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Dawn Waterworth

Other affiliations: Imperial College London
Bio: Dawn Waterworth is an academic researcher from GlaxoSmithKline. The author has contributed to research in topics: Polycystic ovary & Genome-wide association study. The author has an hindex of 14, co-authored 19 publications receiving 2294 citations. Previous affiliations of Dawn Waterworth include Imperial College London.

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Journal ArticleDOI
01 Jul 2009-JAMA
TL;DR: In this article, the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28,112 cases and 100,823 controls, were investigated to investigate the association of these variants with coronary heart disease.
Abstract: Context Plasma levels of C-reactive protein (CRP) are independently associated with risk of coronary heart disease, but whether CRP is causally associated with coronary heart disease or merely a marker of underlying atherosclerosis is uncertain. Objective To investigate association of genetic loci with CRP levels and risk of coronary heart disease. Design, Setting, and Participants We first carried out a genome-wide association (n = 17 967) and replication study (n = 13 615) to identify genetic loci associated with plasma CRP concentrations. Data collection took place between 1989 and 2008 and genotyping between 2003 and 2008. We carried out a mendelian randomization study of the most closely associated single-nucleotide polymorphism (SNP) in the CRP locus and published data on other CRP variants involving a total of 28 112 cases and 100 823 controls, to investigate the association of CRP variants with coronary heart disease. We compared our finding with that predicted from meta-analysis of observational studies of CRP levels and risk of coronary heart disease. For the other loci associated with CRP levels, we selected the most closely associated SNP for testing against coronary heart disease among 14 365 cases and 32 069 controls. Main Outcome Measure Risk of coronary heart disease. Results Polymorphisms in 5 genetic loci were strongly associated with CRP levels (% difference per minor allele): SNP rs6700896 in LEPR (−14.8%; 95% confidence interval [CI], −17.6% to −12.0%; P = 6.2 × 10 −22 ), rs4537545 in IL6R (−11.5%; 95% CI, −14.4% to −8.5%; P = 1.3 × 10 −12 ), rs7553007 in the CRP locus (−20.7%; 95% CI, −23.4% to −17.9%; P = 1.3 × 10 −38 ), rs1183910 in HNF1A (−13.8%; 95% CI, −16.6% to −10.9%; P = 1.9 × 10 −18 ), and rs4420638 in APOE-CI-CII (−21.8%; 95% CI, −25.3% to −18.1%; P = 8.1 × 10 −26 ). Association of SNP rs7553007 in the CRP locus with coronary heart disease gave an odds ratio (OR) of 0.98 (95% CI, 0.94 to 1.01) per 20% lower CRP level. Our mendelian randomization study of variants in the CRP locus showed no association with coronary heart disease: OR, 1.00; 95% CI, 0.97 to 1.02; per 20% lower CRP level, compared with OR, 0.94; 95% CI, 0.94 to 0.95; predicted from meta-analysis of the observational studies of CRP levels and coronary heart disease (z score, −3.45; P Conclusion The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease.

587 citations

Journal ArticleDOI
TL;DR: Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.
Abstract: Fourteen Caucasian families with 81 affected individuals have been assessed in which polycystic ovaries/male pattern baldness (PCO/MPB) segregates as an autosomal dominant phenotype (1). The gene CYP17, coding for P450c17 alpha (17 alpha-hydroxylase; 17/20 lyase) on chromosome 10q24.3 is the rate-limiting step in androgen biosynthesis. We have identified a new single base change in the 5' promoter region of CYP17 by heteroduplex analysis. This creates an additional SP1-type (CCACC box) promoter site, which may cause increased expression. This base change also creates a recognition site for the restriction enzyme MspA1 allowing a simple screening procedure. There is a significant association between the presence of this base change (A2) and the affected state for consecutively identified Caucasian women with PCO as compared either to consecutively matched controls (P = 0.03) with an odds ratio for those with at least one A2 allele of 3.57, or to a random population (P = 0.02) with an odds ratio of 2.50. Within the fourteen families, members with PCO or MPB have a significant association with the occurrence of at least one A2 allele compared to their normal relatives, with an odds ratio of 2.20 (P = 0.05). The base change does not cosegregate with the affected phenotype within the families showing association, demonstrating that this mutation of CYP17 does not cause PCO/MPB. Variation in the A2 allele of the CYP17 gene is a significant factor modifying the expression of PCO/MPB in families where it has been demonstrated to segregate as a single gene disorder, but it is excluded as the primary genetic defect.

461 citations

Journal ArticleDOI
TL;DR: Mapping of susceptibility to PCOS to the INS VNTR implies that PCOS is due, in part, to an inherited alteration in insulin production, which suggests a mechanistic link between type 2 diabetes and PCOS, which is a risk factor for diabetes later in life.

320 citations

Journal ArticleDOI
TL;DR: The data demonstrate that variation in CYP11a may play an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.
Abstract: Biochemical data implicate an underlying disorder of androgen biosynthesis and/or metabolism in the aetiology of polycystic ovary syndrome (PCOS). We have examined the segregation of the genes coding for two key enzymes in the synthesis and metabolism of androgens, cholesterol side chain cleavage (CYP11a) and aromatase (CYP19), with PCOS in 20 multiply-affected families. All analyses excluded CYP19 cosegregation with PCOS, demonstrating that this locus is not a major determinant of risk for the syndrome. However, our results provide evidence for linkage to the CYP11a locus (NPL score = 3.03, p = 0.003). Parametric analysis using a dominant model suggests genetic heterogeneity, generating a maximum HLOD score of 2.7 (alpha = 0.63). An association study of 97 consecutively identified Europids with PCOS and matched controls demonstrates significant allelic association of a CYP11a 5' UTR pentanucleotide repeat polymorphism with hirsute PCOS subjects (p = 0.03). A strong association was also found between alleles of this polymorphism and total serum testosterone levels in both affected and unaffected individuals (p = 0.002). Our data demonstrate that variation in CYP11a may play an important role in the aetiology of hyperandrogenaemia which is a common characteristic of polycystic ovary syndrome.

281 citations

Journal ArticleDOI
TL;DR: The results of recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved and support the proposed interaction of a small number of key genes with environmental, particularly nutritional, factors.
Abstract: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in women of reproductive age. Familial clustering of cases suggests that genetic factors play an important part in its aetiology. A number of studies of families with several cases of PCOS have produced results suggesting an autosomal dominant trait. Detailed analysis of a large number of affected families has, however, cast some doubt about the mode of inheritance. An autosomal dominant trait remains possible but a more complex aetiology seems more likely. The results of our recent studies support the concept of an oligogenic disorder in which genes affecting metabolic pathways in glucose homeostasis and steroid biosynthesis are both involved. We review evidence for an important role for the insulin gene minisatellite in the aetiology of anovulatory PCOS and for the gene coding for P450 cholesterol side chain cleavage (CYP11a) in the mechanism of excessive androgen secretion in women with polycystic ovaries. We propose that the heterogeneity of clinical and biochemical features in PCOS can be explained by the interaction of a small number of key genes with environmental, particularly nutritional, factors.

271 citations


Cited by
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Journal ArticleDOI
François Mach, Colin Baigent, Alberico L. Catapano, Konstantinos C. Koskinas1, Manuela Casula, Lina Badimon1, M. John Chapman, Guy De Backer, Victoria Delgado, Brian A. Ference, Ian D. Graham, Alison Halliday, Ulf Landmesser, Borislava Mihaylova, Terje R. Pedersen, Gabriele Riccardi, Dimitrios J. Richter, Marc S. Sabatine, Marja-Riitta Taskinen, Lale Tokgozoglu, Olov Wiklund, Christian Mueller, Heinz Drexel, Victor Aboyans, Alberto Corsini, Wolfram Doehner, Michel Farnier, Bruna Gigante, Meral Kayıkçıoğlu, Goran Krstacic, Ekaterini Lambrinou, Basil S. Lewis, Josep Masip, Philippe Moulin, Steffen E. Petersen, Anna Sonia Petronio, Massimo F Piepoli, Xavier Pintó, Lorenz Räber, Kausik K. Ray, Željko Reiner, Walter F Riesen, Marco Roffi, Jean-Paul Schmid, Evgeny Shlyakhto, Iain A. Simpson, Erik S.G. Stroes, Isabella Sudano, Alexandros D Tselepis, Margus Viigimaa, Cecile Vindis, Alexander Vonbank, Michal Vrablik, Mislav Vrsalovic, José Luis Zamorano, Jean-Philippe Collet, Stephan Windecker, Veronica Dean, Donna Fitzsimons, Chris P Gale, Diederick E. Grobbee, Sigrun Halvorsen, Gerhard Hindricks, Bernard Iung, Peter Jüni, Hugo A. Katus, Christophe Leclercq, Maddalena Lettino, Béla Merkely, Miguel Sousa-Uva, Rhian M. Touyz, Djamaleddine Nibouche, Parounak H. Zelveian, Peter Siostrzonek, Ruslan Najafov, Philippe van de Borne, Belma Pojskic, Arman Postadzhiyan, Lambros Kypris, Jindřich Špinar, Mogens Lytken Larsen, Hesham Salah Eldin, Timo E. Strandberg, Jean Ferrières, Rusudan Agladze, Ulrich Laufs, Loukianos S. Rallidis, Laszlo Bajnok, Thorbjorn Gudjonsson, Vincent Maher, Yaakov Henkin, Michele Massimo Gulizia, Aisulu Mussagaliyeva, Gani Bajraktari, Alina Kerimkulova, Gustavs Latkovskis, Omar Hamoui, Rimvydas Šlapikas, Laurent Visser, P. Dingli, Victoria Ivanov, Aneta Boskovic, Mbarek Nazzi, Frank L.J. Visseren, Irena Mitevska, Kjetil Retterstøl, Piotr Jankowski, Ricardo Fontes-Carvalho, Dan Gaita, Marat V. Ezhov, Marina Foscoli, Vojislav Giga, Daniel Pella, Zlatko Fras, Leopoldo Pérez de Isla, Emil Hagström, Roger Lehmann, Leila Abid, Oner Ozdogan, Olena Mitchenko, Riyaz S. Patel 

4,069 citations

Journal ArticleDOI
TL;DR: Authors/Task Force Members (François Macha, Colin Baigentb,∗∗,2, Alberico L. Catapanoc), ESC Committee for Practice Guidelines (CPG) (Stephan Windeckeraa), ESC National Cardiac Societies (Djamaleddine Nibouchean, Parounak H. Patelcl)

2,972 citations

Journal ArticleDOI
TL;DR: Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes.
Abstract: It is now clear that PCOS is often associated with profound insulin resistance as well as with defects in insulin secretion. These abnormalities, together with obesity, explain the substantially increased prevalence of glucose intolerance in PCOS. Moreover, since PCOS is an extremely common disorder, PCOS-related insulin resistance is an important cause of NIDDM in women (Table 3). The insulin resistance in at least 50% of PCOS women appears to be related to excessive serine phosphorylation of the insulin receptor. A factor extrinsic to the insulin receptor, presumably a serine/threonine kinase, causes this abnormality and is an example of an important new mechanism for human insulin resistance related to factors controlling insulin receptor signaling. Serine phosphorylation appears to modulate the activity of the key regulatory enzyme of androgen biosynthesis, P450c17. It is thus possible that a single defect produces both the insulin resistance and the hyperandrogenism in some PCOS women (Fig. 19). Recent studies strongly suggest that insulin is acting through its own receptor (rather than the IGF-I receptor) in PCOS to augment not only ovarian and adrenal steroidogenesis but also pituitary LH release. Indeed, the defect in insulin action appears to be selective, affecting glucose metabolism but not cell growth. Since PCOS usually has a menarchal age of onset, this makes it a particularly appropriate disorder in which to examine the ontogeny of defects in carbohydrate metabolism and for ascertaining large three-generation kindreds for positional cloning studies to identify NIDDM genes. Although the presence of lipid abnormalities, dysfibrinolysis, and insulin resistance would be predicted to place PCOS women at high risk for cardiovascular disease, appropriate prospective studies are necessary to directly assess this.

2,571 citations

Journal ArticleDOI
TL;DR: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs), which were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders.
Abstract: The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.

2,361 citations

Journal ArticleDOI
TL;DR: It is now clear that the range of presenting symptoms of women with polycystic ovaries includes not only nonhirsute women with oligomenorrhoea or amenorrhOEa but also hirsute subjects with regular, ovulatory cycles.
Abstract: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women of reproductive age. The classical symptoms are those of hyperandrogenism (hirsutism, persistant acne, androgen dependent alopecia) together with symptoms of anovulation (infertility, amenorrhoea, irregular dysfunctional uterine bleeding).1In the last 10 to 15 years, the use of high resolution pelvic ultrasonography has greatly facilitated identification of polycystic ovaries in women with hirsutism or menstrual disturbance. It is now clear that the range of presenting symptoms of women with polycystic ovaries includes not only non-hirsute women with oligomenorrhoea or amenorrhoea but also hirsute subjects with regular, ovulatory cycles. PCOS occurs in nearly 75% of cases of anovulatory infertility and over 80% of subjects with hirsutism.1 The typical biochemical features of PCOS include hyperandrogenaemia and an increase of serum luteinising hormone (LH) (with normal follicle stimulating hormone) but PCOS is also associated with a characteristic metabolic syndrome that includes hyperinsulinaemia, insulin resistance, and dyslipidaemia.1-4 These features are linked to a significantly increased risk of type II (non-insulin-dependent) diabetes in later life and women with PCOS may also have a greater chance of developing premature cardiovascular disease.3 5 6 The presence of polycystic ovaries is necessary for the development of the syndrome but not all women with polycystic ovaries have PCOS. The typical …

2,119 citations