Genomewide association analysis of coronary artery disease.

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 artery 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<0.001) were then combined to identify additional loci with a high probability of true association. Genotyping in both studies was performed with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: Of thousands of chromosomal loci studied, the same locus had the strongest association with coronary artery disease in both the WTCCC and the German studies: chromosome 9p21.3 (SNP, rs1333049) (P=1.80x10(-14) and P=3.40x10(-6), respectively). Overall, the WTCCC study revealed nine loci that were strongly associated with coronary artery disease (P<1.2x10(-5) and less than a 50% chance of being falsely positive). In addition to chromosome 9p21.3, two of these loci were successfully replicated (adjusted P<0.05) in the German study: chromosome 6q25.1 (rs6922269) and chromosome 2q36.3 (rs2943634). The combined analysis of the two studies identified four additional loci significantly associated with coronary artery disease (P<1.3x10(-6)) and a high probability (>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.

Blood leucocyte telomere DNA content predicts vascular telomere DNA content in humans with and without vascular disease.

AIMS: Previous studies have suggested that reduced telomere length in circulating leucocytes in humans is associated with premature vascular disease and by implication, accelerated vascular ageing. Importantly, a link between telomere length in circulating leucocytes and the blood vessel wall has never been established. We, thus, investigated the relationship between vascular wall and circulating leucocyte telomere length in humans with and without overt vascular disease. METHODS AND RESULTS: Aortic biopsies and paired blood leucocytes were obtained from 20 patients with asymptomatic abdominal aortic aneurysms (AAAs), undergoing elective open repair, and 12 morphologically normal aortas from a group of cadaveric organ donors of similar mean age. Telomere content was compared by quantitative PCR and expressed as telomere:genomic DNA ratio. The telomere:genomic DNA content was significantly reduced in wall biopsies of AAA vs. normal aorta, and this difference remained after adjusting for age and gender. There were strong correlations between leucocyte and vascular telomere content when the AAA and control groups were analysed either separately or grouped irrespective of the presence of vascular disease (r = 0.62, P < 0.001). CONCLUSION: The findings demonstrate that leucocyte DNA content is predictive of vascular telomere content and is an accurate surrogate for human vascular age.

Dopamine transporter gene polymorphism moderates the effects of severe deprivation on ADHD symptoms: developmental continuities in gene-environment interplay.

Early institutional deprivation is a risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. However not all individuals are affected. We tested the hypothesis that this heterogeneity is influenced by gene x environment (GxE) interaction and that genetic polymorphisms involved in dopamine neurotransmission moderate the effects of severe early institutional deprivation on symptoms of ADHD (sADHD). Using a prospective-longitudinal design sADHD were measured at ages 6, 11, and 15 years in a sample of individuals who experienced severe institutional deprivation (up to 42 months of age) in Romanian orphanages and a non-institutionalized comparison group. Individuals were genotyped for polymorphisms in the dopamine D4 receptor (DRD4 48-bp VNTR in exon 3) and dopamine transporter gene (DAT1 haplotypes combining a 40-bp VNTR in 3'UTR and a 30-bp VNTR in intron 8). The risk for sADHD associated with early institutional deprivation was moderated by the DAT1 but not the DRD4 genotypes; an effect that was first apparent in early-, and persisted to mid-adolescence. The results (i) provide evidence for developmental continuities in G x E interaction, (ii) explain some of the heterogeneity in ADHD outcomes following institutional deprivation and, (iii) add to our understanding of environmental determinants of sADHD.

Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction.

BACKGROUND: The appropriate treatment for patients in whom reperfusion fails to occur after thrombolytic therapy for acute myocardial infarction remains unclear. There are few data comparing emergency percutaneous coronary intervention (rescue PCI) with conservative care in such patients, and none comparing rescue PCI with repeated thrombolysis. METHODS: We conducted a multicenter trial in the United Kingdom involving 427 patients with ST-segment elevation myocardial infarction in whom reperfusion failed to occur (less than 50 percent ST-segment resolution) within 90 minutes after thrombolytic treatment. The patients were randomly assigned to repeated thrombolysis (142 patients), conservative treatment (141 patients), or rescue PCI (144 patients). The primary end point was a composite of death, reinfarction, stroke, or severe heart failure within six months. RESULTS: The rate of event-free survival among patients treated with rescue PCI was 84.6 percent, as compared with 70.1 percent among those receiving conservative therapy and 68.7 percent among those undergoing repeated thrombolysis (overall P=0.004). The adjusted hazard ratio for the occurrence of the primary end point for repeated thrombolysis versus conservative therapy was 1.09 (95 percent confidence interval, 0.71 to 1.67; P=0.69), as compared with adjusted hazard ratios of 0.43 (95 percent confidence interval, 0.26 to 0.72; P=0.001) for rescue PCI versus repeated thrombolysis and 0.47 (95 percent confidence interval, 0.28 to 0.79; P=0.004) for rescue PCI versus conservative therapy. There were no significant differences in mortality from all causes. Nonfatal bleeding, mostly at the sheath-insertion site, was more common with rescue PCI. At six months, 86.2 percent of the rescue-PCI group were free from revascularization, as compared with 77.6 percent of the conservative-therapy group and 74.4 percent of the repeated-thrombolysis group (overall P=0.05). CONCLUSIONS: Event-free survival after failed thrombolytic therapy was significantly higher with rescue PCI than with repeated thrombolysis or conservative treatment. Rescue PCI should be considered for patients in whom reperfusion fails to occur after thrombolytic therapy.

Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence.

The current study examined the persistence and phenotypic presentation of inattention/overactivity (I/O) into early adolescence, in a sample of institution reared (IR) children adopted from Romania before the age of 43 months. Total sample comprised 144 IR and 21 non-IR Romanian adoptees, and a comparison group of 52 within-UK adoptees, assessed at ages 6 and 11 years. I/O was rated using Rutter Scales completed by parents and teachers. I/O continued to be strongly associated with institutional deprivation, with continuities between ages 6 and 11 outcomes. There were higher rates of deprivation-related I/O in boys than girls, and I/O was strongly associated with conduct problems, disinhibited attachment and executive function but not IQ more generally, independently of gender. Deprivation-related I/O shares many common features with ADHD, despite its different etiology and putative developmental mechanisms. I/O is a persistent domain of impairment following early institutional deprivation of 6 months or more, suggesting there may be a possible pathway to impairment through some form of neuro-developmental programming during critical periods of early development.

Rescue angioplasty for failed thrombolysis in older patients: insights from the REACT trial.

BACKGROUND: Thrombolysis remains the first-line therapy in a substantial proportion of patients presenting with ST elevation myocardial infarction. The optimal treatment for patients in whom there is failure of reperfusion following thrombolysis is unclear. The Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis (REACT) trial demonstrated, in 427 randomly assigned patients with failed reperfusion following thrombolysis, that event-free survival rates were significantly improved with rescue angioplasty compared with either repeat thrombolysis or conservative treatment. However, the safety and efficacy of rescue angioplasty among older patients remains uncertain. METHODS AND RESULTS: We aimed to determine whether rescue angioplasty was safe and effective in an older population, by evaluating the primary and secondary clinical outcomes among the 105 patients >or=70 years of age in the REACT trial. We observed an increased overall 6-month event rate among older patients. The relative benefit of rescue angioplasty versus repeat thrombolysis or conservative treatment was maintained, and the absolute benefit actually increased in this older age group compared with the study population as a whole. There was no adverse impact of advanced age on bleeding complications. Repeat thrombolysis was no more effective than conservative therapy. CONCLUSIONS: Rescue angioplasty is the preferred management strategy for failed thrombolysis, even for patients >or=70 years of age.

Early adolescent outcomes for institutionally-deprived and non-deprived adoptees. I: disinhibited attachment.

BACKGROUND: Disinhibited attachment is an important sequel of an institutional rearing, but questions remain regarding its measurement, its persistence, the specificity of the association with institutional rearing and on whether or not it constitutes a meaningful disorder. METHOD: Children initially reared in profoundly depriving institutions in Romania and subsequently adopted into UK families were compared with respect to findings at 11 years with children who had not experienced institutional deprivation and who had been adopted within the UK before the age of 6 months. Measures included parental reports, a Strange Situation procedure modified for use in the home and systematic standardised investigator ratings of the children's behaviour. RESULTS: Disinhibited attachment, as reported by parents, showed a high degree of persistence from 6 to 11, but also a reduction over time in its frequency. Investigator ratings validated the parental reports but suggested that much of the fall in rate of disinhibited attachment was a function of the parental measure being less developmentally appropriate at 11 than it had been at 6. Disinhibited attachment was strongly associated with institutional rearing but there was not a significant increase in relation to duration of institutional deprivation beyond the age of 6 months. Mild, but not marked, disinhibited attachment was quite frequent in non-institutionalised adopted children but both the course and correlates indicated that its meaning was probably quite different. In the institution-reared children, disinhibited attachment was associated with a marked increase in service usage and associations with other forms of psychopathology. CONCLUSIONS: Disinhibited attachment constitutes a valid, and handicapping, clinical pattern that is strongly associated with an institutional rearing.

Early adolescent outcomes of institutionally-deprived and non-deprived adoptees. II: language as a protective factor and a vulnerable outcome.

BACKGROUND: There is uncertainty about the extent to which language skills are part of general intelligence and even more uncertainty on whether deprivation has differential effects on language and non-language skills. METHODS: Language and cognitive outcomes at 6 and 11 years of age were compared between a sample of 132 institution-reared Romanian children adopted into UK families under the age of 42 months, and a sample of 49 children adopted within the UK under the age of 6 months who had not experienced either institutional rearing or profound deprivation. RESULTS: The effects of institutional deprivation were basically similar for language and cognitive outcomes at age 6; in both there were few negative effects of deprivation if it ended before the age of 6 months and there was no linear association with duration of deprivation within the 6 to 42 month range. For the children over 18 months on arrival (range 18-42 months), the presence of even very minimal language skills (imitation of speech sounds) at the time of arrival was a strong beneficial prognostic factor for language and cognitive outcomes, but not for social/emotional/behavioural outcomes. Individual variations in adoptive parent characteristics were unrelated to differences in language or cognitive outcomes, possibly as a consequence of the limited variability in the adoptive family group. CONCLUSIONS: Minimal language probably indexes some form of cognitive reserve that, in turn, indexes the degree of institutional deprivation.