Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Mitochondrial DNA abundance in blood is associated with Alzheimer's disease- and dementia-risk.

The mitochondrial cascade hypothesis of Alzheimer's disease (AD) has been portrayed through molecular, cellular, and animal studies; however large epidemiological studies are lacking. This study aimed to explore the association of mitochondrial DNA copy number (mtDNAcn), a marker representative of mtDNA abundance per cell, with risk of incident all-cause dementia, AD, and vascular dementia diagnosis within 17 years and dementia-related blood biomarkers (P-tau181, GFAP, and NfL). Additionally, sex-stratified analyses were completed. In this German population-based cohort study (ESTHER), 9940 participants aged 50-75 years were enrolled by general practitioners and followed for 17 years. Participants were included in this study if information on dementia status and blood-based mtDNAcn measured via real-time polymerase chain reaction were available. In a nested case-control approach, a subsample of participants additionally had measurements of P-tau181, GFAP, and NfL in blood samples taken at baseline. Of 4913 participants eligible for analyses, 386 were diagnosed with incident all-cause dementia, including 130 AD and 143 vascular dementia cases, while 4527 participants remained without dementia diagnosis within 17 years. Participants with low mtDNAcn (lowest 10%) experienced 45% and 65% percent increased risk of incident all-cause dementia and AD after adjusting for age and sex (all-cause dementia: HRadj, 95%CI:1.45, 1.08-1.94; AD: HRadj, 95%CI: 1.65, 1.01-2.68). MtDNAcn was not associated to vascular dementia diagnosis and was more strongly associated with all-cause dementia among women. In the nested case-control study (n = 790), mtDNAcn was not significantly associated with the dementia-related blood biomarkers (P-tau181, GFAP, and NfL) levels in blood from baseline before dementia diagnosis. This study provides novel epidemiological evidence connecting mtDNA abundance, measured via mtDNAcn, to incident dementia and AD at the population-based level. Reduced mitochondrial abundance may play a role in pathogenesis, especially among women.

Cancer-specific risk prediction with a serum microRNA signature.

We recently derived and validated a serum-based microRNA risk score (miR-score) that predicted colorectal cancer (CRC) occurrence with very high accuracy within 14 years of follow-up in a population-based cohort study from Germany (ESTHER cohort). Here, we aimed to evaluate associations of the CRC-specific miR-score with the risk of developing other common cancers, including female breast cancer (BC), lung cancer (LC), and prostate cancer (PC), in the ESTHER cohort. MicroRNAs (miRNAs) were profiled by quantitative real-time PCR in serum samples collected at baseline from randomly selected incident cases of BC (n = 90), LC (n = 88), and PC (n = 93) and participants without diagnosis of CRC, LC, BC, or PC (controls, n = 181) until the end of the 17-year follow-up. Multivariate logistic regression models were used to evaluate the associations of the miR-score with BC, LC, and PC incidence. The miR-score showed strong inverse associations with BC and LC incidence [odds ratio per 1 standard deviation increase: 0.60 (95% confidence interval [CI] 0.43-0.82), p = 0.0017, and 0.64 (95% CI 0.48-0.84),p = 0.0015, respectively]. Associations with PC were not statistically significant but pointed in the positive direction. Our study highlights the potential of serum-based miRNA biomarkers for cancer-specific risk prediction. Further large cohort studies aiming to investigate, validate, and optimize the use of circulating miRNA signatures for cancer risk assessment are warranted.

Genome-wide association study of mitochondrial copy number.

Mitochondrial DNA copy number (mtDNAcn) variation has been associated with increased risk of several human diseases in epidemiological studies. The quantification of mtDNAcn performed with real-time PCR is currently considered the de facto standard among several techniques. However, the heterogeneity of the laboratory methods (DNA extraction, storage, processing) used could give rise to results that are difficult to compare and reproduce across different studies. Several lines of evidence suggest that mtDNAcn is influenced by nuclear and mitochondrial genetic variability, however this relation is largely unexplored. The aim of this work was to elucidate the genetic basis of mtDNAcn variation. We performed a genome-wide association study (GWAS) of mtDNAcn in 6836 subjects from the ESTHER prospective cohort, and included, as replication set, the summary statistics of a GWAS that used 295 150 participants from the UK Biobank. We observed two novel associations with mtDNAcn variation on chromosome 19 (rs117176661), and 12 (rs7136238) that reached statistical significance at the genome-wide level. A polygenic score that we called mitoscore including all known single nucleotide polymorphisms explained 1.11% of the variation of mtDNAcn (p = 5.93 × 10-7). In conclusion, we performed a GWAS on mtDNAcn, adding to the evidence of the genetic background of this trait.

Strong associations of serum selenoprotein P with all-cause mortality and mortality due to cancer, cardiovascular, respiratory and gastrointestinal diseases in older German adults.

BACKGROUND: Selenium is an essential trace mineral. The main function of selenoprotein P (SELENOP) is to transport selenium but it has also been ascribed anti-oxidative effects. METHODS: To assess the association of repeated measurements of serum SELENOP concentration with all-cause and cause-specific mortality serum SELENOP was measured at baseline and 5-year follow-up in 7,186 and 4,164 participants of the ESTHER study, a German population-based cohort aged 50-74 years at baseline. RESULTS: During 17.3 years of follow-up, 2,126 study participants (30%) died. The relationship of serum SELENOP concentration with all-cause mortality was L-shaped, with mortality being significantly higher at SELENOP concentrations < 4.1 mg/L, which is near the bottom tertile's cut-off (4.2 mg/L). All-cause mortality of participants in the bottom SELENOP tertile was significantly increased compared to subjects in the top tertile (hazard ratio [95% confidence interval]: 1.35 [1.21-1.50]). SELENOP in the bottom tertile was further associated with increased cardiovascular mortality (1.24 [1.04-1.49]), cancer mortality (1.31 [1.09-1.58]), respiratory disease mortality (2.06 [1.28-3.32]) and gastrointestinal disease mortality (2.04 [1.25-3.32]). The excess risk of all-cause mortality for those in the bottom SELENOP tertile was more than twice as strong in men as in women (interaction of SELENOP and sex; p = 0.008). CONCLUSIONS: In this large cohort study, serum SELENOP concentration was inversely associated with all-cause and cause-specific mortality. Consistent inverse associations with multiple mortality outcomes might be explained by an impaired selenium transport and selenium deficiency in multiple organs. Trials testing the efficacy of selenium supplements in subjects with low baseline SELENOP concentration are needed. TRIAL REGISTRATION: Retrospectively registered in the German Clinical Trials Register on Feb 14, 2018 (ID: DRKS00014028).

Gender-specific factors associated with case complexity in middle-aged and older adults-Evidence from a large population-based study.

OBJECTIVES: To investigate gender-specific factors associated with case complexity in a population-based sample of middle-aged and older adults using a holistic approach to complexity. METHODS: Data were derived from the 8-year follow-up home visits of the ESTHER study-a German population-based study in middle-aged and older adults. Cross-sectional analyses were conducted for 2932 persons (aged 57-84). Complexity was assessed by the well-established INTERMED for the elderly interview, which uses a holistic approach to the definition of case complexity. The association between various bio-psycho-social variables and case complexity was analyzed using gender-specific logistic regression models, adjusted for sociodemographic factors (age, marital status, education). RESULTS: Prevalence of complexity was 8.3% with significantly higher prevalence in female (10.6%) compared to male (5.8%) participants (p < 0.001). Variables associated with increased odds for complexity in both, women and men were: being divorced (odds ratio [OR] women: 1.86, 95% CI 1.05-3.30; OR men: 3.19, 1.25-8.12), higher total somatic morbidity (women: 1.08, 1.04-1.12; men: 1.06, 1.02-1.11), higher depression severity (women: 1.34, 1.28-1.40; men: 1.35, 1.27-1.44), and higher loneliness scores (women: 1.19, 1.05-1.36; men: 1.23, 1.03-1.47). Women (but not men) with obesity (Body mass index [BMI] ≥30) had higher odds (1.79, 1.11-2.89) for being complex compared to those with a BMI <25. High oxidative stress measured by derivatives of reactive oxygen metabolites in serum was associated with 2.02 (1.09-3.74) higher odds for complexity only in men. CONCLUSIONS: This study provides epidemiological evidence on gender differences in prevalence and factors associated with case complexity in middle-aged and older adults. Moreover, this study adds to the holistic understanding of complexity by identifying novel variables linked to complexity among middle-aged and older individuals. These factors include loneliness for both genders, and high oxidative stress for men. These findings should be confirmed in future longitudinal studies.

Addition of inflammation-related biomarkers to the CAIDE model for risk prediction of all-cause dementia, Alzheimer's disease and vascular dementia in a prospective study.

BACKGROUND: It is of interest whether inflammatory biomarkers can improve dementia prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model. METHODS: The Olink Target 96 Inflammation panel was assessed in a nested case-cohort design within a large, population-based German cohort study (n = 9940; age-range: 50-75 years). All study participants who developed dementia over 20 years of follow-up and had complete CAIDE variable data (n = 562, including 173 Alzheimer's disease (AD) and 199 vascular dementia (VD) cases) as well as n = 1,356 controls were selected for measurements. 69 inflammation-related biomarkers were eligible for use. LASSO logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs). RESULTS: The CAIDE model 2 (including Apolipoprotein E (APOE) ε4 carrier status) predicted all-cause dementia, AD, and VD better than CAIDE model 1 (without APOE ε4) with AUCs of 0.725, 0.752 and 0.707, respectively. Although 20, 7, and 4 inflammation-related biomarkers were selected by LASSO regression to improve CAIDE model 2, the AUCs did not increase markedly. CAIDE models 1 and 2 generally performed better in mid-life (50-64 years) than in late-life (65-75 years) sub-samples of our cohort, but again, inflammation-related biomarkers did not improve their predictive abilities. CONCLUSIONS: Despite a lack of improvement in dementia risk prediction, the selected inflammation-related biomarkers were significantly associated with dementia outcomes and may serve as a starting point to further elucidate the pathogenesis of dementia.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Association between a polymorphic variant in the CDKN2B-AS1/ANRIL gene and pancreatic cancer risk.

Genes carrying high-penetrance germline mutations may also be associated with cancer susceptibility through common low-penetrance genetic variants. To increase the knowledge on genetic pancreatic ductal adenocarcinoma (PDAC) aetiology, the common genetic variability of PDAC familial genes was analysed in our study. We conducted a multiphase study analysing 7745 single nucleotide polymorphisms (SNPs) from 29 genes reported to harbour a high-penetrance PDAC-associated mutation in at least one published study. To assess the effect of the SNPs on PDAC risk, a total of 14 666 PDAC cases and 221 897 controls across five different studies were analysed. The T allele of the rs1412832 polymorphism, that is situated in the CDKN2B-AS1/ANRIL, showed a genome-wide significant association with increased risk of developing PDAC (OR = 1.11, 95% CI = 1.07-1.15, P = 5.25 × 10-9 ). CDKN2B-AS1/ANRIL is a long noncoding RNA, situated in 9p21.3, and regulates many target genes, among which CDKN2A (p16) that frequently shows deleterious somatic and germline mutations and deregulation in PDAC. Our results strongly support the role of the genetic variability of the 9p21.3 region in PDAC aetiopathogenesis and highlight the importance of secondary analysis as a tool for discovering new risk loci in complex human diseases.

Toll-Like Receptor 1 Locus Re-examined in a Genome-Wide Association Study Update on Anti-Helicobacter pylori IgG Titers.

BACKGROUND & AIMS: A genome-wide significant association between anti-Helicobacter pylori (H pylori) IgG titers and Toll-like receptor (TLR1/6/10) locus on 4p14 was demonstrated for individuals of European ancestry, but not uniformly replicated. We re-investigated this association in an updated genome-wide association study (GWAS) meta-analysis for populations with low gastric cancer incidence, address potential causes of cohort heterogeneity, and explore functional implications of genetic variation at the TLR1/6/10 locus. METHODS: The dichotomous GWAS (25% individuals exhibiting highest anti-H pylori IgG titers vs remaining 75%) included discovery and replication sampls of, respectively, n = 15,685 and n = 9676, all of European ancestry. Longitudinal analysis of serologic data was performed on H pylori-eradicated subjects (n = 132) and patients under surveillance for premalignant gastric lesions (n = 107). TLR1/6/10 surface expression, TLR1 mRNA, and cytokine levels were measured in leukocyte subsets of healthy subjects (n = 26) genotyped for TLR1/6/10 variants. RESULTS: The association of the TLR1/6/10 locus with anti-H pylori IgG titers (rs12233670; ß = -0.267 ± SE 0.034; P = 4.42 × 10-15) presented with high heterogeneity and failed replication. Anti-H pylori IgG titers declined within 2-4 years after eradication treatment (P = 0.004), and decreased over time in patients with premalignant gastric lesions (P < 0.001). Variation at the TLR1/6/10 locus affected TLR1-mediated cytokine production and TLR1 surface expression on monocytes (P = 0.016) and neutrophils (P = 0.030), but not mRNA levels. CONCLUSIONS: The association between anti-H pylori IgG titers and TLR1/6/10 locus was not replicated across cohorts, possibly owing to dependency of anti-H pylori IgG titers on therapy, clearance, and antibody decay. H pylori-mediated immune cell activation is partly mediated via TLR1 signaling, which in turn is affected by genetic variation.

Real-world evidence for the effectiveness of vitamin D supplementation in reduction of total and cause-specific mortality.

BACKGROUND: Meta-analyses of randomized controlled trials (RCTs) have demonstrated the efficacy of vitamin D supplementation for reduced cancer mortality, all-cause mortality, and respiratory tract infections. However, whether and to what extent this translates into effectiveness in real-world practice is unknown. METHODS: We assessed the association of vitamin D supplement use (as an over-the-counter drug or as part of a multivitamin product), vitamin D deficiency (25-hydroxyvitamin D, 25[OH]D <30 nmol/L), and insufficiency (25[OH]D 30 to <50 nmol/L) with all-cause and cause-specific mortality in 445,601 participants, aged 40-73 years, from the UK Biobank cohort. RESULTS: A total of 4.3% and a further 20.4% of the study participants reported regularly taking vitamin D or multivitamin supplements, respectively. Still, the majority had either vitamin D deficiency (21.0%) or insufficiency (34.3%). We detected 49 independent determinants of vitamin D deficiency and vitamin D supplement use and used them to adjust Cox regression models for all mortality outcomes. A total of 29,107 (6.5%) participants died during a median follow-up time of 11.8 years. Both vitamin D deficiency and insufficiency were strongly associated with all mortality outcomes. Self-reported vitamin D supplement use (83% over-the-counter/17% prescription drugs) and multivitamin intake were significantly associated with 10% and 5% lower all-cause mortality, respectively. Furthermore, regular vitamin D supplement users had 11%, 11%, and 29% lower cancer, cardiovascular disease, and respiratory disease mortality than nonusers, respectively (not significant for cardiovascular disease mortality). CONCLUSION: This large study suggests that in the real world, the efficacy of vitamin D supplements in reducing mortality may be at least as good as observed in RCTs.

Protocol of the optimal study: Optimization of polypharmacy in geriatric oncology - A randomized controlled trial.

BACKGROUND: Polypharmacy is very common in older cancer patients and these patients are particularly vulnerable to drug-drug interactions and adverse drug reactions because they often receive chemotherapy and symptom-relieving agents. METHODS: The primary aim of the randomized, controlled Optimization of Polypharmacy in Geriatric Oncology (OPTIMAL) trial is to test whether an advisory letter with the results of a comprehensive medication review conducted with the Fit fOR The Aged (FORTA) list to the caring physician in rehabilitation clinics improves the quality of life (QoL) of older cancer patients exposed to polypharmacy more than usual care. The FORTA list detects medication overuse, underuse, and potentially inappropriate drug use among older adults. In the oncology departments of approximately 10 German rehabilitation clinics, we aim to recruit 514 cancer patients (22 common cancers; diagnosis or recurrence requiring treatment in the last 5 years; all stages) who are ≥ 65 years old, regularly take ≥ 5 drugs, and have ≥ 1 medication-related problem. All necessary information about the patients will be provided to a pharmacist at the coordinating center (German Cancer Research Center, Heidelberg), who will perform randomization (1:1) and conduct the medication review with the FORTA list. For the intervention group only, the results are sent by letter to the treating physician in the rehabilitation clinics, who shall discuss medication changes with the patient at the discharge visit, as well as implement them afterwards and disclose them in the discharge letter to the general practitioner. The control group gets the usual care provided in German rehabilitation clinics, which usually does not include a comprehensive medication review but can include medication changes. Patients will be blinded, as they cannot know whether proposed medication changes were part of the study or part of usual care. Study physicians cannot be blinded. The primary endpoint will be the EORTC-QLQ-C30 global health status/QoL score, assessed via self-administered questionnaires 8 months after baseline. DISCUSSION: If the planned study shows that a medication review with the FORTA list improves the QoL of older cancer patients in oncological rehabilitation more than usual care, it would provide the necessary evidence to translate the trial's findings into routine care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS): DRKS00031024.

About the associations of vitamin D deficiency and biomarkers of systemic inflammatory response with all-cause and cause-specific mortality in a general population sample of almost 400,000 UK Biobank participants.

It is unknown whether the well-known association between vitamin D deficiency and mortality could be explained by the immune system modulating effects of vitamin D, which may protect from a systemic inflammatory response (SIR) to adverse health conditions. This study aims to investigate the interrelationships of vitamin D deficiency, biomarkers of SIR, and mortality. We used multivariate logistic regression with adjustment for 51 covariates to assess the associations of vitamin D deficiency with disadvantageous levels of nine biomarkers of SIR in the UK Biobank cohort. Furthermore, we tested with Cox regression and mediation analysis whether biomarkers of SIR and vitamin D deficiency were independently associated with mortality. We included 397,737 participants aged 37-73 years. Vitamin D deficiency was associated with disadvantageous levels of all blood cell count-based biomarkers, but not with C-reactive protein (CRP)-based biomarkers after adjustment for body weight. Vitamin D deficiency and all biomarkers of SIR were significantly associated with all-cause mortality and mortality from cancer, cardiovascular and respiratory disease. The strength of these associations was unaltered if vitamin D deficiency and biomarkers of SIR were put in the same model. This finding was further supported by the mediation analyses. This study showed that vitamin D deficiency is associated with disadvantageous levels of blood cell count-based but not CRP-based biomarkers of SIR. Vitamin D deficiency and systemic inflammation were independently and strongly associated with mortality. The potential of clinical interventions against both vitamin D deficiency and underlying causes of systemic inflammation should be explored.

Medical care and biomarker-based assessment of mortality in two cohorts of patients with chronic coronary syndrome 10 years apart.

BACKGROUND: This study aimed to describe the characteristics and mortality of two cohorts of patients with chronic coronary syndrome (CCS) recruited with identical study designs in the same rehabilitation clinics but approximately 10 years apart. METHODS: The KAROLA cohorts included patients with CCS participating in an inpatient cardiac rehabilitation programme in Germany (KAROLA-I: years 1999/2000, KAROLA-II: 2009-2011). Blood samples and information on sociodemographic factors, lifestyle, and medical treatment were collected at baseline, at the end of rehabilitation, and after one year of follow-up. A biomarker-based risk model (ABC-CHD model) and Cox regression analysis were used to evaluate cardiovascular (CV) and non-CV mortality risk. RESULTS: We included 1130 patients from KAROLA-I (mean age 58.7 years, 84.4% men) and 860 from KAROLA-II (mean age 60.4 years, 83.4% men). Patients in the KAROLA-I cohort had significantly higher concentrations of CV biomarkers and fewer patients were taking CV medications, except for statins. The biomarker-based ABC-CHD model provided a higher estimate of CV death risk for patients in the KAROLA-I cohort (median 3-year risk, 3.8%) than for patients in the KAROLA-II cohort (median 3-year risk, 2.7%, p-value for difference < 0.001). After 10 years of follow-up, 91 (8.1%) patients in KAROLA-I and 45 (5.2%) in KAROLA-II had died from a CV event. CONCLUSIONS: Advances in disease management over the past 20 years may have led to modest improvements in pharmacological treatment during cardiac rehabilitation and long-term outpatient care for patients with CCS. However, modifiable risk factors such as obesity have increased in the more recent cohort and should be targeted to further improve the prognosis of these patients.

Grip strength values and cut-off points based on over 200,000 adults of the German National Cohort - a comparison to the EWGSOP2 cut-off points.

BACKGROUND: The European Working Group on Sarcopenia in Older People (EWGSOP) updated in 2018 the cut-off points for low grip strength to assess sarcopenia based on pooled data from 12 British studies. OBJECTIVE: Comparison of the EWGSOP2 cut-off points for low grip strength to those derived from a large German sample. METHODS: We assessed the grip strength distribution across age and derived low grip strength cut-off points for men and women (peak mean -2.5 × SD) based on 200,389 German National Cohort (NAKO) participants aged 19-75 years. In 1,012 Cooperative Health Research in the Region of Augsburg (KORA)-Age participants aged 65-93 years, we calculated the age-standardised prevalence of low grip strength and time-dependent sensitivity and specificity for all-cause mortality. RESULTS: Grip strength increased in the third and fourth decade of life and declined afterwards. Calculated cut-off points for low grip strength were 29 kg for men and 18 kg for women. In KORA-Age, the age-standardised prevalence of low grip strength was 1.5× higher for NAKO-derived (17.7%) compared to EWGSOP2 (11.7%) cut-off points. NAKO-derived cut-off points yielded a higher sensitivity and lower specificity for all-cause mortality. CONCLUSIONS: Cut-off points for low grip strength from German population-based data were 2 kg higher than the EWGSOP2 cut-off points. Higher cut-off points increase the sensitivity, thereby suggesting an intervention for more patients at risk, while other individuals might receive additional diagnostics/treatment without the urgent need. Research on the effectiveness of intervention in patients with low grip strength defined by different cut-off points is needed.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Gender-specific association of loneliness and health care use in community-dwelling older adults.

BACKGROUND: Loneliness in older adults is common, particularly in women. In this article, gender differences in the association of loneliness and health care use are investigated in a large sample of community-dwelling older adults. METHODS: Data of 2525 persons (ages 55-85 years)-participants of the fourth follow- up (2011-2014) of the ESTHER study- were analyzed. Loneliness and health care use were assessed by study doctors in the course of a home visit. Gender-specific regression models with Gamma-distribution were performed using loneliness as independent variable to predict outpatient health care use, adjusted for demographic variables. RESULTS: In older women, lonely persons were shown to have significantly more visits to general practitioners and mental health care providers in a three-month period compared to less lonely persons (p = .005). The survey found that outpatient health care use was positively associated with loneliness, multimorbidity, and mental illness in older women but not in older men. Older men had significantly more contact with inpatient care in comparison to women (p = .02). CONCLUSIONS: It is important to consider gender when analyzing inpatient and outpatient health care use in older persons. In older women loneliness is associated with increased use of outpatient services.

Association of plasma biomarkers, p-tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long-term clinical Alzheimer's disease risk: Results from a prospective cohort followed over 17 years.

INTRODUCTION: Blood biomarkers for Alzheimer's disease (AD) are the future of AD risk assessment. The aim of this study was to determine the association between plasma-measured phosphorylated tau (p-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) levels and risk of clinical AD incidence with consideration to the impact of cardiovascular health. METHODS: Within a community-based cohort, biomarker levels were measured at baseline using single molecule array technology in 768 participants (aged 50-75) followed over 17 years. Associations among biomarkers and AD, vascular dementia, and mixed dementia incidence were assessed. RESULTS: GFAP was associated with clinical AD incidence even more than a decade before diagnosis (9-17 years), while p-tau181 and NfL were associated with more intermediate AD risk (within 9 years). Significant interaction was detected between cardiovascular health and p-tau181/NfL. DISCUSSION: GFAP may be an early AD biomarker increasing before p-tau181 and NfL and the effect modifying role of cardiovascular health should be considered in biomarker risk stratification.

High cholesterol levels change the association of biomarkers of neurodegenerative diseases with dementia risk: Findings from a population-based cohort.

INTRODUCTION: This study assessed whether in a population with comorbidity of neurodegenerative and cerebrovascular disease (mixed pathology) the association of glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau181 (p-tau181) with dementia risk varied depending on levels of total cholesterol and apolipoprotein E (APOE) ε4 genotype. METHODS: Plasma biomarkers were measured using Simoa technology in 768 participants of a nested case-control study embedded within an ongoing population-based cohort. Logistic and spline regression models, and receiver operating characteristic curves were calculated. RESULTS: The strength of the association between GFAP and NfL with risk of a clinical diagnosis of dementia changed depending on cholesterol levels and on APOE ε4 genotype. No significant association was seen with p-tau181. DISCUSSION: In individuals with mixed pathology blood GFAP and NfL are better predictors of dementia risk than p-tau181, and their associations with dementia risk are amplified by hypercholesterolemia, also depending on APOE ε4 genotype. HIGHLIGHTS: Cholesterol levels changed the association of blood biomarkers with dementia risk. Blood biomarkers seem to perform differently in community- and clinic-based cohorts. Neurofilament light chain might be a biomarker candidate for dementia risk after stroke.

Epigenome-wide association study of incident type 2 diabetes: a meta-analysis of five prospective European cohorts.

AIMS/HYPOTHESIS: Type 2 diabetes is a complex metabolic disease with increasing prevalence worldwide. Improving the prediction of incident type 2 diabetes using epigenetic markers could help tailor prevention efforts to those at the highest risk. The aim of this study was to identify predictive methylation markers for incident type 2 diabetes by combining epigenome-wide association study (EWAS) results from five prospective European cohorts. METHODS: We conducted a meta-analysis of EWASs in blood collected 7-10 years prior to type 2 diabetes diagnosis. DNA methylation was measured with Illumina Infinium Methylation arrays. A total of 1250 cases and 1950 controls from five longitudinal cohorts were included: Doetinchem, ESTHER, KORA1, KORA2 and EPIC-Norfolk. Associations between DNA methylation and incident type 2 diabetes were examined using robust linear regression with adjustment for potential confounders. Inverse-variance fixed-effects meta-analysis of cohort-level individual CpG EWAS estimates was performed using METAL. The methylGSA R package was used for gene set enrichment analysis. Confirmation of genome-wide significant CpG sites was performed in a cohort of Indian Asians (LOLIPOP, UK). RESULTS: The meta-analysis identified 76 CpG sites that were differentially methylated in individuals with incident type 2 diabetes compared with control individuals (p values <1.1 × 10-7). Sixty-four out of 76 (84.2%) CpG sites were confirmed by directionally consistent effects and p values <0.05 in an independent cohort of Indian Asians. However, on adjustment for baseline BMI only four CpG sites remained genome-wide significant, and addition of the 76 CpG methylation risk score to a prediction model including established predictors of type 2 diabetes (age, sex, BMI and HbA1c) showed no improvement (AUC 0.757 vs 0.753). Gene set enrichment analysis of the full epigenome-wide results clearly showed enrichment of processes linked to insulin signalling, lipid homeostasis and inflammation. CONCLUSIONS/INTERPRETATION: By combining results from five European cohorts, and thus significantly increasing study sample size, we identified 76 CpG sites associated with incident type 2 diabetes. Replication of 64 CpGs in an independent cohort of Indian Asians suggests that the association between DNA methylation levels and incident type 2 diabetes is robust and independent of ethnicity. Our data also indicate that BMI partly explains the association between DNA methylation and incident type 2 diabetes. Further studies are required to elucidate the underlying biological mechanisms and to determine potential causal roles of the differentially methylated CpG sites in type 2 diabetes development.