutation in the NPHS2 gene was found in two children with childhood-onset NS. Conclusions: Our results show a low prevalence of disease causing mutations in the NPHS1 (22% early onset, 5.5% overall) and NPHS2 (3.3% early onset and 3.4% overall) genes in the Pakistani NS children as compared to the European populations. In contrast to the high frequency of the NPHS2 gene mutations reported for familial SRNS in Europe, no mutation was found in the familial Pakistani cases. To our knowledge, this is the first comprehensive screening of the NPHS1 and NPHS2 gene mutations in sporadic and familial NS cases from South Asia. [Copyright &y& Elsevier]

Three Pakistani populations residing in northern Pakistan, the Burusho, Kalash and Pathan claim descent from Greek soldiers associated with Alexander's invasion of southwest Asia. Earlier studies have excluded a substantial Greek genetic input into these populations, but left open the question of a smaller contribution. We have now typed 90 binary polymorphisms and 16 multiallelic, short-tandem-repeat (STR) loci mapping to the male-specific portion of the human Y chromosome in 952 males, including 77 Greeks in order to re-investigate this question. In pairwise comparisons between the Greeks and the three Pakistani populations using genetic distance measures sensitive to recent events, the lowest distances were observed between the Greeks and the Pathans. Clade E3b1 lineages, which were frequent in the Greeks but not in Pakistan, were nevertheless observed in two Pathan individuals, one of whom shared a 16 Y-STR haplotype with the Greeks. The worldwide distribution of a shortened (9 Y-STR) version of this haplotype, determined from database information, was concentrated in Macedonia and Greece, suggesting an origin there. Although based on only a few unrelated descendants, this provides strong evidence for a European origin for a small proportion of the Pathan Y chromosomes.European Journal of Human Genetics (2007) 15, 121–126. doi:10.1038/sj.ejhg.5201726; published online 18 October 2006 [ABSTRACT FROM AUTHOR]

To map the disease loci several Pakistani families suffering from autosomal recessive retinitis pigmentosa with preserved para-arteriolar retinal pigment epithelium and Leber congenital amaurosis (LCA) were analyzed. Analysis revealed close genetic linkage between the disease phenotype of some of the families (3330RP, 111RP and 010LCA) and the microsatellite markers on chromosome 1q31. Mutation screening of the candidate gene CRB1 revealed a G to A transversion in exon 7 in arRP family 330RP and a T to C substitution in another arRP family, 111RP. In exon 9 of the CRB1 gene a T to C transversion was found in the family suffering from LCA (010LCA).The LCA phenotype of another family (011LCA) in which the CRB1 locus was excluded, showed linkage with microsatellite markers D17S1294 and D17S796 on chromosome 17p13·1. The association of the candidate gene GUCY2D (17p13·1) with the disease phenotype was excluded as no disease-associated mutation was found in any of its exons. Mutation screening of another candidate gene, AIPL1 located in the same region, showed a novel homozygous C to A substitution in exon 2. These sequence changes are unique for the Pakistani families and some of these have not been reported previously. [Copyright &y& Elsevier]

Objectives: To determine validity of the CLL International prognostic index (IPI) scoring system in Pakistani chronic lymphocytic leukemia patients, as the validity and universal applicability of various prognostic scoring systems such as the CLL-IPI remains a challenge, particularly in under-developed countries like Pakistan. Methods: This prospective single center study was conducted at Department of Hematology, University of Health Sciences, Lahore and included sixty patients with CLL diagnosed between July, 2019 to July, 2022. Patients were followed for a period of two years and 02 year overall survival (OS) was noted. Risk stratification was conducted according to CLL-IPI prognostic model. Results: Among 60 patients, the mean age was 60±11years. Advanced Binet stage B+C and elevated β2-microglobulin >3.5mg/L was observed in 73.3% and 38.3% patients respectively. The estimated median 02 years OS was 16.5 months (95% CI: 10-20 months). In total, 40 of 60 CLL patients (67%) were accessible for follow-up analyses. For the present CLL cohort, 25% patients (n = 10) were classified as CLL-IPI low risk and intermediate risk group, 35% (n = 14) as high risk and 15% (n = 06) as very high-risk group. However, this classification of patients according to CLL-IPI did not yield significant differences in terms of OS (p = 0.24), although the median OS of CLL-IPI very high-risk group was noted as only six months and was not reached for low and intermediate risk groups. Conclusion: To conclude, clinical validation of CLL-IPI scoring system could not be established for the present CLL cohort and needs to be evaluated in further studies with larger sample size. [ABSTRACT FROM AUTHOR]

The infection caused by Severe Acute Respiratory Syndrome-Corona Virus 2 (SARS-CoV-2) has rapidly emerged as a serious pandemic, causing substantial morbidity and sometimes mortality with a significant healthcare burden. Unfortunately, Pakistan is among top twenty countries of the world affected by COVID-19. The clinical spectrum in COVID-19 is diverse, ranging from mild disease having flu-like symptoms to potentially fatal ARDS, cytokine storm, multiple organ failure and death. Common risk factors associated with severe outcome in COVID-19 infection include male gender, older age and presence of comorbidities such as hypertension, diabetes and cardiovascular disease. Here we reviewed the available literature and report that the underlying mechanisms that account for a broad range of symptoms during respiratory viral infections, that have been well studied in the case of influenza viruses, adenoviruses, SARS-CoV and MERS-CoV, suggest that host genetic and epigenetic factors may also play a significant role in determining susceptibility and clinical outcome in COVID-19 infection. In this review we discuss the potential roles of host genetic factors including cellular receptors for COVID-19, HLA and inflammatory cytokine genes. Based on the SARS-CoV-2 genome and protein-protein interactions map between host and viral proteins we also describe the potential roles of several viral proteins in epigenetic modulation of host inflammatory innate immune response by targeting different cellular pathways particularly NF-κB activation, which may lead to the inflammatory cytokine storm and a severe COVID-19 disease. Investigations of these genetic and epigenetic mechanisms during COVID-19, especially in local settings, will be helpful in management of patients with higher risks and in the development of novel antiviral therapeutics. [ABSTRACT FROM AUTHOR]

Background: Interferon-gamma inducible protein-10 (IP-10/CXCL10) is a chemokine involved in the alloimmune response against kidney allograft. We aimed to investigate the association of urinary CXCL10 protein levels with rejection in renal transplant patients. Methods: A total of 273 urine samples from (biopsy-proven) rejection and non-rejection patients and controls were included in this study. CXCL10 levels were analyzed for association with rejection. Results: The data showed statistically significant differences in the CXCL10 levels between rejection vs. non-rejection ( p < 0.001). Among the rejection groups, statistically significant differences for CXCL10 levels were found between ACR vs. NAD ( p < 0.001), ACR vs. BLR ( p = 0.019) and AVR vs. NAD ( p = 0.009). Receiver Operating Characteristic (ROC) curve analysis of CXCL10 showed an area under the curve (AUC) of 0.74 with 72% sensitivity and 71% specificity at 27.5 pg/ml between rejection and non-rejection group. Kaplan-Meier curve analysis among different levels of CXCL10 showed a better rejection-free graft survival in patients with <100 pg/ml when compared to >200 pg/ml (38 ± 6 vs. 12 ± 1.0 weeks; log-rank p < 0.001) and 100-200 pg/ml (38 ± 6 vs. 22 ± 9 weeks; log-rank p = 0.442) concentration. Conclusion: The results indicate significantly increased levels of CXCL10 protein in the urine at the time of allograft rejection. This association of urinary CXCL10 protein levels with rejection could provide an additional tool for the non-invasive monitoring of allograft rejection. [ABSTRACT FROM AUTHOR]

Background: CCL2 is a chemoattractant for monocytes/macrophages, T cells, and natural killer cells. It is shown to be involved in the immunological responses against renal allograft. This study was conducted to access the role of urinary CCL2 expression in predicting the rejection episodes in renal transplant patients. Method: A total of 409 urine samples included in this study. The samples were consisted of (a) biopsy-proven graft rejection (n= 165); (b) non-rejection (n= 93); (c) non-biopsy stable-graft (n= 42), and (d) healthy renal donors (n= 109). The samples were quantified for the CCL2 using the MCP-1/CCL2 ELISA kit. The data were analyzed using the Statistical Package for Social Sciences (SPSS®) and MedCalc®statistical software. Results: Results showed that the CCL2 levels were significantly increased in rejection group when compared with the non-rejection, stable-graft, and control,P< 0.05. The receiver operating curve’s characteristics illustrated that the urinary CCL2 level is a good predictor for graft rejection, with an area under the curve of 0.81 ± 0.03 with optimum sensitivity and specificity of 87% and 62%, respectively, at a cut-off value of 198 pg/mL. Kaplan–Meier curve also showed better cumulative rejection-free graft survival time in group with less than 198 pg/mL of CCL2 as compared to those with expression levels of more than 198 pg/mL (30 weeks vs. 3 weeks; log-rank test,P< 0.001). Conclusion: In our study, noninvasive investigation of CCL2 levels in urine has showed potential to predict rejection episodes. It is suggested that the CCL2, with others markers, may help in early detection and monitoring of graft rejection episodes. [ABSTRACT FROM PUBLISHER]

The primary hyperoxalurias are rare disorders of glyoxylate metabolism. Accurate diagnosis is essential for therapeutic and management strategies. We conducted a molecular study on patients suffering from recurrent calcium‐oxalate stones and nephrocalcinosis and screened primary hyperoxaluria causing genes in a large cohort of early‐onset cases. Disease‐associated pathogenic‐variants were defined as missense, nonsense, frameshift‐indels, and splice‐site variants with a reported minor allele frequency <1% in controls. We found pathogenic‐variants in 34% of the cases. Variants in the AGXT gene causing PH‐I were identified in 81% of the mutation positive cases. PH‐II‐associated variants in the GRHPR gene are found in 15% of the pediatric PH‐positive population. Only 3% of the PH‐positive cases have pathogenic‐variants in the HOGA1 gene, responsible to cause PH‐III. A population‐specific AGXT gene variant c.1049G>A; p.Gly350Asp accounts for 22% of the PH‐I‐positive patients. Pathogenicity of the identified variants was evaluated by in‐silico tools and ACMG guidelines. We have devised a rapid and low‐cost approach for the screening of PH by using targeted‐NGS highlighting the importance of an accurate and cost‐effective screening platform. This is the largest study in Pakistani pediatric patients from South‐Asian region that also expands the mutation spectrum of the three known genes. [ABSTRACT FROM AUTHOR]

BACKGROUND & OBJECTIVE: Self-esteem and optimism are important for students' success. Our objectives were (a) to determine self-esteem and life-orientation (optimism) levels among Optometry students in the Department of Optometry & Vision Sciences at the University of Lahore (UoL) (b) to investigate associations between sociodemographic factors, self-esteem, and optimism. METHODOLOGY: This cross-sectional study was conducted during November 2021 to December 2021 at the Department of Optometry and Vision Sciences, UoL. A total of 168 Optometry students were recruited by convenience sampling. Self-esteem was estimated using Rosenberg Self-Esteem Questionnaire. Life Orientation Test-Revised (LOT-R) questionnaire was used to measure optimism. Ethical approval was obtained from the Institutional Review Board of the UoL. Chi-square was used to determine associations between sociodemographic variables, self-esteem, and optimism. RESULTS: Mean self-esteem score was 18.48±3.86 (range:8-30). About 20% of students had low self-esteem. The mean life orientation score was 14.15±2.8 (range:5-24). About 43% of students had low optimism. Significant associations were found between self-esteem, reason of admission in the Optometry program with p-value=0.001, family income (p=0.037), choice of the Optometry program (p=0.036), and reason of admission in the Optometry program (p=0.032). CONCLUSION: Low self-esteem and low optimism have been observed among a significant percentage of Optometry students at the UoL. Reason of admission in the Optometry program and family income were significantly associated factors. Students' own decision to choose a study program may increase their self-esteem and optimism. Financial assistance for students from the low socioeconomic background may be a positive approach to boost their self-esteem and optimism. Teachers, parents, and counselors should support the students to increase their self-esteem and optimism. [ABSTRACT FROM AUTHOR]

Type III von Willebrand disease is present in the Punjab province of Pakistan along with other inherited bleeding disorders like hemophilia. Cousin marriages are very common in Pakistan so genetic studies help to establish protocols for screening, especially at the antenatal level. Factors behind the phenotypic variation of the severity of bleeding in type III vWD are largely unknown. The study was conducted to determine Mutations/genetic alterations in type III von Willebrand disease and also to determine the association of different mutations, methylation status, ITGA2B/B3 mutations and alloimmunization with the severity of type III vWD. After informed consent and detailed history of the patients, routine tests and DNA extraction from blood, mutational analysis was performed by Next Generation Sequencing on Ion Torrent PGM. DNA methylation status was also checked with the help of PCR. In our cohort, 55 cases were detected with pathogenic mutations. A total of 27 different mutations were identified in 55 solved cases; 16 (59.2%) were novel. The mean bleeding score in truncating mutations and essential splice site mutations was relatively higher than weak and strong missense mutations. The mean bleeding score showed insignificant variation for different DNA methylation statuses of the VWF gene at the cg23551979 CpG site. Mutations in exons 7,10, 25, 28, 31, 43, and intron 41 splice site account for 75% of the mutations. [ABSTRACT FROM AUTHOR]

HLA polymorphisms at the HLA -A, -B, -C, -DRB and -DQB1 loci were investigated in the Gujjar population from the Punjab province of Pakistan. The Gujjars ( n = 97) were genotyped using sequence specific primers for polymerase chain reaction. The allele and haplotype frequencies were calculated and a neighbor-joining (NJ) tree comparing the Gujjar with other populations was constructed. The class I allelic groups with a frequency greater than 10% include A*01, A*02, A*11, A*26 and A*31 at the HLA-A locus, B*08 and B*51 at the HLA-B locus and C*07 and C*14 at the HLA-C locus. Among the 12 allelic groups detected at the DRB1* locus, *03, *13, and *15 were present at frequencies higher than 10% whereas at the DQB1 locus, the allelic groups*06 and *02 accounted for over half of the Gujjar population. HLA-A*31-B*51-DRB1*13 was the most common (8.8%) haplotype in this population. A NJ tree revealed that the Pakistani Gujjar are closely related to the Golla tribe from Andhra Pradesh in India. The two populations are dedicated to the same profession, cattle breeding. HLA analyses of additional Punjab castes would provide valuable information for anthropological, organ transplantation and genetic disease studies. [ABSTRACT FROM AUTHOR]

Isolated (non-syndromic) congenital cataract may be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. Considerable progress has been made in identifying genes and loci for dominantly inherited cataract, but the molecular basis for autosomal recessive disease is less well defined. Hence we undertook genetic linkage studies in four consanguineous Pakistani families with non-syndromic autosomal recessive congenital cataracts. In two families linkage to a 38 cM region 9q13-q22 was detected. Although a locus for recessive congenital cataracts had not been mapped previously to this region, the target interval encompasses the candidate region autosomal recessive adult-onset pulverulent cataracts ( CAAR). The CAAR was mapped previously to 9q13-q22, and may therefore be allelic to non-syndromic autosomal recessive congenital cataracts. The other two families did not demonstrate linkage to 9q, but both had a region of homozygosity at 16q22 containing the heat shock transcription factor 4 ( HSF4) gene. The HSF4 mutations have been reported in four families with autosomal dominant cataracts and, recently, in a single kindred with autosomal recessive congenital cataract. Mutation analysis of HSF4 revealed homozygous mutations (p.Arg175Pro and c.595_599delGGGCC, respectively) in the two families. These findings confirm that mutations in HSF4 may result in both autosomal dominant and autosomal recessive congenital cataract, and highlight the locus heterogeneity in autosomal recessive congenital cataract. [ABSTRACT FROM AUTHOR]

Three populations from northern Pakistan, the Burusho, Kalash, and Pathan, claim descent from soldiers left behind by Alexander the Great after his invasion of the Indo-Pak subcontinent. In order to investigate their genetic relationships, we analyzed nine Alu insertion polymorphisms and 113 autosomal microsatellites in the extant Pakistani and Greek populations. Principal component, phylogenetic, and structure analyses show that the Kalash are genetically distinct, and that the Burusho and Pathan populations are genetically close to each other and the Greek population. Admixture estimates suggest a small Greek contribution to the genetic pool of the Burusho and Pathan and demonstrate that these two northern Pakistani populations share a common Indo-European gene pool that probably predates Alexander’s invasion. The genetically isolated Kalash population may represent the genetic pool of ancestral Eurasian populations of Central Asia or early Indo-European nomadic pastoral tribes that became sequestered in the valleys of the Hindu Kush Mountains. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to find the correlation among the intelligence and academic achievement of MBBS students and to see if the correlation differs between boys and girls. Study Design: Cross Sectional Study. Setting: Ameer Ud Din Medical College / PGMI Lahore. Period: 1st January 2019 to 31st January 2019 Material & Methods: A total of 100 second year MBBS students volunteered to participate (46 males and 54 females). Modified Wechsler Adult Intelligence Scale (WAIS) was used to access the IQ of students. Previous academic records of the students before their admission in medical college and written and oral test marks of second year MBBS students during the year were used for measuring academic achievements of students. The results were analyzed by spearmans correlation, Independent t test and Mann Whitney U test. Results: A statistically significant difference (p = 0.04) between IQ of boys and girls was found with males having mean IQ of 97.4±22.7 as compared to females 89.3±15.5. No significant difference was observed in academic achievements of male and female students. Correlation of IQ with academic achievements was also non-significant. Conclusion: Although males have higher IQ but it has no relationship with academic achievement of medical students. Hard work of the students with average or low IQ could be the reason that there was no difference in the academic achievement when they were compared with the students having higher IQ. [ABSTRACT FROM AUTHOR]

Polymorphisms of vitamin D receptor (VDR) gene have been associated with risk of urolithiasis, but, with inconsistent results and lack data from Pakistani population. Therefore, after including our indigenous study data, a comprehensive meta-analysis was performed to provide an evidence-based estimate of any association between VDR polymorphisms and urolithiasis risk. A total of 483 Pakistani subjects, comprising 235 urolithiasis patients and 248 healthy controls, were genotyped for 6 VDR polymorphisms. Additionally, a systematic literature search with subsequent meta-analysis was conducted and pooled odds ratios (ORs) were used to determine the strength of any existent associations. Trial sequential analysis (TSA) was also performed. Results revealed no significant association of any VDR polymorphism and urolithiasis risk in indigenous Pakistani patients. However, meta-analysis of 29 relevant studies indicated that VDR FokI polymorphism significantly increased the risk of urolithiasis in allelic (f vs. F: OR = 1.13; 95% CI = 1.05–1.22; p ≤ 0.01) and recessive (ff vs. FF + Ff: OR = 1.20; 95% CI = 1.05–1.38; p = 0.01) models with no significant heterogeneity. No associations were evident for VDR ApaI, BsmI and TaqI polymorphic variants and urolithiasis risk after correction for multiple testing. Subgroup analysis by ethnicity suggested significant association for FokI variant among Asians. The TSA results demonstrated that the evidence reflecting association of FokI polymorphism and urolithiasis risk was sufficient and conclusive. In conclusion, this meta-analysis suggests that VDR FokI polymorphism is significantly associated with urolithiasis risk, especially in Asians, whereas ApaI, BsmI and TaqI polymorphisms are not associated. [ABSTRACT FROM AUTHOR]

Introduction: Glanzmann thrombasthenia (GT) is most common of inherited platelet disorders, resulting from quantitative/qualitative defects in platelet surface integrin αIIbβ3, encoded by ITGA2B and ITGB3 genes. Little is known about clinical and molecular characteristics of GT patients from highly consanguineous Pakistani population. Methods: This study analyzed the clinical and molecular spectrum of six GT patients from four unrelated but consanguineous families. Platelet surface expression of αIIbβ3 integrin was determined using flow cytometry analysis. ITGA2B and ITGB3 genes were screened for causative mutations by DNA sequencing. Detected mutations were characterized for their pathogenicity using a variety of in silico tools. Results: Glanzmann thrombasthenia patients in this study generally presented early in life, had a severe course of clinical disease with transfusion dependency for management of bleeding episodes. Molecular analysis revealed 2 homozygous missense mutations in ITGB3 gene, c.422 A˃G (p.Y141C) in three GT patients from a single pedigree with familial segregation and c.1641 C>G (p.C547W) in three unrelated GT patients from three families manifesting type I GT with severe reduction in platelet αIIbβ3 levels. In silico pathogenicity predictions, multiple sequence alignment and 3D protein modeling unanimously suggested deleterious nature of the detected mutations, possibly due to aberrant disulfide bonding. Of note, clinical diversity was observed even among GT patients with same mutation in GT1 family. Conclusion: This study provides an initial yet important account of clinical and genetic characterization of GT in local patients which may spark further studies to help molecular diagnosis, optimal disease management, and genetic counseling based prevention efforts. [ABSTRACT FROM AUTHOR]

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide and causes significant patient morbidity. We previously demonstrated a genetic cause of NL can be identified in 11-29% of pre-dominantly American and European stone formers. Pakistan, which resides within the Afro-Asian stone belt, has a high prevalence of nephrolithiasis (12%) as well as high rate of consanguinity (> 50%). We recruited 235 Pakistani subjects hospitalized for nephrolithiasis from five tertiary hospitals in the Punjab province of Pakistan. Subjects were surveyed for age of onset, NL recurrence, and family history. We conducted high-throughput exon sequencing of 30 NL disease genes and variant analysis to identify monogenic causative mutations in each subject. We detected likely causative mutations in 4 of 30 disease genes, yielding a likely molecular diagnosis in 7% (17 of 235) of NL families. Only 1 of 17 causative mutations was identified in an autosomal recessive disease gene. 10 of the 12 detected mutations were novel mutations (83%). SLC34A1 was most frequently mutated (12 of 17 solved families). We observed a higher frequency of causative mutations in subjects with a positive NL family history (13/109, 12%) versus those with a negative family history (4/120, 3%). Five missense SLC34A1 variants identified through genetic analysis demonstrated defective phosphate transport. We examined the monogenic causes of NL in a novel geographic cohort and most frequently identified dominant mutations in the sodium-phosphate transporter SLC34A1 with functional validation. [ABSTRACT FROM AUTHOR]

Background/aim: Fanconi anemia (FA) is an autosomal recessive disease determined by mutations in at least 16 genes, with distinct distributions in different populations. To the best of our knowledge, there are no reports regarding the molecular basis of the disease in FA patients in Pakistan. The current study aimed to determine the frequency of FANCC gene mutations, i.e. IVS4+4A>T, del322G, and R548X, in FA patients. Materials and methods: Genomic DNA was obtained from 36 FA patients. All samples were analyzed by polymerase chain reaction and restriction fragment length polymorphism techniques. Results: Mutation IVS4+4A>T was identified in 26 (72.2%) patients. It was homozygous in 6 and heterozygous in 20 patients. Del322G and R548X were found with the following prevalences: del322G, 5.6%, and R548X, 5.6%. Patients with these two mutations were compound heterozygotes having concomitant IVS4+4A>T mutation. Conclusion: These results suggest that mutation IVS4+4A>T is the most prevalent mutation in our group of patients. This analysis of Pakistani patients also suggests that there is no significant difference between IVS4+4A>T homozygotes and the rest of the patients with regard to severity of clinical phenotype. [ABSTRACT FROM AUTHOR]

Background: Head and Neck Cancers (HNCs)comprise one of the most frequent cancers in South-Asian region. Vascular Endothelial Growth Factor (VEGF) has a potent role in tumorigenesis and metastasis. Certain common single nucleotide variants (SNVs) in the highly polymorphic VEGF gene are correlated with variations in VEGF functions. The data for these SNVs in HNCs is scarce for South Asian populations. The present study addresses this shortfall. It investigates the association of two VEGF SNVs, -2578C/A (rs699947) in the promoter region and + 936C/T (rs3025039) in 3'-UTR, with the risk of HNCs and tumour characteristics.Methods: The study comprised 323 participants with 121 HNC patients and 202 controls. Germline DNA was isolated from peripheral blood samples. PCR-RFLP methods were optimized and validated by Sanger sequencing. After Hardy-Weinberg evaluation, the independent associations were analyzed under the assumptions of different genetic models. The χ2 test of independence or Fisher's Exact test (significant p-values at < 0.05) were performed and ORs (odds ratios) with 95% confidence interval were tabulated.Results: VEGF -2578 A-allele, CA + AA, and AA genotypes had significant protective association against HNCs. The respective ORs were: 0.651 (0.469-0.904), 0.613 (0.381 - 0.985), and 0.393 (0.193-0.804). VEGF + 936 T-allele, CT, and CT + TT genotypes had significantly increased susceptibility for HNCs. The respective ORs were 1.882 (1.001 - 3.536), 2.060 (1.035 - 4.102), and 2.023 (1.032 - 3.966). Additionally, VEGF + 936 CT and CT + TT genotypes showed significant associations with higher tumour grade (p-values < 0.029, and < 0.037, respectively).Conclusion: The present study is the foremost report of independent and unique associations of the investigated VEGF SNVs with HNCs. [ABSTRACT FROM AUTHOR]

Abstract: Background: Gene polymorphisms of the chemokine receptors CCR2 and CCR5 (CCR2V64I, CCR5-59029G>A and CCR5Δ32) have been shown to be associated with renal allograft rejection. The aim of this study was to investigate the association of these polymorphisms with allograft rejection among Pakistani transplant patients. Method: A total of 606 renal transplant patients and an equal number of their donors were included in this study. DNA samples were used to amplify polymorphic regions of CCR2V64I, CCR5-59029G>A and CCR5Δ32 by polymerase chain reaction using sequence specific primers. The amplified products of CCRV64I and CCR5-59029G>A were digested with restriction enzymes (BsaB1 and Bsp12861) respectively. The CCR5Δ32 genotypes were determined by sizing the PCR amplicons. The association of these polymorphisms with the biopsy proven rejection and other clinical parameters was evaluated using the statistical software SPSS v.17. Results: In this study, the G/G genotype of CCR2V64I was associated with a high frequency of allograft rejection (p=0.009; OR=2.14; 95% CI=1.2–3.7). Rejection episode(s) in the GA+AA genotypes were found to be significantly lower as compared to the GG genotype (p=0.009; OR=0.4; 95% CI=0.2–0.8). The Kaplan–Meier curve also indicated a reduced overall allograft survival for patients with the G/G genotype of CCR2V64I (59.2±1.4weeks, log p=0.008). There was a significant association with rejection by female donors possessing the CCR2 GG genotype (p=0.02; OR=2.6; CI=1.1–6.3) and male donors with the CCR5-59029 GG genotype (p=0.004; OR=1.7; CI=1.03–3.01). Conclusion: This study shows an association of the CCR2V64I (G/G) genotype with renal allograft rejection. However, no such association was found for the CCR5 gene polymorphisms. Therapeutic interventions such as blocking the CCR2 receptor (especially G polymorphism) may yield better survival of renal allograft in this patient group. Further, chemokine receptors may be added to the spectrum of the immunogenetic factors that are known to be associated with renal allograft rejection. [Copyright &y& Elsevier]

Abstract: Nephrotic syndrome is a common pediatric glomerular disease associated with heavy proteinuria. Since, the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is a putative genetic risk factor for NS, in this study, ACE (I/D) polymorphism was analyzed in 268 NS and 223 control samples by a PCR-based method. The genotypic and allelic frequencies were determined and the association between ACE I/D polymorphism and NS was evaluated. The frequency distribution of the II, ID and DD genotypes was 82 (30.6%), 128 (47.8%) and 58 (21.6%) in the NS patients and 9 (4.0%), 171 (76.7%) and 43 (19.3%) in the control samples respectively. In the Pakistani pediatric NS population, the II genotypic and allelic frequencies were found to be significantly associated with the disease (OR=6.755; C.I=3–14.9). No significant association was found between this polymorphism and the response to standard steroid therapy. Thus, in contrast to reports from other parts of the world, the II genotype was found to be significantly associated with NS in the Indian and Malay populations and in the Pakistani population described here. To our knowledge, this is the first report from Pakistan describing the association of the ACE I/D polymorphism with pediatric NS. On the basis of these results, it is suggested that analysis of the ACE (I/D) polymorphism should be performed for the early diagnosis in the high risk NS patients in South Asia. [Copyright &y& Elsevier]

Mitochondrial aldehyde dehydrogenase (ALDH2) is one of the most important enzymes in human alcohol metabolism. The oriental ALDH2*504Lys variant functions as a dominant negative, greatly reducing activity in heterozygotes and abolishing activity in homozygotes. This allele is associated with serious disorders such as alcohol liver disease, late onset Alzheimer disease, colorectal cancer, and esophageal cancer, and is best known for protection against alcoholism. Many hundreds of papers in various languages have been published on this variant, providing allele frequency data for many different populations. To develop a highly refined global geographic distribution of ALDH2*504Lys, we have collected new data on 4,091 individuals from 86 population samples and assembled published data on a total of 80,691 individuals from 366 population samples. The allele is essentially absent in all parts of the world except East Asia. The ALDH2*504Lys allele has its highest frequency in Southeast China, and occurs in most areas of China, Japan, Korea, Mongolia, and Indochina with frequencies gradually declining radially from Southeast China. As the indigenous populations in South China have much lower frequencies than the southern Han migrants from Central China, we conclude that ALDH2*504Lys was carried by Han Chinese as they spread throughout East Asia. Esophageal cancer, with its highest incidence in East Asia, may be associated with ALDH2*504Lys because of a toxic effect of increased acetaldehyde in the tissue where ingested ethanol has its highest concentration. While the distributions of esophageal cancer and ALDH2*504Lys do not precisely correlate, that does not disprove the hypothesis. In general the study of fine scale geographic distributions of ALDH2*504Lys and diseases may help in understanding the multiple relationships among genes, diseases, environments, and cultures. [ABSTRACT FROM AUTHOR]

The ADH1B Arg47His polymorphism has been convincingly associated with alcoholism in numerous studies of several populations in Asia and Europe. In a review of literature from the past 30 years, we have identified studies that report allele frequencies of this polymorphism for 131 population samples from many different parts of the world. The derived ADH1B⋆47His allele reaches high frequencies only in western and eastern Asia. To pursue this pattern, we report here new frequency data for 37 populations. Most of our data are from South and Southeast Asia and confirm that there is a low frequency of this allele in the region between eastern and western Asia. The distribution suggests that the derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia. [ABSTRACT FROM AUTHOR]

Cone–rod retinal dystrophy (CORD) characteristically leads to early impairment of vision due to the simultaneous involvement of both cone and rod photoreceptor cells. Several loci/genes have been identified for CORD, including the cone–rod dystrophy (CORD8) locus [OMIM#605549] identified for a Pakistani family. All members of this family underwent detailed clinical re-examination to determine the nature of the dystrophy. All affected individuals suffered from bilateral CORD8 with an autosomal recessive mode of inheritance. The CORD8 locus, mapped on chromosome 1q12–q24, consisted of a very large critical disease region of 21 cM. Analysis with more recently available microsatellite markers within the reported region showed heterozygosity with some of the new markers, and the crossovers lead to a refinement of the disease region from 21 to 11.53 cM. Mutation screening has excluded some of the candidate genes in the region. The disease phenotype of this family could be due to a mutation in a novel gene located within the refined CORD8 locus. [ABSTRACT FROM AUTHOR]

Abstract: The C-type lectin DC-SIGN is involved in early interactions between human innate immune cells and a variety of pathogens. Here we sought to evaluate whether DC-SIGN interacts with the leprosy bacillus, Mycobacterium leprae, and whether DC-SIGN genetic variation influences the susceptibility and/or pathogenesis of the disease. A case–control study conducted in a cohort of 272 individuals revealed no association between DC-SIGN variation and leprosy. However, our results clearly show that DC-SIGN recognizes M. leprae, indicating that mycobacteria recognition by this lectin is not as narrowly restricted to the Mycobacterium tuberculosis complex as previously thought. Altogether, our results provide further elucidation of M. leprae interactions with the host innate immune cells and emphasize the importance of DC-SIGN in the early interactions between the human host and the infectious agents. [Copyright &y& Elsevier]

Explores the genetic relationship between two major language isolate populations by using allelic frequencies 182 tri- and tetra-autosomal microsatellites. Total number of alleles; Total number of unique alleles; Average heterozygosities.

Leber congenital amaurosis (LCA, MIM 204000) accounts for at least 5% of all inherited retinal disease and is the most severe inherited retinopathy with the earliest age of onset. Individuals affected with LCA are diagnosed at birth or in the first few months of life with severely impaired vision or blindness, nystagmus and an abnormal or flat electroretinogram (ERG). Mutations in GUCY2D (ref. 3), RPE65 (ref. 4) and CRX (ref. 5) are known to cause LCA, but one study identified disease-causing GUCY2D mutations in only 8 of 15 families whose LCA locus maps to 17p13.1 (ref. 3), suggesting another LCA locus might be located on 17p13.1. Confirming this prediction, the LCA in one Pakistani family mapped to 17p13.1, between D17S849 and D17S960?a region that excludes GUCY2D. The LCA in this family has been designated LCA4 (ref. 6). We describe here a new photoreceptor/pineal-expressed gene, AIPL1 (encoding aryl-hydrocarbon interacting protein-like 1), that maps within the LCA4 candidate region and whose protein contains three tetratricopeptide (TPR) motifs, consistent with nuclear transport or chaperone activity. A homozygous nonsense mutation at codon 278 is present in all affected members of the original LCA4 family. AIPL1 mutations may cause approximately 20% of recessive LCA, as disease-causing mutations were identified in 3 of 14 LCA families not tested previously for linkage. [ABSTRACT FROM AUTHOR]

Background and Objective: Premature ovarian failure is a worldwide concern effecting 1% of females of reproductive age. The objective of the present study was to analyze the role of inhibin alpha (INHα) gene mutation (769G>A) in patients with premature ovarian failure (POF) in the local population. Methods: This case-control association studywas conducted in Department of Gynecology, Jinnah Hospital and The Children's Hospital and Institute of Child Health from July 2015-July 2016. A total of n = 100 were recruited for this study and divided into two gropus females with equal number (n = 50)of patients andnormal controls of reproductive age (14 - 40 years). The screening of theINHα for 769G>A variation in exon 2 was done through DNA sequencing. Results: A higher frequency of the major allele G was seen in both the patients (99%) and the controls (87%) while comparing to minor allele A (1% in patients and 13% in controls). None of the patients was found to be homozygous (AA = 0%) for allele A, whereas, four of the controls were homozygous (AA = 8%). The frequency of the minor A allele in controls was found to be statistically significant (P-value = 0.002). Conclusion: An association of decreased risk of POFwith A allele of the 769G>A variant rather than increasing the risk of development of ovarian failure. [ABSTRACT FROM AUTHOR]

Background and Objective: Premature ovarian failure is a worldwide concern effecting 1% of females of reproductive age. The objective of the present study was to analyze the role of inhibin alpha (INHα) gene mutation (769G>A) in patients with premature ovarian failure (POF) in the local population. Methods: This case-control association studywas conducted in Department of Gynecology, Jinnah Hospital and The Children's Hospital and Institute of Child Health from July 2015-July 2016. A total of n = 100 were recruited for this study and divided into two gropus females with equal number (n = 50)of patients andnormal controls of reproductive age (14 - 40 years). The screening of theINHα for 769G>A variation in exon 2 was done through DNA sequencing. Results: A higher frequency of the major allele G was seen in both the patients (99%) and the controls (87%) while comparing to minor allele A (1% in patients and 13% in controls). None of the patients was found to be homozygous (AA = 0%) for allele A, whereas, four of the controls were homozygous (AA = 8%). The frequency of the minor A allele in controls was found to be statistically significant (P-value = 0.002). Conclusion: An association of decreased risk of POFwith A allele of the 769G>A variant rather than increasing the risk of development of ovarian failure. [ABSTRACT FROM AUTHOR]

Background: Urolithiasis is a worldwide urological problem with significant contribution of genetic factors. Pakistan, which resides within the Afro-Asian stone belt, has a high reported prevalence (12%) of urolithiasis. Osteopontin (SPP1) is a urinary macromolecule with a suggested critical role in modulating renal stone formation, genetic polymorphisms of which may determine individual risk of developing urolithiasis. However, results of previous studies regarding SPP1 polymorphisms and susceptibility to urolithiasis have apparent inconsistencies with no data available for local population. Methods: A total of 235 urolithiasis patients and 243 healthy controls, all of Pakistani ancestry, underwent genotyping for six SPP1 genetic polymorphisms in an effort to investigate potential association with urolithiasis using indigenous candidate gene association study design. Further, a comprehensive meta-analysis following a systematic literature search was also done to ascertain an evidence based account of any existent association regarding SPP1 promoter polymorphisms and risk of developing urolithiasis. Results: Three SPP1 promoter polymorphisms, rs2853744:G > T, rs11730582:T > C and rs11439060:delG>G, were found to be significantly associated with risk of urolithiasis in indigenous genetic association study (OR = 3.14; p = 0.006, OR = 1.78; p = 0.006 and OR = 1.60; p = 0.012, respectively). We also observed a 1.68-fold positive association of a tri-allelic haplotype of these SPP1 promoter polymorphisms (G-C-dG) with risk of urolithiasis (OR = 1.68; p = 0.0079). However, no association was evident when data were stratified according to gender, age at first presentation, stone recurrence, stone multiplicity, parental consanguinity and family history of urolithiasis. The overall results from meta-analysis, which included 4 studies, suggested a significant association of SPP1 rs2853744:G > T polymorphism with susceptibility of urolithiasis (OR = 1.37; p = 0.004), but not for other SPP1 polymorphic variants analyzed. Conclusions: In conclusion, we report significant association of 3 SPP1 polymorphisms with urolithiasis for the first time from South Asia, however, this association persisted only for SPP1 rs2853744:G > T polymorphism after meta-analysis of pooled studies. Further studies with a larger sample size will be required to validate this association and assess any potential usefulness in diagnosis and prognosis of renal stone disease. [ABSTRACT FROM AUTHOR]

Background: The Glutathione S-transferases (GSTs) genes deletion polymorphisms have been associated with the progression of several cancers. The association studies between the 2 GSTs (GSTM1 and GSTT1) null polymorphisms with the susceptibility to renal cell carcinoma (RCC) have been inconclusive. Therefore, with the inclusion of our own data, we performed a comprehensive meta-analysis to assess the association between these 2 polymorphisms and the risk of RCC.Methods: A systematic literature search was carried out for studies published in the PubMed, EMBASE, Cochrane library, and Google Scholar from 1997 to December 2014. Results were stated as pooled odds ratios (ORs) for nonparametric data after heterogeneity analysis with 95% CI using fixed effect or random effect model.Results: We systematically selected 13 relevant studies after thorough searches from the databases. Data showed no association between the GSTM1 and the GSTT1 null genotypes and the risk of RCC (OR = 1.01; CI: 0.92-1.11; P = 0.89 for GSTM1 and OR = 1.14; CI: 0.91-1.42; P = 0.25 for GSTT1). No association was found when the data were stratified according to the geographical/ethnic basis, source of control, and the risk factor evaluation. Subgroup analysis of occupational exposure to pesticides showed an inverse association of the active genotypes of both GSTM1 and GSTT1 polymorphisms with the exposed group of RCC (P<0.00001 and P<0.00001, respectively). The combined null genotype of the GSTM1/GSTT1 significantly increased the susceptibility to RCC by 1.4-fold (P = 0.001). This association remained significant for the Asian populations in subgroup analysis (OR = 1.8; CI: 1.30-2.49; P = 0.0004).Conclusion: In conclusion, this meta-analysis suggests that the 2 GSTs deletion polymorphisms independently have no association with the risk of RCC. However, combination of both deletions increases the risk of developing the RCC. [ABSTRACT FROM AUTHOR]