Robin Haring

University of Greifswald, Griefswald, Mecklenburg-Vorpommern, Germany

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Publications (71)359.24 Total impact

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    ABSTRACT: Background Elevated glycated hemoglobin (HbA1c) is associated with increased risk of cardiovascular disease (CVD) and mortality but little is known about potential mechanisms underlying the reported associations. Methods We used data from 1,798 non-diabetic participants from the population-based cohort Study of Health in Pomerania (SHIP) to investigate cross-sectional and longitudinal associations of HbA1c with subclinical atherosclerosis (common carotid artery intima-media thickness [CCA-IMT]), cardiac structure (left ventricular mass [LVM]), and cardiac function (fractional shortening). Results Cross-sectional analyses revealed a positive association between HbA1c and mean CCA-IMT with a 0.02 mm (95% confidence interval: 0.01–0.04) increase in CCA-IMT per 1% increase in HbA1c, and a similar positive trend across HbA1c quartiles (overall p-value <0.01). We also observed a graded association between HbA1c and high CCA-IMT (>75th percentile) with an odds ratio of 1.42 (95% CI: 1.11–1.81) per 1% increase in HbA1c. Longitudinal analyses showed no consistent associations of baseline HbA1c with mean follow-up CCA-IMT. There were no consistent associations of HbA1c with cardiac remodeling in cross-sectional and longitudinal analyses, respectively. Conclusions The association between HbA1c and CCA-IMT in non-diabetic adults may be a crucial link between high-normal HbA1c levels and an increased risk of CVD and mortality.
    Diabetes Research and Clinical Practice 09/2014; · 2.54 Impact Factor
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    ABSTRACT: Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
    Nature 07/2014; 514(7520):92-7. · 42.35 Impact Factor
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    ABSTRACT: Low total testosterone (TT) and sex hormone-binding globulin (SHBG) concentrations have been associated with the metabolic syndrome (MetS) in men, but the reported strength of association varies considerably.
    PLoS ONE 07/2014; 9(7):e100409. · 3.53 Impact Factor
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    ABSTRACT: Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
    PLoS Medicine 07/2014; 11(7):e1001680. · 15.25 Impact Factor
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    ABSTRACT: Individualized Medicine aims at providing optimal treatment for an individual patient at a given time based on his specific genetic and molecular characteristics. This requires excellent clinical stratification of patients as well as the availability of genomic data and biomarkers as prerequisites for the development of novel diagnostic tools and therapeutic strategies. The University Medicine Greifswald, Germany, has launched the "Greifswald Approach to Individualized Medicine" (GANI_MED) project to address major challenges of Individualized Medicine. Herein, we describe the implementation of the scientific and clinical infrastructure that allows future translation of findings relevant to Individualized Medicine into clinical practice.Methods/design: Clinical patient cohorts (N > 5,000) with an emphasis on metabolic and cardiovascular diseases are being established following a standardized protocol for the assessment of medical history, laboratory biomarkers, and the collection of various biosamples for bio-banking purposes. A multi-omics based biomarker assessment including genome-wide genotyping, transcriptome, metabolome, and proteome analyses complements the multi-level approach of GANI_MED. Comparisons with the general background population as characterized by our Study of Health in Pomerania (SHIP) are performed. A central data management structure has been implemented to capture and integrate all relevant clinical data for research purposes. Ethical research projects on informed consent procedures, reporting of incidental findings, and economic evaluations were launched in parallel.
    Journal of translational medicine. 05/2014; 12(1):144.
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    ABSTRACT: Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by x-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA, n=14,260), velocity of sound (VOS, n=15,514) and BMD (n=4,566) in 13 discovery cohorts. Independent replication involved 7 cohorts with GWA data (in silico n=11,452) and new genotyping in 15 cohorts (de novo n=24,902). In combined random effects meta-analysis of the discovery and replication cohorts, 9 SNPs had genome-wide significant (p<5×10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708), and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (p<8.23×10(-14)). In meta-analyses involving 25 cohorts with up to 14,985 fracture cases, six of 10 SNPs associated with heel bone properties at p<5×10(-6) also had the expected direction of association with any fracture (p<0.05), including 3 SNPs with p<0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007), and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.
    Human Molecular Genetics 01/2014; · 6.68 Impact Factor
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    ABSTRACT: Low total testosterone (TT) serum concentrations in men have been associated with various cardiometabolic risk factors. But given error-prone immunoassays used for TT assessment, upcoming mass spectrometry methods question the validity of these risk associations. Thus, we performed the first comparative study quantifying potential differences in the association of TT with cardiometabolic risk factors between the two methods. We used data from 1,512 men aged 20-81 years, recruited for the cross-sectional population-based Study of Health in Pomerania (SHIP), Germany. TT was repeatedly measured by chemiluminescent immunoassay (CLIA, Immulite 2500) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). We tested for significant differences between coefficients from CLIA- and LC-MS/MS-based multiple linear regression models associating TT with major cardiometabolic risk factors including adiposity, lipid metabolism, blood pressure, diabetic status, and inflammation. TT measurements by CLIA and LC-MS/MS yielded a Pearson correlation coefficient of 0.84. Only three of the ten tested associations for TT with cardiometabolic risk factor showed significant differences between the two measurement methods: in comparison to LC-MS/MS, CLIA-based TT assessment significantly underestimated risk associations of TT with waist circumference (ß: -0.54 vs. -0.63), body mass index (ß: -0.19 vs. -0.22), and ln-glucose levels (ß: -0.006 vs. -0.008). In the present comparative study, the CLIA platform showed a reasonable measurement error and yielded comparable risk associations, providing little support to measure TT concentrations in men from the general population exclusively by LC-MS/MS.
    European Journal of Endocrinology 07/2013; · 3.69 Impact Factor
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    ABSTRACT: Previous research has suggested a positive association between testosterone (T) and entrepreneurial behavior in males. However, this evidence was found in a study with a small sample size and has not been replicated. In the present study, we aimed to verify this association using two large, independent, population-based samples of males. We tested the association of T with entrepreneurial behavior, operationalized as self-employment, using data from the Rotterdam Study (N = 587) and the Study of Health in Pomerania (N = 1,697). Total testosterone (TT) and sex hormone-binding globulin (SHBG) were measured in the serum. Free testosterone (FT), non-SHBG-bound T (non-SHBG-T), and the TT / SHBG ratio were calculated and used as measures of bioactive serum T, in addition to TT adjusted for SHBG. Using logistic regression models, we found no significant associations between any of the serum T measures and self-employment in either of the samples. To our knowledge, this is the first large-scale study on the relationship between serum T and entrepreneurial behavior.
    Physiology & Behavior 06/2013; · 3.03 Impact Factor
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    ABSTRACT: : The association between sex hormones and blood pressure (BP) in women has been investigated mostly in cross-sectional studies yielding inconsistent results. : Data from 1428 women from the population-based Study of Health in Pomerania were used. Associations of total testosterone, androstenedione, sex hormone-binding globulin (SHBG), and free testosterone concentrations with BP and hypertension were analyzed in multivariable cross-sectional and longitudinal regression models in the full sample and stratified by menopausal status. : A positive association between total testosterone and BP was revealed in the full sample [SBP: β per standard deviation (SD) increase: 3.22; pulse pressure (PP): β per SD increase: 2.30] and among postmenopausal women (DBP: β per SD increase: 3.33; SBP: β per SD increase: 7.11; PP: β per SD increase: 3.77). Longitudinal analyses also showed a positive association between baseline total testosterone and follow-up BP. Furthermore, low total testosterone concentrations were associated with a decreased risk of prevalent hypertension in all women [relative risk (RR) quartile 1 (Q1) vs. Q4, 0.79; 95% confidence interval, CI 0.67-0.94]. Low SHBG was associated with prevalent hypertension in postmenopausal women (RR 1.27; 95% CI 1.06-1.53) and with incident hypertension in the full sample (RR 1.73; 95% CI 1.10-2.75). : The present population-based study is the first to show a consistent positive association between total testosterone and BP in both, cross-sectional and longitudinal analyses, suggesting high total testosterone as a risk marker of increased BP, as well as prevalent hypertension in women.
    Journal of Hypertension 06/2013; 31(6):1106-13. · 4.22 Impact Factor
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    ABSTRACT: BACKGROUND: To investigate potential associations of serum prolactin concentration (PRL) with metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM), previously observed in small and selected study samples, in a large population-based cohort. METHODS: Data from 3,993 individuals (2,027 women) aged 20-79 years from the population-based Study of Health of Pomerania (SHIP) were used to analyse cross-sectional and longitudinal associations of PRL with MetS and T2DM risk in age- and multivariable-adjusted Poisson regression models. PRL were log-transformed and modelled as continuous (per standard deviation (SD) increase) and categorical predictor (sex-specific quartiles) variable, separately for men and woman. RESULTS: Cross-sectional analyses showed an inverse association between low PRL concentrations and prevalent T2DM risk in men and women after multivariable-adjustment (men: Q1 vs. Q4: relative risk (RR), 1.55; 95% confidence interval (CI), 1.13 -- 2.14; women: Q1 vs. Q4: RR, 1.70; 95% CI, 1.10 -- 2.62). Likewise, higher PRL concentrations were associated with significantly lower T2DM risk (RR per SD increase in log-PRL: 0.83; 95% CI, 0.72 -- 0.95 in men, and 0.84; 95% CI, 0.71 -- 0.98 in women, respectively). An inverse association between PRL and MetS risk was not retained after multivariable adjustment. Longitudinal analyses yielded no association of PRL with incident MetS or T2DM. CONCLUSION: The present study is the first large population-based study reporting a cross-sectional inverse association between PRL and prevalent T2DM in both genders. But the absent longitudinal associations do not support a causal role of PRL as a risk factor of incident MetS or T2DM.
    BMC Endocrine Disorders 03/2013; 13(1):12. · 1.67 Impact Factor
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    ABSTRACT: Prospective studies showed that low serum testosterone concentrations are associated with various cardiometabolic risk factors and mortality. However, the causal nature of these associations is controversial. We studied 1 882 men aged 20-79 years with serum testosterone concentrations and genotyping data from the longitudinal population-based Study of Health in Pomerania. Testosterone concentrations were cross-sectionally associated with cardiometabolic risk factors, including anthropometric, lipid, blood pressure and glycaemic parameters; and prospectively with all-cause mortality (277 deaths, 14.7%) during the 10-year follow-up. To overcome problems of residual confounding, reverse causation, or regression dilution bias in the investigated testosterone-outcome associations, we used two-stage least square regression models with previously identified polymorphisms at the SHBG gene (rs12150660) and X chromosome (rs5934505) as multiple genetic instruments in an instrumental variable (IV) approach, also known as Mendelian randomization. In standard regression analyses, testosterone was robustly associated with a wide range of cardiometabolic risk factors. In subsequent IV analyses, no such significant associations were observed. Similarly, prospective analyses showed a consistent association of low testosterone concentrations with increased all-cause mortality risk, which was not apparent in subsequent IV analyses. The present Mendelian randomization analyses did not detect any evidence for causal associations of testosterone concentrations with cardiometabolic risk factors and mortality, suggesting that previously reported associations might largely result from residual confounding or reverse causation. Although testosterone assessment might improve risk prediction, implementation of testosterone replacement therapy requires further evidence of a direct effect on cardiometabolic outcomes from double-blinded randomized controlled trials and large-scale Mendelian randomization meta-analyses.
    Andrology 03/2013; 1(1):17-23. · 3.37 Impact Factor
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    ABSTRACT: Research in the last decade has revealed that bone is not only a target tissue for numerous circulating hormones but functions as an endocrine organ itself. As a recent study demonstrated a stimulatory effect of the osteoblast-derived hormone osteocalcin (OCN) on testosterone production in mice, we investigated whether such an association can be replicated in humans. We used data from 1338 men (25-86 years) in the population-based epidemiological Study of Health in Pomerania and from 110 male outpatients with bone disorders (18-85 years) for the study. We analysed cross-sectional associations between OCN and total testosterone serum concentrations (TT), as well as associations between further markers of bone turnover [bone-specific alkaline phosphatase (BAP), serum C-terminal telopeptides of Type I collagen (CTX), urinary deoxypyridinoline] and TT using ordinary least square (OLS) regression models. Multivariable OLS models revealed a positive association between OCN and TT in the population-based (β coefficients for a one standard deviation increase, 0.590; standard error (SE), 0.175; p-value, <0.01) and patient-based (β coefficient, 0.575; SE, 0.132; p-value, <0.01) samples even after adjustment for age and body mass index (both samples), and time of blood sampling (population-based sample only). Furthermore, we observed positive associations between BAP and TT (β coefficient, 0.403; SE, 0.170; p-value, 0.02) as well as between CTX and TT (β coefficient, 0.733; SE, 0.172; p-value, <0.01) in men from the general population. The present investigation shows that OCN is associated with TT in the general population and in patients with bone disorders, and may thus indicate general male health status. Additional longitudinal observational studies are warranted to confirm our findings and future experimental research is necessary to elucidate potential mechanisms underlying the observed associations.
    Andrology 01/2013; · 3.37 Impact Factor
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    ABSTRACT: BACKGROUND: Across the industrialized world, men experience an earlier onset of cardiovascular disease (CVD) and a life expectancy 5 to 10 years shorter than women. Low total testosterone (TT) concentrations in men have been suggested as a novel CVD risk factor, but its contribution to this gender gap is less well studied. METHODS: We used data of 4152 individuals (2113 women and 2039 men) aged 20 to 79 years from the longitudinal population-based cohort Study of Health in Pomerania, Germany. Multivariable Poisson and Cox proportional hazard regression models were used to investigate the risk of incident cardiovascular morbidity (5-year examination follow-up), as well as all-cause and CVD mortality (10-year follow-up) between men and women. Additionally, the added risk attributable to low TT in men (<10th percentile) was assessed. RESULTS: Compared with women, men were uniformly at higher risk of incident cardiovascular morbidity, including overweight, hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus. Men were also at increased all-cause mortality (hazard ratio = 2.05; 95% CI, 1.61-2.60) and 10-year CVD risk compared with women. In subgroup analyses, men with low TT showed the highest 10-year CVD and mortality risk compared with both men with higher TT and women. TT was also negatively associated with cardiovascular risk as defined by the Framingham risk score (P < 0.001), after multivariable adjustment. CONCLUSIONS: Analyzing a large population-based sample, we observed that men have a generally higher risk of incident cardiovascular morbidity and mortality. Furthermore, men with low TT concentrations were identified as high-risk individuals with regard to 10-year CVD and mortality risk.
    Gender Medicine 11/2012; · 1.55 Impact Factor
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    ABSTRACT: Dehydroepiandrosterone (DHEA) is the major precursor of human sex steroid synthesis and is inactivated via sulfonation to DHEAS. A previous genome-wide association study (GWAS) associated the single nucleotide polymorphism (SNP) rs2637125, located near the coding region of DHEA sulfotransferase, SULT2A1, with serum DHEAS concentrations. However, the functional relevance of this SNP with regard to DHEA sulfonation is unknown. Using data from 3,300 participants of the population-based cohort Study of Health in Pomerania (SHIP), we identified 43 individuals being homozygote for the minor allele of the SNP rs2637125 (AA), and selected two sex- and age-matched individuals with AG and GG genotype (N=172), respectively. Steroid analysis including measurement of serum DHEA and DHEAS was carried out by liquid chromatography/mass spectrometry, employing steroid oxime analysis for enhancing the sensitivity of DHEA detection. We applied quantile regression models to compare median hormone levels across SULT2A1 genotypes. Median comparisons by SULT2A1 genotype (AA vs. AG and GG genotypes, respectively) showed no differences in the considered hormones including DHEAS, DHEA, androstenedione, as well as cortisol and cortisone concentrations. SULT2A1 genotype also had no effect on the DHEA/DHEAS ratio. Sex-stratified analyses, as well as alternative use of the SULT2A1 SNP rs182420 yielded similar negative results. Genetic variants of SULT2A1 do not appear to have an effect on individual DHEA and DHEAS concentrations or the DHEA/DHEAS ratio as a marker of DHEA sulfonation capacity.
    Journal of Molecular Endocrinology 11/2012; 50(1). · 3.62 Impact Factor
    This article is viewable in ResearchGate's enriched format
  • Growth Hormone & IGF Research 10/2012; 22:S14. · 1.33 Impact Factor
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    ABSTRACT: Objectives: A dentition of at least 20 teeth is associated with sufficient masticatory efficiency and is a stated health goal of the World Health Organisation. We examined whether subjects with missing, unreplaced teeth had an increased mortality risk. Methods: We used data prospectively collected from those participants in the population-based Study of Health in Pomerania who had fewer than 20 remaining teeth, resulting in a sample of 1,803 participants with a mean age of 64 years. Of those, 188 subjects had 9 or more unreplaced teeth. During a median follow–up period of 9.9 years, 362 subjects died, 128 of whom of cardiovascular causes. Results: We found that having 9 or more unreplaced teeth was related to all–cause mortality (rate ratio 1.53, 95% CI: 1.11–2.10; adjusted for variables according to causal diagrams: remaining teeth, age, sex, education, income, marital status, partnership, and oral health behaviour) and cardiovascular mortality (rate ratio 1.94, 95% CI: 1.15–3.25). When adjusting not only for the variables according to causal diagrams but also for smoking, alcohol consumption, physical activity, obesity, hypertension, diabetes, and dyslipidemia, the rate ratio was 1.43 (95% CI: 1.05–1.96) for all–cause mortality and 1.88 (95% CI: 1.10–3.21) for cardiovascular mortality. Conclusions: A reduced, unrestored dentition is associated with increased mortality risk. Clinicians and dietitians have a responsibility to consider individual chewing ability in nutritional recommendations.
    PER/IADR Congress 2012; 09/2012
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    ABSTRACT: BACKGROUND: Emerging data from longitudinal studies suggest that low sex steroid concentrations in men are associated with increased cardiovascular risk and mortality. The impact of longitudinal trajectory patterns from serial sex steroid and gonadotrophin measurements on the observed associations is unknown to date. METHODS: We prospectively evaluated 254 elderly men (mean age: 75.5 years) of the Framingham Heart Study with up to four serial measurements of serum total testosterone (TT), dehydroepiandrosterone sulfate (DHEAS), follicle stimulating hormone (FSH), luteinizing hormone (LH), and total estradiol (EST); and constructed age- and multivariable-adjusted Cox proportional hazard regression models relating baseline hormone concentrations and their mean, slope, and variation over time (modelled as continuous and categorized into quartiles) to the incidence of clinical cardiovascular disease (CVD) and all-cause mortality at 5-years and 10-years of follow-up. RESULTS: We observed no association between baseline concentrations of sex steroids, gonadotrophins, and their trajectories with incident clinical CVD over 5-years and 10-years follow-up. Although higher baseline TT concentrations were associated with lower mortality risk at 5-years (hazard ratio per quartile increment, 0.74; 95% confidence interval, 0.56 - 0.98), correction for multiple statistical testing (p <0.005) rendered this association statistically non-significant. Repeat analyses at the 10-year follow-up time point also demonstrated no significant association between sex steroids, gonadotrophins, or their trajectories and mortality. CONCLUSION: Investigating longitudinal trajectory patterns of serial sex steroid and gonadotrophin measurements, the present study found no consistent associations with incident clinical CVD and all-cause mortality risk in elderly men in the community. © 2012 Blackwell Publishing Ltd.
    Clinical Endocrinology 08/2012; · 3.35 Impact Factor
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    ABSTRACT: AimsIncreased serum prolactin (PRL) concentrations have been associated with adverse cardiovascular risk profiles, but the relation between PRL and mortality risk is unknown.Methods and resultsWe evaluated 3929 individuals (1946 men and 1983 women) aged 20-81 (mean 50.3 years) from the population-based Study of Health in Pomerania (SHIP). Associations of continuous [per standard deviation (SD) increase] and categorized (sex-specific tertiles) serum PRL concentrations with all-cause and cause-specific mortality were analysed separately for men and women by age- and multivariable-adjusted Cox regression models. During a median follow-up period of 10.1 years (38 231 person-years), 419 deaths (10.7%), 132 cardiovascular deaths (3.4%), and 152 cancer deaths (3.9%) were observed. After multivariable adjustment, we observed a positive association of PRL with all-cause mortality in men and women [hazard ratio (HR) per SD increase: 1.17, 95% confidence interval (CI): 1.07-1.29 and HR: 1.22, 95% CI: 1.03-1.46, respectively]. Similarly, individuals with PRL concentrations in the highest tertile (when compared with lowest PRL tertile) experienced the highest mortality risk (men: HR, 1.75; 95% CI, 1.32-2.32; women: HR, 1.66; 95% CI, 1.08-2.56), with a significant trend across PRL tertiles (P- for trend <0.05). Cause-specific mortality analyses yielded similar associations for cardiovascular death in both sexes, but for cancer death only in men.Conclusion This is the first study to report an independent positive association of PRL concentrations with all-cause and cardiovascular mortality. Further studies are required to confirm our findings and to elucidate the potential role of PRL as a useful biomarker of cardiovascular risk and mortality assessment.
    European Heart Journal 07/2012; · 14.72 Impact Factor
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    ABSTRACT: Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.
    PLoS Genetics 07/2012; 8(7):e1002805. · 8.17 Impact Factor
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    ABSTRACT: The additional clinical value of clustering cardiovascular risk factors to define the metabolic syndrome (MetS) is still under debate. However, it is unclear which cardiovascular risk factors tend to cluster predominately and how individual risk factor states change over time. We used data from 3,187 individuals aged 20-79 years from the population-based Study of Health in Pomerania for a network-based approach to visualize clustered MetS risk factor states and their change over a five-year follow-up period. MetS was defined by harmonized Adult Treatment Panel III criteria, and each individual's risk factor burden was classified according to the five MetS components at baseline and follow-up. We used the map generator to depict 32 (2(5)) different states and highlight the most important transitions between the 1,024 (32(2)) possible states in the weighted directed network. At baseline, we found the largest fraction (19.3%) of all individuals free of any MetS risk factors and identified hypertension (15.4%) and central obesity (6.3%), as well as their combination (19.0%), as the most common MetS risk factors. Analyzing risk factor flow over the five-year follow-up, we found that most individuals remained in their risk factor state and that low high-density lipoprotein cholesterol (HDL) (6.3%) was the most prominent additional risk factor beyond hypertension and central obesity. Also among individuals without any MetS risk factor at baseline, low HDL (3.5%), hypertension (2.1%), and central obesity (1.6%) were the first risk factors to manifest during follow-up. We identified hypertension and central obesity as the predominant MetS risk factor cluster and low HDL concentrations as the most prominent new onset risk factor.
    PLoS ONE 06/2012; 7(6):e39461. · 3.53 Impact Factor

Publication Stats

1k Citations
359.24 Total Impact Points


  • 2007–2014
    • University of Greifswald
      • • Institute of Clinical Chemistry and Laboratory Medicine
      • • Institute of Community Medicine
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2012
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2011
    • King's College London
      • Department of Twin Research and Genetic Epidemiology
      London, ENG, United Kingdom
    • University of Gothenburg
      • Centre for Bone and Arthritis Research (CBAR) (1)
      Göteborg, Vaestra Goetaland, Sweden