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Samantha Alvarez-Madrazo,
Scott M Mackenzie,
Eleanor Davies,
Robert Fraser,
Wai-Kwong Lee,
Morris Brown,
Mark J Caulfield,
Anna F Dominiczak,
Martin Farrall,
Mark Lathrop,
Thomas Hedner,
Olle Melander,
Patricia B Munroe, Nilesh Samani,
Paul M Stewart,
Björn Wahlstrand,
John Webster,
Colin N A Palmer,
Sandosh Padmanabhan,
John M Connell
[show abstract]
[hide abstract]
ABSTRACT: The locus encompassing the corticosteroidogenic genes CYP11B2 and CYP11B1 is of potential importance in essential hypertension. We analyzed the association of polymorphisms at this locus with risk of essential hypertension, using 2 white case-control collections for discovery (n=3340) and confirmation (n=2929). Single-marker and haplotype analyses were performed, with the CYP11B2 Intron 2 Conversion polymorphism showing strongest association with hypertension in both cohorts and in combined analysis (odds ratio=1.16, P=8.54×10(-5)). The CYP11B1 ACA haplotype associated with increased risk of hypertension relative to the alternative, GTC (odds ratio=1.11; P=7.4×10(-3)), whereas the CYP11B2 TWtC haplotype seemed protective relative to the contrasting CConvT (odds ratio=0.88, P=2.2×10(-3)). Analysis spanning the whole CYP11B1/CYP11B2 locus showed that haplotypes associated with raised risk of hypertension tend to coexist. Functional analysis of heterozygous human adrenal tissue demonstrated decreased CYP11B2 expression and increased CYP11B1 expression for those alleles associating with reduced risk of hypertension. These results confirm the hypertensive influence of this locus, with data suggesting a complex digenic mechanism whereby altered relative CYP11B1 and CYP11B2 gene expression could have a chronic effect on enzyme activity and corticosteroid synthesis.
Hypertension 11/2012; · 6.21 Impact Factor
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Lam C Tsoi,
Sarah L Spain,
Jo Knight,
Eva Ellinghaus,
Philip E Stuart,
Francesca Capon,
Jun Ding,
Yanming Li,
Trilokraj Tejasvi,
Johann E Gudjonsson, [......],
Matthew Waller,
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Rajan P Nair,
Andre Franke,
Jonathan N W N Barker,
Goncalo R Abecasis,
James T Elder,
Richard C Trembath
[show abstract]
[hide abstract]
ABSTRACT: To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.
Nature Genetics 11/2012; · 35.53 Impact Factor
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Aspasia Angelakopoulou,
Tina Shah,
Reecha Sofat,
Sonia Shah,
Diane J Berry,
Jackie Cooper,
Jutta Palmen,
Ioanna Tzoulaki,
Andrew Wong,
Barbara J Jefferis, [......],
Meena Kumari,
Elina Hypponen,
Chris Power,
Steve E Humphries,
Philippa J Talmud,
Jackie Price,
Richard W Morris,
Shu Ye,
Juan P Casas,
Aroon D Hingorani
[show abstract]
[hide abstract]
ABSTRACT: To evaluate the associations of emergent genome-wide-association study-derived coronary heart disease (CHD)-associated single nucleotide polymorphisms (SNPs) with established and emerging risk factors, and the association of genome-wide-association study-derived lipid-associated SNPs with other risk factors and CHD events.
Using two case-control studies, three cross-sectional, and seven prospective studies with up to 25 000 individuals and 5794 CHD events we evaluated associations of 34 genome-wide-association study-identified SNPs with CHD risk and 16 CHD-associated risk factors or biomarkers. The Ch9p21 SNPs rs1333049 (OR 1.17; 95% confidence limits 1.11-1.24) and rs10757274 (OR 1.17; 1.09-1.26), MIA3 rs17465637 (OR 1.10; 1.04-1.15), Ch2q36 rs2943634 (OR 1.08; 1.03-1.14), APC rs383830 (OR 1.10; 1.02, 1.18), MTHFD1L rs6922269 (OR 1.10; 1.03, 1.16), CXCL12 rs501120 (OR 1.12; 1.04, 1.20), and SMAD3 rs17228212 (OR 1.11; 1.05, 1.17) were all associated with CHD risk, but not with the CHD biomarkers and risk factors measured. Among the 20 blood lipid-related SNPs, LPL rs17411031 was associated with a lower risk of CHD (OR 0.91; 0.84-0.97), an increase in Apolipoprotein AI and HDL-cholesterol, and reduced triglycerides. SORT1 rs599839 was associated with CHD risk (OR 1.20; 1.15-1.26) as well as total- and LDL-cholesterol, and apolipoprotein B. ANGPTL3 rs12042319 was associated with CHD risk (OR 1.11; 1.03, 1.19), total- and LDL-cholesterol, triglycerides, and interleukin-6.
Several SNPs predicting CHD events appear to involve pathways not currently indexed by the established or emerging risk factors; others involved changes in blood lipids including triglycerides or HDL-cholesterol as well as LDL-cholesterol. The overlapping association of SNPs with multiple risk factors and biomarkers supports the existence of shared points of regulation for these phenotypes.
European Heart Journal 07/2011; 33(3):393-407. · 10.48 Impact Factor
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The Australo-Anglo-American Spondyloarthritis Consortium (TASC,
the Wellcome Trust Case Control Consortium,
David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Alexander Dilthey, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
Nature Genetics 07/2011; 43(8):761-767. · 35.53 Impact Factor
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Journal of Cardiovascular Magnetic Resonance. 01/2011;
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Journal of Cardiovascular Magnetic Resonance. 01/2011;
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David M Evans,
Chris C A Spencer,
Jennifer J Pointon,
Zhan Su,
David Harvey,
Grazyna Kochan,
Udo Oppermann,
Udo Opperman,
Alexander Dilthey,
Matti Pirinen, [......],
Matthew Waller,
Paul Weston,
Pamela Whittaker,
Sara Widaa,
Nicholas W Wood,
Gilean McVean,
John D Reveille,
B Paul Wordsworth,
Matthew A Brown,
Peter Donnelly
[show abstract]
[hide abstract]
ABSTRACT: Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.
Nature Genetics 01/2011; 43(8):761-7. · 35.53 Impact Factor
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Benjamin Brown,
Jérémie Nsengimana,
Jennifer Barrett,
Richard Lawrence,
Lori Steiner,
Suzanne Cheng,
Bishop D Timothy, Nilesh Samani,
Stephen Ball,
Anthony Balmforth,
Alistair Hall
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
Inflammatory cytokines play a crucial role in coronary artery disease (CAD). We investigated the association between 48 coding and three non-coding single nucleotide polymorphisms (SNPs) from 35 inflammatory genes and the development of CAD, using a large discordant sibship collection (2699 individuals in 891 families).
Methods
Family-based association tests (FBAT) and conditional logistic regression (CLR) were applied to single SNPs and haplotypes and, in CLR, traditional risk factors of CAD were adjusted for.
Results
An association was observed between CAD and a common three-locus haplotype in the interleukin one ( IL-1 ) cluster with P = 0.006 in all CAD cases, P = 0.01 in myocardial infarction (MI) cases and P = 0.0002 in young onset CAD cases (<50 years). The estimated odds ratio (OR) per copy of this haplotype is 1.21 (95% confidence interval [95CI] = 1.04 - 1.40) for CAD; 1.30 (95CI = 1.09 - 1.56) for MI and 1.50 (95CI = 1.22 - 1.86) for young onset CAD. When sex, smoking, hypertension and hypercholesterolaemia were adjusted for, the haplotype effect remained nominally significant ( P = 0.05) in young onset CAD cases, more so ( P = 0.002) when hypercholesterolaemia was excluded. As many as 82% of individuals affected by CAD had hypercholesterolaemia compared to only 29% of those unaffected, making the two phenotypes difficult to separate.
Conclusion
Despite the multiple hypotheses tested, the robustness of family design to population confoundings and the consistency with previous findings increase the likelihood of true association. Further investigation using larger data sets is needed in order for this to be confirmed.
See the related commentary by Keavney: http://www.biomedcentral.com/1741-7015/8/6
BMC Medicine. 01/2010;
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Journal of hypertension 12/2009; 27(12):2344-5. · 4.02 Impact Factor
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Jeffrey C Barrett,
James C Lee,
Charles W Lees,
Natalie J Prescott,
Carl A Anderson,
Anne Phillips,
Emma Wesley,
Kirstie Parnell,
Hu Zhang,
Hazel Drummond, [......],
Paul Weston,
Sara Widaa,
Pamela Whittaker,
Antony P Attwood,
Jonathan Stephens,
Jennifer Sambrook,
Willem H Ouwehand,
Wendy L McArdle,
Susan M Ring,
David P Strachan
[show abstract]
[hide abstract]
ABSTRACT: Ulcerative colitis is a common form of inflammatory bowel disease with a complex etiology. As part of the Wellcome Trust Case Control Consortium 2, we performed a genome-wide association scan for ulcerative colitis in 2,361 cases and 5,417 controls. Loci showing evidence of association at P < 1 x 10(-5) were followed up by genotyping in an independent set of 2,321 cases and 4,818 controls. We find genome-wide significant evidence of association at three new loci, each containing at least one biologically relevant candidate gene, on chromosomes 20q13 (HNF4A; P = 3.2 x 10(-17)), 16q22 (CDH1 and CDH3; P = 2.8 x 10(-8)) and 7q31 (LAMB1; P = 3.0 x 10(-8)). Of note, CDH1 has recently been associated with susceptibility to colorectal cancer, an established complication of longstanding ulcerative colitis. The new associations suggest that changes in the integrity of the intestinal epithelial barrier may contribute to the pathogenesis of ulcerative colitis.
Nature Genetics 11/2009; 41(12):1330-4. · 35.53 Impact Factor
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Elin Org,
Susana Eyheramendy,
Peeter Juhanson,
Christian Gieger,
Peter Lichtner,
Norman Klopp,
Gudrun Veldre,
Angela Döring,
Margus Viigimaa,
Siim Sõber, [......],
Anna Dominiczak,
John Connell, Nilesh Samani,
Martin Farrall,
Mark J Caulfield,
Patricia B Munroe,
Thomas Illig,
H-Erich Wichmann,
Thomas Meitinger,
Maris Laan
[show abstract]
[hide abstract]
ABSTRACT: Hypertension is a complex disease that affects a large proportion of adult population. Although approximately half of the inter-individual variance in blood pressure (BP) level is heritable, identification of genes responsible for its regulation has remained challenging. Genome-wide association study (GWAS) is a novel approach to search for genetic variants contributing to complex diseases. We conducted GWAS for three BP traits [systolic and diastolic blood pressure (SBP and DBP); hypertension (HYP)] in the Kooperative Gesundheitsforschung in der Region Augsburg (KORA) S3 cohort (n = 1644) recruited from general population in Southern Germany. GWAS with 395,912 single nucleotide polymorphisms (SNPs) identified an association between BP traits and a common variant rs11646213 (T/A) upstream of the CDH13 gene at 16q23.3. The initial associations with HYP and DBP were confirmed in two other European population-based cohorts: KORA S4 (Germans) and HYPEST (Estonians). The associations between rs11646213 and three BP traits were replicated in combined analyses (dominant model: DBP, P = 5.55 x 10(-5), effect -1.40 mmHg; SBP, P = 0.007, effect -1.56 mmHg; HYP, P = 5.30 x 10(-8), OR = 0.67). Carriers of the minor allele A had a decreased risk of hypertension. A non-significant trend for association was also detected with severe family based hypertension in the BRIGHT sample (British). The novel susceptibility locus, CDH13, encodes for an adhesion glycoprotein T-cadherin, a regulator of vascular wall remodeling and angiogenesis. Its function is compatible with the BP biology and may improve the understanding of the pathogenesis of hypertension.
Human Molecular Genetics 04/2009; 18(12):2288-96. · 7.64 Impact Factor
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Nicole Soranzo,
Augusto Rendon,
Christian Gieger,
Chris I Jones,
Nicholas A Watkins,
Stephan Menzel,
Angela Döring,
Jonathan Stephens,
Holger Prokisch,
Wendy Erber, [......],
Thomas Illig,
Stephen F Garner,
Angela Rankin,
Christa Meisinger,
John R Bradley,
Swee Lay Thein,
Alison H Goodall,
Tim D Spector,
Panos Deloukas,
Willem H Ouwehand
[show abstract]
[hide abstract]
ABSTRACT: Mean platelet volume (MPV) and platelet count (PLT) are highly heritable and tightly regulated traits. We performed a genome-wide association study for MPV and identified one SNP, rs342293, as having highly significant and reproducible association with MPV (per-G allele effect 0.016 +/- 0.001 log fL; P < 1.08 x 10(-24)) and PLT (per-G effect -4.55 +/- 0.80 10(9)/L; P < 7.19 x 10(-8)) in 8586 healthy subjects. Whole-genome expression analysis in the 1-MB region showed a significant association with platelet transcript levels for PIK3CG (n = 35; P = .047). The G allele at rs342293 was also associated with decreased binding of annexin V to platelets activated with collagen-related peptide (n = 84; P = .003). The region 7q22.3 identifies the first QTL influencing platelet volume, counts, and function in healthy subjects. Notably, the association signal maps to a chromosome region implicated in myeloid malignancies, indicating this site as an important regulatory site for hematopoiesis. The identification of loci regulating MPV by this and other studies will increase our insight in the processes of megakaryopoiesis and proplatelet formation, and it may aid the identification of genes that are somatically mutated in essential thrombocytosis.
Blood 03/2009; 113(16):3831-7. · 9.90 Impact Factor
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Siim Sõber,
Elin Org,
Katrin Kepp,
Peeter Juhanson,
Susana Eyheramendy,
Christian Gieger,
Peter Lichtner,
Norman Klopp,
Gudrun Veldre,
Margus Viigimaa, [......],
Anna Dominiczak,
John Connell, Nilesh Samani,
Martin Farrall,
Mark J Caulfield,
Patricia B Munroe,
Thomas Illig,
H-Erich Wichmann,
Thomas Meitinger,
Maris Laan
[show abstract]
[hide abstract]
ABSTRACT: The outcome of Genome-Wide Association Studies (GWAS) has challenged the field of blood pressure (BP) genetics as previous candidate genes have not been among the top loci in these scans. We used Affymetrix 500K genotyping data of KORA S3 cohort (n = 1,644; Southern-Germany) to address (i) SNP coverage in 160 BP candidate genes; (ii) the evidence for associations with BP traits in genome-wide and replication data, and haplotype analysis. In total, 160 gene regions (genic region+/-10 kb) covered 2,411 SNPs across 11.4 Mb. Marker densities in genes varied from 0 (n = 11) to 0.6 SNPs/kb. On average 52.5% of the HAPMAP SNPs per gene were captured. No evidence for association with BP was obtained for 1,449 tested SNPs. Considerable associations (P<10(-3)) were detected for the genes, where >50% of HAPMAP SNPs were tagged. In general, genes with higher marker density (>0.2 SNPs/kb) revealed a better chance to reach close to significance associations. Although, none of the detected P-values remained significant after Bonferroni correction (P<0.05/2319, P<2.15 x 10(-5)), the strength of some detected associations was close to this level: rs10889553 (LEPR) and systolic BP (SBP) (P = 4.5 x 10(-5)) as well as rs10954174 (LEP) and diastolic BP (DBP) (P = 5.20 x 10(-5)). In total, 12 markers in 7 genes (ADRA2A, LEP, LEPR, PTGER3, SLC2A1, SLC4A2, SLC8A1) revealed considerable association (P<10(-3)) either with SBP, DBP, and/or hypertension (HYP). None of these were confirmed in replication samples (KORA S4, HYPEST, BRIGHT). However, supportive evidence for the association of rs10889553 (LEPR) and rs11195419 (ADRA2A) with BP was obtained in meta-analysis across samples stratified either by body mass index, smoking or alcohol consumption. Haplotype analysis highlighted LEPR and PTGER3. In conclusion, the lack of associations in BP candidate genes may be attributed to inadequate marker coverage on the genome-wide arrays, small phenotypic effects of the loci and/or complex interaction with life-style and metabolic parameters.
PLoS ONE 01/2009; 4(6):e6034. · 4.09 Impact Factor
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Wolfgang Lieb,
Tanja Zeller,
Massimo Mangino,
Anika Götz,
Peter Braund,
Juergen J Wenzel,
Christian Horn,
Carole Proust,
Patrick Linsel-Nitschke,
Philippe Amouyel, [......],
Pierre Ducimetière,
Francois Cambien,
Christian Hengstenberg,
Klaus Stark,
Alistair S Hall,
Heribert Schunkert,
Stefan Blankenberg, Nilesh J Samani,
Jeanette Erdmann,
Laurence Tiret
[show abstract]
[hide abstract]
ABSTRACT: Coronary artery disease (CAD) and myocardial infarction (MI) have a genetic basis, but the precise genetic underpinning remains controversial. Recently, an association of the LRP8 R952Q polymorphism (rs5174) with familial premature CAD/MI was reported. We analysed rs5174 (or the perfect proxy rs5177) in 1,210 patients with familial MI and 1,015 controls from the German MI Family study, in 1,926 familial CAD (1,377 with MI) patients and 2,938 controls from the Wellcome Trust Case Control Consortium (WTCCC) MI/CAD cohort, in 346 CAD patients and 351 controls from the AtheroGene study and in 295 men with incident CAD and 301 controls from the Prospective Epidemiological Study of MI study and found no evidence for association in any of the populations studied. In the WTCCC and the German MI Family studies, additional single-nucleotide polymorphisms in the LRP8 gene were analysed and displayed no evidence for association either.
Journal of Molecular Medicine 08/2008; 86(10):1163-70. · 4.67 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Matrix metalloproteinase (MMP) activity is central to the development of left ventricular (LV) remodelling and dysfunction after acute myocardial infarction (AMI). We assessed the relationships with LV structure and function and outcome, of tissue inhibitors of metalloproteinase-1 (TIMP-1) and MMP-9, and compared with N-terminal pro-B-type natriuretic peptide (NTproBNP).
We studied 404 patients with AMI. Primary outcome measures were the associations of TIMP-1, MMP-9, and NTproBNP with death or heart failure, and with LV dimensions, function and remodelling (ΔLVEDV, change in LV end-diastolic volume between discharge and follow-up). Cut-off concentrations for prediction of death or heart failure were identified from receiver operator characteristic (ROC) curves. In multivariable analysis, TIMP-1 and NTproBNP had predictive value for LV ejection fraction pre-discharge (TIMP-1 P = 0.023; N-BNP P = 0.007) and at follow-up (TIMP-1 P = 0.001; N-BNP P = 0.003). MMP-9, TIMP-1, and NTproBNP correlated directly with LV volumes. MMP-9 (P = 0.005) and TIMP-1 (P = 0.036), but not NTproBNP, correlated with ΔLVEDV. For the combined endpoint of death or heart failure the area under the ROC curve was 0.640 for MMP-9, 0.799 for NTproBNP and 0.811 for TIMP-1. Patients with TIMP-1 > 135 ng/mL (P < 0.001) or NTproBNP >1472 fmol/mL (P < 0.001) had increased risk of endpoint. Consideration of both NTproBNP and TIMP-1 further improved risk stratification.
TIMP-1 and MMP-9 correlate with echocardiographic parameters of LV dysfunction and remodelling after AMI and may identify patients at risk of subsequent LV remodelling and adverse prognosis.
European Heart Journal 07/2008; 29(17):2116-24. · 10.48 Impact Factor
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Ana Carolina Braga Marçano,
Beverley Burke,
Johannie Gungadoo,
Chris Wallace,
Pamela J Kaisaki,
Peng Y Woon,
Martin Farrall,
David Clayton,
Morris Brown,
Anna Dominiczak,
John M Connell,
John Webster,
Mark Lathrop,
Mark Caulfield, Nilesh Samani,
Dominique Gauguier,
Patricia B Munroe
[show abstract]
[hide abstract]
ABSTRACT: Inositol polyphosphate phosphatase-like 1 (INPPL1, SHIP2) is a negative regulator of insulin signalling and has previously been found to be associated with hypertension, obesity and type 2 diabetes in a cohort of families with diabetes in the UK presenting features of 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 families with severe hypertension from the BRIGHT study transmission disequilibrium test cohort.
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 in metabolic syndrome patients specifically.
Journal of Medical Genetics 09/2007; 44(9):603-5. · 6.36 Impact Factor
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Circulation 08/2007; 116(1):e5-6. · 14.74 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: 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.
A questionnaire-based telephone survey.
13 tertiary paediatric cardiac centres in the UK and 13 large hospitals referring patients to these centres.
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.
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.
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.
Archives of Disease in Childhood 06/2007; 92(5):409-11. · 2.88 Impact Factor
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Jordana Tzenova Bell,
Chris Wallace,
Richard Dobson,
Steven Wiltshire,
Charles Mein,
Janine Pembroke,
Morris Brown,
David Clayton, Nilesh Samani,
Anna Dominiczak,
John Webster,
G Mark Lathrop,
John Connell,
Patricia Munroe,
Mark Caulfield,
Martin Farrall
[show abstract]
[hide abstract]
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.
Human Molecular Genetics 05/2006; 15(8):1365-74. · 7.64 Impact Factor
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Sandosh Padmanabhan,
Chris Wallace,
Patricia B Munroe,
Richard Dobson,
Morris Brown, Nilesh Samani,
David Clayton,
Martin Farrall,
John Webster,
Mark Lathrop,
Mark Caulfield,
Anna F Dominiczak,
John M Connell
[show abstract]
[hide abstract]
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 <20 mm Hg. Of the nonresponders, there were 89 sibling pairs (AB) who were both on antihypertensive therapy that inhibit the renin-angiotensin system (angiotensin-converting enzyme inhibitors, angiotensin II type-1 receptor blockers, or beta-blockers), and 76 sibling pairs (CD) who were both on drugs that do not (calcium channel blockers or diuretics). Nonparametric linkage analysis carried out using markers from a 10-cM genome scan and additional "grid tightening" markers showed significant linkage in the AB group on chromosome 2p (logarithm of odds=4.84 at 90.68 Kosambi cM) and suggestive linkage for the CD group on chromosome 10q (logarithm of odds=2.83 at 125.96 Kosambi cM). The AB linkage locus attained genomewide significance after simulation using 10,000 replicates (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.
Hypertension 03/2006; 47(3):603-8. · 6.21 Impact Factor
