Association of CYP3A5*3 polymorphism with development of acute leukemia.

BACKGROUND: CYP3A5 was observed to be an important genetic contributor to inter individual differences in CYP3A-dependent drug metabolism in acute leukemic patients. Loss of CYP3A5 expression was mainly conferred by a single nucleotide polymorphism at 6986A>G (CYP3A5*3). We investigated the association between CYP3A5*3 polymorphism and acute leukemia. MATERIALS AND METHODS: Two hundred and eighty nine acute leukemia cases comprising of 145 acute lymphocytic leukemia (ALL), 144 acute myeloid leukemia and 241 control samples were analyzed for CYP3A5*3 polymorphism using PCR-RFLP method. Statistical analysis was performed with SPSS version (15.0) to detect the association between CYP3A5*3 polymorphism and acute leukemia. RESULTS: The CYP3A5*3 polymorphism 3/3 genotype was significantly associated with acute leukemia development (χ2- 133.53; df-2, P 0.000). When the data was analyzed with respect to clinical variables, mean WBC, blast % and LDH levels were increased in both ALL and AML cases with 3/3 genotype. The epidemiological variables did not contribute to the genotype risk to develop either AML or ALL. CONCLUSION: The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients.

Association of CYP1A1*2 polymorphisms with breast cancer risk: a case control study.

BACKGROUND: The Cytochrome P-4501A1 (CYP1A1) gene, located on chromosome 15q, is involved in the metabolism of carcinogens mainly polycyclic aromatic hydrocarbons as well as estrogen. It is considered as candidate gene for low-penetrance breast cancer susceptibility. Hence the present study aims to discuss the role of CYP1A1 polymorphisms in breast cancer. MATERIALS AND METHODS: A total of 250 breast cancer patients and the same number of healthy age-matched controls were analyzed for the polymorphism of CYP1A1*2 by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: In the present study, association of CYP1A1*2 (Ile 462Val) polymorphism with breast cancer was studied. Only one breast cancer patient was observed to be homozygous for Val allele but none among controls. The frequency of heterozygous Ile/Val genotype was found to be increased significantly in breast cancer patients (68.1%) as compared to controls (51.0%). Higher frequency of heterozygotes for Val allele was observed among premenopausal breast cancer patients and patients with high BMI, positive for HER2/neu status and advanced stage of the disease in comparison to the corresponding groups. No significant association of CYP1A1*2 polymorphism was observed with occupation, estrogen receptor and progesterone receptor status of breast cancer patients. CONCLUSIONS: In conclusion, our results suggest a significant correlation between CYP1A1*2 expression and the occurrence of breast cancer.

PvuII polymorphism of estrogen receptor-α gene in breast cancer.

BACKGROUND: Estrogen receptor (ER) is a ligand-inducible transcription factor that mediates estrogen action in target tissue. Several common polymorphisms of the ERα gene have been reported to be associated with alterations in receptor expression in breast cancer. MATERIALS AND METHODS: A case-control study was designed to compare 250 breast cancer patients with 250 age-matched healthy controls. The frequency distribution of PvuII polymorphism in the ERα gene was assessed by PCR-RFLP method. RESULTS: The frequency of the PP genotype (35.3%) was increased significantly in breast cancer patients when compared to controls (19.8%), with a corresponding increase in P allele frequency (χ2= 16.4; P = 0.0003). The OR for genotypes PP vs. Pp was 1.989 (95% CI: 1.2708 to 3.113). Premenopausal women with breast cancer had an elevated frequency of the PP genotype (22.8%) as compared to postmenopausal women (16.8%). The frequency of the PP genotype was increased in patients positive for ER and HER-2/neu as compared to those with receptor-negative status. The pp and p allele frequencies were increased in progesterone-receptor-negative status. When stage of the disease was considered, both Pp and pp genotype frequencies were elevated in patients with advanced stage breast cancer. The frequency of the P allele and PP genotype frequencies tended to increase with increase in body mass index, whereas the Pp genotype frequency was elevated only in obese patients. The reverse was observed in the case of pp genotype frequency. CONCLUSION: The study thus highlighted the influence of ERα PvuII polymorphism on the development and progression of breast cancer.

Association of apolipoprotein E (RFLP) polymorphism with myopia.

BACKGROUND: Myopia or nearsightedness is a spherical error of refraction, whereby the images are focused in front of retina. Eye, being an organ rich in activated oxygen species, requires a high level of antioxidants to protect the unsaturated fatty acids. Apolipoprotein E (APOE) is one of the proteins that is produced by Muller cells within the retina and is also endowed with antioxidant properties. Genetic polymorphism of APO E is controlled by three common alleles e3, e2 and e4 and rare e1, e4v at the APOE structural gene locus. Different isoforms of APO E differ in their antioxidant properties, and the e4 allele has lesser ability to combat oxidative stress. AIMS: Myopia being a disease influenced by oxidative stress, the present study was undertaken to find association of myopia with APO E polymorphism. MATERIALS AND METHODS: A total of 187 myopic cases and 192 controls were genotyped for apolipoprotein E polymorphism. RESULTS: In both controls and myopic cases, E3/3 genotype was found to be the most frequent one. There was an increase in E3/4 genotype frequency among male probands, high myopia cases and probands with early age at onset, suggesting that the E3/4 genotype might confer risk for myopia development. CONCLUSION: This association with E3/4 genotype might predispose susceptible individuals to develop high myopia and early onset myopia.

Association of erythrocyte acid phosphatase phenotypes with myopia.

Acid phosphatase is a polymorphic nonspecific orthophosphate monoesterase which catalyses the cleaving of phosphoric acid and subsequent breakdown of several monophosphoric esters under acidic pH conditions. Acid phosphatase has a physiologic function as a flavin mononucleotide phosphatase (FMN) and regulates the intracellular concentrations of flavin coenzymes that are electron carriers in the oxidative phosphorylation pathway. Myopia or nearsightedness is caused by both environmental and genetic factors. Myopic eyes when subjected to excessive oxidative stress results in retinal detachments .In the present study there is a significant elevation of AA phenotype in myopes when compared to controls. The AA phenotype is more susceptible to oxidative stress and its lower enzyme activity is known to be associated with increased intrauterine growth that further results in increased axial length in progressive myopia. The AA phenotype also confers risk for myopia development in males, early age group and cases with parental consanguinity.

Study of families of nonsyndromic hearing impairment segregating with mutations in Cx26 gene.

Autosomal recessive nonsyndromic hearing impairment (ARNSHI) is the most common form with profound hereditary hearing impairment linked to DFNB1 locus (connexin26 gene) at 13q12. Mutations in connexin26 (Cx26) gene are known to be frequently associated with ARNSHI. Here, we report results on 13 families with NSHI screened for entire coding region of Cx26 using ARMS-PCR, restriction digestion analysis, SSCP and sequencing. Cx26 mutations were found in seven of the 13 families with inheritance of W24X (G to A at 71bp) in six and R127H (G to A at 380bp) in one of them. The observations imply that the G to A transition at position 71 in exon2 of Cx26 gene could play a major role in the phenotypic expression of recessive hearing impairment while R127H could be an associated polymorphism in Indian population.

Quantitative variation of superoxide dismutase levels in leukaemias.

Superoxde dismutase is dimeric antioxidant enzyme responsible for quenching of superoxide radicals which are released during the chemical reactions of the various metabolic pathways .The enzyme levels of SOD are altered to a considerable extent in various diseased states exhibiting either elevation or depletion in their enzymatic activity.As this phenomenon was found to be more evident in leukaemias, we have estimated the Cu-Zn SOD levels in the red cells of the leukaemic patients in order to evaluate the efficiency of anti oxidant system and its relation to leukaemiogenesis. The overall mean SOD levels in the leukaemic patients (AML, ALL and CML) were significantly low (124.97±6.46) as compared to that of the normal controls (287.08±6.79). In respect to the age, the mean SOD levels were found to be elevated indicating the extent of the free radicals might have stimulated the production of the antioxidants.In response to chemotherapy, the mean SOD levels were observed to be elevated but not the extent of the normal levels among the treated groups in AML(127.40±8.67) and CML (174.73±53.59) types of leukaemias as compared to that of the untreated groups. In general the stage of leukaemia did not cause any variation in the SOD levels. However, the L2 in ALL (107.49±4.88), blast crisis in CML (154.00±19.86) showed reduced levels of SOD.

Retinitis pigmentosum co-segregating with Enamel Hypoplasia (Amelogenesis Imperfecta)-A new Syndrome.

A family with the segregation of retinitis pigmentosum (RP) in combination with enamel hypoplasia (amelogenesis imperfecta - AI) is recorded. Family information collected over three generations revealed expression of the condition in two of the cousins born to half sibs. Parents of both the patients are cousins and are phenotypically normal. None of the sibs and other relatives of the patients are affected with any ophthalmic condition or dental anomalies. Ophthalmic evaluation of the patients revealed retinitis pigmentosa with nystagmus and optic atrophy and dental examination showed the presence of AI with hypoplastic enamel,' severe attrition of incisors and molars with narrowing of root canal and pulp chambers. Retinitis pigmentosum is a highly heterogeneous condition with 11 genes identified for an autosomal dominant, 13 for autosomal recessive and 5 for X-linked inheritance. Amelogenesis imperfecta is also a genetically heterogeneous condition showing all the three types of segregation. To the best of our knowledge co-segregation of RP with AI has not been reported. The family reported here may be considered as a new syndrome caused by a rare autosomal recessive gene with pleitropic effect affecting the retina and as well as the normal dentition. Alternatively it could also represent a rare coincidence of the two conditions.

Marfan Like Syndrome With Multiple Ocular Abnormalities.

An 18 year old female with multiple ocular disorders showed more or less cardinal features similar to that of an autosomal dominantly inherited Marfan Syndrome. Related features with variable symptoms were seen in her sibs. Major and minor manifestations of MFS like cardio-vascular, respiratory problems, spine deformities, arachnodactyly were not observed. Pedigree analysis showed high incidence of consanguinity.

A Study on Heritability of Pattern Intensity Index and Asymmetry of Digital Dermatoglyphic Pattern Frequency in Muslims of Assam.

The frequency distribution of digital dermatoglyphic patterns was studied in 50 muslim families from Lakshmipur district from Assam. The study revealed asymmetry in the distribution of various patterns on individual digits though bimannual differences were not present. The mean pattern intensify index was found to be 13.54 + 3.76 corresponding to the presence of more number of loops and whorls in the data. Heritability, as calculated from mid parent child regression was found to be 82% indicating the presence of stronger genetic component in the formation of dermatoglyphic patterns. There was significant inter-familial variance suggesting the presence of genetic and environmental factors. The higher values of intra-familial variance also indicate influence of polygenes with additive effects on dermatoglyphic patterns.

Effect of Chemotherapy on Malondialdehyde levels in Leukaemias.

Leukemia are the family of hematological malignancies of bone marrow resulting in uncontrolled proliferation of white blood cells. We have analyzed the MDA levels in 108 leukaemic patients. In the present study, the mean of the plasma MDA levels in leukaemic patients were found to be significantly elevated (572.41+11.79) as compared to that of the normal controls (375.84+5.48) indicating the possible role of invivo peroxidation of membrane lipids in the etiology of leukaemias. Sexwise comparision of the MDA levels in the leukaemic groups showed an elevated levels of lipid peroxidatrion byproducts among the affected males (588.23+14.49) as compared to that of the femeles (541.61+ 19.57). With respect to the age, the MDA levels were seen to be progressively increasing with advancing age. The highest levels of MDA were found in the age group of 30-40 years in an the types of leukaemia. In general the treated group showed comparatively low levels of MDA (543.13+13.46) to that of the untreated group (631.21+20.05) indicating the effect of chemotherapy on MDA levels. With respect to stage, the M5 stage among the AML type (619.67+28.22), L3 among the ALL type (769.00) and blast crisis among the CML group (619.67+112.89) were exhibiting elevated levels of MDA.

Serum Lactate Dehydrogenase (LDH) Levels In Breast Cancer.

L-Lactate dehydrogenase is an oxidoreductase that catalyzes the reversible inter-conversion of pyruvate to L-lactate under anaerobic conditions. Levels of Lactate dehydrogenase are known to be elevated in the blood stream following severe tissue injuries and necrosis. Since cancer is a proliferating and invasive disease known to cause severe tissue damage and tumour cells respire anaerobically, the present study was planned to evaluate variations in the levels of serum LDH in breast cancer as compared to normal. LDH levels were estimated in 130 patients with a confirmed diagnosis of breast cancer and also in 110 healthy age matched randomly selected controls. Appropriate statistical tests were used to assess variations in LDH levels with respect to the presence of disease, age at onset and menopausal status of the proband, stage of the disease and mode of anti-cancer therapy followed Lactate dehydrogenase levels were found to be significantly elevated in breast cancer (302.45 + 7.67) as compared to control (173.77 + 3.4). Significant elevations in LDH levels were also observed with increasing age at onset, onset of menopause, advance stage of cancer and due to the anti-cancer treatment followed. These results suggest an immense potential for LDH as a prognostic marker for breast cancer.

A Study On The Genetics Of Sense Of Humour.

An attempt was made to assess the role of genetic factors in the expression of humour. The IPAT Humour Test was used to evaluate humour as a quantitative parameter. Correlation coefficients were calculated between pairs of first degree relatives. Variation in mean scores obtained for each of the 13 components of humour for the comparable pairs was high, and the correlations in general were poor. Our results may be explained on the basis of cultural and environmental influences.

A Study On The Heritability And Interfamilial Variation Of Digital Dermatoglyphic Patterns.

Forty eight random families from the population of Andhra Pradesh were selected for the analysis of digital dermatoglyphic patterns and patterns intensity index (PII). The loops were found to be more frequent in the present sample followed by whorls and arches. Sex difference was not evident in the frequency distribution of digital patterns. There was no significant bilateral assymetry in the distribution of digital patterns between the right and left hands of the individuals. The dermatoglyphic patterns showed a specific trend in their distribution on individual fingers, i.e., whorls occurred frequently on finger IV, ulnar loops on finger V, radial loops on finger II and arches on finger II. The pattern intensity index as calculated from the different digital patterns exhibited high heritability values. The correlation coefficients of pattern intensity index between various familial relationships were found to be significant indicating the involvement of genetic factors, mostly autosomal. The partitioning of total phenotypic variance into various components of variance revealed the action of polygenes with more of additive effect, dominance deviation being negligible. This was confirmed by analysis of variance (ANOVA). In general, our study indicated the involvement of polygenes with additive effect and also of environmental components which might be intra-uterine in origin.

Association Of GC Phenotypes With Pre-eclampsia-Possibility For A Causal Role.

Pre-eclampsia is a hypertensive disorder of pregnancy and has been reported to be associated with altered vitamin D levels. GC being a vitamin D binding protein, may be playing a functional role in the pathophysiology of the disease. The present investigation conducted on 100 pre-eclamptic and hypertensive controls with a corresponding decrease in GC 1-1 phenotype as compared to normotensive controls. There was no difference in the frequency of GC 2-2 phenotype between eclamptic women and controls. A similar trent was observed in moderate and severe cases of pre-eclampsia and in multigravid women with recurrence of pre-eclampsia. Relative risk estimates revealed an increased risk for moderate and severe types of pre-eclampsia when their phenotypes were of GC 2-1. The increase in heterozygote frequency of GC in pre-eclampsia and hypertensive controls as compared to normotensive controls, indicates the risk of GC 2-1 phenotype which could be due to a direct physiological effect against the disease through increased physiological versatility where the two alleles of GC may vary functionally. It may be possible that the binding capacity of GC alleles 1 and 2 with vitamin D may be varying on similar lines as haptoglobin with haemoglobin. The altered levels of vitamin D as reported by many authors and the increased risk of GC 2-1 phenotype observed in the present study indicate a possibility for a causal relationship of this phenotype with the disease probably With a functional role.