Context:
Measurement of IGF-I is a cornerstone in diagnosis and monitoring of GH-related diseases, but considerable discrepancies exist between analytical methods. A recent consensus conference ...defined criteria for validation of IGF-I assays and for establishment of normative data.
Objectives:
Our objectives were development and validation of a novel automated IGF-I immunoassay (iSYS; Immunodiagnostic Systems) according to international guidelines and establishment of method-specific age- and sex-adjusted reference intervals and analysis of their robustness.
Setting and Participants:
We conducted a multicenter study with samples from 12 cohorts from the United States, Canada, and Europe including 15 014 subjects (6697 males and 8317 females, 0–94 years of age).
Main Outcome Measures:
We measured concentrations of IGF-I as determined by the IDS iSYS IGF-I assay.
Results:
A new IGF-I assay calibrated against the recommended standard (02/254) and insensitive to the 6 high-affinity IGF binding proteins was developed and rigorously validated. Age- and sex-adjusted reference intervals derived from a uniquely large cohort reflect the age-related pattern of IGF-I secretion: a decline immediately after birth followed by an increase until a pubertal peak (at 15 years of age). Later in life, values decrease continuously. The impact of gender is small, although across the lifespan, women have lower mean IGF-I concentrations. Geographical region, sampling setting (community or hospital based), and rigor of exclusion criteria in our large cohort did not affect the reference intervals.
Conclusions:
Using large cohorts of well-characterized subjects from different centers allowed construction of robust reference ranges for a new automated IGF-I assay. The strict adherence to recent consensus criteria for IGF-I assays might facilitate clinical application of the results.
Lipin, a novel molecular protein expressed by adipocytes, has marked effects on adipose tissue mass, insulin sensitivity, and glucose homeostasis. Thus, we hypothesized that genetic variants within ...LPIN1 are associated with traits of the metabolic syndrome.
A total of 15 single nucleotide polymorphisms (SNPs) covering the LPIN1 gene region were genotyped in an age- and sex-stratified sample of the general population (Monitoring Trends and Determinants on Cardiovascular Diseases Study Augsburg; DNA and phenotypes of 1,416 Caucasians). Ten SNPs were also genotyped for replication in an independent sample of 1,030 subjects recruited throughout Germany. The metabolic syndrome was defined via the sum of its core components and, additionally, by a factor score derived from factor analysis. Permutation-based methods were used to test the association between genetic LPIN1 variants and metabolic traits for empirical significance.
Linkage disequilibrium (LD) analysis revealed three LD blocks encompassing LPIN1. We identified three associated three-marker haplotypes: one common haplotype (26.8% frequency) increases the risk for the metabolic syndrome (odds ratio 1.6 95% CI 1.2-2.2), while the other two, being less common (5.7 and 4.0%), are strongly associated with lower blood pressure levels (systolic blood pressure 127 +/- 18 vs. 135 +/- 20 mmHg; P = 0.0001), a lower BMI (24.6 +/- 3.6 vs. 26.9 +/- 4.1 kg/m(2); P = 3.7 x 10(-7)) and waist circumference (82 +/- 12 vs. 90 +/- 12 cm; P = 3.2 x 10(-8)), lower A1C levels (5.1 +/- 0.7 vs. 5.3 +/- 0.9%; P = 0.0002), as well as a lower metabolic syndrome factor score (-0.67 +/- 1.00 vs. 0.04 +/- 1.24; P = 1.4 x 10(-7)). Furthermore, the frequencies of arterial hypertension (23.7 vs. 46.4%; P = 0.00001), obesity (12.9 vs. 30.8%; P = 0.0003), diabetes (2.2 vs. 8.2%; P = 0.041), and the presence of three or more metabolic syndrome components (3.3 vs. 13.7%; P = 0.002) were significantly lower than in subjects not carrying one of these protective haplotypes. Strong associations were also observed in the replication sample using the same haplotypes but with effects in the opposite direction. CONCLUSIONS These data suggest that allelic variants of the LPIN1 gene have significant effects in human metabolic traits and thus implicate lipin in the pathophysiology of the metabolic syndrome.
The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within ...a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status ("susceptible" P = 0.025, "nonsusceptible" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease ("susceptible" P = 0.002, "nonsusceptible" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.
The purpose of this study was to assess whether increasing serum uric acid (UA) levels are related to cardiovascular disease (CVD) mortality, all-cause mortality, and incident (fatal and nonfatal) ...myocardial infarction (MI) in men from the general population taking into account C-reactive protein (CRP), a sensitive marker of systemic inflammation.
The study was based on 3604 men (45 to 74 years of age) who participated in 1 of the 3 MONICA Augsburg surveys between 1984 and 1995. All participants were prospectively followed within the framework of the Cooperative Health Research in the Region of Augsburg (KORA). Up to December 31, 2002, there occurred 809 total deaths, 359 CVD deaths, and 297 incident MIs. In a Cox model, comparing extreme quartiles of the UA distribution, the hazard ratio for CVD mortality was 1.44 (95% confidence interval CI 1.04 to 2.0), and for all-cause mortality it was 1.40 (95% CI 1.13 to 1.74) after adjustment for conventional cardiovascular risk factors, CRP, and diuretic intake. However, UA was not associated with incident MI after multivariable adjustment.
High UA levels were independently associated with CVD mortality as well as all-cause mortality but not with incident MI in middle-aged men from the general population.
Multimorbidity is a common problem in aged populations with a wide range of individual and societal consequences. The objective of the study was to explore patterns of comorbidity and multimorbidity ...in an elderly population using different analytical approaches. Data were gathered from the population-based KORA-Age project, which included 4,127 persons aged 65-94 years living in the city of Augsburg and its two surrounding counties in Southern Germany. Information on the presence of 13 chronic conditions was collected in a standardized telephone interview and a self-administered questionnaire. Patterns of comorbidity and multimorbidity were analyzed using prevalence figures, logistic regression models and exploratory tetrachoric factor analysis. The prevalence of multimorbidity (≥2 diseases) was 58.6% in the total sample. Hypertension and diabetes (Odds Ratio OR 2.95, 99.58% confidence interval CI 2.19-3.96), as well as hypertension and stroke (OR 2.00, 99.58% CI 1.26-3.16) most often occurred in combination. This association was independent of age, sex and the presence of other conditions. Using factor analysis, we identified four patterns of multimorbidity: the first pattern includes cardiovascular and metabolic diseases, the second includes joint, liver, lung and eye diseases, the third covers mental and neurologic diseases and the fourth pattern includes gastrointestinal diseases and cancer. 44% of the persons were assigned to at least one of the four multimorbidity patterns; 14% could be assigned to both the cardiovascular/metabolic and the joint/liver/lung/eye pattern. Further common pairs were the mental/neurologic pattern combined with the cardiovascular/metabolic pattern (7.2%) or the joint/liver/lung/eye pattern (5.3%), respectively. Our results confirmed the existence of co-occurrence of certain diseases in elderly persons, which is not caused by chance. Some of the identified patterns of multimorbidity and their overlap may indicate common underlying pathological mechanisms.
Metabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire ...spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained in the field of diabetes research when combining metabolomics data collected on a complementary set of analytical platforms in the framework of an epidemiological study.
40 individuals with self-reported diabetes and 60 controls (male, over 54 years) were randomly selected from the participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study, representing an extensively phenotyped sample of the general German population. Concentrations of over 420 unique small molecules were determined in overnight-fasting blood using three different techniques, covering nuclear magnetic resonance and tandem mass spectrometry. Known biomarkers of diabetes could be replicated by this multiple metabolomic platform approach, including sugar metabolites (1,5-anhydroglucoitol), ketone bodies (3-hydroxybutyrate), and branched chain amino acids. In some cases, diabetes-related medication can be detected (pioglitazone, salicylic acid).
Our study depicts the promising potential of metabolomics in diabetes research by identification of a series of known and also novel, deregulated metabolites that associate with diabetes. Key observations include perturbations of metabolic pathways linked to kidney dysfunction (3-indoxyl sulfate), lipid metabolism (glycerophospholipids, free fatty acids), and interaction with the gut microflora (bile acids). Our study suggests that metabolic markers hold the potential to detect diabetes-related complications already under sub-clinical conditions in the general population.
To examine gender-specific associations between sleep duration and sleep complaints and incident myocardial infarction (MI).
Cohort study.
A representative population sample of middle-aged subjects ...in Germany.
The study was based on 3508 men and 3388 women (aged 45 to 74 years) who participated in one of the 3 MONICA (Monitoring trends and determinants on cardiovascular diseases) Augsburg surveys between 1984 and 1995, who were free of MI and angina pectoris at baseline and were followed up until 2002.
N/A.
A total of 295 cases of incident MI among men and 85 among women occurred during a mean follow-up period of 10.1 years. Compared with women sleeping 8 hours, the multivariable adjusted hazard ratio (HR) of MI among women sleeping < or =5 hours was 2.98 (95% CI, 1.48-6.03), and among women sleeping > or =9 hours 1.40 (95% CI, 0.74-2.64); the corresponding HRs among men were 1.13 (95% CI, 0.66-1.92) and 1.07 (95% CI, 0.75-1.53). In multivariable analysis the relative risk of an incident MI for men and women with difficulties maintaining sleep was 1.12 (95% CI, 0.84-1.48) and 1.53 (95% CI, 0.99-2.37), respectively, and for men and women with difficulties initiating sleep the relative risk was 1.16 (95% CI, 0.82-1.63) and 1.30 (95% CI, 0.81-2.06), respectively.
Modest associations between short sleep duration and difficulties maintaining sleep and incident MI were seen in middle-aged women but not men from the general population.
Serum metabolites are associated cross-sectionally with kidney function in population-based studies.
Using flow injection and liquid chromatography tandem mass spectrometry methods, we examined ...longitudinal associations of baseline concentrations of 140 metabolites and their 19 460 ratios with kidney function decline and chronic kidney disease (CKD) incidence over 7 years in 1104 participants of the Cooperative Health Research in the Region of Augsburg S4/F4 study.
Corrected for multiple testing, a significant association with annual change in the estimated glomerular filtration rate was observed for spermidine (P = 5.8 × 10(-7)) and two metabolite ratios, the phosphatidylcholine diacyl C42:5-to-phosphatidylcholine acyl-alkyl C36:0 ratio (P = 1.5 × 10(-6)) and the kynurenine-to-tryptophan ratio (P = 1.9 × 10(-6)). The kynurenine-to-tryptophan ratio was also associated with significantly higher incidence of CKD at the follow-up visit with an odds ratio of 1.36 per standard deviation increase; 95% confidence interval 1.11-1.66, P = 2.7 × 10(-3)). In separate analyses, the predictive ability of the metabolites was assessed: both the three significantly associated metabolite (ratios) as well as a panel of 35 metabolites selected from all metabolites in an unbiased fashion provided as much but not significantly more prognostic information than selected clinical predictors as judged by the area under the curve.
Baseline serum concentrations of spermidine and two metabolite ratios were associated with kidney function change over subsequent years in the general population. In separate analyses, baseline serum metabolites were able to predict incident CKD to a similar but not better extent than selected clinical parameters. Our longitudinal findings provide a basis for targeted studies of certain metabolic pathways, e.g. tryptophan metabolism, and their relation to kidney function decline.
Type 2 diabetes (T2D) can be prevented in pre‐diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre‐diabetes. ...We quantified 140 metabolites for 4297 fasting serum samples in the population‐based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre‐diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P‐values ranging from 2.4 × 10−4 to 2.1 × 10−13. Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)‐Potsdam cohort. Using metabolite–protein network analysis, we identified seven T2D‐related genes that are associated with these three IGT‐specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.
A targeted metabolomics approach was used to identify candidate biomarkers of pre‐diabetes. The relevance of the identified metabolites is further corroborated with a protein‐metabolite interaction network and gene expression data.
Synopsis
A targeted metabolomics approach was used to identify candidate biomarkers of pre‐diabetes. The relevance of the identified metabolites is further corroborated with a protein‐metabolite interaction network and gene expression data.
Three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine C2) were found with significantly altered levels in pre‐diabetic individuals compared with normal controls.
Lower levels of glycine and LPC (18:2) were found to predict risks for pre‐diabetes and type 2 diabetes (T2D).
Seven T2D‐related genes (PPARG, TCF7L2, HNF1A, GCK, IGF1, IRS1 and IDE) are functionally associated with the three identified metabolites.
The unique combination of methodologies, including prospective population‐based and nested case–control, as well as cross‐sectional studies, was essential for the identification of the reported biomarkers.
Abstract Objective Physical activity is suggested to play a key role in the prevention of several chronic diseases. However, data on the association between physical activity and multimorbidity are ...lacking. Methods Using data from 1007 men and women aged 65–94 years who participated in the population-based KORA (Cooperative Health Research in the Region of Augsburg)-Age project conducted in Augsburg/Germany and two adjacent counties in 2008/09, 13 chronic conditions were identified, and physical activity scores were calculated based on the self-reported physical activity scale for the elderly (PASE). Multivariable sex-specific logistic regression was applied to determine the association of the continuous physical activity score with multimorbidity (≥ 2 out of 13 diseases). Results Physical activity (mean PASE score ± SD) was higher in men (125.1 ± 59.2) than in women (112.2 ± 49.2). Among men, the odds ratio (OR) for multimorbidity was 0.73 (95% CI: 0.60–0.90) for a 1 standard deviation increase of the PASE score. No significant results could be observed for women (OR: 1.05; 95% CI: 0.83–1.33). Conclusion We demonstrated an inverse association between physical activity and multimorbidity among men. Further prospective studies have to confirm the temporality of effects.
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