Clinical characteristics associated with the prescribing of SSRI medication in adolescents with major unipolar depression.

Unipolar major depressions (MD) emerge markedly during adolescence. National Institute for Health and Care Excellence (NICE) UK recommends psychological therapies, with accompanying selective serotonin reuptake inhibitors (SSRIs) prescribed in severe cases only. Here, we seek to determine the extent and rationale of SSRI prescribing in adolescent MD before entering a randomised clinical trial. SSRI prescribing, together with their clinical characteristics was determined in 465 adolescent patients with MD prior to receiving a standardised psychological therapy as part of the Improving mood with psychoanalytic and cognitive therapies (IMPACT) clinical trial. Overall, 88 (19 %) had been prescribed antidepressants prior to psychological treatment. The clinical correlates varied by gender: respectively, depression severity in boys and self-harming behaviours in girls. Prescribing also differed between clinical research centres. Medical practitioners consider severity of depression in boys as an indicator for antidepressant prescribing. Self-injury in girls appears to be utilised as a prescribing aid which is inconsistent with past and current revised UK NICE guidelines.

A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region.

In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A --> G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 x 10(-10).

Magnetic resonance imaging of a randomized controlled trial investigating predictors of recovery following psychological treatment in adolescents with moderate to severe unipolar depression: study protocol for Magnetic Resonance-Improving Mood with Psychoanalytic and Cognitive Therapies (MR-IMPACT).

BACKGROUND: Major depressive disorders (MDD) are a debilitating and pervasive group of mental illnesses afflicting many millions of people resulting in the loss of 110 million working days and more than 2,500 suicides per annum. Adolescent MDD patients attending NHS clinics show high rates of recurrence into adult life. A meta-analysis of recent research shows that psychological treatments are not as efficacious as previously thought. Modest treatment outcomes of approximately 65% of cases responding suggest that aetiological and clinical heterogeneity may hamper the better use of existing therapies and discovery of more effective treatments. Information with respect to optimal treatment choice for individuals is lacking, with no validated biomarkers to aid therapeutic decision-making. METHODS/DESIGN: Magnetic resonance-Improving Mood with Psychoanalytic and Cognitive Therapies, the MR-IMPACT study, plans to identify brain regions implicated in the pathophysiology of depressions and examine whether there are specific behavioural or neural markers predicting remission and/or subsequent relapse in a subsample of depressed adolescents recruited to the IMPACT randomised controlled trial (Registration # ISRCTN83033550). DISCUSSION: MR-IMPACT is an investigative biomarker component of the IMPACT pragmatic effectiveness trial. The aim of this investigation is to identify neural markers and regional indicators of the pathophysiology of and treatment response for MDD in adolescents. We anticipate that these data may enable more targeted treatment delivery by identifying those patients who may be optimal candidates for therapeutic response. TRIAL REGISTRATION: Adjunctive study to IMPACT trial (Current Controlled Trials: ISRCTN83033550).

Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with Type 1 diabetes.

ADMA (asymmetric dimethylarginine), an endogenous inhibitor of nitric oxide synthase, is considered a major risk factor for cardiovascular disease and progression of renal disease. In the present study we aim to investigate the effect of acute variations in plasma glucose and insulin on plasma ADMA levels in young people with T1D (Type 1 diabetes). Fifteen young patients (ten males) with T1D, median age 18.3 (13.2-24.4) years, HbA(1c) (glycated haemoglobin) 9% (6.4-13.6%), underwent an overnight (18:00-08:00 hours) variable insulin infusion for euglycaemia, followed by a hyperinsulinaemic-euglycaemic clamp (08:00-12:00 hours). Blood samples were collected every 15 min for determination of ADMA, SDMA (symmetric dimethylarginine), valine, phenylalanine, arginine, creatinine and glucose. Insulin levels were assessed every 30 min. During the overnight period, glucose levels increased following the evening meal. In response to the protein intake there was a significant increase in ADMA, arginine, valine, phenylalanine and creatinine. For the remaining part of the night, glucose levels progressively decreased reaching 5 mmol/l by 04:00 hours. ADMA and SDMA did not change significantly. During the hyperinsulinaemic clamp, a significant fall in ADMA was observed, from 0.468+/-0.056 to 0.364+/-0.050 micromol/l (P<0.001). A significant fall was also found in SDMA, valine, phenylalanine, arginine and the ADMA/SDMA ratio (all P<0.001), but not in creatinine levels. No correlation was found between insulin sensitivity and ADMA. We conclude that acute changes in glycaemia do not significantly affect plasma ADMA levels whereas infusion of insulin significantly reduces ADMA, suggesting an important role for insulin in the regulation of this cardiovascular risk factor.

Cognitive behavioural therapy and short-term psychoanalytical psychotherapy versus a brief psychosocial intervention in adolescents with unipolar major depressive disorder (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled superiority trial.

BACKGROUND: Psychological treatments for adolescents with unipolar major depressive disorder are associated with diagnostic remission within 28 weeks in 65-70% of patients. We aimed to assess the medium-term effects and costs of psychological therapies on maintenance of reduced depression symptoms 12 months after treatment. METHODS: We did this multicentre, pragmatic, observer-blind, randomised controlled superiority trial (IMPACT) at 15 National Health Service child and adolescent mental health service (CAMHS) clinics in three regions in England. Adolescent patients (aged 11-17 years) with a diagnosis of DSM IV major depressive disorder were randomly assigned (1:1:1), via a web-based randomisation service, to receive cognitive behavioural therapy (CBT) or short-term psychoanalytical therapy versus a reference brief psychological intervention. Randomisation was stochastically minimised by age, sex, self-reported depression sum score, and region. Patients and clinicians were aware of group allocation, but allocation was concealed from outcome assessors. Patients were followed up and reassessed at weeks 6, 12, 36, 52, and 86 post-randomisation. The primary outcome was self-reported depression symptoms at weeks 36, 52, and 86, as measured with the self-reported Mood and Feelings Questionnaire (MFQ). Because our aim was to compare the two psychological therapies with the brief psychosocial intervention, we first established whether CBT was inferior to short-term psychoanalytical psychotherapy for the same outcome. Primary analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN83033550. FINDINGS: Between June 29, 2010, and Jan 17, 2013, we randomly assigned 470 patients to receive the brief psychosocial intervention (n=158), CBT (n=155), or short-term psychoanalytical therapy (n=157); 465 patients comprised the intention-to-treat population. 392 (84%) patients had available data for primary analysis by the end of follow-up. Treatment fidelity and differentiation were established between the three interventions. The median number of treatment sessions differed significantly between patients in the brief psychosocial intervention group (n=6 [IQR 4-11]), CBT group (n=9 [5-14]), and short-term psychoanalytical therapy group (n=11 [5-23]; p<0·0001), but there was no difference between groups in the average duration of treatment (27·5 [SD 21·5], 24·9 [17·7], 27·9 [16·8] weeks, respectively; Kruskal-Wallis p=0·238). Self-reported depression symptoms did not differ significantly between patients given CBT and those given short-term psychoanalytical therapy at weeks 36 (treatment effect 0·179, 95% CI -3·731 to 4·088; p=0·929), 52 (0·307, -3·161 to 3·774; p=0·862), or 86 (0·578, -2·948 to 4·104; p=0·748). These two psychological treatments had no superiority effect compared with brief psychosocial intervention at weeks 36 (treatment effect -3·234, 95% CI -6·611 to 0·143; p=0·061), 52 (-2·806, -5·790 to 0·177; p=0·065), or 86 (-1·898, -4·922 to 1·126; p=0·219). Physical adverse events (self-reported breathing problems, sleep disturbances, drowsiness or tiredness, nausea, sweating, and being restless or overactive) did not differ between the groups. Total costs of the trial interventions did not differ significantly between treatment groups. INTERPRETATION: We found no evidence for the superiority of CBT or short-term psychoanalytical therapy compared with a brief psychosocial intervention in maintenance of reduced depression symptoms 12 months after treatment. Short-term psychoanalytical therapy was as effective as CBT and, together with brief psychosocial intervention, offers additional patient choice for psychological therapy, alongside CBT, for adolescents with moderate to severe depression who are attending routine specialist CAMHS clinics. FUNDING: National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme, and the Department of Health.

Cognitive-behavioural therapy and short-term psychoanalytic psychotherapy versus brief psychosocial intervention in adolescents with unipolar major depression (IMPACT): a multicentre, pragmatic, observer-blind, randomised controlled trial.

BACKGROUND: Although there are effective psychological treatments for unipolar major depression in adolescents, whether or not one or more of the available therapies maintain reduced depressive symptoms 1 year after the end of treatment is not known. This is a non-trivial issue because maintaining lowered depressive symptoms below a clinical threshold level reduces the risk for diagnostic relapse into the adult years. OBJECTIVE: To determine whether or not either of two specialist psychological treatments, cognitive-behavioural therapy (CBT) or short-term psychoanalytic psychotherapy (STPP), is more effective than a reference brief psychosocial intervention (BPI) in maintaining reduction of depression symptoms in the year after treatment. DESIGN: Observer-blind, parallel-group, pragmatic superiority randomised controlled trial. SETTING: A total of 15 outpatient NHS clinics in the UK from East Anglia, north-west England and North London. PARTICIPANTS: Adolescents aged 11-17 years with Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition major depression including those with suicidality, depressive psychosis and conduct disorder. Patients were randomised using stochastic minimisation controlling for age, sex and self-reported depression sum score; 470 patients were randomised and 465 were included in the analyses. INTERVENTIONS: In total, 154 adolescents received CBT, 156 received STPP and 155 received BPI. The trial lasted 86 weeks and study treatments were delivered in the first 36 weeks, with 52 weeks of follow-up. MAIN OUTCOME MEASURES: Mean sum score on self-reported depressive symptoms (primary outcome) at final study assessment (nominally 86 weeks, at least 52 weeks after end of treatment). Secondary measures were change in mean sum scores on self-reported anxiety symptoms and researcher-rated Health of the Nation scales for children and adolescents measuring psychosocial function. Following baseline assessment, there were a further five planned follow-up reassessments at nominal time points of 6, 12, 52 and 86 weeks post randomisation. RESULTS: There were non-inferiority effects of CBT compared with STPP [treatment effect by final follow-up = -0.578, 95% confidence interval (CI) -2.948 to 4.104; p = 0.748]. There were no superiority effects for the two specialist treatments (CBT + STPP) compared with BPI (treatment effect by final follow-up = -1.898, 95% CI -4.922 to 1.126; p = 0.219). At final assessment there was no significant difference in the mean depressive symptom score between treatment groups. There was an average 49-52% reduction in depression symptoms by the end of the study. There were no differences in total costs or quality-of-life scores between treatment groups and prescribing a selective serotonin reuptake inhibitor (SSRI) during treatment or follow-up did not differ between the therapy arms and, therefore, did not mediate the outcome. CONCLUSIONS: The three psychological treatments differed markedly in theoretical and clinical approach and are associated with a similar degree of clinical improvement, cost-effectiveness and subsequent maintenance of lowered depressive symptoms. Both STPP and BPI offer an additional patient treatment choice, alongside CBT, for depressed adolescents attending specialist Child and Adolescent Mental Health Services. Further research should focus on psychological mechanisms that are associated with treatment response, the maintenance of positive effects, determinants of non-response and whether or not brief psychotherapies are of use in primary care and community settings. LIMITATIONS: Neither reason for SSRI prescribing or monitoring of medication compliance was controlled for over the course of the study, and the economic results were limited by missing data. TRIAL REGISTRATION: Current Controlled Trials ISRCTN83033550. FUNDING: This project was funded by the National Institute for Heath Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 12. See the National Institute for Heath Research Journals Library website for further project information. Funding was also provided by the Department of Health. The funders had no role in the study design, patient recruitment, data collection, analysis or writing of the study, any aspect pertinent to the study or the decision to submit to The Lancet.

Analysis of the vitamin D receptor gene sequence variants in type 1 diabetes.

Vitamin D is known to modulate the immune system, and its administration has been associated with reduced risk of type 1 diabetes. Vitamin D acts via its receptor (VDR). Four single nucleotide polymorphisms (SNPs) of the VDR gene have been commonly studied, and evidence of association with type 1 diabetes has been reported previously. We sequenced the VDR gene region and developed its SNP map. Here we analyzed association of the 98 VDR SNPs in up to 3,763 type 1 diabetic families. First, we genotyped all 98 SNPs in a minimum of 458 U.K. families with two affected offspring. We further tested eight SNPs, including four SNPs associated with P < 0.05 in the first set and the four commonly studied SNPs, in up to 3,305 additional families from the U.K., Finland, Norway, Romania, and U.S. We only found weak evidence of association (P = 0.02-0.05) of the rs4303288, rs12721366, and rs2544043 SNPs. We then tested these three SNPs in an independent set of 1,587 patients and 1,827 control subjects from the U.K. and found no evidence of association. Overall, our results indicate that common sequence variation in the VDR gene has no major effect in type 1 diabetes in the populations tested.

Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus.

In the genetic analysis of common, multifactorial diseases, such as type 1 diabetes, true positive irrefutable linkage and association results have been rare to date. Recently, it has been reported that a single nucleotide polymorphism (SNP), 1858C>T, in the gene PTPN22, encoding Arg620Trp in the lymphoid protein tyrosine phosphatase (LYP), which has been shown to be a negative regulator of T-cell activation, is associated with an increased risk of type 1 diabetes. Here, we have replicated these findings in 1,388 type 1 diabetic families and in a collection of 1,599 case and 1,718 control subjects, confirming the association of the PTPN22 locus with type 1 diabetes (family-based relative risk (RR) 1.67 [95% CI 1.46-1.91], and case-control odds ratio (OR) 1.78 [95% CI 1.54-2.06]; overall P = 6.02 x 10(-27)). We also report evidence for an association of Trp(620) with another autoimmune disorder, Graves' disease, in 1,734 case and control subjects (P = 6.24 x 10(-4); OR 1.43 [95% CI 1.17-1.76]). Taken together, these results indicate a more general association of the PTPN22 locus with autoimmune disease.

Adolescents with current major depressive disorder show dissimilar patterns of age-related differences in ACC and thalamus.

OBJECTIVE: There is little understanding of the neural system abnormalities subserving adolescent major depressive disorder (MDD). In a cross-sectional study we compare currently unipolar depressed with healthy adolescents to determine if group differences in grey matter volume (GMV) were influenced by age and illness severity. METHOD: Structural neuroimaging was performed on 109 adolescents with current MDD and 36 healthy controls, matched for age, gender, and handedness. GMV differences were examined within the anterior cingulate cortex (ACC) and across the whole-brain. The effects of age and self-reported depressive symptoms were also examined in regions showing significant main or interaction effects. RESULTS: Whole-brain voxel based morphometry revealed no significant group differences. At the whole-brain level, both groups showed a main effect of age on GMV, although this effect was more pronounced in controls. Significant group-by-age interactions were noted: A significant regional group-by-age interaction was observed in the ACC. GMV in the ACC showed patterns of age-related differences that were dissimilar between adolescents with MDD and healthy controls. GMV in the thalamus showed an opposite pattern of age-related differences in adolescent patients compared to healthy controls. In patients, GMV in the thalamus, but not the ACC, was inversely related with self-reported depressive symptoms. CONCLUSIONS: The depressed adolescent brain shows dissimilar age-related and symptom-sensitive patterns of GMV differences compared with controls. The thalamus and ACC may comprise neural markers for detecting these effects in youth. Further investigations therefore need to take both age and level of current symptoms into account when disaggregating antecedent neural vulnerabilities for MDD from the effects of MDD on the developing brain.

Symmetric dimethylarginine, an endogenous marker of glomerular filtration rate, and the risk for microalbuminuria in young people with type 1 diabetes.

OBJECTIVES: To perform a cross-sectional comparison of endogenous markers of glomerular filtration rate (GFR) (plasma symmetric dimethylarginine (SDMA) and estimated GFR (eGFR)) with a direct measure of GFR (using the plasma clearance of Inutest (In-GFR)), and a longitudinal evaluation of these markers in relation to the development of microalbuminuria, in young people with type 1 diabetes (T1D). METHODS: Longitudinal stored blood samples (n=1105) were available from 417 young people from the Oxford Regional Prospective Study (an inception cohort of 527 children followed for a median of 10.3 (interquartile range 7.1-12.3) years), for measurement of SDMA and creatinine. Additional annually collected data on anthropometric parameters, HbA1c, insulin dose and three early morning albumin:creatinine ratios were available. In-GFR was measured in a representative subgroup of 183 subjects. MAIN OUTCOME MEASURES: SDMA and eGFR. RESULTS: SDMA and eGFR were significantly and similarly associated with In-GFR (r=-0.38 and r=0.36, p<0.001). Overall SDMA levels were lower in microalbuminuric (n=116) than normoalbuminuric subjects (n=301) (0.385 + or - 0.063 vs 0.412 + or - 0.059 micromol/l, p<0.001), probably reflecting hyperfiltration. The pattern of change in SDMA levels with age differed between microalbuminuric and normoalbuminuric subjects. Whereas SDMA levels declined in both groups until the age of 16 years, thereafter they tended to rise only in microalbuminuric subjects, probably reflecting a decline in renal function. CONCLUSIONS: In this longitudinal study of young people with T1D, measurement of SDMA, in contrast to eGFR, proved to be a reliable marker in identifying changes in filtration rates associated with the development of microalbuminuria (MA).

Maternal but not paternal association of ambulatory blood pressure with albumin excretion in young offspring with type 1 diabetes.

OBJECTIVE: Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean +/- SD age 15.8 +/- 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS: All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP beta = 0.18, 24-h DBP beta = 0.22, daytime SBP beta = 0.25, daytime DBP beta = 0.23, and nighttime DBP beta = 0.18; all P < 0.01). Maternal 24-h DBP (beta = 0.19, P = 0.004), daytime DBP (beta = 0.09, P = 0.04), and nighttime SBP (beta = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (beta = 0.16, P = 0.02), daytime DBP (beta = 0.16 P = 0.02), and nighttime DBP (beta = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05). CONCLUSIONS: In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk.

Prevalence of abnormal lipid profiles and the relationship with the development of microalbuminuria in adolescents with type 1 diabetes.

OBJECTIVE: To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes. RESEARCH DESIGN AND METHODS: The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10-21.1), and median diabetes duration was 4.8 years (0.2-17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available. RESULTS: Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P < 0.001). A significant proportion of subjects presented sustained lipid abnormalities during follow-up: total cholesterol >5.2 mmol/l (18.6%), non-HDL cholesterol >3.4 mmol/l (25.9%), TG >1.7 mmol/l (20.1%), and LDL cholesterol >3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P < 0.001); A1C was independently related to all parameters (P < 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P < 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient +/- SE): 0.03 +/- 0.01/1 mmol/l, P = 0.009, and 0.32 +/- 0.014/1 mmol/l, P = 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n = 115) than in normoalbuminuric subjects (n = 780): total cholesterol 4.7 +/- 1.2 vs. 4.5 +/- 0.8 mmol/l (P = 0.04) and non-HDL cholesterol 3.2 +/- 1.2 vs. 2.9 +/- 0.8 mmol/l (P = 0.03). CONCLUSIONS: In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy.

C-reactive protein in relation to the development of microalbuminuria in type 1 diabetes: the Oxford Regional Prospective Study.

OBJECTIVES: To perform a longitudinal evaluation of high-sensitivity C-reactive protein (hs-CRP) in young people with type 1 diabetes in relation to the development of microalbuminuria (MA). RESEARCH DESIGN AND METHODS: hs-CRP was measured in 329 blood samples collected from 49 subjects with type 1 diabetes with MA and 49 normoalbuminuric subjects matched for age, sex, and duration of diabetes. RESULTS: In subjects developing MA, a progressive rise in hs-CRP was detected with levels significantly higher in the years after the onset of MA when compared with levels before MA onset (P = 0.003; age-adjusted P = 0.06). After the onset of MA, hs-CRP levels were significantly higher in subjects with MA when compared with normoalbuminuric subjects (median 1.9 mg/l [range 0.2-9.8] vs. 1.1 mg/l [0.2-6.4]; P = 0.02; adjusted P = 0.036). CONCLUSIONS: In this population of young subjects with type 1 diabetes, there was a significant increase in hs-CRP levels after the onset of MA, likely reflecting a general state of inflammation.

Risk of microalbuminuria and progression to macroalbuminuria in a cohort with childhood onset type 1 diabetes: prospective observational study.

OBJECTIVES: To describe independent predictors for the development of microalbuminuria and progression to macroalbuminuria in those with childhood onset type 1 diabetes. DESIGN: Prospective observational study with follow-up for 9.8 (SD 3.8) years. SETTING: Oxford regional prospective study. PARTICIPANTS: 527 participants with a diagnosis of type 1 diabetes at mean age 8.8 (SD 4.0) years. MAIN OUTCOME MEASURES: Annual measurement of glycated haemoglobin (HbA1c) and assessment of urinary albumin:creatinine ratio. RESULTS: Cumulative prevalence of microalbuminuria was 25.7% (95% confidence interval 21.3% to 30.1%) after 10 years of diabetes and 50.7% (40.5% to 60.9%) after 19 years of diabetes and 5182 patient years of follow-up. The only modifiable adjusted predictor for microalbuminuria was high HbA1c concentrations (hazard ratio per 1% rise in HbA1c 1.39, 1.27 to 1.52). Blood pressure and history of smoking were not predictors. Microalbuminuria was persistent in 48% of patients. Cumulative prevalence of progression from microalbuminuria to macroalbuminuria was 13.9% (12.9% to 14.9%); progression occurred at a mean age of 18.5 (5.8) years. Although the sample size was small, modifiable predictors of macroalbuminuria were higher HbA(1c) levels and both persistent and intermittent microalbuminuria (hazard ratios 1.42 (1.22 to 1.78), 27.72 (7.99 to 96.12), and 8.76 (2.44 to 31.44), respectively). CONCLUSION: In childhood onset type 1 diabetes, the only modifiable predictors were poor glycaemic control for the development of microalbuminuria and poor control and microalbuminuria (both persistent and intermittent) for progression to macroalbuminuria. Risk for macroalbuminuria is similar to that observed in cohorts with adult onset disease but as it occurs in young adult life early intervention in normotensive adolescents might be needed to improve prognosis.

Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms.

As part of an ongoing search for genes associated with type 1 diabetes (T1D), a common autoimmune disease, we tested the biological candidate gene IL2RA (CD25), which encodes a subunit (IL-2R alpha) of the high-affinity interleukin-2 (IL-2) receptor complex. We employed a tag single-nucleotide polymorphism (tag SNP) approach in large T1D sample collections consisting of 7,457 cases and controls and 725 multiplex families. Tag SNPs were analyzed using a multilocus test to provide a regional test for association. We found strong statistical evidence in the case-control collection (P=6.5x10(-8)) for a T1D locus in the CD25 region of chromosome 10p15 and replicated the association in the family collection (P=7.3x10(-3); combined P=1.3x10(-10)). These results illustrate the utility of tag SNPs in a chromosome-regional test of disease association and justify future fine mapping of the causal variant in the region.