Depression is one of the most poorly understood diseases due to its elusive pathogenesis. There is an urgency to identify molecular and biological mechanisms underlying depression and the gut ...microbiome is a novel area of interest. Here we investigate the relation of fecal microbiome diversity and composition with depressive symptoms in 1,054 participants from the Rotterdam Study cohort and validate these findings in the Amsterdam HELIUS cohort in 1,539 subjects. We identify association of thirteen microbial taxa, including genera Eggerthella, Subdoligranulum, Coprococcus, Sellimonas, Lachnoclostridium, Hungatella, Ruminococcaceae (UCG002, UCG003 and UCG005), LachnospiraceaeUCG001, Eubacterium ventriosum and Ruminococcusgauvreauiigroup, and family Ruminococcaceae with depressive symptoms. These bacteria are known to be involved in the synthesis of glutamate, butyrate, serotonin and gamma amino butyric acid (GABA), which are key neurotransmitters for depression. Our study suggests that the gut microbiome composition may play a key role in depression.
Macrophage-mediated inflammation is thought to have a causal role in osteoarthritis-related pain and severity, and has been suggested to be triggered by endotoxins produced by the gastrointestinal ...microbiome. Here we investigate the relationship between joint pain and the gastrointestinal microbiome composition, and osteoarthritis-related knee pain in the Rotterdam Study; a large population based cohort study. We show that abundance of Streptococcus species is associated with increased knee pain, which we validate by absolute quantification of Streptococcus species. In addition, we replicate these results in 867 Caucasian adults of the Lifelines-DEEP study. Finally we show evidence that this association is driven by local inflammation in the knee joint. Our results indicate the microbiome is a possible therapeutic target for osteoarthritis-related knee pain.
Objective
Cam deformity and acetabular dysplasia have been recognized as relevant risk factors for hip osteoarthritis (OA) in a few prospective studies with limited sample sizes. To date, however, no ...evidence is available from prospective studies regarding whether the magnitude of these associations differs according to sex, body mass index (BMI), and age.
Methods
Participants in the Rotterdam Study cohort including men and women ages 55 years or older without OA at baseline (n = 4,438) and a mean follow‐up of 9.2 years were included in the study. Incident radiographic OA was defined as a Kellgren/Lawrence grade of ≥2 or a total hip replacement at follow‐up. Alpha and center‐edge angles were measured to determine the presence of cam deformity and acetabular dysplasia/pincer deformity, respectively. Odds ratios (ORs) were calculated to assess the associations between both deformities and the development of OA.
Results
Subjects with cam deformity (OR 2.11, 95% confidence interval 95% CI 1.55–2.87) and those with acetabular dysplasia (OR 2.19, 95% CI 1.50–3.21) had a 2‐fold increased risk of developing OA compared with subjects without deformity, while pincer deformity did not increase the risk of OA. Stratification analyses showed that the associations of cam deformity and acetabular dysplasia with OA were driven by younger individuals, whereas BMI did not influence the associations. Female sex appears to modify the risk of hip OA related to acetabular dysplasia.
Conclusion
Individuals with cam deformity and those with acetabular dysplasia are predisposed to OA; these associations were independent of other well‐known risk factors. Interestingly, both deformities predisposed to OA only in relatively young individuals. Therefore, early identification of these conditions is important.
The gut microbiota has been shown to play diverse roles in human health and disease although the underlying mechanisms have not yet been fully elucidated. Large cohort studies can provide further ...understanding into inter-individual differences, with more precise characterization of the pathways by which the gut microbiota influences human physiology and disease processes. Here, we aimed to profile the stool microbiome of children and adults from two population-based cohort studies, comprising 2,111 children in the age-range of 9 to 12 years (the Generation R Study) and 1,427 adult individuals in the range of 46 to 88 years of age (the Rotterdam Study). For the two cohorts, 16S rRNA gene profile datasets derived from the Dutch population were generated. The comparison of the two cohorts showed that children had significantly lower gut microbiome diversity. Furthermore, we observed higher relative abundances of genus Bacteroides in children and higher relative abundances of genus Blautia in adults. Predicted functional metagenome analysis showed an overrepresentation of the glycan degradation pathways, riboflavin (vitamin B2), pyridoxine (vitamin B6) and folate (vitamin B9) biosynthesis pathways in children. In contrast, the gut microbiome of adults showed higher abundances of carbohydrate metabolism pathways, beta-lactam resistance, thiamine (vitamin B1) and pantothenic (vitamin B5) biosynthesis pathways. A predominance of catabolic pathways in children (valine, leucine and isoleucine degradation) as compared to biosynthetic pathways in adults (valine, leucine and isoleucine biosynthesis) suggests a functional microbiome switch to the latter in adult individuals. Overall, we identified compositional and functional differences in gut microbiome between children and adults in a population-based setting. These microbiome profiles can serve as reference for future studies on specific human disease susceptibility in childhood, adulthood and specific diseased populations.
CONTEXT Mutations in the low-density lipoprotein receptor–related protein 5 (LRP5) gene cause rare syndromes characterized by altered bone mineral density (BMD). More common LRP5 variants may affect ...osteoporosis risk in the general population. OBJECTIVE To generate large-scale evidence on whether 2 common variants of LRP5 (Val667Met, Ala1330Val) and 1 variant of LRP6 (Ile1062Val) are associated with BMD and fracture risk. DESIGN AND SETTING Prospective, multicenter, collaborative study of individual-level data on 37 534 individuals from 18 participating teams in Europe and North America. Data were collected between September 2004 and January 2007; analysis of the collected data was performed between February and May 2007. Bone mineral density was assessed by dual-energy x-ray absorptiometry. Fractures were identified via questionnaire, medical records, or radiographic documentation; incident fracture data were available for some cohorts, ascertained via routine surveillance methods, including radiographic examination for vertebral fractures. MAIN OUTCOME MEASURES Bone mineral density of the lumbar spine and femoral neck; prevalence of all fractures and vertebral fractures. RESULTS The Met667 allele of LRP5 was associated with reduced lumbar spine BMD (n = 25 052 number of participants with available data; 20-mg/cm2 lower BMD per Met667 allele copy; P = 3.3 × 10−8), as was the Val1330 allele (n = 24 812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 × 10−9). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 × 10−5) and 8 mg/cm2 (P = 5.0 × 10−6) for the Met667 and Val1330 alleles, respectively (n = 25 193). Findings were consistent across studies for both LRP5 alleles. Both alleles were associated with vertebral fractures (odds ratio OR, 1.26; 95% confidence interval CI, 1.08-1.47 for Met667 2001 fractures among 20 488 individuals and OR, 1.12; 95% CI, 1.01-1.24 for Val1330 1988 fractures among 20 096 individuals). Risk of all fractures was also increased with Met667 (OR, 1.14; 95% CI, 1.05-1.24 per allele 7876 fractures among 31 435 individuals)) and Val1330 (OR, 1.06; 95% CI, 1.01-1.12 per allele 7802 fractures among 31 199 individuals). Effects were similar when adjustments were made for age, weight, height, menopausal status, and use of hormone therapy. Fracture risks were partly attenuated by adjustment for BMD. Haplotype analysis indicated that Met667 and Val1330 variants both independently affected BMD. The LRP6 Ile1062Val polymorphism was not associated with any osteoporosis phenotype. All aforementioned associations except that between Val1330 and all fractures and vertebral fractures remained significant after multiple-comparison adjustments. CONCLUSIONS Common LRP5 variants are consistently associated with BMD and fracture risk across different white populations. The magnitude of the effect is modest. LRP5 may be the first gene to reach a genome-wide significance level (a conservative level of significance herein, unadjusted P < 10−7 that accounts for the many possible comparisons in the human genome) for a phenotype related to osteoporosis.
Cross-sectional open population based study (nested in a prospective cohort study).
To explore the association of the different individual radiographic features, including osteophytes and disc space ...narrowing, with self-reported low back pain (LBP). Different definitions of lumbar disc degeneration with self-reported LBP and disability were considered in a large open population sample. Furthermore, in order to disentangle the discrepancies in reported strength of the associations, we characterized the frequency of the different individual radiographic features of lumbar disc degeneration and definitions of lumbar disc degeneration, as well as their association with LBP status, by age, gender, and vertebral level.
Currently within the literature, there have been no studies that have explored different definitions of lumbar disc degeneration and their association with LBP within one study sample.
The intervertebral disc spaces (L1/2 to L5-S1) were evaluated for the presence and severity of anterior osteophytes and disc space narrowing using a semiquantitative score (grade 0-3). Logistic regression was used to determine the association between these individual radiographic features of lumbar disc degeneration and different definitions of lumbar disc degeneration for LBP.
Lumbar radiographs were scored for 1204 men, and 1615 women. Osteophytes were the most frequent radiographic feature observed, with men having the greatest frequency. Disc space narrowing was more frequent in women than men. Both radiographic features increased in frequency with age.Disc space narrowing appeared more strongly associated with LBP than osteophytes, especially in men (odds ratio OR = 1.9; 95% confidence interval CI: 1.4-2.8). Disc space narrowing at 2 or more levels appeared more strongly associated with LBP than disc space narrowing at only 1 level (OR = 2.4; 95% CI: 1.6-3.4). After excluding level L5-S1, the strength of almost all associations increased.
We are the first to report different possible lumbar disc degeneration definitions and their associations with LBP. Disc space narrowing at 2 or more levels appeared more strongly associated with LBP than other radiographic features, especially after excluding level L5-S1.
Osteoarthritis MIM 165720 is a common late-onset articular joint disease for which no pharmaceutical intervention is available to attenuate the cartilage degeneration. To identify a new ...osteoarthritis susceptibility locus, a genome-wide linkage scan and combined linkage association analysis were applied to 179 affected siblings and four trios with generalized osteoarthritis (The GARP study). We tested, for confirmation by association, 1478 subjects who required joint replacement and 734 controls in a UK population. Additional replication was tested in 1582 population-based females from the Rotterdam study that contained 94 cases with defined hip osteoarthritis and in 267 Japanese females with symptomatic hip osteoarthritis and 465 controls. Suggested evidence for linkage in the GARP study was observed on chromosome 14q32.11 (log of odds = 3.03, P = 1.9×10−4). Genotyping tagging single-nucleotide polymorphisms covering three important candidate genes revealed a common coding variant (rs225014; Thr92Ala) in the iodothyronine-deiodinase enzyme type 2 (D2) gene (DIO2 MIM 601413) which significantly explained the linkage signal (P = 0.006). Confirmation and replication by association in the additional osteoarthritis studies indicated a common DIO2 haplotype, exclusively containing the minor allele of rs225014 and common allele of rs12885300, with a combined recessive odds ratio of 1.79, 95% confidence interval (CI) 1.37–2.34 with P = 2.02×10−5 in female cases with advanced/symptomatic hip osteoarthritis. The gene product of this DIO2 converts intracellular pro-hormone-3,3′,5,5′-tetraiodothyronine (T4) into the active thyroid hormone 3,3′,5-triiodothyronine (T3) thereby regulating intracellular levels of active T3 in target tissues such as the growth plate. Our results indicate a new susceptibility gene (DIO2) conferring risk to osteoarthritis.
Objective
Polygenic risk scores (PRS) allow risk stratification using common single‐nucleotide polymorphisms (SNPs), and clinical applications are currently explored for several diseases. This study ...was undertaken to assess the risk of hip and knee osteoarthritis (OA) using PRS.
Methods
We analyzed 12,732 individuals from a population‐based cohort from the Rotterdam Study (n = 11,496), a clinical cohort (Cohort Hip and Cohort Knee CHECK study; n = 908), and a high‐risk cohort of overweight women (Prevention of Knee OA in Overweight Females PROOF study; n = 328), for the association of the PRS with prevalence/incidence of radiographic OA, of clinical OA, and of total hip replacement (THR) or total knee replacement (TKR). The hip PRS and knee PRS contained 44 and 24 independent SNPs, respectively, and were derived from a recent genome‐wide association study meta‐analysis. Standardized PRS (with Z transformation) were used in all analyses.
Results
We found a stronger association of the PRS for clinically defined OA compared to radiographic OA phenotypes, and we observed the highest PRS risk stratification for TKR/THR. The odds ratio (OR) per SD was 1.3 for incident THR (95% confidence interval 95% CI 1.1–1.5) and 1.6 (95% CI 1.3–1.9) for incident TKR in the Rotterdam Study. The knee PRS was associated with incident clinical knee OA in the CHECK study (OR 1.3 95% CI 1.1–1.5), but not for the PROOF study (OR 1.2 95% CI 0.8–1.7). The OR for OA increased gradually across the PRS distribution, up to 2.1 (95% CI 1.4–3.2) for individuals with the 10% highest PRS compared to the middle 50% of the PRS distribution.
Conclusion
Our findings validated the association of PRS across OA definitions. Since OA is becoming frequent and primary prevention is not commonly applicable, PRS‐based risk assessment could play a role in OA prevention. However, the utility of PRS is dependent on the setting. Further studies are needed to test the integration of genetic risk assessment in diverse health care settings.
We aimed to investigate the prognostic value of two biomarkers of tissue inflammation, matrix metalloproteinase-dependent degradation of C-reactive protein (CRPM) and connective tissue type I ...collagen turnover (C1M), on the incidence and progression of radiographic osteoarthritis (OA) in the Rotterdam Study, a prospective cohort. Moreover, the independent effect of these biomarkers with respect to the established biomarkers of OA progression, like urinary type II collagen degradation (uCTX-II) and serum cartilage oligomeric protein (COMP), was evaluated.
Serum levels of C1M, CRPM, COMP and CRP of 1335 participants aged >55 years were measured in fasting serum using ELISA. The commercial ELISA detecting CTX-II was used in urine. Radiographs at baseline and 5-year follow-up were scored for OA stage by Kellgren-Lawrence grade. The associations between progression and incidence of OA and the baseline biomarkers were examined using logistic regression and generalized estimating equations adjusted for age, sex, BMI, and possible other confounders.
The uCTX-II, COMP, and CRP concentrations were associated with the incidence and progression of OA. Moreover, OA progression was positively associated with CRPM (OR = 1.3, p = 0.01) and CRP (OR = 1.3, p = 0.01) levels with similar effect size as uCTX-II (OR = 1.3, p = 0.01) and COMP (OR = 1.2, p = 0.02). CRPM had prognostic value for progression of OA independent from the uCTX-II and COMP.
Our study confirmed the associations between uCTX-II and COMP concentrations and OA progression. Importantly, we showed for the first time that CRPM predicts the risk of OA progression independent of the established biomarkers uCTX-II and COMP.
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