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Biomedical subjects

K Ranade

Publications and source records attributed to K Ranade.

15 recordsLinked to original sources
PubMed2003

Genome-wide scan of bipolar disorder in 65 pedigrees: supportive evidence for linkage at 8q24, 18q22, 4q32, 2p12, and 13q12.

The purpose of this study was to assess 65 pedigrees ascertained through a Bipolar I (BPI) proband for evidence of linkage, using nonparametric methods in a genome-wide scan and for possible parent of origin effect using several analytical methods. We identified 15 loci with nominally significant evidence for increased allele sharing among affected relative pairs. Eight of these regions, at 8q24, 18q22, 4q32, 13q12, 4q35, 10q26, 2p12, and 12q24, directly overlap with previously reported evidence of linkage to bipolar disorder. Five regions at 20p13, 2p22, 14q23, 9p13, and 1q41 are within several Mb of previously reported regions. We report our findings in rank order and the top five markers had an NPL>2.5. The peak finding in these regions were D8S256 at 8q24, NPL 3.13; D18S878 at 18q22, NPL 2.90; D4S1629 at 4q32, NPL 2.80; D2S99 at 2p12, NPL 2.54; and D13S1493 at 13q12, NPL 2.53. No locus produced statistically significant evidence for linkage at the genome-wide level. The parent of origin effect was studied and consistent with our previous findings, evidence for a locus on 18q22 was predominantly from families wherein the father or paternal lineage was affected. There was evidence consistent with paternal imprinting at the loci on 13q12 and 1q41.

Adolescent↗
PubMed2001

Genetic variation in aldosterone synthase predicts plasma glucose levels.

The mineralocorticoid hormone, aldosterone, is known to play a role in sodium homeostasis. We serendipitously found, however, highly significant association between single-nucleotide polymorphisms in the aldosterone synthase gene and plasma glucose levels in a large population of Chinese and Japanese origin. Two polymorphisms--one in the putative promoter (T-344C) and another resulting in a lysine/arginine substitution at amino acid 173, which are in complete linkage disequilibrium in this population--were associated with fasting plasma glucose levels (P = 0.000017) and those 60 (P = 0.017) and 120 (P = 0.0019) min after an oral glucose challenge. A C/T variant in intron 1, between these polymorphisms, was not associated with glucose levels. Arg-173 and -344C homozygotes were most likely to be diabetic [odds ratio 2.51; 95% confidence interval (C.I.) 1.39-3.92; P = 0.0015] and have impaired fasting glucose levels (odds ratio 3.53; 95% C.I. 2.02-5.5; P = 0.0000036). These results suggest a new role for aldosterone in glucose homeostasis.

Adult↗
PubMed2001

Genetic variation in the human urea transporter-2 is associated with variation in blood pressure.

The kidney, by regulating the volume of fluid in the body, plays a key role in regulating blood pressure (BP). The kidney uses primarily sodium and, to a lesser extent, urea to maintain the appropriate volume of fluid. Genetic variation in proteins that determine sodium reabsorption and excretion is known to significantly influence BP. However, the influence of genetic variation in urea transporters on BP has not been examined. We determined therefore whether nucleotide variation in the kidney-specific human urea transporter, HUT2, is associated with variation in BP. After determining the genomic structure of the coding sequence, seven single nucleotide polymorphisms (SNPs) were identified. Two of the SNPs result in Val/Ile and Ala/Thr amino acid substitutions at positions 227 and 357 in the HUT2 open reading frame, respectively. Another SNP is silent and four others are in introns or the 3' untranslated region. Over 1000 hypertensive and low-normotensive individuals of Chinese origin were typed for five of these SNPs using a high-throughput genotyping method. The Ile227 and Ala357 alleles were associated with low diastolic BP in men but not women, with odds ratios 2.1 [95% confidence interval (CI) 1.5-2.7, P < 0.001] and 1.5 (95% CI 1.2-1.8, P < 0.001), respectively. There was a similar trend for systolic BP, and odds ratios for the Ile227 and Ala357 alleles were 1.7 (95% CI 1.2-2.3, P = 0.002) and 1.3 (95% CI 1.1-1.6, P = 0.007), respectively, in men.

Blood Pressure↗
PubMed2001

The glycine allele of a glycine/arginine polymorphism in the beta2-adrenergic receptor gene is associated with essential hypertension in a population of Chinese origin.

BACKGROUND: Several studies implicate polymorphisms in the human beta-adrenergic receptor gene (ADRB2) in the susceptibility to hypertension. We sought to replicate these results in a population of Chinese origin primarily from Taiwan and the San Francisco Bay area. METHODS: We genotyped >800 hypertensive subjects and individuals with low-normal blood pressure that were derived largely from the same families as the hypertensive patients for three polymorphisms in the ADRB2 gene: a C/T transition at position 47 (C-47T) in the 5' leader cistron; another C/T transition that results in a glycine/ arginine substitution at codon 16 (Gly16Arg), and a G/C transversion that causes a glutamate/glutamine substitution at codon 27 (Glu27Gln). RESULTS: The Gly16Arg was significantly associated with hypertension (P < .03). Under a dominant model, for hypertension the relative risk for the Gly/Gly and Gly/Arg genotypes versus the Arg/Arg genotype was 1.35 (95% confidence limits [CL] 1.08, 1.70); for low-normal blood pressure the relative risk was 0.79 (95% CL 0.66, 0.94). This polymorphism explained approximately 1% of the variance in systolic and diastolic blood pressures in our study population. There was no evidence of association between the C-47T and Glu27Gln polymorphisms and hypertension in this population. CONCLUSIONS: The Glyl6 allele in the beta2-adrenergic receptor gene is a susceptibility allele for essential hypertension in a population of Chinese origin.

Arginine↗
PubMed2001

Fluorescence polarization in homogeneous nucleic acid analysis II: 5'-nuclease assay.

When the temperature and viscosity of the solvent is held constant, the degree of fluorescence polarization (FP) detected when a fluorescent dye is excited by plane polarized light depends mostly on the molecular weight of the dye molecule. By monitoring the FP of a fluorescent dye molecule, one can detect significant changes in the molecular weight of a fluorescent molecule without separation or purification. The 5'-nuclease (TaqMan) assay is a robust single nucleotide polymorphism genotyping method where an allele-specific probe that binds to a perfectly complementary target is cleaved by the 5'-nuclease activity of Taq DNA polymerase. Because the TaqMan probe is labeled with a fluorescent dye, it has high FP value when intact but a low FP value after cleavage. In this study, we compared the results of the 5'-nuclease assay based on standard fluorescence intensity readings and FP readings when genotyping 90 individuals with 20 single nucleotide polymorphisms. Our results show that FP is just as robust and reliable as the standard fluorescence detection method. Use of FP detection makes it possible to reduce the cost of TaqMan probes by abrogating the need for a fluorescence quencher.

Fluorescence Polarization↗
PubMed2001

High-throughput genotyping with single nucleotide polymorphisms.

To make large-scale association studies a reality, automated high-throughput methods for genotyping with single-nucleotide polymorphisms (SNPs) are needed. We describe PCR conditions that permit the use of the TaqMan or 5' nuclease allelic discrimination assay for typing large numbers of individuals with any SNP and computational methods that allow genotypes to be assigned automatically. To demonstrate the utility of these methods, we typed >1600 individuals for a G-to-T transversion that results in a glutamate-to-aspartate substitution at position 298 in the endothelial nitric oxide synthase gene, and a G/C polymorphism (newly identified in our laboratory) in intron 8 of the 11-beta hydroxylase gene. The genotyping method is accurate-we estimate an error rate of fewer than 1 in 2000 genotypes, rapid-with five 96-well PCR machines, one fluorescent reader, and no automated pipetting, over one thousand genotypes can be generated by one person in one day, and flexible-a new SNP can be tested for association in less than one week. Indeed, large-scale genotyping has been accomplished for 23 other SNPs in 13 different genes using this method. In addition, we identified three "pseudo-SNPs" (WIAF1161, WIAF2566, and WIAF335) that are probably a result of duplication.

Alleles↗
PubMed2000

Lack of evidence for an association between alpha-adducin and blood pressure regulation in Asian populations.

Recent studies have found the tryptophan allele of a glycine to tryptophan polymorphism at position 460 (G460W) of the alpha-adducin protein to be associated with essential hypertension in European populations. We examined whether the tryptophan allele is associated with hypertension in a different population, comprised of subjects of Chinese origin from Taiwan, and Chinese and Japanese origin from the San Francisco Bay area and Hawaii. We adapted the 5' allelic discrimination assay or TaqMan to type individuals for the G460W polymorphism, and using this method we typed more than 1000 individuals. The frequency of the W allele was slightly increased in the treated subjects in the Chinese population (0.458 v 0.423) but not the Japanese population (0.549 v 0.558). We considered dominant, recessive, and additive models in our analysis. There was a significant result for a recessive model for systolic blood pressure in the Chinese population (chi2 6.84, df = 2, P < .05), but only suggestive evidence for diastolic blood pressure (chi2 3.30). In contrast, in the Japanese population, there was no evidence for a positive association under any model. For the combined Chinese and Japanese samples, the evidence for association with alpha-adducin was not significant.

Adult↗
PubMed2000

Full-genome scan for linkage in 50 families segregating the bipolar affective disease phenotype.

A genome scan of approximately 12-cM initial resolution was done on 50 of a set of 51 carefully ascertained unilineal multiplex families segregating the bipolar affective disorder phenotype. In addition to standard multipoint linkage analysis methods, a simultaneous-search algorithm was applied in an attempt to surmount the problem of genetic heterogeneity. The results revealed no linkage across the genome. The results exclude monogenic models and make it unlikely that two genes account for the disease in this sample. These results support the conclusion that at least several hundred kindreds will be required in order to establish linkage of susceptibility loci to bipolar disorder in heterogeneous populations.

Bipolar Disorder↗
PubMed2000

Lack of association of the angiotensinogen-6 polymorphism with blood pressure levels in the comprehensive NHLBI Family Blood Pressure Program. National Heart, Lung and Blood Institute.

OBJECTIVE: To evaluate the association between the angiotensinogen-6 polymorphism (AGT-6) and blood pressure levels. DESIGN: Data were analysed from the first 4,322 subjects of the NHLBI Family Blood Pressure Program (FBPP), consisting of four networks (GenNet, GENOA, HyperGEN and SAPPHIRe), each conducting a multicentre observational family study to identify and characterize the genetic determinants of hypertension and blood pressure. The four studies use different designs (concordant sibpairs, discordant pairs, sibships, extended pedigrees), target different ethnic groups (Caucasian, African-American, Japanese, Chinese), and have different inclusion/exclusion criteria. However, the protocols and definitions were standardized across networks before data collection to allow maximum poolability. METHODS: Each network/racial group was analysed separately, using generalized linear models that accounted for the non-independence of family members and/or the confounding of anti-hypertensive medications as needed. The results were also pooled using a pre-planned meta-analysis technique. RESULTS: AGT-6 was not significantly associated with blood pressure in any network/racial group. In the meta-analysis, the pooled effect of AGT-6 was small [hazard ratio = 1.10, 95% confidence interval (CI) = 0.99-1.22, P= 0.0647 for systolic; hazard ratio = 1.04, 95% CI = 0.89-1.21, P= 0.6383 for diastolic]. A post-hoc analysis restricting to subjects meeting JNC VI criteria for Stage I hypertension (blood pressure > 140/90 mmHg or medicated) showed a stronger statistically significant relationship for systolic blood pressure (hazard ratio = 1.44, 95% CI = 1.04-2.00, P= 0.0283). CONCLUSIONS: AGT-6 has minimal to no effect on the inter-individual variation of blood pressure levels, and is at best a 'minor gene' for blood pressure in the population as a whole.

Adolescent↗
PubMed1996

A locus for Fanconi anemia on 16q determined by homozygosity mapping.

We report the results of a genomewide scan using homozygosity mapping to identify genes causing Fanconi anemia, a genetically heterogeneous recessive disorder. By studying 23 inbred families, we detected linkage to a locus causing Fanconi anemia near marker D16S520 (16q24.3). Although -65% of our families displayed clear linkage to D16S520, we found strong evidence (P = .0013) of genetic heterogeneity. This result independently confirms the recent mapping of the FAA gene to chromosome 16 by Pronk et al. Family ascertainment was biased against a previously identified FAC gene on chromosome 9, and no linkage was observed to this locus. Simultaneous search analysis suggested several additional chromosomal regions that could account for a small fraction of Fanconi anemia in our families, but the sample size is insufficient to provide statistical significance. We also demonstrate the strong effect of marker allele frequencies on LOD scores obtained in homozygosity mapping and discuss ways to avoid false positives arising from this effect.

Chromosome Mapping↗
PubMed1995

Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.

BACKGROUND: A gene on chromosome 9p, p16INK4, has been implicated in the pathogenesis of cutaneous malignant melanoma in 19 melanoma-prone families. In 10 of these kindreds mutations that impaired the function of the p16INK4 protein (p16M alleles) cosegregated with the disease. By contrast, in the other nine kindreds the mutation did not alter the function of p16INK4 (p16W alleles). We looked for differences in clinical and genetic epidemiologic features in these two groups of families. METHODS: We compared the median ages at diagnosis of melanoma, number of melanomas, thickness of the tumors, and number of nevi in the kindreds. We estimated prospectively the risks of melanoma or other cancers in families followed for 6 to 18 years and the risks of other cancers since 1925 (the entire period) by comparing the number of cancer cases observed with the number expected. RESULTS: The risk of invasive melanoma was increased by a factor of 75 in kindreds with p16M alleles and a factor of 38 in kindreds with p16W alleles. Although this difference was not significant (P = 0.14), there was a striking difference in the risk of other tumors. In kindreds with p16M alleles, the risk of pancreatic cancer was increased by a factor of 13 in the prospective period (2 cases observed, 0.15 expected; standardized incidence ratio, 13.1; 95 percent confidence interval, 1.5 to 47.4) and by a factor of 22 in the entire period (7 cases observed, 0.32 expected; standardized incidence ratio, 21.8; 95 percent confidence interval, 8.7 to 44.8). In contrast, we found no cases of pancreatic cancer in kindred with p16W alleles. CONCLUSIONS: The development of pancreatic cancer in kindreds prone to melanoma may require a p16M mutation. Genetic factors, such as the kind of mutation found in p16INK4, may explain the inconsistent occurrence of other cancers in these kindreds.

Adult↗
PubMed1995

Mutations associated with familial melanoma impair p16INK4 function.

Cell division is controlled by a series of positive and negative regulators which act at sequential points throughout the cell cycle. Disturbance of these checks could contribute to cancer by allowing excessive cell proliferation. The point in G1 at which cells irrevocably commit to DNA synthesis is controlled by protein complexes consisting of cyclin-dependent kinases (CDK4 or CDK6) and cyclins (D1, D2 or D3). These complexes are inhibited by low molecular weight proteins, such as p16INK4 (refs 1,2), p15INK4B (ref. 3) and p18 (ref. 4). Deletion or mutation of these CDK-inhibitors could lead to unchecked cell growth, suggesting that members of the p16INK4 family may be tumour suppressor genes. The recent detection of p16INK4 (MTS1) mutations in familial melanoma kindreds, many human tumour cell lines, and primary tumours is consistent with this idea. Previously, we described eight germline p16INK4 substitutions in 18 familial melanoma kindreds. Genetic analyses suggested that five mutations predisposed carriers to melanoma, whereas two missense mutations had no phenotypic effect. We now describe biochemical analyses of the missense germline mutations and a single somatic mutation detected in these families. Only the melanoma-predisposing mutants were impaired in their ability to inhibit the catalytic activity of the cyclin D1/CDK4 and cyclin D1/CDK6 complexes in vitro. Our data provide a biochemical rationale for the hypothesis that carriers of certain p16INK4 mutations are at increased risk of developing melanoma.

Animals↗
PubMed1993

A switch in translation mediated by an antisense RNA.

Antisense RNAs regulate expression of target genes in a variety of ways--transcription termination, translation initiation, and mRNA stability. We describe a case in which the target gene encodes two polypeptides, and antisense RNA causes a switch in its translation by selectively inhibiting synthesis of one of the polypeptides. Bacteriophage P22 is a temperate Salmonella phage; in the prophage state it expresses only a handful of its genes. One of these genes, sieB, aborts the lytic development of some phages. P22 itself is insensitive to the lethal effect of SieB because it harbors a determinant called esc. We show that the sieB gene encodes two polypeptides--SieB, which is the exclusion protein, and Esc, which is a truncated version of SieB that inhibits its action. Superinfecting P22 synthesizes an antisense RNA, sas, that inhibits synthesis of SieB but allows continued synthesis of Esc, thus allowing P22 to bypass SieB-mediated exclusion. This translational switch induced by sas RNA is essential to vegetatively developing P22; a mutation that prevents this switch causes P22 to commit SieB-mediated suicide. Finally, we show that P22's Esc allows it to circumvent the SieB-mediated exclusion system of bacteriophage lambda.

Bacteriolysis↗
PubMed1993

Superinfection exclusion (sieB) genes of bacteriophages P22 and lambda.

The superinfection exclusion gene (sieB) of Salmonella phage P22 was mapped with phage deletion mutants. The DNA sequence in the region was reexamined in order to find an open reading frame consistent with the deletion mapping. Several discrepancies with the previously published sequence were discovered. The revised sequence revealed a single open reading frame of 242 codons with six likely translation initiation codons. On the basis of deletion and amber mutant phenotypes, the second of these six sites was inferred to be the translation initiation site of the sieB gene. The sieB gene encodes a polypeptide with 192 amino acid residues with a calculated molecular weight of 22,442, which is in reasonable agreement with that estimated from polyacrylamide gels. The transcription start site of sieB was identified by the use of an RNase protection assay. The sieB promoter thus identified was inactivated by a 2-base substitution in its -10 hexamer. The sieB gene of coliphage lambda was also identified. The promoter for lambda sieB was identified by homology to that of P22 sieB.

Amino Acid Sequence↗