Showing papers by "Nilesh J. Samani published in 2006"

Two-dimensional genome-scan identifies novel epistatic loci for essential hypertension

Abstract: It is well established that gene interactions influence common human diseases, but to date linkage studies have been constrained to searching for single genes across the genome. We applied a novel approach to uncover significant gene-gene interactions in a systematic two-dimensional (2D) genome-scan of essential hypertension. The study cohort comprised 2076 affected sib-pairs and 66 affected half-sib-pairs of the British Genetics of HyperTension study. Extensive simulations were used to establish significance thresholds in the context of 2D genome-scans. Our analyses found significant and suggestive evidence for loci on chromosomes 5, 9, 11, 15, 16 and 19, which influence hypertension when gene-gene interactions are taken into account (5q13.1 and 11q22.1, two-locus lod score=5.72; 5q13.1 and 19q12, two-locus lod score=5.35; 9q22.3 and 15q12, two-locus lod score=4.80; 16p12.3 and 16q23.1, two-locus lod score=4.50). For each significant and suggestive pairwise interaction, the two-locus genetic model that best fitted the data was determined. Regions that were not detected using single-locus linkage analysis were identified in the 2D scan as contributing significant epistatic effects. This approach has discovered novel loci for hypertension and offers a unique potential to use existing data to uncover novel regions involved in complex human diseases.

Chromosome 2p Shows Significant Linkage to Antihypertensive Response in the British Genetics of Hypertension Study

Abstract: There is a lack of consistently linked loci influencing blood pressure and hypertension status, and this may be because of genetic or phenotypic heterogeneity. We hypothesize that stratification of subjects by response to antihypertensive drug groups could be used to stringently define subsets that will have reduced genetic and etiologic heterogeneity, by partitioning contrasting mechanisms of hypertension and, thus, enhancing gene finding. We investigated the British Genetics of Hypertension Study population, which is composed of 2142 severely hypertensive white affected sibling pairs. Nonresponse to antihypertensive therapy was defined as an on-treatment blood pressure of >140/90 mm Hg or a difference between prediagnosis and on-treatment blood pressure of P =0.005). This locus may contain a gene for the salt-sensitive form of hypertension and/or a pharmacogenetic locus affecting drug response. We have demonstrated for the first time identification of a significant locus by partitioning different pathways of hypertension using drug response.

Increased support for linkage of a novel locus on chromosome 5q13 for essential hypertension in the british genetics of hypertension study

Abstract: Human hypertension arises from a combination of genetic factors and lifestyle influences. With cardiovascular disease set to become the number 1 cause of death worldwide, it is important to understand the etiologic mechanisms for hypertension, because these might provide new routes to improved treatment. The British Genetics of Hypertension Study has recently published a primary genome screen that identified 4 chromosomal regions of interest. We have now genotyped additional markers to confirm the most promising regions for follow-up studies. Thirty-four additional microsatellites were genotyped in our severely hypertensive affected sibling pair resource (now 1635 families with 2142 affected sibling pairs), leading to a substantial increase in information content in the regions of interest. We found increased support for linkage of chromosome 5q13 to human hypertension (multipoint logarithm of odds=2.50) with 3 adjacent markers yielding single point logarithm of odds scores of 3.22, 2.84, and 2.51. The placement of additional markers on 2q, 6q, and 9q diminished support for linkage in these regions. However, the addition of new data and families identified novel regions of interest on chromosomes 1q and 11q. The 3 positive markers in the chromosome 5 region were also genotyped in 712 distinct parent-offspring trios with the same severe phenotype to replicate linkage and association. Borderline support for replication was found (P=0.07). We found increased evidence for linkage and borderline-significant evidence for association for a hypertension susceptibility locus on chromosome 5q13 that is worthy of detailed fine mapping and assessment of candidate genes.

Linkage Analysis Using Co-Phenotypes in the BRIGHT Study Reveals Novel Potential Susceptibility Loci for Hypertension

Abstract: Identification of the genetic influences on human essential hypertension and other complex diseases has proved difficult, partly because of genetic heterogeneity. In many complex-trait resources, additional phenotypic data have been collected, allowing comorbid intermediary phenotypes to be used to characterize more genetically homogeneous subsets. The traditional approach to analyzing covariate-defined subsets has typically depended on researchers’ previous expectations for definition of a comorbid subset and leads to smaller data sets, with a concomitant attrition in power. An alternative is to test for dependence between genetic sharing and covariates across the entire data set. This approach offers the advantage of exploiting the full data set and could be widely applied to complex-trait genome scans. However, existing maximum-likelihood methods can be prohibitively computationally expensive, especially since permutation is often required to determine significance. We developed a less computationally intensive score test and applied it to biometric and biochemical covariate data, from 2,044 sibling pairs with severe hypertension, collected by the British Genetics of Hypertension (BRIGHT) study. We found genomewide-significant evidence for linkage with hypertension and several related covariates. The strongest signals were with leaner-body-mass measures on chromosome 20q (maximum LOD=4.24) and with parameters of renal function on chromosome 5p (maximum LOD=3.71). After correction for the multiple traits and genetic locations studied, our global genomewide P value was .046. This is the first identity-by-descent regression analysis of hypertension to our knowledge, and it demonstrates the value of this approach for the incorporation of additional phenotypic information in genetic studies of complex traits.

Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin.

Abstract: Objective To determine whether the response to angiotensin-converting enzyme inhibitor (ACEI) monotherapy in subjects of African origin is determined by genetic variants within the angiotensinogen (AGT) gene. Methods A total of 194 hypertensive patients of African ancestry were recruited from district clinics in Johannesburg, South Africa. Eighty patients received open-label ACEI (enalapril or lisinopril) monotherapy, and 114 open-label calcium antagonist (nifedipine) as a drug class comparator. Twenty-four hour ambulatory blood pressure (ABP) monitoring was performed at baseline (off medication) and after 2 months of therapy. DNA was analysed for functional variants (-217G→A and -20A→C) of the AGT gene. The impact of genotype on ABP responses to ACEI monotherapy or calcium antagonists; and on plasma aldosterone and renin levels after ACEI monotherapy was assessed. Results Adjusting for baseline ABP and type of ACEI in the ACEI-treated group, the -217G→A variant predicted ABP responses to ACEI (n = 77; P<0.01), but not to nifedipine (n = 108). ACEI in patients with the AA genotype of the -217G→A variant failed to elicit an antihypertensive response [change in ABP, mmHg: systolic blood pressure (SBP) +0.84 ± 2.89, P = 0.78; diastolic blood pressure (DBP) -0.47 ± 1.74, P = 0.79]. In contrast, those patients with at least one copy of the -217G allele developed a 7.23 ± 1.55 and 5.38 ± 1.12 mmHg decrease (P < 0.0001) in SBP and DBP, respectively, after ACEI administration. Similarly, the -20A→C variant predicted ABP responses to ACEI monotherapy (P<0.01) but not to nifedipine. Moreover, patients who were AA genotype for both variants failed to develop an antihypertensive response to ACEI (change in ABP, mmHg: SBP +1.06 ± 3.05, P = 0.73; DBP -0.39 ± 1.83, P = 0.83); whereas patients with at least one copy of both the -217G and the -20C allele developed substantial decreases in ABP (change in ABP, mmHg: SBP -14.08 ± 3.72, P<0.0001; DBP -9.62 ± 2.74, P<0.0001). Patients with at least one copy of the -217G allele demonstrated a significant reduction in the aldosterone-to-renin ratio (-0.098 ± 0.035, P<0.01), whereas in those patients who were -217AA genotype the ratio was unchanged (-0.03 ± 0.16, P = 0.85). Conclusion Functional variants of the AGT gene contribute to the variability of antihypertensive responses to ACEI monotherapy in individuals of African ancestry, with genotype determining whether or not responses occur.

Cerebral critical closing pressure estimation from Finapres and arterial blood pressure measurements in the aorta

Abstract: Estimates of cerebral critical closing pressure (CrCP) and resistance–area product (RAP) are often derived using noninvasive measurements of arterial blood pressure (ABP) in the finger, but the errors introduced by this approach, in relation to intra-vascular measurements of ABP, are not known. Continuous recordings of ABP (Finapres and solid-state catheter-tip transducer in the ascending aorta), cerebral blood flow velocity (CBFV, bilateral Doppler), ECG and transcutaneous CO2 were performed following coronary catheterization. CrCP and RAP were calculated for each of 12 784 cardiac cycles from 27 subjects using the classical linear regression (LR) of the instantaneous CBFV–ABP relationship and also the first harmonic (H1) of the Fourier transform. There was a better agreement between LR and H1 for the aortic measurements than for the Finapres (p < 0.000 01). For LR there were no significant differences for either CrCP or RAP due to the source of ABP measurement, but for H1 the differences were highly significant (p < 0.000 03). The coherence functions between either CrCP or RAP values calculated with aortic pressure (input) or the Finapres (output) were significantly higher for H1 than for LR for most harmonics below 0.2 Hz. When using the Finapres to estimate CrCP and RAP values, the LR method produces similar results to intra-arterial measurements of ABP for time-averaged values, but H1 should be preferred in applications analysing beat-to-beat changes in these parameters.