Cystic fibrosis in India: a systematic review.

OBJECTIVES: CF, caused due to abnormal transport of chloride, sodium and bicarbonate ions across epithelial cell membranes, is a multi-organ disorder. More than 1000 mutations causing CF, have been identified in the CFTR gene, of which AF508 is the most severe, predominant mutation. However, data on CF in India is limited. Also, facilities for CF diagnosis are not available at all diagnostic centres across India. RESULTS: AF508 mutation has been reported in 19-56% Indian patients. Also, the spectrum of mutations has been anticipated to be different, due to the identification of a wide range of novel and rare mutations. In addition to mutations, polymorphisms with clinical relevance and practical diagnostic value have also been identified. Clinical profile in Indian patients was also observed to be different. CONCLUSION: Though, Cystic Fibrosis has always been considered to be a rare disease in India, we hope that the identification of the wide range of mutations, leads us to the recognition of a probable increased incidence of CF in Indian patients. And this would attract greater attention to the diagnosis of this disease, so that a clinically appropriate assay can be developed for their detection as a preliminary test for CF diagnosis. The results observed during the study can be a step forward in planning a molecular screening and providing appropriate genetic counseling programs, which are lacking in our country at the moment.

Prevalence of metabolic syndrome in urban India.

Background. Metabolic syndrome (MS) is characterised by a constellation of individual risk factors of cardiovascular disease. Materials and Methods. The current study was a population-based survey of cohort of subjects in the metropolitan city of Mumbai. A total of 548 subjects, who attended the CARDIAC evaluation camp, were recruited in the study. Participants with complete fasting lipid profiles, blood glucose, and known cardiac risk markers were evaluated. Results. On applying modified NCEP ATP III, we found out that nearly 95% of the subjects had at least one abnormal parameter. We found the prevalence of MS in our study population to be 19.52%. The prevalence of MS in males was almost double than females (P = .008). The overall prevalence of BMI (>23 kg/m(2)) was 79.01%. Increased hypertriglyceridemia and decreased levels of HDL-C were found to be more in males (P < .0001). Conclusion. The low percentage of subjects with normal and controlled parameters suggests that there is a need for awareness programs and lifestyle interventions for the prevention and control of MS.

TPMT and DPD polymorphisms: Efficient screening method for Indian patients considering taking Thiopurine and 5-FU drugs.

INTRODUCTION: Development of DNA-based tests for TPMT/DPD polymorphisms can help clinicians and patients to make important decisions about cancer treatment. Also, due to lack of Indian data, we aimed at the development and validation of these tests in Indian patients. MATERIALS AND METHODS: Molecular assays were used for identifying TPMT/DPD variations; validated by DNA sequencing. RESULTS: Molecular assays have been used for screening TPMT*2, *3A, *3B, *3C alleles and IVS14+1(G-->A) in DPD gene. A patient, exhibiting neutropenia on 6-MP was observed to be G460A-homozygote, while, two Acute Lymphoblastic Leukemia (ALL) patients with side-effects exhibited wild-type alleles. Two patients showing 6-MP side-effects and responding well to the same drug at later stage also carried wild-type alleles. DISCUSSION: G460A homozygosity in a patient allowed clinicians to stop 6-MP treatment, improving patient's health status. Two ALL patients showing side-effects were wild-type, indicating presence of unidentified rare variations. Two patients with wild-type allele showed side-effects during 6-MP treatment, but responded well to same drug at later stage, suggesting side-effects to be attributable to multiple biological and environmental processes. Absence of IVS14+1(G-->A) in DPD gene will not exclude possibility of another mutation. CONCLUSION: Molecular assays for determining common TPMT/DPD variations, can provide accurate diagnosis and efficient therapies in future clinical studies.

An Indian family of multiple endocrine neoplasia type 1 (MEN1): molecular diagnosis, treatment and follow up.

BACKGROUND/OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal, dominant syndrome, characterized mainly by the combination of tumors involving the parathyroid, pancreatic and pituitary glands. Genetic sequencing leading to early treatment of family members has not yet been reported in Indian patients. METHODS: We performed molecular analysis of the MEN1 gene to identify mutations in an Indian family with MEN1 syndrome. The proband was identified with multiple peptic ulcers because of multifocal recurrent gastrinomas, as well as parathyroid and pituitary adenomas. All the 10 exons of the MEN1 gene were amplified using the polymerase chain reaction (PCR). The MEN1 gene was then screened by direct DNA sequencing. RESULTS: The proband is asymptomatic 3 years after total pancreatectomy and removal of parathyroid adenomas. DNA sequencing revealed the presence of a heterozygous Y227X mutation in exon 4 of the MEN1 gene in the proband. Four of the seven mutant-carrying family members are at present asymptomatic. Following screening, one asymptomatic child has been identified with and treated for insulinoma and parathyroid adenoma. CONCLUSION: Detection of the MEN1 gene mutation enables selection of family members for screening and long-term follow up.

MEN1 935-1G>C splicing mutation in an Indian patient with multiple endocrine neoplasia type 1.

BACKGROUND AND OBJECTIVE: Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant syndrome characterized mainly by multiple tumors involving parathyroid, pancreatic, and pituitary glands. To date, there have been no genetic studies reported on MEN1 in the Indian population. In order to begin to establish molecular diagnosis to improve the management of MEN1 in India, we performed a molecular analysis of the MEN1 gene in a patient of Indian origin. METHODS: Molecular analysis of the MEN1 gene was performed to identify mutations in an Indian patient previously diagnosed with sporadic MEN1. All the 10 exons of the MEN1 gene were amplified using the polymerase chain reaction and screened by direct DNA sequencing. RESULTS: The DNA sequencing results revealed the presence of an intronic, heterozygous, splicing mutation 935-1G>C in intron 5 of the MEN1 gene. CONCLUSION: This study provides the first data on genetic analysis of MEN1 in Indian patients.

Lipid, lipoprotein, apolipoprotein and lipoprotein(a) levels: reference intervals in a healthy Indian population.

The role of lipids, lipoproteins and lipoprotein(a) [Lp(a)] in coronary artery disease (CAD) is known but the role of major apolipoproteins (apos) other than apo A-I and apo B remains unclear. In this study, using immunoturbidimetry we have estimated serum levels of total cholesterol, HDL-C, LDL-C, triglyceride, LDL-apoB and all major apos; A-I, A-II, B, C-II, C-III and E, in 751 healthy Indian subjects (470 men and 281 women, age 25-65 years), determined their percentiles, and established reference intervals. The effects of age, smoking and alcohol on all these analytes were also evaluated. This is the first study to provide reference intervals for all apos, in both sexes from a general population. The percentiles and the reference intervals have clinical relevance and will be useful in assessing the risk of CAD in patients with hyperlipidemia and other diseases.

Application of multiplex ARMS and SSCP/HD analysis in molecular diagnosis of cystic fibrosis in Indian patients.

BACKGROUND: Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CFTR gene. The most severe, DeltaF508, mutation accounts for nearly 70% of CF cases worldwide. Besides DeltaF508, there are other point mutations, namely G542X, G551D, R553X, N1303K, and 621+1(G-->T), which are common among Caucasians. Additionally, a polyT polymorphism in intron 8 is also involved in the pathogenesis of CF. However, neither the prevalence nor the types of mutations causing CF in India are known. In this study, we aimed at estimating the frequency of the above common mutations and polymorphism in clinically suspected CF cases. We also carried out partial analysis of the CFTR gene, limited to exons 10 and 11, to identify other variations in these exons. METHODS: The multiplex amplification refractory mutation system (ARMS) test was applied for rapid simultaneous analysis of six most common CF mutations, in 100 normal and 39 elevated sweat chloride cases. The scanning of exons 10 and 11 was carried out by single-stranded conformation polymorphism/heteroduplex (SSCP/HD) analysis, followed by DNA sequencing in 50 normal and 37 elevated sweat chloride cases. A single ARMS-polymerase chain reaction assay was used to distinguish the 5T, 7T, and 9T alleles in 100 normal and 33 elevated sweat chloride cases. RESULTS: The multiplex ARMS analysis identified the DeltaF508 mutation at an allele frequency of 24% in Indian CF cases. However, the other predominant CF mutations were found to be absent. The 7T polyT variant was observed to be the most common allele, followed by the 9T, and 5T, which was the lowest. The DeltaF508 mutation was observed in all instances with the 9T variant. The SSCP/HD and DNA sequencing additionally revealed a known polymorphism (M470V, exon 10) and a known mutation [1525-1(G-->A), intron 9]. The 1525-1(G-->A) mutation, observed in a single 4-year-old male, is predicted to code for a class II defective CFTR protein. CONCLUSION: The findings of this study suggest a difference in relative frequencies and spectrum of CFTR mutations in Indian CF cases. A larger screening study of the entire CFTR gene in clinically well defined CF cases is required to delineate common mutations in the CFTR gene and enable molecular diagnosis of CF in India.