Showing papers by "Nilesh J. Samani published in 2007"

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

Genomewide association analysis of coronary artery disease.

Abstract: A b s t r ac t Background Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. Methods We first identified chromosomal loci that were strongly associated with coronary ar- tery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI (Myocardial Infarction) Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single- nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). Conclusions We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Abstract: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.

Plasma matrix metalloproteinase-9 and left ventricular remodelling after acute myocardial infarction in man: a prospective cohort study

Abstract: Aim To describe temporal profiles of plasma matrix metalloproteinases (MMP-2 and MMP-9), and their relationship with echocardiographic (Echo) parameters of left ventricular (LV) function and remodelling, after acute myocardial infarction (AMI) in man. Methods and results Plasma MMP-2 and MMP-9 were assayed at intervals (0–12, 12–24, 24–48, 48–72, 72–96, and > 96 h) in 91 patients with AMI (ST-elevation/non-ST-elevation 77/24; 73% male; 40% anterior site) and on a single occasion in 172 age- and sex-matched control subjects with stable coronary artery disease. Echo assessment of LV volumes, LV ejection fraction (LVEF), and wall motion index score were assessed before discharge and at follow-up (median 176, range 138–262 days) for patients and on a single occassion in controls. Plasma MMP-2 was similar at all times after AMI, elevated when compared with control ( P = 0.005–0.001) and unrelated to LV function or volume during index admission or at follow-up. Maximal MMP-9 was seen at 0–12 h and was elevated when compared with control ( P = 0.002) followed by fall to a plateau. Both maximal and plateau MMP-9 concentration correlated with white blood cell (WBC, P = 0.023 to < 0.001) and neutrophil count ( P = 0.014 to < 0.001). Maximal MMP-9 had independent predictive value for lower LVEF ( P = 0.004) during admission and for greater change in LV end-diastolic volume between admission and follow-up ( R = 0.3, P = 0.016). In contrast, higher plateau levels of MMP-9 were associated with relative preservation of LV function (increasing LVEF, P = 0.002; decreasing WMIS, P = 0.009) and less change in end-systolic volume and end-diastolic volumes after discharge ( P = 0.001 and 0.024, respectively). Conclusion Both MMP-9 and MMP-2 are elevated following AMI. The biphasic profile of plasma MMP-9 is related to LV remodelling and function following AMI in man. Higher early levels of MMP-9 associate with the extent of LV remodelling and circulating WBC levels. In contrast, higher plateau levels later after AMI are associated with relative preservation of LV function. Temporal profile, rather than absolute magnitude, of MMP-9 activity appears to be important for LV remodelling after AMI.

Telomere length is shorter in healthy offspring of subjects with coronary artery disease: support for the telomere hypothesis

Abstract: Background: Telomeres are shorter in subjects with coronary artery disease (CAD) and may indicate premature biological ageing However, whether shorter telomeres are a primary abnormality or secondary to the disease is unclear Objective: To investigate whether shorter telomeres are a primary abnormality or secondary to CAD, telomere lengths in healthy young adults with contrasting familial risk of CAD were compared Design: Case–control study Methods: Mean telomere restriction fragment (TRF) length in DNA from circulating leucocytes was determined by Southern blotting in 45 healthy offspring of subjects with premature CAD (case offspring) and 59 offspring from families without such a history (control offspring) Correlation in mean TRF length was also assessed in 67 offspring–parent pairs Results: On average, a decrease of 275 (107) bp in mean TRF per year of age was found The unadjusted mean TRF length was 634 kb (95% CI 613 to 655) for case offspring and 675 kb (95% CI 657 to 694) for offspring of controls (p = 0004) The adjusted difference in mean TRF between case and control offspring was 472 bp (95% CI 253 to 691, p r = 037, p = 0002) Conclusion: These findings suggest that inheritance of shorter telomeres is associated with increased familial risk of CAD They support the hypothesis that telomere length is a primary abnormality involved in the pathogenesis of CAD

Influence of noninvasive peripheral arterial blood pressure measurements on assessment of dynamic cerebral autoregulation

Abstract: Assessment of dynamic cerebral autoregulation (CA) requires continuous recording of arterial blood pressure (ABP). In humans, noninvasive ABP recordings with the Finapres device have often been used for this purpose. We compared estimates of dynamic CA derived from Finapres with those from invasive recordings in the aorta. Measurements of finger noninvasive ABP (Finapres), intra-aortic ABP (Millar catheter), surface ECG, transcutaneous CO2, and bilateral cerebral blood flow velocity (CBFV) in the middle cerebral arteries were simultaneously and continuously recorded in 27 patients scheduled for percutaneous coronary interventions. Phase, gain, coherence, and CBFV step response from both the Finapres and intra-arterial catheter were estimated by transfer function analysis. A dynamic autoregulation index (ARI) was also calculated. For both hemispheres, the ARI index and the CBFV step response recovery at 4 s were significantly greater for the Finapres-derived estimates than for the values obtained from aortic pressure. The transfer function gain for frequencies 0.1 Hz, but not at lower frequencies. The Finapres gives higher values for the efficiency of dynamic CA compared with values derived from aortic pressure measurements, as indicated by biases in the ARI index, CBFV step response, gain, and phase. Despite the significance of these biases, their relatively small amplitude indicates a good level of agreement between indexes of CA derived from the Finapres compared with corresponding estimates obtained from invasive measurements of aortic ABP.

The effect of preoperative atrial fibrillation on survival following mitral valve repair for degenerative mitral regurgitation.

Abstract: Objective: There is conflictingevidence with regardto the impact of preoperative atrialfibrillation(AF) on the post mitral valve (MV) repair on the early and late outcome. Methods: A total of 349 patients undergoing various MVrepair procedures for degenerative mitral regurgitation (MR) between 1997and 2003were studied.Preoperatively, 152(44%) of these patientswere in AF and 197(56%) patientswere in sinusrhythm (SR).The clinical features and the outcome in these two cohorts of patients were compared. Results: The patients in the AF group were older than their counterparts in the SR group (66 7v s 62 9 years) (p = 0.01), had a higher mean NYHA class score (2.4 0.6 vs 2.2 0.7) (p = 0.04) and were more likely to have impaired left ventricular function (60% vs 36%) (p < 0.0001). A similar proportion of patients in the AF (38%) and SR (30%) groups had additional cardiac surgical procedures (p = 0.12). Operative mortality was 3.9% in AF group versus 0.5% in SR group (p = 0.04), and operative morbidity was 27% versus 17%, respectively (p = 0.03). At latest follow up, 4% of patients that were in SR preoperatively developed AF; conversely, 2% of the patients in the AF group converted to SR. The rates of recurrent grade II or III MR (4% vs 5%) (p = 0.8) and MV re-operation (2.6% vs 2.5%) (p = 1.0) were similar in the AF and SR groups. Kaplan—Meier survival at 7 years was 75 6% versus 90 3% (p = 0.005). On Cox proportional hazards regression model, impaired LV function [(p = 0.02), hazard ratio 0.25 (95% confidence intervals (C.I.) 0.078—0.84)] and AF [(p = 0.03), hazard ratio 2.70 (95% C.I. 1.09—6.68)] were significant adverse predictors of survival. Conclusions: This study shows that in patients undergoing MV repair for degenerative MR, preoperative AF has a major negative impact on the early and late survival. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.

Genetic Dissection of a Blood Pressure Quantitative Trait Locus on Rat Chromosome 1 and Gene Expression Analysis Identifies SPON1 as a Novel Candidate Hypertension Gene

Abstract: A region with a major effect on blood pressure (BP) is located on rat chromosome 1. We have previously isolated this region in reciprocal congenic strains (WKY.SHR-Sa and SHR.WKY-Sa) derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY) and shown that there are 2 distinct BP quantitative trait loci, BP1 and BP2, in this region. Sisa1, a congenic substrain from the SHR.WKY-Sa animals carrying an introgressed segment of 4.3Mb, contains BP1. Here, we report further dissection of BP1 by the creation of 2 new mutually exclusive congenic substrains (Sisa1a and Sisa1b) and interrogation of candidate genes by expression profiling and targeted transcript sequencing. Only 1 of the substrains (Sisa1a) continued to demonstrate a BP difference but with a reduced introgressed segment of 3Mb. Exonic sequencing of the 20 genes located in the Sisa1a region did not identify any major differences between SHR and WKY. However, microarray expression profiling of whole kidney samples and subsequent quantitative RT-PCR identified a single gene, Spon1 that exhibited significant differential expression between the WKY and SHR genotypes at both 6 and 24 weeks of age. Western blot analysis confirmed an increased level of the Spon1 gene product in SHR kidneys. Spon1 belongs to a family of genes with antiangiogenic properties. These findings justify further investigation of this novel positional candidate gene in BP control in hypertensive rat models and humans.

Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency.

Abstract: The −344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11β-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11β-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the −344 and intron conversion variants. Eighty-three variants associated with −344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (−1889 G/T and −1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the −1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11β-hydroxylase efficiency. A similar pattern was observed for the −1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11β-hydroxylase efficiency associated previously with the CYP11B2 −344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.

Complementary intron sequence motifs associated with human exon repetition: a role for intragenic, inter-transcript interactions in gene expression

Abstract: Motivation: Exon repetition describes the presence of tandemly repeated exons in mRNA in the absence of duplications in the genome. The regulation of this process is not fully understood. We therefore investigated the entire flanking intronic sequences of exons involved in exon repetition for common sequence elements. Results: A computational analysis of 48 human single exon repetition events identified two common sequence motifs. One of these motifs is pyrimidine-rich and is more common in the upstream intron, whilst the other motif is highly enriched in purines and is more common in the downstream intron. As the two motifs are complementary to each other, they support a model by which exon repetition occurs as a result of trans-splicing between separate pre-mRNA transcripts from the same gene that are brought together during transcription by complementary intronic sequences. The majority of the motif instances overlap with the locations of mobile elements such as Alu elements. We explore the potential importance of complementary intron sequences in a rat gene that undertakes natural exon repetition in a strain specific manner. The possibility that distant complementary sequences can stimulate inter-transcript splicing during transcription suggests an unsuspected new role for potential secondary structures in endogenous genes. Availability: Contact: rd67@le.ac.uk Supplementary information: Supplementary data are available at Bioinformatics online.

Phenotypic consequences of variation across the aldosterone synthase and 11-beta hydroxylase locus in a hypertensive cohort: data from the MRC BRIGHT Study.

Abstract: Summary Background Aldosterone is an important cardiovascular hormone; 15% of hypertensive subjects have alteration in aldosterone regulation, defined by a raised ratio of aldosterone to renin (ARR). Studies of the aldosterone synthase gene (CYP11B2) have focused on a single nucleotide polymorphism in the 5′promoter region (–344 C/T). In normotensive subjects, the T allele associates with raised levels of the 11-deoxysteroids, deoxycorticosterone and 11-deoxycortisol which are substrates for 11β-hydroxylase, encoded by the adjacent and homologous gene, CYP11B1. We have speculated that this altered 11β-hydroxylase efficiency leads to increased ACTH drive to the adrenal gland to maintain cortisol production and reported herein the association between the –344 C/T single nucleotide polymorphism (SNP) and adrenal steroid production in subjects with essential hypertension. Methods The CYP11B2–344 C/T polymorphism was genotyped and urinary excretion of adrenal steroid metabolites was measured (by GCMS) in 511 unrelated hypertensives from the Medical Research Council (MRC) British Genetics of Hypertension (BRIGHT) study. Results Thirty-five per cent of subjects were homozygous for the –344T allele whilst 16% were CC homozygotes. There was no difference in cortisol excretion rate between the two genotype groups but the index of adrenal 11β-hydroxylation (ratio of tetrahydrodeoxycortisol/total cortisol) was significantly higher in the TT group (P < 0·005) than in the CC group. Excretion rates of the major urinary metabolite of aldosterone (tetrahydroaldosterone) correlated strongly with the ACTH-regulated steroids, cortisol (r = 0·437, P < 0·0001) and total androgen metabolites (r = 0·4, P < 0·0001) in TT but not CC subjects. Conclusions Hypertensives homozygous for the –344 T allele of CYP11B2 demonstrate altered 11β-hydroxylase efficiency (CYP11B1); this is consistent with the hypothesis of a genetically determined increase in adrenal ACTH drive in these subjects. The correlation between excretion of aldosterone and cortisol metabolites and suggests that, in TT subjects, ACTH exerts an important common regulatory influence on adrenal corticosteroid production in subjects with hypertension.

Images in cardiovascular medicine. Lipomatous metaplasia in ischemic cardiomyopathy: a common but unappreciated entity.

Abstract: A 68-year-old man with a 14 year prior history of anterior myocardial infarction was referred for viability assessment. He had established 3-vessel coronary artery disease with a proximally occluded left anterior descending coronary artery. He complained of worsening shortness of breath and diminishing exercise tolerance. Cardiac magnetic resonance imaging demonstrated a nondilated left ventricle with minor aneurysmal transformation that affected the mid-anterior wall and …

Variations in captopril formulations used to treat children with heart failure: a survey in the United kingdom.

Abstract: Background and objective: Different liquid formulations of a drug prepared for use in children cannot be assumed to have therapeutic equivalence. The objective of this study was to ascertain the interhospital constancy of unlicensed liquid captopril formulations used to treat children with heart failure in the UK. Design: A questionnaire-based telephone survey. Setting: 13 tertiary paediatric cardiac centres in the UK and 13 large hospitals referring patients to these centres. Participants: The study included pharmacists responsible for providing the pharmaceutical input to children with congenital heart disease or a pharmacist designated to cover paediatric services. Technical staff employed by “specials” manufacturers also participated. Results: Four hospitals dispensed captopril tablets for crushing and dissolving in water before administration; the remaining 22 used nine different liquid formulations of captopril. Only three cardiac centres and their referring hospitals were found to be using the same liquid captopril formulations; 10 centres and their referring hospitals were using completely different captopril formulations. Conclusions: This survey shows that paediatric cardiac centres and their referring hospitals use a variety of unlicensed liquid captopril formulations interchangeably. This degree of inconsistency raises issues about optimal captopril dosing and potential toxicity, such that its use may influence paediatric cardiac surgical and interventional outcomes.

Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction

Abstract: This paper was published as Clinical Science, 2007, 112 (7), pp. 411-416. It is available from http://www.clinsci.org/cs/112/cs1120411.htm. Doi: 10.1042/CS20060271

Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential hypertension

Abstract: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and was previously found to be associated with hypertension, obesity and type 2 diabetes in a cohort of British diabetic families presenting features of the metabolic syndrome. In particular, a haplotype of three genetic polymorphisms (rs2276047, rs9886 and an insertion/deletion polymorphism in intron 1) was found to be strongly associated with increased susceptibility to hypertension. To assess if INPPL1 variants play a direct role in the development of essential hypertension, we genotyped the three previously associated INPPL1 polymorphisms in a cohort of 712 severely hypertensive TDT families from the BRIGHT study. We found no evidence of significant association between hypertension and any of the three INPPL1 polymorphisms or haplotypes (p > 0.1). These results suggest that INPPL1 variants may be involved in mechanisms causing hypertension specifically in the context of the metabolic syndrome.

Enhanced linkage of a locus on chromosome 2 to premature coronary artery disease in the absence of hypercholesterolemia

Abstract: Linkage studies of complex diseases have so far had limited success in producing significant and replicable results, in part owing to genetic heterogeneity. We recently reported the results of a large genome-wide linkage scan for coronary artery disease (CAD) based on 1933 families. The greatest evidence for linkage was to a region of chromosome 2, with a logarithm of odds (LOD) score of 1.86, based on the non-parametric SALL statistic, which did not reach genome-wide significance (P>0.3). Inclusion of a covariate in linkage analysis can be a powerful method of accounting for disease heterogeneity. As CAD is a heterogeneous disease, we carried out a linkage analysis of chromosome 2 incorporating covariates. Increased evidence for linkage was found when hypercholesterolemia was considered (LOD score including covariate of 4.4) reaching genome-wide significance as assessed by simulation (P=0.04). Results showed that the original evidence for linkage was largely attributable to the subset of 108 non-hypercholesterolemic affected sibling pairs. In separate linkage analyses of subsets of hypercholesterolemic and non-hypercholesterolemic sibling pairs, the maximum LOD scores were 1.09 in the former group and 3.74 in the latter. This result illustrates the potential to increase the power of linkage analysis in the presence of heterogeneity by inclusion of covariates. This linked locus on chromosome 2 should now be investigated further to identify the gene(s) influencing risk of CAD in subjects with a normal level of total cholesterol. Candidate genes include the interleukin 1 cluster and two potential regulators of high-density lipoprotein cholesterol level, PLA2R1 and OSBPL6.

Transient drifts between Finapres and continuous intra-aortic measurements of blood pressure.

Abstract: Objectives The accuracy of noninvasive measurements of arterial blood pressure (BP), in comparison to intra-arterial recordings, is normally quantified by the bias, which is usually assumed to be a constant parameter. We tested the hypothesis that continuous beat-to-beat differences are not random and aimed to describe the temporal pattern of any transient drifts. Methods Forty participants were studied after undergoing elective cardiac catheterization. Continuous recordings of noninvasive finger BP (Finapres), intra-aortic BP (Millar catheter-tip transducer) and electrocardiogram were carried out for two periods of 10 min each. The mean of continuous beat-to-beat differences between the two BP sources was removed for the entire recording (null bias) and any linear trends were also removed. Stochastic properties of the time series of differences were described by the autocorrelation function. The temporal pattern of transient drifts was characterized by the coherent averaging of positive and negative transients, synchronized by their peak/trough values. Results On average, autocorrelation functions for differences between mean, systolic and diastolic values were significantly greater than zero for at least 24 beats, implying nonrandom differences. For mean BP, the peak value of positive and negative transient drifts were 4.98±3.61% and −6.75±7.48%, respectively. The average duration of these transients was approximately 20 s. Patients receiving (N=26) and not receiving β-blockers (N=14) had similar autocorrelation functions indicative of nonrandom differences. The former showed lower peak/trough values in comparison with the latter, but differences were not statistically significant. Conclusion The presence of transient drifts in beat-to-beat differences between finger and aortic BP can lead to erroneous results if biases are calculated using very short segments of data. Clinical and/or research applications using the Finapres, such as dynamic cerebral autoregulation modelling or sequence analysis for assessment of baroreceptor sensitivity can also be corrupted by the presence of nonrandom short-term fluctuations of the difference signal unless results are averaged for multiple segments of data.

Association studies in current cardiovascular genetics - functional variants, tags or both?

Abstract: Association studies in current cardiovascular genetics – functional variants, tags or both?

Genetic epidemiology of hypertension

Abstract: This paper was published as Genetics of hypertension / editors, Anna F. Dominiczak, John M.C. Connell, Handbook of hypertension ; v. 24, pp. 5-28. It is available from http://www.elsevier.com/wps/find/bookdescription.cws_home/710533/description#toc

Genetic association analysis of inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) variants with essential

Abstract: 10 This study showed that three INPPL1 polymorphisms (two SNPs, rs2276047 in intron 9 and rs9886 in the 39 untranslated region and an insertion/deletion polymorphism in intron 1), were significantly (p,,0.0001) associated with obesity, type 2 diabetes and hypertension (components of the metabolic syndrome) in patients in the DIF study. The same polymorphisms were subsequently genotyped in 905 French patients with type 2 diabetes and 305 controls without diabetes. Analysis of genotype and haplotype frequencies found no association with type 2 diabetes in the case-control study. However, comparison of the French patients with diabetes with and without hypertension demonstrated significant association between the insertion allele of the insertion/deletion polymorph- ism and hypertension (p = 0.01). In addition, the most common haplotype was significantly (p,0.01) more frequent in French patients with diabetes and hypertension compared with patients with hypertension who did not have diabetes. 10

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.