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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 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]

Primary hyperoxalurias (PH) are a group of rare heterogeneous disorders characterized by deficiencies in glyoxylate metabolism. To date, three genes have been identified to cause three types of PH (I, II, and III). The HOGA1 gene caused type III in around 10% of the PH cases. Disease‐associated pathogenic variants have been reported from several populations and a comprehensive spectrum of these mutations and genotype–phenotype correlation has never been presented. In this study, we describe new cases of the HOGA1 gene pathogenic variants identified in our population. We report the first case of ESKD with successful kidney transplantation with 5 years of follow‐up. Furthermore, a comprehensive overview of PH type III associated HOGA1 gene variants was carried out. Compiling the data from the literature, we reviewed 57 distinct HOGA1 gene pathogenic variants in 175 patients worldwide. The majority of reported variants are missense variants that predicted a loss of function mechanism as the underlying pathology. There has been evidence of the presence of founder mutations in several populations like Europeans, Ashkenazi Jews, Arab, and Chinese populations. No significant genotype–phenotype correlation was identified concerning the ages of onset of the disease and biochemical and metabolic parameters. Nephrocalcinosis was rare in patients with disease‐associated variants. Most of the patients were presented with urolithiasis early in life; only five cases reported disease progression after the second decade of life. The establishment of impairment of renal function in 8% of all the reported cases makes this type a relatively severe form of primary hyperoxaluria, not a benign etiology as suggested previously. [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]

A frequency data report from South and Southeast Asia confirms that low frequency of ADH1B*47His allele in the region between eastern and western Asia and derived allele increased in frequency independently in western and eastern Asia after humans had spread across Eurasia.

Allelic frequencies of 182 tri- and tetra-autosomal microsatellites were used to examine phylogenetic relationships among 19 extant human populations. In particular, because the languages of the Basques and Hunza Burusho have been suggested to have an ancient relationship, this study sought to explore the genetic relationship between these two major language isolate populations and to compare them with other human populations. The work presented here shows that the microsatellite allelic diversity and the number of unique alleles were highest in sub-Saharan Africans. Neighbor-joining trees based on genetic distances and principal component analyses separated populations from different continents, and are consistent with an African origin for modern humans. For the first time, with biparentally transmitted markers, the microsatellite tree also shows that the San are the first branch of the human tree before the branch leading to all other Africans. In contrast to an earlier study, these results provided no evidence of a genetic relationship among the two language isolate groups. Genetic relationships, as ascertained by these microsatellites, are dictated primarily by geographic proximity rather than by remote linguistic origin, Mantel test, [R.sub.0] = 0.484, g = 3.802 (critical g value = 1.645; P = 0.05). Am J Phys Anthropol 122:259-268, 2003. KEY WORDS autosomal short tandem repeats; principal components analysis; human origins

Purpose: Deletion of Glutathione S-Transferase Theta 1 (GSTT1) encoding gene is implicated in breast cancer susceptibility, clinical outcomes, and survival. Contradictory results have been reported in different studies. The present investigation based on a representative Pakistani population evaluated the GSTT1 -absent genotype in breast cancer risk and prognosis. Methods: A prospective study comprising case-control analysis and case series analysis components was designed. Peripheral blood samples were collected from enrolled participants. After DNA extraction, GSTT1 g enotyping was carried out by a multiplex PCR with β-globin as an amplification control. Association evaluation of GSTT1 genotypes with breast cancer risk, specific tumor characteristics, and survival were the primary endpoints. Results: A total of 264 participants were enrolled in the molecular investigation (3 institutions). The study included 121 primary breast cancer patients as cases and 143 age-matched female subjects, with no history of any cancer, as controls. A significant genetic association between GSTT1 -absent genotype and breast cancer susceptibility (p -value: 0.03; OR: 2.13; 95% CI: 1.08-4.29) was reported. The case-series analysis showed lack of association of GSTT1 genotypes with menopause (p- value: 0.86), tumor stage (p -value: 0.12), grade (p -value: 0.32), and size (p -value: 0.07). The survival analysis revealed that GSTT1 -absent genotype cases had a statistically significant shorter overall survival (OS) than those with the GSTT1 -present genotype cases (mean OS: 23 months vs 33 months). The HR (95% CI) for OS in patients carrying GSTT1 -absent genotype was 8.13 (2.91-22.96) when compared with the GSTT1 -present genotype. Conclusions: The present study is the first report of an independent significant genetic association between GSTT1 -absent genotype and breast cancer susceptibility in a Pakistani population. It is also the foremost report of the association of this genotype with OS in breast cancer cases. Upon further validation, GSTT1 variation may serve as a marker for devising better population-specific strategies. The information may have translational implications in the screening and treatment of breast cancers. [ABSTRACT FROM AUTHOR]

A gene associated with isolated congenital microphthalmia (CMIC) has been mapped to chromosome 14q32, probably between markers D14S987 and D14S267. The condition is inherited as an autosomal recessive trait in a five-generation consanguineous family from Pakistan with six affected members living. Over 150 polymorphic markers were typed for 16 family members, and homozygosity mapping was carried out.

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]

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]

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]

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]

Mutations in the NPHS1, NPHS2, LAMB2, and the WT1 genes are responsible for causing nephrotic syndrome (NS) in two third of the early onset cases. This study was carried out to assess the frequencies of mutations in these genes in a cohort of pediatric NS patients. A total of 64 pediatric familial or sporadic SRNS cases were recruited. Among these, 74% had a disease onset of up to 3 years of age. We found one homozygous frameshift mutation in the NPHS1 gene in one CNS case and two homozygous mutations in the NPHS2 gene. Six mutations in four cases in the LAMB2 gene were also identified. No mutation was detected in the WT1 gene in isolated SRNS cases. LAMB2 gene missense mutations were segregating in NS cases with no extra-renal abnormalities. Analysis of the population genomic data (1000 genome and gnomAD databases) for the prevalence estimation revealed that NS is more prevalent than previously determined from clinical cohorts especially in Asian population compared with overall world populations (prevalence worldwide was 1in 189036 and in South-Asian was 1in 56689). Our results reiterated a low prevalence of mutations in the NPHS1, NPHS2, LAMB2, and WT1 genes in the studied population from Pakistan as compared to some European population that showed a high prevalence of mutations in these genes. This is a comprehensive screening of the genes causing early onset NS in sporadic and familial NS cases suggesting a more systematic and robust approach for mutation identification in all the 45 disease-causing genes in NS in our population is required. [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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]