Ulf Schminke

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Genome-wide association study reveals three susceptibility loci for common migraine in the general population

Migraine is a common, heterogeneous and heritable neurological disorder. Its pathophysiology is incompletely understood, and its genetic influences at the population level are unknown. In a population-based genome-wide analysis including 5,122 migraineurs and 18,108 non-migraineurs, rs2651899 (1p36.32, PRDM16), rs10166942 (2q37.1, TRPM8) and rs11172113 (12q13.3, LRP1) were among the top seven associations (P < 5 × 10−6) with migraine. These SNPs were significant in a meta-analysis among three replication cohorts and met genome-wide significance in a meta-analysis combining the discovery and replication cohorts (rs2651899, odds ratio (OR) = 1.11, P = 3.8 × 10−9; rs10166942, OR = 0.85, P = 5.5 × 10−12; and rs11172113, OR = 0.90, P = 4.3 × 10−9). The associations at rs2651899 and rs10166942 were specific for migraine compared with non-migraine headache. None of the three SNP associations was preferential for migraine with aura or without aura, nor were any associations specific for migraine features. TRPM8 has been the focus of neuropathic pain models, whereas LRP1 modulates neuronal glutamate signaling, plausibly linking both genes to migraine pathophysiology.

Three-Dimensional Ultrasound Observation of Carotid Artery Plaque Ulceration

BACKGROUND AND PURPOSE Carotid artery plaque ulceration is associated with an increased risk of cerebral embolism. However, because of the rather poor diagnostic quality of conventional 2-D ultrasound and angiography compared with the evaluation of pathological specimens, little information exists on the natural course of carotid plaque ulceration. Recently, the introduction of 3-D ultrasound has made reproducible investigation of plaque morphology possible, providing a reliable plaque surface analysis. METHODS We performed 3-D ultrasound examinations of 17 carotid artery plaques with an ulcerated surface in a prospective study of 16 patients (10 men, 6 women; mean+/-SD age 68.9+/-7.1 years) over a mean observation period of 17.6+/-6.3 months. Exactly parallel B-mode ultrasound scans (slice distance 0.1 mm) were acquired with a 5-MHz linear array probe clamped in a carriage device and driven by a mechanical step motor. The recorded images were reconstructed into a volumetric data set in a Cartesian coordinate system. RESULTS At the end of the observation period, surface configuration had changed in 4 cases (23.5%). Plaque ulceration regressed in 3 cases, whereas ulcer progression occurred in 1 case. The remaining 13 plaques (76. 5%) showed an unchanged surface configuration. CONCLUSIONS Through the use of 3-D ultrasound, it is possible to noninvasively examine the regression and progression of carotid artery plaque ulceration.

Lifestyle Risk Factors for Ischemic Stroke and Transient Ischemic Attack in Young Adults in the Stroke in Young Fabry Patients Study

Background and Purpose— Although many stroke patients are young or middle-aged, risk factor profiles in these age groups are poorly understood. Methods— The Stroke in Young Fabry Patients (sifap1) study prospectively recruited a large multinational European cohort of patients with cerebrovascular events aged 18 to 55 years to establish their prevalence of Fabry disease. In a secondary analysis of patients with ischemic stroke or transient ischemic attack, we studied age- and sex-specific prevalences of various risk factors. Results— Among 4467 patients (median age, 47 years; interquartile range, 40–51), the most frequent well-documented and modifiable risk factors were smoking (55.5%), physical inactivity (48.2%), arterial hypertension (46.6%), dyslipidemia (34.9%), and obesity (22.3%). Modifiable less well-documented or potentially modifiable risk factors like high-risk alcohol consumption (33.0%) and short sleep duration (20.6%) were more frequent in men, and migraine (26.5%) was more frequent in women. Women were more often physically inactive, most pronouncedly at ages <35 years (18–24: 38.2%; 25–34: 51.7%), and had high proportions of abdominal obesity at age 25 years or older (74%). Physical inactivity, arterial hypertension, dyslipidemia, obesity, and diabetes mellitus increased with age. Conclusions— In this large European cohort of young patients with acute ischemic cerebrovascular events, modifiable risk factors were highly prevalent, particularly in men and older patients. These data emphasize the need for vigorous primary and secondary prevention measures already in young populations targeting modifiable lifestyle vascular risk factors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00414583.

Association Between Behavior-Dependent Cardiovascular Risk Factors and Asymptomatic Carotid Atherosclerosis in a General Population

Background and Purpose— Physical inactivity and unfavorable dietary and lifestyle patterns are related to cardiovascular disease and premature death. Their relationship to atherosclerosis of the carotid arteries and subsequent stroke is unclear. The objective of this study was to investigate the association between those behavioral cardiovascular risk factors and asymptomatic atherosclerosis of the carotid arteries in a population of former East Germany. Methods— The Study of Health in Pomerania (SHIP) is a cross-sectional survey in northeast Germany. In 1632 individuals aged 45 to 70 years, high-resolution B-mode ultrasound was used to assess the mean intima-media thickness of the right and left common carotid arteries. Carotid plaques and stenosis were recorded. Physical activity, dietary patterns, and cardiovascular risk factors were assessed in interviews with the use of standardized scales. Physically active participants with optimal dietary patterns were classified in the optimal lifestyle group, and those inactive with unfavorable diet were classified in the unfavorable group. Results— After adjustment for sex and age, significant decreasing trends were found for both intima-media thickness and severe asymptomatic atherosclerosis from unfavorable to optimal lifestyle patterns in never smokers but not in smokers. Regression analysis revealed an increased risk of severe asymptomatic atherosclerosis in subjects with an unfavorable lifestyle pattern compared with those with an optimal pattern (odds ratio 2.68; 95% CI, 1.13 to 6.37), following a significant linear trend. Conclusions— Physical activity and optimal diet are associated with reduced risk of early atherosclerosis in subjects who never smoked, while no benefit of an otherwise optimal lifestyle is observed in smokers.

Alexithymia, hypertension, and subclinical atherosclerosis in the general population

OBJECTIVES As a personality trait, alexithymia is assumed to present a longstanding risk factor for emotional dysregulation that also affects the autonomic nervous system. Therefore, we hypothesize that alexithymia is associated with hypertension and carotid atherosclerosis in the general population. METHODS A total of 1168 subjects (age <65 years) from the Study of Health in Pomerania (SHIP) were eligible for complete case analyses. Alexithymia was assessed with the 20-item Toronto-Alexithymia-Scale (TAS-20). An extensive interview and physical examination were performed. Extracranial carotid arteries were examined bilaterally with B-mode ultrasonography. Regression models were adjusted for sociodemographic factors and classical risk factors for cardiovascular diseases and mental distress. RESULTS In the adjusted logistic regression models, alexithymia was significantly associated with hypertension (OR=1.60; 95% CI=1.14-2.25) and with atherosclerotic plaques (OR=1.70; 95% CI=1.14-2.54). Hypertension changed the effect of alexithymia on atherosclerosis only marginally (OR=1.76 to 1.70). CONCLUSION Alexithymia may represent a relevant and independent risk factor for hypertension and carotid atherosclerosis at the population level. None of the putative confounders mediated a relevant proportion of the risk. Prospective studies are needed to confirm this association.

Current management and risk of recurrent stroke in cerebrovascular patients with right-to-left cardiac shunt.

Background: Right-to-left cardiac shunt (RLS) is considered a risk factor for stroke, especially in patients aged <55 years. We aimed to investigate the current management and prognosis in consecutive patients with RLS and otherwise cryptogenic cerebrovascular events. Methods: In total, 1,126 patients with cryptogenic stroke or TIA were included from 17 German neurology departments. During a mean follow-up of 28.4 months, we assessed current antithrombotic medication, percutaneous device closure (PDC) and recurrent cerebrovascular events in 899 patients (79.8%). Stroke recurrence was compared between 548 patients without RLS and 351 patients with RLS under various prevention regimens. Results: RLS was detected in 35.9% of cryptogenic cerebrovascular patients, but could not be evaluated as an independent predictor for recurrent stroke (adjusted HR 1.6, 95% CI: 0.9–2.7). In RLS-positive patients, the Kaplan-Meier estimate for stroke during the first year was 4.1% (95% CI: 1.9–6.3%) and 1.7% (95% CI: 0.9–2.4%) per year thereafter. At the last follow-up before recurrent stroke or end of study, 117 RLS-positive patients (33.3%) had received a PDC, 154 (43.9%) were receiving antiplatelets, 63 (17.9%) received anticoagulation, and 17 (4.8%) received none of the above. No association with recurrent stroke was found for the secondary preventive regime. Conclusion: Our multicenter hospital-based cohort study confirmed low recurrent event rates in RLS patients with otherwise cryptogenic stroke or TIA, as well as a great heterogeneity of current management. Despite the lack of scientific evidence, a substantial number of RLS-positive patients underwent PDC for secondary stroke prevention.

Burden Analysis of Rare Microdeletions Suggests a Strong Impact of Neurodevelopmental Genes in Genetic Generalised Epilepsies

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

Common Carotid Intima-Media Thickness and Framingham Risk Score Predict Incident Carotid Atherosclerotic Plaque Formation Longitudinal Results From the Study of Health in Pomerania

Background and Purpose— Cross-sectional studies describe a positive association between common carotid artery intima-media thickness (CCA-IMT) and carotid plaques (CP). However, longitudinal data on the predictive value of CCA-IMT for occurrence of CP are limited. Therefore, the role of increasing CCA-IMT in the atherosclerotic process is still discussed controversially. Methods— We investigated the predictive value of CCA-IMT and the Framingham risk score (FRS) for incident CP formation in a population-based longitudinal study of 1922 subjects aged 45 to 81 years who underwent ultrasonography of both carotid arteries and received vascular risk factor assessment at baseline and after 5 years. CP was defined as any protruding focal thickening of the intima-media complex. Incident CP formation during follow-up was defined as the appearance of at least 1 CP in a previously plaque-free arterial segment (right and left common, internal, and external carotid arteries and carotid bifurcation). Results— Among the 636 subjects without CP at baseline, 418 (66%) had at least 1 incident CP during follow-up. In a multivariable negative binominal regression model adjusted for age, gender, and the FRS, the number of arterial segments affected by incident CP was 1.53-fold higher (CI, 1.12–2.07; P<0.01) for subjects in the highest quartile of the overall CCA-IMT distribution compared to those in the lowest quartile. Conclusions— Both CCA-IMT and FRS independently predict incident CP formation. The risk of CP formation may actually be underestimated in subjects with low FRS and high IMT.

Association Between Alcohol Consumption and Subclinical Carotid Atherosclerosis The Study of Health in Pomerania

Background and Purpose— Epidemiologic studies have shown a J-shaped association between alcohol consumption and vascular diseases. However, only few studies have reported on the association between alcohol intake and subclinical atherosclerosis. The aim of the study was to investigate the relation between alcohol intake and carotid intima-media thickness (IMT) in participants of the population-based Study of Health in Pomerania. Methods— In 1230 men and 1190 women, the mean IMT of the right and left common carotid arteries was measured by B-mode ultrasonography. Alcohol consumption was assessed with a computer-assisted face-to-face interview. Results— In men, carotid IMT as a function of alcohol intake was depicted as a J-shaped curve with a nadir for the alcohol intake category of 61 to 80g/d. Linear regression models controlled for age, diabetes, systolic blood pressure, leisure time physical activity, food frequency patterns, smoking status, and education revealed a significant inverse association between IMT and alcohol intake ≤80g/d in men (β=−0.009, P<0.02), which became insignificant after further controlling for HDL cholesterol and fibrinogen (β=−0.007, P=NS). In women, neither a J-shaped relation nor significant differences in IMT between the drinking and nondrinking groups were found. Conclusions— Alcohol consumption is inversely correlated with carotid IMT in men but not in women. However, the total daily level of alcohol intake that shows a maximum protective effect against atherosclerosis is above the threshold where severe alcohol related comorbidity and organ damage have been reported.