Biomarkers in osteoarthritis

Biomarkers aid the study of osteoarthritis (OA) in a number of different ways. In this article we summarise briefly their multiple uses and reflect on how the study reported in a previous edition of Arthritis Research & Therapy should promote further investigation of cartilage oligomeric matrix protein (COMP). COMP is foremost among hitherto investigated biomarkers and is most consistently shown to predict knee OA progression. Precisely what role it plays in OA pathogenesis remains unclear and elucidating this may be key to defining, and then targeting, the cellular pathways involved in OA

Decreasing initial telomere length in humans intergenerationally understates age-associated telomere shortening

Telomere length shortens with aging, and short telomeres have been linked to a wide variety of pathologies. Previous studies suggested a discrepancy in age-associated telomere shortening rate estimated by cross-sectional studies versus the rate measured in longitudinal studies, indicating a potential bias in cross-sectional estimates. Intergenerational changes in initial telomere length, such as that predicted by the previously described effect of a father's age at birth of his offspring (FAB), could explain the discrepancy in shortening rate measurements. We evaluated whether changes occur in initial telomere length over multiple generations in three large datasets and identified paternal birth year (PBY) as a variable that reconciles the difference between longitudinal and cross-sectional measurements. We also clarify the association between FAB and offspring telomere length, demonstrating that this effect is substantially larger than reported in the past. These results indicate the presence of a downward secular trend in telomere length at birth over generational time with potential public health implications

Innate and adaptive immune traits are differentially affected by genetic and environmental factors

The diversity and activity of leukocytes is controlled by genetic and environmental influences to maintain balanced immune responses. However, the relative contribution of environmental compared with genetic factors that affect variations in immune traits is unknown. Here we analyse 23,394 immune phenotypes in 497 adult female twins. 76% of these traits show a predominantly heritable influence, whereas 24% are mostly influenced by environment. These data highlight the importance of shared childhood environmental influences such as diet, infections or microbes in shaping immune homeostasis for monocytes, B1 cells, γδ T cells and NKT cells, whereas dendritic cells, B2 cells, CD4(+) T and CD8(+) T cells are more influenced by genetics. Although leukocyte subsets are influenced by genetics and environment, adaptive immune traits are more affected by genetics, whereas innate immune traits are more affected by environment

A Survey of UK Public Interest in Internet-Based Personal Genome Testing

Background:In view of the increasing availability of commercial internet-based Personal Genome Testing (PGT), this study aimed to explore the reasons why people would consider taking such a test and how they would use the genetic risk information provided. Methodology/Principal Findings: A self-completion questionnaire assessing public awareness and interest in PGT and motivational reasons for undergoing PGT was completed by 4,050 unselected adult volunteers from the UK-based TwinsUK register, aged 17 to 91 (response rate 62%). Only 13% of respondents were aware of the existence of PGT. After reading a brief summary about PGT, one in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely. A TwinsUK research focus group also indicated that consumers would consult their GP to help interpret results of PGT. Conclusions/Significance: This hypothetical study suggests that increasing publicity and decreasing costs of PGT may lead to increased uptake, driven in part by the general public's desire to monitor and improve their health. Although the future extent of the clinical utility of PGT is currently unknown, it is crucial that consumers are well informed about the current limitations of PGT. Our results suggest that health professionals will inevitably be required to respond to individuals who have undergone PGT. This has implications for health service providers regarding both cost and time

Diet and bone mineral density study in postmenopausal women from the TwinsUK registry shows a negative association with a traditional English dietary pattern and a positive association with wine

Background: The effect of diet on bone mineral density (BMD) remains controversial, mainly because of difficulties in isolating dietary factors from the confounding influences of age, lifestyle, and genetic factors. Objective: The aim of this study was to use a novel method to examine the relation between BMD and diet. Design: A co-twin control study design with linear regression modeling was used to test for associations between BMD and habitual intakes of calcium, vitamin D, protein, and alcohol plus 5 previously identified dietary patterns in postmenopausal women from the TwinsUK registry. This approach exploited the unique matching of twins to provide an estimate of an association that was not confounded by age, genetic background, or shared lifestyle. Results: In >2000 postmenopausal women (BMD data on 1019, 1218, and 1232 twin pairs at the hip neck, hip, and spine, respectively), we observed a positive association between alcohol intake (from wine but not from beer or spirits) and spine BMD (P = 0.01) and a negative association with a traditional 20th-century English diet at the hip neck (P = 0.01). Both associations remained borderline significant after adjustment for mean twin-pair intakes (P = 0.04 and P = 0.055, respectively). Other dietary patterns and intakes of calcium, vitamin D, and protein were unrelated to BMD. Conclusion: Our results showed that diet has an independent but subtle effect on BMD; wine intake was positively associated with spine BMD, whereas a traditional (20th-century) English diet had a negative association with hip BMD

Predicting incident radiographic knee osteoarthritis in middle-aged women within 4 years:the importance of knee-level prognostic factors.

ObjectiveDevelop and internally validate risk models and a clinical risk score tool to predict incident radiographic knee osteoarthritis (RKOA) in middle‐aged women.MethodsWe analysed 649 women in the Chingford 1000 Women study. The outcome was incident RKOA, defined as Kellgren/Lawrence grade 0‐1 at baseline and ≥2 at year 5. We estimated predictors' effects on the outcome using logistic regression models. Two models were generated. The clinical model considered patient characteristics, medication, biomarkers, and knee symptoms. The radiographic model considered the same factors, plus radiographic factors (e.g., angle between the acetabular roof and ilium's vertical cortex (hip α‐angle)). The models were internally validated. Model performance was assessed using calibration and discrimination (area under the receiver characteristic curve, AUC).ResultsThe clinical model contained age, quadriceps circumference, and a cartilage degradation marker (CTX‐II) as predictors (AUC = 0.692). The radiographic model contained older age, greater quadriceps circumference, knee pain, knee baseline Kellgren/Lawrence grade 1 (versus 0), greater hip α‐angle, greater spinal bone mineral density, and contralateral RKOA at baseline as predictors (AUC = 0.797). Calibration tests showed good agreement between the observed and predicted incident RKOA. A clinical risk score tool was developed from the clinical model.ConclusionTwo models predicting incident RKOA within 4 years were developed; including radiographic variables improved model performance. First‐time predictor hip α‐angle and contralateral RKOA suggest osteoarthritis origins beyond the knee. The clinical tool has the potential to help physicians identify patients at risk of RKOA in routine practice, but should be externally validated

ABO antigen and secretor statuses are not associated with gut microbiota composition in 1,500 twins

Background: Host genetics is one of several factors known to shape human gut microbiome composition, however, the physiological processes underlying the heritability are largely unknown. Inter-individual differences in host factors secreted into the gut lumen may lead to variation in microbiome composition. One such factor is the ABO antigen. This molecule is not only expressed on the surface of red blood cells, but is also secreted from mucosal surfaces in individuals containing an intact FUT2 gene (secretors). Previous studies report differences in microbiome composition across ABO and secretor genotypes. However, due to methodological limitations, the specific bacterial taxa involved remain unknown.Results: Here, we sought to determine the relationship of the microbiota to ABO blood group and secretor status in a large panel of 1503 individuals from a cohort of twins from the United Kingdom. Contrary to previous reports, robust associations between either ABO or secretor phenotypes and gut microbiome composition were not detected. Overall community structure, diversity, and the relative abundances of individual taxa were not significantly associated with ABO or secretor status. Additionally, joint-modeling approaches were unsuccessful in identifying combinations of taxa that were predictive of ABO or secretor status.Conclusions: Despite previous reports, the taxonomic composition of the microbiota does not appear to be strongly associated with ABO or secretor status in 1503 individuals from the United Kingdom. These results highlight the importance of replicating microbiome-associated traits in large, well-powered cohorts to ensure results are robust

Dietary influence on systolic and diastolic blood pressure in the TwinsUK cohort

Nutrition plays a key role in blood pressure (BP) regulation. Here, we examine associations between nutrient intakes and BP in a large predominantly female population-based cohort. We assessed the correlation between 45 nutrients (from food frequency questionnaires) and systolic BP/diastolic BP (SBP/DBP) in 3889 individuals from TwinsUK not on hypertensive treatments and replicated in an independent subset of monozygotic twins discordant for nutrient intake (17–242 pairs). Results from both analyses were meta-analysed. For significant nutrients, we calculated heritability using structural equation modelling. We identified and replicated 15 nutrients associated with SBP, 9 also being associated with DBP, adjusting for covariates and multiple testing. 14 of those had a heritable component (h2: 27.1–57.6%). Strong associations with SBP were observed for riboflavin (Beta(SE) = −1.49(0.38), P = 1.00 × 10−4) and tryptophan (−0.31(0.01), P = 5 × 10−4), while with DBP for alcohol (0.05(0.07), P = 1.00 × 10−4) and lactose (−0.05(0.0), P = 1.3 × 10−3). Two multivariable nutrient scores, combining independently SBP/DBP-associated nutrients, explained 22% of the variance in SBP and 13.6% of the variance in DBP. Moreover, bivariate heritability analysis suggested that nutrients and BP share some genetic influences. We confirm current understanding and extend the panel of dietary nutrients implicated in BP regulation underscoring the value of nutrient focused dietary research in preventing and managing hypertension