ABCMdb

PMID: 15837081

Wegman JJ, Hu X, Tan H, Bergen AA, Trip MD, Kastelein JJ, Smulders YM
Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype.
Int J Cardiol. 2005 Apr 28;100(3):389-93., 2005-04-28 [PubMed]

Sentences

No. Mutations Sentence Comment

0 ABCC6 p.Arg1141* Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype Jurgen J. Wegmana , Xiaofeng Hub , Hendra Tanc , Arthur A.B. Bergenb , Mieke D. Tripd , John J.P. Kastelein, Yvo M. Smulderse,* a Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands b The Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands c Department of Ophthalmology, Academic Medical Center, University of Amsterdam, The Netherlands d Department of Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands e Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands Received 26 February 2004; received in revised form 28 June 2004; accepted 5 July 2004 Available online 2 February 2005 Abstract Background: Pseudoxanthoma elasticum (PXE) is an inherited disorder of elastic tissue. Login to comment 1 ABCC6 p.Arg1141* We recently found that heterozygosity for the frequent (0.8% prevalence in Dutch population) R1141X mutation in the PXE gene coding for the ABCC6 transporter, is associated with a fourfold risk of premature coronary artery disease. Login to comment 3 ABCC6 p.Arg1141* The objective of our study was to determine if skin and/or eye abnormalities related to a PXE phenotype could be found in patients with premature coronary artery disease, with and without the R1141X mutation. Login to comment 4 ABCC6 p.Arg1141* Methods: R1141X mutation carriers with premature coronary artery disease (cases) and patients with premature coronary artery disease with no-or not known-mutation (controls) were studied. Login to comment 8 ABCC6 p.Arg1141* Conclusions: Carriers for the ABCC6 R1141X mutation, which is frequent and confers a high risk of premature coronary artery disease, do not commonly have skin or eye abnormalities consistent with a mild PXE phenotype. Login to comment 32 ABCC6 p.Arg1141* We subsequently observed a relatively high prevalence of 3.2% heterozygosity for the R1141X mutation in the ABCC6 gene, in a population with premature coronary artery disease, as opposed to 0.8% prevalence in a large population-based sample [17]. Login to comment 33 ABCC6 p.Arg1141* Heterozygosity for the R1141X mutation certainly does not commonly lead to the typical PXE phenotype, but how often a mild PXE phenotype characterises such patients is unknown. Login to comment 34 ABCC6 p.Arg1141* In the present study, we specifically looked for typical skin changes and ocular abnormalities in patients with premature coronary artery disease and heterozygosity for the R1141X mutation, in order to assess if these patients have mild PXE-like characteristics. Login to comment 36 ABCC6 p.Arg1141* This was done for two reasons: First, R1141X is not the only mutation causing PXE in Dutch patients [7] and, second, the phenotypical presentations, particularly the angioid streaks in fundo, are not entirely specific for PXE [11]. Login to comment 42 ABCC6 p.Arg1141* Seven patients who were under the age of 50 years at the time of their coronary artery disease event (occurring between 1995 and 2001), who carried the R1141X mutation in the ABCC6 gene, and who we were able to contact and obtain consent from, were selected as cases from the database of the atherosclerosis outpatient clinic [17]. Login to comment 45 ABCC6 p.Arg1141* In 21 patients in the control group, the absence of the R1141X mutation in the ABCC6 gene was confirmed by DNA analysis. Login to comment 64 ABCC6 p.Arg1141* Results The summary demographic and clinical data of the 7 R1141X mutation-positive patients and the 31 controls are listed in Table 1. Login to comment 74 ABCC6 p.Arg1141* Discussion Our study examined discrete PXE-like characteristics in 38 patients with premature coronary artery disease, 7 of whom were identified as carriers of the R1141X mutation in the ABCC6 gene. Login to comment 78 ABCC6 p.Arg1141* Second, more importantly, our results suggest that, although heterozygosity for the R1141X PXE mutation is frequent and confers a sharply increased risk of coronary artery disease [17], these patients, or at least the majority of them, cannot easily be identified by a discrete PXE phenotype. Login to comment 82 ABCC6 p.Arg1141* The absence of a macroscopically detectable dermatological and retinal PXE phenotype in coronary artery disease patients who are carriers of the R1141X mutation is important. Login to comment 83 ABCC6 p.Arg1141* ABCC6 p.Arg1141* The prevalence of this mutation in a large (n=1057) sample of the Dutch population was 0.8%, and the odds ratio for coronary artery disease associated with the Table 1 Summary of demographic and clinical data on ABCC6/MRP6 R1141X mutation-positive patients and controls R1141X positive Control Number of patients 7 31 Male gender 5 (71%) 24 (77%) Age (years) 42.9 (4.8) 40.6 (5.7) History of smoking 4 (57%) 24 (77%) First-degree family history of CAD 4 (57%) 7 (23%) Systolic blood pressure (mmHg) 127.1 (14.1) 129.5 (14.7) Diastolic blood pressure (mmHg) 78.6 (6.3) 79.3 (8.3) Total cholesterol (mmol/l) 5.7 (1.0) 5.4 (1.1) HDL cholesterol (mmol/l) 1.1 (0.2) 1.1 (0.3) LDL cholesterol (mmol/l) 3.8 (1.1) 3.5 (0.9) Triglycerides (mmol/l) 1.9 (0.9-3.1) 1.4 (0.4-4.6) Skin/fundus abnormalities none none Data are number (%), mean (standard deviation), or median (range). Login to comment 84 ABCC6 p.Arg1141* Table 2 Individual patient data on the ABCC6/MRP6 R1141X mutation-positive patients, who all had a coronary event before the age of 50 years Patient #1 Patient #2 Patient #3 Patient #4 Patient #5 Patient #6 Patient #7 Gender male male male male female female male Age at time of first coronary event 37 50 43 48 42 38 42 Family history parental parental parental none sibs none none Smoking history (pack years) 25 30 none 60 none none 12 Blood pressure (mmHg) 115/80 120/80 130/80 110/70 125/75 150/90 140/75 Total cholesterol (mmol/l) 5.4 5.2 5.2 6.7 6.7 4.1 6.6 LDL cholesterol (mmol/l) 3.1 3.4 3.2 4.4 5.1 2.3 5.0 HDL cholesterol (mmol/l) 0.9 1.0 1.3 1.0 0.9 1.2 1.2 Triglycerides (mmol/l) 3.1 1.7 1.6 2.8 1.6 1.4 0.9 Skin abnormalities absent absent absent absent absent absent absent Fundus examination normal normal normal normal normal normal normal J.J. Wegman et al. / International Journal of Cardiology 100 (2005) 389-393 391 mutation was 4.2 [17]. Login to comment 86 ABCC6 p.Arg1141* However, given our present findings in coronary artery disease patients, and the rarity of the PXE phenotype in the population, it appears that the majority of individuals who are heterozygous for R1141X do not have the typical PXE phenotype. Login to comment 101 ABCC6 p.Arg1141* Secondly, the R1141X mutation was not determined in all controls. Login to comment 102 ABCC6 p.Arg1141* Statistically, however, the chance of finding an appreciable number of R1141X mutations in these 10 patients is small. Login to comment 103 ABCC6 p.Arg1141* Even if 1 or 2 of these patients would be R1141X-positive, this would in no way affect our conclusion, but only strengthen our deduction that such patients do not commonly have a PXE phenotype. Login to comment 109 ABCC6 p.Arg1141* In a recent study, in which we presented the mutation spectrum of ABCC6 in 59 PXE patients from The Netherlands, we identified the R1141X to be the most common mutation [7]. Login to comment 110 ABCC6 p.Arg1141* The R1141X mutation was identified in 32.2 % of Dutch patients [24]. Login to comment