Showing papers by "Nilesh J. Samani published in 2005"

Mapping of a Major Locus that Determines Telomere Length in Humans

Abstract: Telomere length is a crucial factor for both normal chromosomal function and senescence. Mean telomere length in humans shows considerable interindividual variation and strong genetic determination. To see if a locus (or loci) affecting telomere length in humans could be mapped, we performed a quantitative-trait linkage analysis of mean leukocyte telomere-restriction–fragment (TRF) lengths, measured by Southern blotting, in 383 adult subjects comprising 258 sib pairs. Heritability of mean (±SE) TRF was 81.9%±11.8%. There was significant linkage (LOD score 3.20) of mean TRF length to a locus on chromosome 12, which explained 49% of the overall variability in mean TRF length. We present preliminary analysis of a strong candidate gene in the region, the DNA helicase DDX11. In conclusion, we report mapping of the first locus that determines mean telomere length in humans. Identification of the gene involved and elucidation of its mechanism of action could have important implications for our understanding of chromosomal assembly, telomere biology, and susceptibility to age-related diseases.

Left atrial radiofrequency ablation during mitral valve surgery for continuous atrial fibrillation: a randomized controlled trial.

Abstract: ContextAlthough left atrial radiofrequency ablation (RFA) is increasingly used for the treatment of chronic atrial fibrillation during mitral valve surgery, its efficacy to restore sinus rhythm and any resulting benefits have not been examined in the context of an adequately powered randomized trial.ObjectiveTo determine whether intraoperative RFA of the left atrium increases the long-term restoration of sinus rhythm and improves exercise capacity.Design, Setting, and PatientsRandomized, double-blind trial performed in a single UK tertiary referral center with enrollment between December 2001 and November 2003. A total of 101 patients referred for mitral valve surgery with at least 6 months’ history of uninterrupted atrial fibrillation were assessed for eligibility; 97 were enrolled. Patients were followed up for 12 months.InterventionPatients were randomly assigned to undergo mitral valve surgery and RFA of the left atrium (n = 49) or mitral valve surgery alone (controls; n = 48).Main Outcome MeasuresThe primary outcome measure was presence of sinus rhythm at 12 months; secondary measures were patient functional status and exercise capacity (assessed by shuttle-walk test), left atrial contractility, and left atrial and left ventricular dimension and function and plasma levels of B-type natriuretic peptide.ResultsAt 12 months, sinus rhythm was present in 20 (44.4%) of 45 RFA patients and in 2 (4.5%) of 44 controls (rate ratio, 9.8; 95% CI, 2.4-86.3; P<.001). Restoration of sinus rhythm in the RFA group was accompanied by a greater improvement in mean (SD) shuttle-walk distance compared with controls (+94 [102] m vs +48 [82] m; P = .003) and a greater reduction in the plasma level of B-type natriuretic peptide (−104 [87] fmol/mL vs −51 [82] fmol/mL; P = .03). Patients randomized to receive RFA had similar rates of postoperative complications and deaths as control patients.ConclusionsRadiofrequency ablation of the left atrium during mitral valve surgery for continuous atrial fibrillation significantly increases the rate of sinus rhythm restoration 1 year postoperatively, improving patient exercise capacity. On the basis of its efficacy and safety, routine use of RFA of the left atrium during mitral valve surgery may be justified.Trial RegistrationClinicalTrials.gov Identifier: NCT00238706.

Association of WNK1 Gene Polymorphisms and Haplotypes With Ambulatory Blood Pressure in the General Population

Abstract: Background—Blood pressure (BP) is a heritable trait of major public health concern. The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis. Mutations in the WNK1 and WNK4 genes cause a rare monogenic hypertensive syndrome, pseudohypoaldosteronism type II. We investigated whether polymorphisms in these WNK genes influence BP in the general population. Methods and Results—Associations between 9 single-nucleotide polymorphisms (SNPs) in WNK1 and 1i nWNK4 with ambulatory BP were studied in a population-based sample of 996 subjects from 250 white European families. The heritability estimates of mean 24-hour systolic BP (SBP) and diastolic BP (DBP) were 63.4% and 67.9%, respectively. We found statistically significant (P0.05) associations of several common SNPs and haplotypes in WNK1 with mean 24-hour SBP and/or DBP. The minor allele (C) of rs880054, with a frequency of 44%, reduced mean 24-hour SBP and DBP by 1.37 (95% confidence interval, 2.45 to 0.23) and 1.14 (95% confidence interval, 1.93 to 0.38) mm Hg, respectively, per copy of the allele. Conclusions—Common variants in WNK1 contribute to BP variation in the general population. This study shows that a gene causing a rare monogenic form of hypertension also plays a significant role in BP regulation in the general population. The findings provide a basis to identify functional variants of WNK1, elucidate any interactions of these variants with dietary intake or with response to antihypertensive drugs, and determine their impact on cardiovascular morbidity and mortality. (Circulation. 2005;112:3423-3429.)

A genomewide linkage study of 1,933 families affected by premature coronary artery disease: The British Heart Foundation (BHF) Family Heart Study.

Abstract: Coronary artery disease (CAD) and its most important complication, myocardial infarction (MI), are the leading cause of premature death in the Western world. CAD has a substantial genetic basis, especially when it occurs early. We investigated the genetic determinants of premature CAD by performing a genomewide linkage analysis of 4,175 affected subjects from 1,933 families recruited throughout the United Kingdom. Each family had at least two available siblings with CAD, with validated onset before age 66 years. Linkage analysis was performed using 416 microsatellite markers. We observed suggestive linkage, for both CAD and MI, to a region on chromosome 2. For CAD, a LOD score of 1.86 was observed at marker D2S2271, which, in an ordered subset analysis, increased to 2.70 in families (n=1,698) with a minimum age at diagnosis of 56 years or younger. For MI, an overlapping peak with a LOD score of 1.15 was observed at marker D2S2216, which increased to 2.1 in families (n=801) with a minimum age at diagnosis of 59 years or younger. Exclusion mapping showed that 100% of the autosomal genome could be excluded for locus-specific sibling relative risks of 1.5 and 1.6 for CAD and MI, respectively. The region identified on chromosome 2 overlaps linked regions observed in two other smaller genome scans for CAD. Together, these findings strongly suggest that there is a locus on chromosome 2 that influences coronary atherosclerosis risk. The exclusion of a common locus that increases risk of CAD to siblings by >50% has important implications for strategies for further defining the genetic basis of CAD

Haplotypes of the WNK1 gene associate with blood pressure variation in a severely hypertensive population from the British Genetics of Hypertension study

Abstract: Mutations in the WNK1 gene cause Gordon’s syndrome, a rare Mendelian form of hypertension. We assessed whether common WNK1 variants might also contribute to essential hypertension (EH), a multifactorial disorder affecting >25% of the adult population worldwide. A panel of 19 single nucleotide polymorphisms (SNPs) spanning the gene was selected from public databases and was genotyped in 100 white European families to determine the pattern of linkage disequilibrium, haplotype structure and tagging SNPs for the WNK1 locus. Eight tagging SNPs were identified with 90% power to predict common WNK1 haplotypes and SNPs. Family-based association tests were used to test for association with EH and severity of hypertension in 712 severely hypertensive families from the MRC British Genetics of Hypertension study resource. No association was found between WNK1 polymorphisms or haplotypes with hypertension; however, one SNP rs1468326, located 3 kb from the WNK1 promoter, was found to be nominally associated with severity of hypertension, with both systolic blood pressure (BP) (Z 51 2.24, P 5 0.025) and diastolic BP (Z 51 1.99, P 5 0.046). We also found nominal support for association of one common WNK1 haplotype with increased systolic BP (Z 51 1.91, P 5 0.053). This is the first study to perform haplotype association analysis of the WNK1 gene with EH. This finding of association between a SNP near the promoter region and the severity of hypertension suggests that increased expression of WNK1 might contribute to BP variability and susceptibility to EH similar to the mechanism of hypertension observed in Gordon’s syndrome.

A genome-wide survey demonstrates widespread non-linear mRNA in expressed sequences from multiple species.

Abstract: We describe here the results of the first genome-wide survey of candidate exon repetition events in expressed sequences from human, mouse, rat, chicken, zebrafish and fly. Exon repetition is a rare event, reported in <10 genes, in which one or more exons is tandemly duplicated in mRNA but not in the gene. To identify candidates, we analysed database sequences for mRNA transcripts in which the order of the spliced exons does not follow the linear genomic order of the individual gene [events we term rearrangements or repetition in exon order (RREO)]. Using a computational approach, we have identified 245 genes in mammals that produce RREO events. RREO in mRNA occurs predominantly in the coding regions of genes. However, exon 1 is never involved. Analysis of the open reading frames suggests that this process may increase protein diversity and regulate protein expression via nonsense-mediated RNA decay. The sizes of the exons and introns involved around these events suggest a gene model structure that may facilitate non-linear splicing. These findings imply that RREO affects a significant subset of genes within a genome and suggests that non-linear information encoded within the genomes of complex organisms could contribute to phenotypic variation.

Mitral valve repair for active culture positive infective endocarditis

Abstract: Objective: To describe the clinical and echocardiographic outcome after mitral valve (MV) repair for active culture positive infective MV endocarditis. Patients and methods: Between 1996 and 2004, 36 patients (mean (SD) age 53 (18) years) with positive blood culture up to three weeks before surgery (or positive culture of material removed at operation) and intraoperative evidence of endocarditis underwent MV repair. Staphylococci and streptococci were the most common pathogens. All patients had moderate or severe mitral regurgitation (MR). Mean New York Heart Association (NYHA) class was 2.3 (1.0). Follow up was complete (mean 38 (19) months). Results: Operative mortality was 2.8% (one patient). At follow up, endocarditis has not recurred. One patient developed severe recurrent MR and underwent valve replacement and one patient had moderate MR. There were two late deaths, both non-cardiac. Kaplan-Meier five year freedom from recurrent moderate to severe MR, freedom from repeat operation, and survival were 94 (4)%, 97 (3)%, and 93 (5)%, respectively. At the most recent review the mean NYHA class was 1.17 (0.3) (p Conclusions: MV repair for active culture positive endocarditis is associated with low operative mortality and provides satisfactory freedom from recurrent infection, freedom from repeat operation, and survival. Hence, every effort should be made to repair infected MVs and valves should be replaced only when repair is not possible.

Mapping of genetic determinants of the sympathoneural response to stress

Abstract: Activation of the sympathoadrenal system (SAS, comprising the sympathetic nervous system and the adrenal medulla) in response to stressful stimuli is an important defense mechanism as well as a con...