Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.

Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 × 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 × 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.

A pattern of unspecific somatic symptoms as long-term premonitory signs of type 2 diabetes: findings from the population-based MONICA/KORA cohort study, 1984-2009.

BACKGROUND: Unspecific symptoms often proceed a serious chronic disease condition long before the onset of the disease. The role of an unspecific premonitory symptom (UPMS) pattern as premonitory signs of subsequent type 2 diabetes mellitus (T2DM) diagnosis independent of established cardio-metabolic risk factors is unclear and therefore was examined in the present study. METHODS: The study population consisted of 10,566 participants aged 25-74 years at baseline drawn from the population-based MONICA/KORA Cohort Study conducted in 1984-2009 in the Augsburg region (Germany). Unspecific premonitory symptoms were assessed following the Somatic Symptom Scale-8 (SSS-8). The impact of the score on T2DM risk within a mean follow-up time of 16 years was estimated by Cox regression. RESULTS: Within follow-up, 974 newly diagnosed T2DM cases were observed. The risk for T2DM increased by a hazard ratio (HR) of 1.03 (95% CI 1.01-1.04, p value < 0.001) for a one unit increase of the UPMS score in a Cox model adjusted for age, sex and survey. Additional adjustment for cardio-metabolic risk factors attenuated this effect (HR = 1.02) but significance remained (p value = 0.01). CONCLUSIONS: Suffering from an elevated burden of unspecific somatic symptoms is associated with T2DM long before the onset and independent of established cardio-metabolic risk factors. Further research is needed to obtain insight in potential underlying pathophysiological mechanisms.

Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.

PURPOSE: Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). METHODS: We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. KEY FINDINGS: We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92-51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. SIGNIFICANCE: We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Genome-wide association analysis identifies multiple loci related to resting heart rate.

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Blood pressure and lipid management fall far short in persons with type 2 diabetes: results from the DIAB-CORE Consortium including six German population-based studies.

BACKGROUND: Although most deaths among patients with type 2 diabetes (T2D) are attributable to cardiovascular disease, modifiable cardiovascular risk factors appear to be inadequately treated in medical practice. The aim of this study was to describe hypertension, dyslipidemia and medical treatment of these conditions in a large population-based sample. METHODS: The present analysis was based on the DIAB-CORE project, in which data from five regional population-based studies and one nationwide German study were pooled. All studies were conducted between 1997 and 2006. We assessed the frequencies of risk factors and co-morbidities, especially hypertension and dyslipidemia, in participants with and without T2D. The odds of no or insufficient treatment and the odds of pharmacotherapy were computed using multivariable logistic regression models. Types of medication regimens were described. RESULTS: The pooled data set comprised individual data of 15, 071 participants aged 45-74 years, including 1287 (8.5%) participants with T2D. Subjects with T2D were significantly more likely to have untreated or insufficiently treated hypertension, i.e. blood pressure of > = 140/90 mmHg (OR = 1.43, 95% CI 1.26-1.61) and dyslipidemia i.e. a total cholesterol/HDL-cholesterol ratio > = 5 (OR = 1.80, 95% CI 1.59-2.04) than participants without T2D. Untreated or insufficiently treated blood pressure was observed in 48.9% of participants without T2D and in 63.6% of participants with T2D. In this latter group, 28.0% did not receive anti-hypertensive medication and 72.0% were insufficiently treated. In non-T2D participants, 28.8% had untreated or insufficiently treated dyslipidemia. Of all participants with T2D 42.5% had currently elevated lipids, 80.3% of these were untreated and 19.7% were insufficiently treated. CONCLUSIONS: Blood pressure and lipid management fall short especially in persons with T2D across Germany. The importance of sufficient risk factor control besides blood glucose monitoring in diabetes care needs to be emphasized in order to prevent cardiovascular sequelae and premature death.

Personal attributes that influence the adequate management of hypertension and dyslipidemia in patients with type 2 diabetes. Results from the DIAB-CORE Cooperation.

BACKGROUND: Hypertension and dyslipidemia are often insufficiently controlled in persons with type 2 diabetes (T2D) in Germany. In the current study we evaluated individual characteristics that are assumed to influence the adequate treatment and control of hypertension and dyslipidemia and aimed to identify the patient group with the most urgent need for improved health care. METHODS: The analysis was based on the DIAB-CORE project in which cross-sectional data from five regional population-based studies and one nationwide German study, conducted between 1997 and 2006, were pooled. We compared the frequencies of socio-economic and lifestyle factors along with comorbidities in hypertensive participants with or without the blood pressure target of<140/90 mmHg. Similar studies were also performed in participants with dyslipidemia with and without the target of total cholesterol/HDL cholesterol ratio<5. Furthermore, we compared participants who received antihypertensive/lipid lowering treatment with those who were untreated. Univariable and multivariable logistic regression models were used to assess the odds of potentially influential factors. RESULTS: We included 1287 participants with T2D of whom n=1048 had hypertension and n=636 had dyslipidemia. Uncontrolled blood pressure was associated with male sex, low body mass index (BMI), no history of myocardial infarction (MI) and study site. Uncontrolled blood lipid levels were associated with male sex, no history of MI and study site. The odds of receiving no pharmacotherapy for hypertension were significantly greater in men, younger participants, those with BMI<30 kg/m(2) and those without previous MI or stroke. Participants with dyslipidemia received lipid lowering medication less frequently if they were male and had not previously had an MI. The more recent studies HNR and CARLA had the greatest numbers of well controlled and treated participants. CONCLUSION: In the DIAB-CORE study, the patient group with the greatest odds of uncontrolled co-morbidities and no pharmacotherapy was more likely comprised of younger men with low BMI and no history of cardiovascular disease.

Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies.

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.

Are German patients burdened by the practice charge for physician visits ('Praxisgebuehr')? A cross sectional analysis of socio-economic and health related factors.

BACKGROUND: In 2004, a practice charge for physician visits ('Praxisgebuehr') was implemented in the German health care system, mainly in order to reduce expenditures of sickness funds by reducing outpatient physician visits. In the statutory sickness funds, all adults now have to pay euro 10 at their first physician visit in each 3 month period, except for vaccinations and preventive services. This study looks at the effect of this new patient fee on delaying or avoiding physician visits, with a special emphasis on different income groups. METHODS: Six representative surveys (conducted between 2004 and 2006) of the Bertelsmann Healthcare Monitor were analysed, comprising 7,769 women and men aged 18 to 79 years. The analyses are based on stratified analyses and logistic regression models, including a focus on the subgroup having a chronic disease. RESULTS: Two results can be highlighted. First, avoiding or delaying a physician visit due to this fee is seen most often among younger and healthier adults. Second, those in the lowest income group are much more affected in this way than the better of. The multivariate analysis in the subgroup of respondents having a chronic disease shows, for example, that this reaction is reported 2.45 times more often in the lowest income group than in the highest income group (95% CI: 1.90-3.15). CONCLUSION: The analyses indicate that the effects of the practice charge differ by socio-economic group. It would be important to assess these effects in more detail, especially the effects on health care quality and health outcomes. It can be assumed, however, that avoiding or delaying physician visits jeopardizes both, and that health inequalities are increasing due to the practice charge.

Blood Pressure Control Has Improved in People with and without Type 2 Diabetes but Remains Suboptimal: A Longitudinal Study Based on the German DIAB-CORE Consortium.

BACKGROUND: Hypertension is a very common comorbidity and major risk factor for cardiovascular complications, especially in people with Type 2 Diabetes (T2D). Nevertheless, studies in the past have shown that blood pressure is often insufficiently controlled in medical practice. For the DIAB-CARE study, we used longitudinal data based on the German DIAB-CORE Consortium to assess whether health care regarding hypertension has improved during the last decade in our participants. METHODS: Data of the three regional population-based studies CARLA (baseline 2002-2006 and follow-up 2007-2010), KORA (baseline 1999-2001 and follow-up 2006-2008) and SHIP (baseline 1997-2001 and follow-up 2002-2006) were pooled. Stratified by T2D status we analysed changes in frequencies, degrees of awareness, treatment and control. Linear mixed models were conducted to assess the influence of sex, age, study, and T2D status on changes of systolic blood pressure between the baseline and follow-up examinations (mean observation time 5.7 years). We included 4,683 participants aged 45 to 74 years with complete data and accounted for 1,256 participants who were lost to follow-up by inverse probability weighting. RESULTS: Mean systolic blood pressure decreased in all groups from baseline to follow-up (e.g. - 8.5 mmHg in those with incident T2D). Pulse pressure (PP) was markedly higher in persons with T2D than in persons without T2D (64.14 mmHg in prevalent T2D compared to 52.87 mmHg in non-T2D at baseline) and did not change much between the two examinations. Awareness, treatment and control increased considerably in all subgroups however, the percentage of those with insufficiently controlled hypertension remained high (at about 50% of those with hypertension) especially in prevalent T2D. Particularly elderly people with T2D often had both, high blood pressure ≥140/90 mmHg and a PP of ≥60 mmHg. Blood pressure in men had improved more than in women at follow-up, however, men still had higher mean SBP than women at follow-up. CONCLUSION: Blood pressure management has developed positively during past years in Germany. While hypertension prevalence, awareness and treatment were substantially higher in participants with T2D than in those without T2D at follow-up, hypertension control was achieved only in about half the number of people in each T2D group leaving much room for further improvement.

Psoriasis and cardiometabolic traits: modest association but distinct genetic architectures.

Psoriasis has been linked to cardiometabolic diseases, but epidemiological findings are inconsistent. We investigated the association between psoriasis and cardiometabolic outcomes in a German cross-sectional study (n=4,185) and a prospective cohort of German Health Insurance beneficiaries (n=1,811,098). A potential genetic overlap was explored using genome-wide data from >22,000 coronary artery disease and >4,000 psoriasis cases, and with a dense genotyping study of cardiometabolic risk loci on 927 psoriasis cases and 3,717 controls. After controlling for major confounders, in the cross-sectional analysis psoriasis was significantly associated with type 2 diabetes (T2D, adjusted odds ratio (OR)=2.36; 95% confidence interval CI=1.26-4.41) and myocardial infarction (MI, OR=2.26; 95% CI=1.03-4.96). In the longitudinal study, psoriasis slightly increased the risk for incident T2D (adjusted relative risk (RR)=1.11; 95% CI=1.08-1.14) and MI (RR=1.14; 95% CI=1.06-1.22), with highest risk increments in systemically treated psoriasis, which accounted for 11 and 17 excess cases of T2D and MI per 10,000 person-years. Except for weak signals from within the major histocompatibility complex, there was no evidence of genetic risk loci shared between psoriasis and cardiometabolic traits. Our findings suggest that psoriasis, in particular severe psoriasis, increases the risk for T2D and MI, and that the genetic architecture of psoriasis and cardiometabolic traits is largely distinct.

The association between patient-reported self-management behavior, intermediate clinical outcomes, and mortality in patients with type 2 diabetes: results from the KORA-A study.

OBJECTIVE: Little is known about the impact of diabetes self-management behavior (SMB) on long-term outcomes. We aimed to examine the association among patient-reported SMB, intermediate clinical outcomes, and mortality in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Data were collected from 340 patients with type 2 diabetes of the KORA-A study (1997/1998) who were recruited from two previous population-based surveys (n = 161) and a myocardial infarction registry (n = 179) in southern Germany. Based on previous methodological work, a high level of SMB was defined as being compliant with at least four of six different self-care dimensions, comprising physical exercise, foot care, blood glucose self-monitoring, weight monitoring, having a diet plan, and keeping a diabetes diary. The vital status of the participants was observed until 2009. Multivariable linear, logistic, and Cox regression models were applied to assess the association with intermediate clinical outcomes at baseline and to predict mortality over the follow-up period, adjusted for sociodemographic, behavioral, and disease-related factors. RESULTS: In the cross-sectional perspective, a high level of SMB was weakly associated with a lower glycated hemoglobin A1c level (-0.44% [-4.8 mmol/mol] [95% CI -0.88 to 0.00]), but not with low-density lipoprotein cholesterol, systolic blood pressure, or the presence of microalbuminuria, peripheral arterial disease, or polyneuropathy. During a mean follow-up time of 11.6 years, 189 patients died. SMB was a preventive factor for all-cause (hazard ratio 0.61 [95% CI 0.40-0.91]) and cardiovascular mortality (0.65 [95% CI 0.41-1.03]). CONCLUSIONS: Although measuring SMB is difficult and the used operationalization might be limited, our results give some indication that a high level of SMB is associated with prolonged life expectancy in patients with type 2 diabetes and highlight the potential impact of the patients' active contribution on the long-term trajectory of the disease. We assume that the used proxy for SMB is associated with unmeasured, but important, dimensions of health behavior.

Treatment pattern of type 2 diabetes differs in two German regions and with patients' socioeconomic position.

BACKGROUND: Diabetes treatment may differ by region and patients' socioeconomic position. This may be particularly true for newer drugs. However, data are highly limited. METHODS: We examined pooled individual data of two population-based German studies, KORA F4 (Cooperative Health Research in the Region of Augsburg, south), and the HNR (Heinz Nixdorf Recall study, west) both carried out 2006 to 2008. To ascertain the association between region and educational level with anti-hyperglycemic medication we fitted poisson regression models with robust error variance for any and newer anti-hyperglycemic medication, adjusting for age, sex, diabetes duration, BMI, cardiovascular disease, lifestyle, and insurance status. RESULTS: The examined sample comprised 662 participants with self-reported type 2 diabetes (KORA F4: 83 women, 111 men; HNR: 183 women, 285 men). The probability to receive any anti-hyperglycemic drug as well as to be treated with newer anti-hyperglycemic drugs such as insulin analogues, thiazolidinediones, or glinides was significantly increased in southern compared to western Germany (prevalence ratio (PR); 95% CI: 1.12; 1.02-1.22, 1.52;1.10-2.11 respectively). Individuals with lower educational level tended to receive anti-hyperglycemic drugs more likely than their better educated counterparts (PR; 95% CI univariable: 1.10; 0.99-1.22; fully adjusted: 1.10; 0.98-1.23). In contrast, lower education was associated with a lower estimated probability to receive newer drugs among those with any anti-hyperglycemic drugs (PR low vs. high education: 0.66; 0.48-0.91; fully adjusted: 0.68; 0.47-0.996). CONCLUSIONS: We found regional and individual social disparities in overall and newer anti-hyperglycemic medication which were not explained by other confounders. Further research is needed.

Are diabetes risk scores useful for the prediction of cardiovascular diseases? Assessment of seven diabetes risk scores in the KORA S4/F4 cohort study.

AIM: To evaluate the utility of diabetes prediction models for CVD prediction as stated in two earlier studies. METHODS: 845 subjects from the population based German KORA (Cooperative Health Research in the Region of Augsburg) S4/F4 cohort study (aged 55 to 74 years, without diabetes, former stroke, and former myocardial infarction at baseline) were followed for up to ten years for incident stroke and myocardial infarction. Seven diabetes risk scores developed from four different studies were applied to the KORA cohort to assess their predictive ability for CVD. RESULTS: Areas under the receiver-operating curve (AROCs) for the prediction of CVD ranged from 0.60 to 0.65 when diabetes risk scores were applied to the KORA cohort. When diabetes risk scores were used to predict CVD and type 2 diabetes, respectively, AROCs for the prediction of CVD were 0.09 to 0.24 lower than AROCs for the prediction of type 2 diabetes. Furthermore, we used KORA data to develop prediction models for either diabetes or CVD, and found that they differed widely in selected predictor variables. CONCLUSION: In the older population, diabetes risk scores are not useful for the prediction of CVD, and prediction models for diabetes and CVD, respectively, require different parameters.

Association between markers of fatty liver disease and impaired glucose regulation in men and women from the general population: the KORA-F4-study.

OBJECTIVE: To investigate whether the elevated liver enzymes gamma-glutamyltransferase (GGT), glutamate-pyruvate transaminase (GPT), glutamate-oxalacetate transaminase (GOT) and alkaline phosphatase (AP) and non-alcoholic fatty liver disease (NAFLD) respectively are independently associated with pre-diabetic states, namely impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) or known and newly diagnosed diabetes (NDD), in men and women from the general German population. METHODS: The study was based on 3009 subjects (1556 females, 1453 males) aged 32 to 81 years who participated in the KORA-F4-Study in 2006/2008 in Augsburg, Southern Germany. All non-diabetic participants underwent an oral glucose tolerance test to assess disturbances in glucose metabolism. NAFLD was estimated by liver enzyme concentrations and the Bedogni Fatty Liver Index (FLI). RESULTS: 229 participants (7.6%) reported known diabetes, 106 had NDD (3.5%), 107 (3.6%) had IFG, 309 (10.3%) had IGT, 69 (2.3%) were affected with both metabolic disorders (IFG/IGT) and 74 (2.5%) could not be classified. GGT and GPT were significantly elevated in persons with pre-diabetes and diabetes (GGT in diabetic persons OR = 1.76, [1.47-2.09], in IFG OR = 1.79 [1.50-2.13], GPT in diabetic persons OR = 1.51, [1.30-1.74], in NDD OR = 1.77 [1.52-2.06]), GOT and AP only inconsistently in some pre-diabetes groups. The effects were sharpened in models using an increase of two or three out of three enzymes as an estimate of fatty liver and especially in models using the FLI. Overall frequency of NAFLD applying the index was 39.8% (women: 27.3% and men: 53.2%). In participants with fatty liver disease, the OR for NDD adjusted for sex and age was 8.48 [5.13-14.00], 6.70 [3.74-12.01] for combined IFG and IGT and 4.78 [3.47-6.59] for known diabetes respectively. CONCLUSIONS: Elevated GGT and GPT-values as well as estimates of fatty liver disease are significantly associated with pre-diabetes and diabetes and thus very useful first indicators of a disturbed glucose metabolism.