Familial, structural, and environmental correlates of MRI-defined bone marrow lesions: a sibpair study

The aim of this study was to estimate the heritability and describe the correlates of bone marrow lesions in knee subchondral bone. A sibpair design was used. T2- and T1-weighted MRI scans were performed on the right knee to assess bone marrow lesions at lateral tibia and femora and medial tibia and femora, as well as chondral defects. A radiograph was taken on the same knee and scored for individual features of osteoarthritis (radiographic osteoarthritis; ROA) and alignment. Other variables measured included height, weight, knee pain, and lower-limb muscle strength. Heritability was estimated with the program SOLAR (Sequential Oligogenetic Linkage Analysis Routines). A total of 115 siblings (60 females and 55 males) from 48 families, representing 95 sib pairs, took part. The adjusted heritability estimates were 53 ± 28% (mean ± SEM; p = 0.03) and 65 ± 32% (p = 0.03) for severity of bone marrow lesions at lateral and medial compartments, respectively. The estimates were reduced by 8 to 9% after adjustment for chondral defects and ROA (but not alignment). The adjusted heritability estimate was 99% for prevalent bone marrow lesions at both lateral and medial compartments. Both lateral and medial bone marrow lesions were significantly correlated with age, chondral defects, and ROA of the knee (all p < 0.05). Medial bone marrow lesions were also more common in males and were correlated with body mass index (BMI). Thus, bone marrow lesions have a significant genetic component. They commonly coexist with chondral defects and ROA but only share common genetic mechanisms to a limited degree. They are also more common with increasing age, male sex, and increasing BMI

Ensemble learning for detecting gene-gene interactions in colorectal cancer

Colorectal cancer (CRC) has a high incident rate in both men and women and is affecting millions of people every year. Genome-wide association studies (GWAS) on CRC have successfully revealed common single-nucleotide polymorphisms (SNPs) associated with CRC risk. However, they can only explain a very limited fraction of the disease heritability. One reason may be the common uni-variable analyses in GWAS where genetic variants are examined one at a time. Given the complexity of cancers, the non-additive interaction effects among multiple genetic variants have a potential of explaining the missing heritability. In this study, we employed two powerful ensemble learning algorithms, random forests and gradient boosting machine (GBM), to search for SNPs that contribute to the disease risk through non-additive gene-gene interactions. We were able to find 44 possible susceptibility SNPs that were ranked most significant by both algorithms. Out of those 44 SNPs, 29 are in coding regions. The 29 genes include ARRDC5, DCC, ALK, and ITGA1, which have been found previously associated with CRC, and E2F3 and NID2, which are potentially related to CRC since they have known associations with other types of cancer. We performed pairwise and three-way interaction analysis on the 44 SNPs using information theoretical techniques and found 17 pairwise (p < 0.02) and 16 three-way (p ≤ 0.001) interactions among them. Moreover, functional enrichment analysis suggested 16 functional terms or biological pathways that may help us better understand the etiology of the disease

RNA-binding protein CUGBP1 regulates insulin secretion via activation of phosphodiesterase 3B in mice

International audienceAims/hypothesis: CUG-binding protein 1 (CUGBP1) is a multifunctional RNA-binding protein that regulates RNA processing at several stages including translation, deadenylation and alternative splicing, as well as RNA stability. Recent studies indicate that CUGBP1 may play a role in metabolic disorders. Our objective was to examine its role in endocrine pancreas function through gain- and loss-of-function experiments and to further decipher the underlying molecular mechanisms.Methods: A mouse model in which type 2 diabetes was induced by a high-fat diet (HFD; 60% energy from fat) and mice on a standard chow diet (10% energy from fat) were compared. Pancreas-specific CUGBP1 overexpression and knockdown mice were generated. Different lengths of the phosphodiesterase subtype 3B (PDE3B) 3′ untranslated region (UTR) were cloned for luciferase reporter analysis. Purified CUGBP1 protein was used for gel shift experiments.Results: CUGBP1 is present in rodent islets and in beta cell lines; it is overexpressed in the islets of diabetic mice. Compared with control mice, the plasma insulin level after a glucose load was significantly lower and glucose clearance was greatly delayed in mice with pancreas-specific CUGBP1 overexpression; the opposite results were obtained upon pancreas-specific CUGBP1 knockdown. Glucose- and glucagon-like peptide1 (GLP-1)-stimulated insulin secretion was significantly attenuated in mouse islets upon CUGBP1 overexpression. This was associated with a strong decrease in intracellular cAMP levels, pointing to a potential role for cAMP PDEs. CUGBP1 overexpression had no effect on the mRNA levels of PDE1A, 1C, 2A, 3A, 4A, 4B, 4D, 7A and 8B subtypes, but resulted in increased PDE3B expression. CUGBP1 was found to directly bind to a specific ATTTGTT sequence residing in the 3′ UTR of PDE3B and stabilised PDE3B mRNA. In the presence of the PDE3 inhibitor cilostamide, glucose- and GLP-1-stimulated insulin secretion was no longer reduced by CUGBP1 overexpression. Similar to CUGBP1, PDE3B was overexpressed in the islets of diabetic mice.Conclusions/interpretation: We conclude that CUGBP1 is a critical regulator of insulin secretion via activating PDE3B. Repressing this protein might provide a potential strategy for treating type 2 diabetes

The Association Between an Addictive Tendency Toward Food and Metabolic Characteristics in the General Newfoundland Population

Background: Our previous study of 29 obese food addiction (FA) patients found that FA is associated with lipid profiles and hormones which may be a factor in cardiovascular disease (CVD) and insulin resistance (IR). However, there is currently no data available regarding the relationship between FA symptoms and metabolic characteristics of CVD and IR in the general population. We designed this study to investigate the correlation between FA symptoms with lipid profiles and IR in men and women of the general Newfoundland population. Methods: 710 individuals (435 women and 275 men) recruited from the general Newfoundland population were used in analysis. FA symptoms were evaluated using the Yale Food Addiction Scale (YFAS). Glucose, insulin, HDL, LDL, total cholesterol and triglycerides levels were measured. IR was evaluated using the homeostatic model of assessment (HOMA). Participants were grouped by sex and menopausal status. Age, physical activity, calories and total % body fat were controlled. Results: Partial correlation analysis revealed that in men, YFAS symptom counts were significantly correlated with HOMA-b (r = 0.196, p = 0.021), triglycerides (r = 0.140, p = 0.025) and inversely correlated with HDL (r = −0.133, p = 0.033). After separating by menopausal status, pre-menopausal women exhibited no correlations and post-menopausal women had a significantcorrelation with triglycerides (r = 0.198, p = 0.016). Conclusion: FA is significantly correlated with several markers of metabolic disturbance in men and to a lesser extent, post-menopausal women, in the general population. Further research is required to explain sex specific associations and elucidate any potentially causal mechanisms behind this correlation

Macrophage migration inhibitory factor may play a protective role in osteoarthritis

Background Osteoarthritis (OA) is the most prevalent form of arthritis and the major cause of disability and overall diminution of quality of life in the elderly population. Currently there is no cure for OA, partly due to the large gaps in our understanding of its underlying molecular and cellular mechanisms. Macrophage migration inhibitory factor (MIF) is a procytokine that mediates pleiotropic inflammatory effects in inflammatory diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, data on the role of MIF in OA is limited with conflicting results. We undertook this study to investigate the role of MIF in OA by examining MIF genotype, mRNA expression, and protein levels in the Newfoundland Osteoarthritis Study. Methods One hundred nineteen end-stage knee/hip OA patients, 16 RA patients, and 113 healthy controls were included in the study. Two polymorphisms in the MIF gene, rs755622, and -794 CATT5-8, were genotyped using polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) and PCR followed by automated capillary electrophoresis, respectively. MIF mRNA levels in articular cartilage and subchondral bone were measured by quantitative polymerase chain reaction. Plasma concentrations of MIF, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 beta (IL-1β) were measured by enzyme-linked immunosorbent assay. Results rs755622 and -794 CATT5-8 genotypes were not associated with MIF mRNA or protein levels or OA (all p ≥ 0.19). MIF mRNA level in cartilage was lower in OA patients than in controls (p = 0.028) and RA patients (p = 0.004), while the levels in bone were comparable between OA patients and controls (p = 0.165). MIF protein level in plasma was lower in OA patients than in controls (p = 3.01 × 10−10), while the levels of TNF-α, IL-6 and IL-1β in plasma were all significantly higher in OA patients than in controls (all p ≤ 0.0007). Multivariable logistic regression showed lower MIF and higher IL-1β protein levels in plasma were independently associated with OA (OR per SD increase = 0.10 and 8.08; 95% CI = 0.04–0.19 and 4.42–16.82, respectively), but TNF-α and IL-6 became non-significant. Conclusions Reduced MIF mRNA and protein expression in OA patients suggested MIF might have a protective role in OA and could serve as a biomarker to differentiate OA from other joint disorders

Association Between Gut Microbiota and Symptomatic Hand Osteoarthritis: Data From the Xiangya Osteoarthritis Study

Objective: Systemic inflammatory factors have been implicated in symptomatic hand osteoarthritis (OA). Gut microbiome dysbiosis promotes systemic inflammation. The aim of this study was to examine the association between the gut microbiome and the presence of symptomatic hand OA in a population-based study. Methods: Study participants were subjects of the Xiangya Osteoarthritis Study, a community-based observational study conducted in the Hunan Province of China. Symptomatic hand OA was defined as the presence of both symptoms and radiographic OA in the same hand. The gut microbiome was analyzed using 16S ribosomal RNA gene sequencing in stool samples. We examined the relation of α-diversity, β-diversity, relative abundance of taxa, and potential bacterial functional pathways to symptomatic hand OA. Results: A total of 1,388 participants (mean age 61.3 years, 57.4% women) were included in the study, of whom 72 had symptomatic hand OA (prevalence of symptomatic hand OA 5.2%). Beta-diversity of the gut microbiome, but not α-diversity, was significantly associated with the presence of symptomatic hand OA (P = 0.003). Higher relative abundance of the genera Bilophila and Desulfovibrio as well as lower relative abundance of the genus Roseburia was associated with symptomatic hand OA. Most functional pathways (i.e., those annotated in the KEGG Ortholog hierarchy) that were observed to be altered in participants with symptomatic hand OA belonged to the amino acid, carbohydrate, and lipid metabolic pathways. Conclusion: This large, population-based study provides the first evidence that alterations in the composition of the gut microbiome were observed among study participants who had symptomatic hand OA, and a low relative abundance of Roseburia but high relative abundance of Bilophila and Desulfovibrio at the genus level were associated with prevalent symptomatic hand OA. These findings may help investigators understand the role of the microbiome in the development of symptomatic hand OA and could contribute to potential translational opportunities

Insulin-like growth factor I gene promoter polymorphism, collagen type II alpha1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam Study

OBJECTIVE: To examine the role of an IGF-I gene promoter polymorphism in the prevalence of radiographic osteoarthritis (ROA), and study its interaction with the COL2A1 gene. METHODS: Individuals genotyped for IGF-I (n = 1546) and COL2A1 gene polymorphisms (n = 808) were selected from a random sample (n = 1583) derived from the Rotterdam study. The presence of ROA was defined as a Kellgren score of 2 or more in at least one of four joints (knee, hip, hand, and spine). Genotype specific odds ratios (OR) were adjusted for age, sex, body mass index, and bone mineral density using logistic regression. Interaction with the COL2A1 genotype was tested. RESULTS: Overall, no association was found between the IGF-I polymorphism and ROA. In subjects aged 65 years or younger (n = 971), the prevalence of ROA increased with the absence of the 192 base pair (bp) allele (p for trend = 0.03). Compared with homozygotes for the 192 bp allele, the prevalence of ROA was 1.4 times higher in heterozygotes (95% confidence interval, 1.0 to 1.8) and 1.9 times higher in non-carriers (1.1 to 3.3). There was evidence of interaction between the IGF-I and COL2A1 genes. Individuals with the risk genotype of both genes had an increased prevalence of ROA (OR 3.4 (1.1 to 10.7)). No effect was observed in subjects older than 65 years. CONCLUSIONS: SUBJECTS: with genetically determined low IGF-I expression (non-carriers of the 192 bp allele) may be at increased risk of ROA before the age of 65 years. Furthermore, an interaction between the IGF-I and COL2A1 genes is suggested

A genome-wide association study suggests that a locus within the ataxin 2 binding protein 1 gene is associated with hand osteoarthritis: The Treat-OA consortium

To identify the susceptibility gene in hand osteoarthritis (OA) the authors used a two-stage approach genomewide association study using two discovery samples (the TwinsUK cohort and the Rotterdam discovery subset; a total of 1804 subjects) and four replication samples (the Chingford Study, the Chuvasha Skeletal Aging Study, the Rotterdam replication subset and the Genetics, Arthrosis, and Progression (GARP) Study; a total of 3266 people). Five single-nucleotide polymorphisms (SNPs) had a likelihood of association with hand OA in the discovery stage and one of them (rs716508), was successfully confirmed in the replication stage (meta-analysis p = 1.81×10-5). The C allele conferred a reduced risk of 33% to 41% using a case-control definition. The SNP is located in intron 1 of the A2BP1 gene. This study also found that the same allele of the SNP significantly reduced bone density at both the hip and spine (p<0.01), suggesting the potential mechanism of the gene in hand OA might be via effects on subchondral bone. The authors' findings provide a potential new insight into genetic mechanisms in the development of hand OA