The latest news from the GENOMOS study

Most common age-related diseases such as osteoporosis, have strong genetic influences and therefore intense efforts are ongoing to identify the underlying genetic variants. Knowledge of these variants can help in understanding the disease process and might benefit development of interventions and diagnostics. Association studies have now become the standard approach to uncover the genetic effects of common variants. Yet, in all fields of complex disease genetics - including osteoporosis - progress in identifying these genetic factors has been hampered by often controversial results. Because of the complicated genetic architecture of the diseases and the small effect size for each individual risk alleles, this is mostly due to low statistical power and limitations of analytical methods. It is now recognised that association analysis followed by replication and prospective multi-centred meta-analysis is currently the best way forward to identify genetic markers for complex traits, such as osteoporosis. To accomplish this, large (global) collaborative consortia have been established that have large collections of DNA samples from subjects with a certain phenotype and that use standardized methodology and definitions, to quantify by meta-analysis the subtle effects of the responsible gene variants. The GENOMOS consortium has played such a role in the field of osteoporosis and has initially identified and refuted associations of well known candidate genes. This consortium is now expected to play an important role in validation of risk alleles coming from Genome Wide Association Studies (GWAS) for osteoporosis, some of which have just been published. Together with genetic studies on more rare syndromes, the GWA approach in combination with the GENOMOS consortium, is likely to help in clarifying the genetic architecture of complex bone traits such as BMD, and - eventually - in understanding the genetics of clinically relevant endpoints in osteoporosis, i.e., fracture risk. Such genetic insights will be useful in understanding biology and are likely to also find applications in clinical practice.</p

The Caenorhabditis eleguns genome contains monomorphic minisatellites and simple sequences

Many species have been shown to contain tandemly repeated short sequence DNA kinown as minisatellites and simple sequence motifs. Due to allelic variation in the copy number of the repeat unit these loci are usually highly polymorphic. Here we demonstrate the presence of sequences in the genome of the nematode Caenorhabditis elegans which are homologous to two sets of short sequence DNA. However, when two independent strains were compared no polymorphism for these sequences could be detected.</p

Genetic Vitamin D Receptor Polymorphisms and Risk of Disease

[...] Below, we present a more detailed description of the genomic organization of the VDR gene, including discussion on polymorphisms, linkage disequilibrium, and haplotypes. We then describe association studies of VDR polymorphisms in relation to different diseases. Historically speaking, studies of VDR polymorphisms in relation to bone endpoints, including osteoporosis in particular, have received most attention while the analysis of VDR polymorphisms in relation to other diseases, including breast and prostate cancer and immune-related disorders, has reached the literature somewhat later on. This allows studies on associations with bone endpoints to be compared to a certain extent and to illustrate some of the difficulties in interpreting the results. [...

Identity and Paternity Testing of Cattle:Application of a Deoxyribonucleic Acid Profiling Protocol

We have applied DNA profiling for identity and parentage studies of cattle using a standardized procedure based on synthetic micro- and minisatellite multilocus core probes in Southern blot hybridization assays. This protocol is useful for paternity analysis of cattle and for real case work (e.g., identity and paternity disputes).</p

Burden of genetic risk variants in multiple sclerosis families in the Netherlands

Background: Approximately 20% of multiple sclerosis patients have a family history of multiple sclerosis. Studies of multiple sclerosis aggregation in families are inconclusive. Objective: To investigate the genetic burden based on currently discovered genetic variants for multiple sclerosis risk in patients from Dutch multiple sclerosis multiplex families versus sporadic multiple sclerosis cases, and to study its influence on clinical phenotype and disease prediction. Methods: Our study population consisted of 283 sporadic multiple sclerosis cases, 169 probands from multiplex families and 2028 controls. A weighted genetic risk score based on 102 non-human leukocyte antigen loci and HLA-DRB1*1501 was calculated. Results: The weighted genetic risk score based on all loci was significantly higher in familial than in sporadic cases. The HLA-DRB1*1501 contributed significantly to the difference in genetic burden between the groups. A high weighted genetic risk score was significantly associated with a low age of disease onset in all multiple sclerosis patients, but not in the familial cases separately. The genetic risk score was significantly but modestly better in discriminating familial versus sporadic multiple sclerosis from controls. Conclusion: Familial multiple sclerosis patients are more loaded with the common genetic variants than sporadic cases. The difference is mainly driven by HLA-DRB1*1501. The predictive capacity of genetic loci is poor and unlikely to be useful in clinical settings.</p

Bone mineral density and chronic lung disease mortality: the Rotterdam study

Context: Low bone mineral density (BMD) has been associated with increased all-cause mortality. Cause-specific mortality studies have been controversial. Objective: The aim of the study was to investigate associations between BMD and all-cause mortality and in-depth cause-specific mortality. Design and Setting: We studied two cohorts from the prospective Rotterdam Study (RS), initiated in 1990 (RS-I) and 2000 (RS-II) with average follow-up of 17.1 (RS-I) and 10.2 (RS-II) years until January 2011. Baseline femoral neck BMD was analyzed in SD values. Deaths were classified according to International Classification of Diseases into seven groups: cardiovascular diseases, cancer, infections, external, dementia, chronic lung diseases, and other causes. Gender-stratified Cox and competing-risks models were adjusted for age, body mass index, and smoking. Participants: The study included 5779 subjects from RS-I and 2055 from RS-II. Main Outcome Measurements: We measured all-cause and cause-specific mortality. Results: A significant inverse association between BMD and all-cause mortality was found in males [expressed as hazard ratio (95% confidence interval)]: RS-I, 1.07 (1.01-1.13), P = .020; RS-II, 1.31 (1.12-1.55), P = .001); but it was not found in females: RS-I, 1.05 (0.99-1.11), P = .098; RS-II, 0.91 (0.74-1.12), P = .362. An inverse association with chronic lung disease mortality was found in males [RS-I, 1.75 (1.34-2.29), P < .001; RS-II, 2.15 (1.05-4.42), P = .037] and in RS-I in females [1.72 (1.16-2.57); P = .008], persisting after multiple adjustments and excluding prevalent chronic obstructive pulmonary disease. A positive association between BMD and cancer mortality was detected in females in RS-I [0.89 (0.80-0.99); P = .043]. No association was found with cardiovascular mortality. Conclusions: BMD is inversely associated with mortality. The strong association of BMD with chronic lung disease mortality is a novel finding that needs further analysis to clarify underlying mechanisms

Advanced glycation end products measured by skin autofluorescence and subclinical cardiovascular disease:the Rotterdam Study

Background: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. Methods: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. Results: 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. Conclusions: Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. Trial registration: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.</p

Advanced glycation end products measured by skin autofluorescence and subclinical cardiovascular disease:the Rotterdam Study

Background: Advanced glycation end products (AGEs) have been linked to cardiovascular disease (CVD), especially coronary heart disease (CHD), but their role in CVD pathogenesis remains unclear. Therefore, we investigated cross-sectional associations of skin AGEs with subclinical atherosclerosis, arterial stiffness, and hypertension after confirming their relation with CHD. Methods: In the population-based Rotterdam Study, skin AGEs were measured as skin autofluorescence (SAF). Prevalent MI was obtained from digital medical records. Carotid plaques, carotid intima-media thickness (IMT), coronary artery calcification (CAC), pulse wave velocity (PWV), and hypertension were assessed. Associations of SAF with endophenotypes were investigated in logistic and linear regression models adjusting for common cardiovascular risk factors. Effect modification by sex, diabetes mellitus, and chronic kidney disease (CKD) was tested. Results: 3001 participants were included (mean age 73 (SD 9) years, 57% women). One unit higher SAF was associated with the presence of carotid plaques (OR 1.2 (0.92, 1.57)), a higher max IMT (0.08 SD (0.01, 0.15)), higher CAC (OR 2.2 (1.39, 3.48)), and PWV (0.09 SD (0.01, 0.16)), but not with hypertension (OR 0.99 (0.81, 1.21)). The associations with endophenotypes were more pronounced in men and participants with diabetes or CKD with significant interactions. Conclusions: Previously documented associations between SAF and CVD, also found in our study, may be explained by the endophenotypes atherosclerosis and arterial stiffness, especially in men and individuals with diabetes or CKD, but not by hypertension. Longitudinal studies are needed to replicate these findings and to test if SAF is an independent risk factor or biomarker of CVD. Trial registration: The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; www.trialregister.nl) and the WHO International Clinical Trials Registry Platform (ICTRP; www.who.int/ictrp/network/primary/en/) under shared catalogue number NTR6831.</p

The association between dietary and skin advanced glycation end products: the Rotterdam Study

BackgroundAdvanced glycation end products (AGEs) accumulate in tissues with age and in conditions such as diabetes mellitus and chronic kidney disease (CKD), and they may be involved in age-related diseases. Skin AGEs measured as skin autofluorescence (SAF) are a noninvasive reflection of long-term AGE accumulation in tissues. Whether AGEs present in the diet (dAGEs) contribute to tissue AGEs is unclear.ObjectivesOur aim was to investigate the association between dietary and skin AGEs in the Rotterdam Study, a population-based cohort of mainly European ancestry.MethodsIn 2515 participants, intake of 3 dAGEs [carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL)] was estimated using FFQs and the content of AGEs measured in commonly consumed foods. SAF was measured 5 y (median value) later using an AGE Reader. The association of dAGEs with SAF was analyzed in linear regression models and stratified for diabetes and chronic kidney disease (CKD, defined as estimated glomerular filtration rate ≤60 mL/min) status.ResultsMean ± SD intake was 3.40 ±0.89 mg/d for CML, 28.98 ±7.87 mg/d for MGH1, and 3.11 ±0.89 mg/d for CEL. None of them was associated with SAF in the total study population. However, in stratified analyses, CML was positively associated with SAF after excluding both individuals with diabetes and individuals with CKD: 1 SD higher daily CML intake was associated with a 0.03 (95% CI: 0.009, 0.05) arbitrary units higher SAF. MGH1 and CEL intake were not significantly associated with SAF. Nevertheless, the associations were stronger when the time difference between dAGEs and SAF measurements was shorter.ConclusionsHigher dietary CML intake was associated with higher SAF only among participants with neither diabetes nor CKD, which may be explained by high AGE formation in diabetes and decreased excretion in CKD or by dietary modifications in these disease groups. The dAGE–SAF associations were also modified by the time difference between measurements. Our results suggest that dAGEs can influence tissue AGE accumulation and possibly thereby age-related diseases. This trial was registered at the Netherlands National Trial Register as NTR6831 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831) and at the WHO International Clinical Trials Registry Platform as NTR6831 (http://www.who.int/ictrp/network/primary/en/).<br/