Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Genetic risk score has added value over initial clinical grading stage in predicting disease progression in age-related macular degeneration.

Several prediction models for progression of age-related macular degeneration (AMD) have been developed, but the added value of using genetic information in those models in addition to clinical characteristics is ambiguous. In this prospective cohort study, we explored the added value of genetics using a genetic risk score (GRS) based on 52 AMD-associated variants, in addition to the clinical severity grading at baseline as quantified by validated drusen detection software, to predict disease progression in 177 AMD patients after 6.5 years follow-up. The GRS was strongly associated with the drusen coverage at baseline (P < 0.001) and both the GRS and drusen coverage were associated with disease progression. When the GRS was added as predictor in addition to the drusen coverage, R2 increased from 0.46 to 0.56. This improvement by the GRS was predominantly seen in patients with a drusen coverage <15%. In patients with a larger drusen coverage, the GRS had less added value to predict progression. Thus, genetic information has added value over clinical characteristics in predicting disease progression in AMD, but only in patients with a less severe disease stage. Patients with a high GRS should be made aware of their risk and could be selected for clinical trials for arresting progression.

Digital Mammography Screening: Does Age Influence the Detection Rates of Low-, Intermediate-, and High-Grade Ductal Carcinoma in Situ?

PURPOSE: To investigate the association between age at screening and detection rates for ductal carcinoma in situ (DCIS) separately for different nuclear grades after introduction of a population-based digital mammography screening program. MATERIALS AND METHODS: The retrospective study was approved by the ethics board and did not require informed consent. In 733 905 women aged 50-69 years who participated in a screening program for the first time in 2005-2008 (baseline examinations were performed with digital mammography), DCIS detection rates were determined for 5-year age groups (detection rates per 1000 women screened) to distinguish high-, intermediate-, and low-grade DCIS. Multivariable logistic regression was used to compare detection rates between age groups by adjusting for screening units (P < .05). RESULTS: There were 989 graded DCIS diagnoses among 733 905 women (detection rate, 1.35‰): 419 diagnoses of high-grade DCIS (detection rate, 0.57‰), 388 diagnoses of intermediate-grade DCIS (detection rate, 0.53‰), and 182 diagnoses of low-grade DCIS (detection rate, 0.25‰). Detection rate for types of DCIS combined increased significantly across age groups (50-54 years, detection rate of 1.15‰ [254 of 220 985 women]; 55-59 years, detection rate of 1.23‰ [218 of 177 782 women]; 60-64 years, detection rate of 1.34‰ [201 of 150 415 women]; and 65-69 years, detection rate of 1.71‰ [316 of 184 723 women]; P < .001). Of note, the detection rate for high-grade DCIS showed a significant increase with age (odds ratio, 1.18 per 5-year age group; P < .0001). The increase was lower for intermediate-grade DCIS (odds ratio, 1.11; P = .016) and not significant for low-grade DCIS (P = .10). CONCLUSION: Total DCIS detection rates increase with age, mostly because of an increase in high- and intermediate-grade DCIS, which are precursor lesions that carry a higher risk for transition to more aggressive invasive breast cancer than low-grade DCIS.

Relationship between N-terminal pro-brain natriuretic peptide, obesity and the risk of heart failure in middle-aged German adults.

BACKGROUND: Both high concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP) and obesity are related to higher heart failure risk. However, inverse relationships between NT-proBNP and obesity have been reported. Therefore, it was investigated whether the association between NT-proBNP and the risk of heart failure differed according to obesity status. METHODS: A case-cohort study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam, comprising a random sub-cohort (non-cases = 1,150, cases = 13, mean age: 50.5±9.0 years) and heart failure cases outside the sub-cohort (n = 197). Weighted Cox proportional hazards regression was used to examine the association between NT-proBNP and heart failure risk during a mean follow-up time of 8 years. Stratified analyses were performed according to obesity status as defined by body mass index (<30 kg/m2 versus ≥30 kg/m2). RESULTS: Overall, NT-proBNP was associated with higher risk of heart failure after multivariable adjustment (hazard ratio (HR) and 95% confidence interval (CI): 2.56 (1.49-4.41) for the top versus bottom tertile of NT-proBNP, ptrend:<0.01). In stratified analyses, the shape of association was linear in non-obese and U-shaped in obese participants: HRs (95%CI) from the first to the third tertile of NT-proBNP for non-obese: reference, 1.72 (0.85-3.49), 2.72 (1.42-5.22), and for obese: 3.29 (1.04-10.40), reference, 3.74 (1.52-9.21). CONCLUSIONS: Although high circulating concentrations of NT-proBNP were positively associated with incident heart failure in the entire sample, the association differed according to obesity status. In obese, an increased risk of heart failure was also observed in those with low NT-proBNP concentrations. If confirmed, this observation warrants further investigation to understand underlying pathophysiological mechanisms.

Plasma fibroblast growth factor 23, parathyroid hormone, 25-hydroxyvitamin D3, and risk of heart failure: a prospective, case-cohort study.

CONTEXT: Bone mineral metabolism may play a role in the development of heart failure (HF). OBJECTIVE: The aim of the study was to investigate the relationships of plasma fibroblast growth factor (FGF) 23, PTH, and 25-hydroxyvitamin D3 [25(OH)D3] with incident congestive HF in a population-based cohort of men and women aged 40-65 and 35-65 years, respectively, at baseline. DESIGN: We conducted a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, including a randomly drawn sample of the total cohort free of HF and all incident HF cases that occurred during a mean follow-up of 8.2 ± 1.6 years. PARTICIPANTS AND SETTING: A total of 221 incident congestive HF cases and 1228 individuals free of HF were included in the study. MAIN OUTCOME MEASURES: Incident congestive HF was measured. RESULTS: In a multivariable model, each doubling of FGF23 [ie, per log (base 2) unit higher FGF23] was associated with a 29% higher HF risk (hazard ratio, 1.29 [95% confidence interval (CI), 1.07-1.56]). After multivariable adjustment, including estimated glomerular filtration rate, PTH was not related to HF risk (hazard ratio per doubling of PTH, 1.21 [95% CI, 0.99-1.48]). However, an interaction was observed between PTH and obesity, suggesting a relationship with HF risk in obese, but not in nonobese individuals. The hazard ratio for HF per doubling of 25(OH)D3 was 1.02 (95% CI, 0.73-1.41). CONCLUSIONS: Our findings provide epidemiological evidence for a positive relationship between FGF23 and risk of HF. The role of PTH in the development of HF remains unclear, in particular in obese individuals, until further confirmation in other studies. 25(OH)D3 was not related to HF.

The trade-off between population and individual benefit of screening.

In cancer screening there is a delicate balance between the benefit for the population and the individual benefit. In different European mammography and other screening programmes major differences were observed regarding detection rates and false positive rates. With massive screening programmes starting in Germany, careful evaluation of their performance and achievement is mandatory, including a determination of the false negative rates. This requires the determination of interval cancer rates on the basis of complete population-based cancer registries.

Short-period heart rate variability in the general population as compared to patients with acute myocardial infarction from the same source population.

BACKGROUND: Our aim was to compare the distribution and determinants of heart rate variability (HRV) measures in a middle-aged population with patients of the same sex and age after an acute myocardial infarction (AMI), and to show, whether HRV values defined as abnormal from the general population are indicative for a worse prognosis even in AMI patients. METHODS: HRV was studied in a random sample of 149 middle-aged men and 137 women from the general population (45-65 years) as well as 129 consecutive AMI patients (25-74 years). Spectral analysis was used to compute low frequency (LF), high frequency (HF), and total frequency power. To the AMI population of age 45-65 years (N = 85) a sample out of the general population was matched by age and sex by 2:1 matching (N = 149). All AMI patients were followed for a median of 43 months (range 1-47) for death or malignant arrhythmia. RESULTS: All measures of HRV were significantly and substantially lower in AMI patients than the general population (P < 0.001). Expression in relative terms revealed that the proportionate contributions of HF and LF to total power were significantly different in the two populations with relatively lower LF power in AMI patients (P < 0.01). The negative correlation with heart rate and HRV measures was significantly more pronounced in AMI patients (P < 0.01). The 2.5th percentile of the LF power distribution in the general population (3.08 ln ms2) corresponds to the 25th percentile in the AMI population. Subjects of the whole AMI population with values below this LF cutpoint revealed a significant increased risk of death or malignant arrhythmia during follow-up (odds ratio 5.1; 95% confidence interval: 1.3; 23). CONCLUSIONS: AMI patients had strongly diminished HRV compared to the general population. The relatively lower LF power indicates an alteration of the sympathico-vagal balance, and the significantly stronger correlation of heart rate with HRV may be indicative for a more pronounced effect of sympathetic activation on autonomic modulation in the case of myocardial infarction. Finally, a value below the 2.5th percentile of the population LF power distribution may identify subjects at risk and warrant further testing.