Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.

The sequences of 150,119 genomes in the UK Biobank.

Detailed knowledge of how diversity in the sequence of the human genome affects phenotypic diversity depends on a comprehensive and reliable characterization of both sequences and phenotypic variation. Over the past decade, insights into this relationship have been obtained from whole-exome sequencing or whole-genome sequencing of large cohorts with rich phenotypic data1,2. Here we describe the analysis of whole-genome sequencing of 150,119 individuals from the UK Biobank3. This constitutes a set of high-quality variants, including 585,040,410 single-nucleotide polymorphisms, representing 7.0% of all possible human single-nucleotide polymorphisms, and 58,707,036 indels. This large set of variants allows us to characterize selection based on sequence variation within a population through a depletion rank score of windows along the genome. Depletion rank analysis shows that coding exons represent a small fraction of regions in the genome subject to strong sequence conservation. We define three cohorts within the UK Biobank: a large British Irish cohort, a smaller African cohort and a South Asian cohort. A haplotype reference panel is provided that allows reliable imputation of most variants carried by three or more sequenced individuals. We identified 895,055 structural variants and 2,536,688 microsatellites, groups of variants typically excluded from large-scale whole-genome sequencing studies. Using this formidable new resource, we provide several examples of trait associations for rare variants with large effects not found previously through studies based on whole-exome sequencing and/or imputation.

2023 EULAR classification criteria for hand osteoarthritis.

OBJECTIVES: The objective of this study is to develop classification criteria for overall hand osteoarthritis (OA), interphalangeal OA and thumb base OA based on self-reported data and radiographic features. METHODS: The classification criteria sets were developed in three phases. In phase 1, we identified criteria that discriminated hand OA from controls. In phase 2, we used a consensus-based decision analysis approach to derive a clinician-based evaluation of the relative importance of the criteria. In phase 3, we refined the scoring system, determined the cut-offs for disease classification and compared the sensitivity and specificity of the European Alliance of Associations for Rheumatology (EULAR) criteria with the 1990 American College of Rheumatology (ACR) criteria. RESULTS: In persons with hand symptoms and no other disease (including psoriasis) or acute injury that can explain the hand symptoms (mandatory criteria), hand OA can be classified based on age, duration of morning stiffness, number of joints with osteophytes and joint space narrowing, and concordance between symptoms and radiographic findings. Using a sum of scores based on each diagnostic element, overall hand OA can be classified if a person achieves 9 or more points on a 0-15 scale. The cut-off for interphalangeal OA and thumb base OA is 8 points. While the EULAR criteria demonstrated better sensitivity than the ACR criteria in the phase 1 data set, the performance of the two criteria sets was similar in two external cohorts. CONCLUSIONS: International experts developed the EULAR criteria to classify overall hand OA, interphalangeal OA and thumb base OA in clinical studies using a rigorous methodology.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

OBJECTIVES: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. METHODS: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. RESULTS: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. CONCLUSIONS: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.

[Iatrogenic femoral AV-fistula].

The common femoral artery is a widely used for access in endovascular interventions. Various complications, such as hematoma, pseudoaneurysm and AV-fistula (AVF), can arise from arterial punctures with estimated prevalence between 1-10%. AVF is a rare complication with prevalence p<1%. AVF can cause a hemodynamic change in the form of a arteriovenous shunt (AV-shunt). AV-shunts in the groin are usually small and asymptomatic but tend to be symptomatic with larger and persistent AVFs which can present with leg claudication or high outpute heart failure.

Multiomics analysis of rheumatoid arthritis yields sequence variants that have large effects on risk of the seropositive subset.

OBJECTIVES: To find causal genes for rheumatoid arthritis (RA) and its seropositive (RF and/or ACPA positive) and seronegative subsets. METHODS: We performed a genome-wide association study (GWAS) of 31 313 RA cases (68% seropositive) and ~1 million controls from Northwestern Europe. We searched for causal genes outside the HLA-locus through effect on coding, mRNA expression in several tissues and/or levels of plasma proteins (SomaScan) and did network analysis (Qiagen). RESULTS: We found 25 sequence variants for RA overall, 33 for seropositive and 2 for seronegative RA, altogether 37 sequence variants at 34 non-HLA loci, of which 15 are novel. Genomic, transcriptomic and proteomic analysis of these yielded 25 causal genes in seropositive RA and additional two overall. Most encode proteins in the network of interferon-alpha/beta and IL-12/23 that signal through the JAK/STAT-pathway. Highlighting those with largest effect on seropositive RA, a rare missense variant in STAT4 (rs140675301-A) that is independent of reported non-coding STAT4-variants, increases the risk of seropositive RA 2.27-fold (p=2.1×10-9), more than the rs2476601-A missense variant in PTPN22 (OR=1.59, p=1.3×10-160). STAT4 rs140675301-A replaces hydrophilic glutamic acid with hydrophobic valine (Glu128Val) in a conserved, surface-exposed loop. A stop-mutation (rs76428106-C) in FLT3 increases seropositive RA risk (OR=1.35, p=6.6×10-11). Independent missense variants in TYK2 (rs34536443-C, rs12720356-C, rs35018800-A, latter two novel) associate with decreased risk of seropositive RA (ORs=0.63-0.87, p=10-9-10-27) and decreased plasma levels of interferon-alpha/beta receptor 1 that signals through TYK2/JAK1/STAT4. CONCLUSION: Sequence variants pointing to causal genes in the JAK/STAT pathway have largest effect on seropositive RA, while associations with seronegative RA remain scarce.

[Cardiac Lipoma - Case presentation].

Cardiac lipomas are very rare benign tumors of the heart. They are usually asymptomatic and are often an incidental finding on cardiac imaging. This case report involves an 82-year-old female with a history of diabetes admitted because of poor glycemic control. An echocardiogram requested because of arrhythmias and heart failure revealed a tumor in the right atrium. Computed tomographic and ultrasound appearances were consistent with a lipoma and demonstrated a large mass in the right atrium, causing a significant stenosis of the superior vena cava but no clinical symptoms or signs of superior vena cava syndrome.

[Parenchymal lung changes on CT in patients with coronavirus disease 2019 (COVID-19)].

Introduction Infections due to COVID-19 can lead to life threatening pneumonia. Accompanying severe disease are more prominent pulmonary changes on Computed Tomography (CT) scan of the chest. The goal of this study was to describe pulmonary CT changes during acute COVID-19 and at follow up and whether the extent of changes correlate with severity of illness, demographics or other risk factors. Materials and methods Included in this study are all individuals that had confirmed COVID-19 and came for a follow up CT of the chest at Landspitali from May to September 2020. Information regarding medical history was obtained retrospectively from medical charts. All CT scans were reviewed using an international staging system to evaluate the extent of lung changes. Results Eighty-five patients with a mean age of 59 years were included in the study. Sixty patients (71%) were hospitalized during the acute phase and 18 (21%) were admitted to the ICU. During the acute phase more pronounced lung involvement was seen in males and patients admitted to the ICU. At follow-up females had less lung involvement but there was a significant relationship between a higher CT score and age, ICU admissions and days in the ICU. Full recovery was seen at follow-up CT in 31% of patients (median 68,5 days between acute and follow-up imaging). Conclusion Patients with severe COVID-19 have more pronounced lung involvement on CT than patients with milder disease during the acute phase and follow-up. Older patients and males are at greater risk of acute and persistent COVID-19 related lung changes.

Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus.

Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10-2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05-1.11, Pmeta=3.12 × 10-10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.

2018 update of the EULAR recommendations for the management of hand osteoarthritis.

Since publication of the European League Against Rheumatism (EULAR) recommendations for management of hand osteoarthritis (OA) in 2007 new evidence has emerged. The aim was to update these recommendations. EULAR standardised operating procedures were followed. A systematic literature review was performed, collecting the evidence regarding all non-pharmacological, pharmacological and surgical treatment options for hand OA published to date. Based on the evidence and expert opinion from an international task force of 19 physicians, healthcare professionals and patients from 10 European countries formulated overarching principles and recommendations. Level of evidence, grade of recommendation and level of agreement were allocated to each statement. Five overarching principles and 10 recommendations were agreed on. The overarching principles cover treatment goals, information provision, individualisation of treatment, shared decision-making and the need to consider multidisciplinary and multimodal (non-pharmacological, pharmacological, surgical) treatment approaches. Recommendations 1-3 cover different non-pharmacological treatment options (education, assistive devices, exercises and orthoses). Recommendations 4-8 describe the role of different pharmacological treatments, including topical treatments (preferred over systemic treatments, topical non-steroidal anti-inflammatory drugs (NSAIDs) being first-line choice), oral analgesics (particularly NSAIDs to be considered for symptom relief for a limited duration), chondroitin sulfate (for symptom relief), intra-articular glucocorticoids (generally not recommended, consider for painful interphalangeal OA) and conventional/biological disease-modifying antirheumatic drugs (discouraged). Considerations for surgery are described in recommendation 9. The last recommendation relates to follow-up. The presented EULAR recommendations provide up-to-date guidance on the management of hand OA, based on expert opinion and research evidence.

Hand and knee osteoarthritis are associated with reduced diameters in retinal vessels: the AGES-Reykjavik study.

To investigate the association between osteoarthritis (OA) and microvascular pathology, we examined the relationship between retinal microvascular caliber and osteoarthritis of the hand and knee in an elderly population. The AGES-Reykjavik is a population-based, multidisciplinary longitudinal cohort study of aging. Retinal vessel caliber, hand osteoarthritis and total knee joint replacements due to OA were examined in 4757 individuals (mean age 76 ± 5 years; 57% female). Incident knee joint replacements during 5-year follow-up (n = 2961, mean age 75 ± 5 years; 58% female) were also assessed. Logistic regression analysis, adjusting for age, sex, and body mass index, showed an association between narrow arteriolar caliber and hand OA, as well as knee replacement. After adjustment for other covariates, including statin therapy, this association was significant for both hand OA in men and women [OR 1.10(1.03-1.17), p < 0.01] (per unit standard deviation decrease in CRAE) and TKR prevalence [OR 1.15 (1.01-1.32), p = 0.04], especially for men [OR 1.22 (1.00-1.51) p = 0.04] and also for incident TKRs in men [OR 1.50 (1.07-2.10), p = 0.04]. Narrow venular caliber was associated with hand OA in women [OR 1.10 (1.01-1.21), p = 0.03]. Retinal arterial narrowing in hand and knee OA is present in males as well as females. Venular narrowing in hand OA in women was an unexpected finding and is in contrast with the venular widening usually observed in cardiovascular diseases.

Longitudinal validity of using digital hand photographs for assessing hand osteoarthritis progression over 7 years in community-dwelling older adults with hand pain.

BACKGROUND: To determine the longitudinal construct validity of assessing hand OA progression on digital photographs over 7 years compared with progression determined from radiographs, clinical features and change in symptoms. METHODS: Participants were community-dwelling older adults (≥50 years) in North Staffordshire, UK. Standardized digital hand photographs were taken at baseline and 7 years, and hand joints graded for OA severity using an established photographic atlas. Radiographic hand OA was assessed using the Kellgren and Lawrence grading system. Hand examination determined the presence of nodes, bony enlargement and deformity. Symptoms were reported in self-complete questionnaires. Radiographic and clinical progression and change in symptoms were compared to photographic progression. Differences were examined using analysis of covariance and Chi-Square tests. RESULTS: Of 253 individuals (61% women, mean age 63 years) the proportion with photographic progression at the joint and joint group-level was higher in individuals with radiographic or clinical progression compared to those without, although differences were not statistically significant. At the person-level, those with moderate photographic progression over 7 years had significantly higher summed radiographic and clinical scores (adjusted for baseline scores) compared to those with no or mild photographic progression. Similar findings were observed for change in symptoms, although differences were small and not statistically significant. CONCLUSION: Assessing hand OA on photographs shows modest longitudinal construct validity over 7 years compared with change in radiographic and clinical hand OA at the person-level. Using photographs to assess overall long-term change in a person with hand OA may be a reasonable alternative when hand examinations and radiographs are not feasible.

Age related prevalence of hand osteoarthritis diagnosed by photography (HOASCORE).

BACKGROUND: Hand photography has been used in a number of studies to determine the presence and severity of hand osteoarthritis (HOA). The aim of this study was to present age and gender specific prevalences of HOA diagnosed by this method. METHODS: Six thousand three hundred forty three photographs (from 3676 females and 2667 males aged 40-96) were scored for hand osteoarthritis by a 0-3 grade (0 = no evidence of OA, 1 = possible OA, 2 = definite OA and 3 = severe OA) for each of the three main sites, distal interphalangeal joints (DIP), proximal interphalangeal joints (PIP) and thumb base (CMC1). An aggregate score of 0-9 was thus obtained (HOASCORE) to reflect the severity of HOA in each case. RESULTS: DIP joints were most commonly affected, followed by the thumb base and the PIP joints. Having definite DIP joint OA starts at a younger age compared with the other two sites, and there is a marked female preponderance in the age groups from 55 to 69, but after 70 the gender differences are less marked and the prevalence is fairly stable. PIP joint prevalence also indicates a female preponderance from 60 to 79. Thumb base OA has a more marked female preponderance and a rising prevalence thoughout life. The prevalence of individuals with no evidence of photographic OA (HOASCORE = 0) drops from 88% to 57% between the age categories 40-49 and 50-54 and decreased to 33% in the 70-74 age group with a slower decline after that age. DIP and PIP prevalence were strongly associated with each other with an OR of 16.6(12.8-21.5),p < 0.001 of having definite OA at the other site. This was less marked for the thumb base with an OR of 2.2(1.8-2.7, p < 0.001), and 2.7(2.0-3.5, p < 0.001) of having definite DIP or PIP HOA respectively. CONCLUSIONS: The prevalence of hand OA in DIP, PIP and thumb base joints obtained by the photographic HOASCORE method is higher in women and increases after the age of fifty. These results are in line with those obtained by clinical examination and radiography. The advantage of the method lies in easy applicability and low cost.

Incidence and prevalence of total joint replacements due to osteoarthritis in the elderly: risk factors and factors associated with late life prevalence in the AGES-Reykjavik Study.

BACKGROUND: Total joint replacements (TJRs) should be considered as one of few definite endpoints in osteoarthritis research. We analyzed factors associated with late-life prevalence and risk factors for incidence of TJRs due to osteoarthritis in a population based cohort. METHODS: After exclusion of inflammatory arthritis and fractures as causes of TJR, 5170 participants in the AGES-Reykjavik Study (mean age (SD) 76.4(6), 58% females) were included for osteoarthritis studies. Three thousand one hundred thirty-three of them had a follow-up visit 5 years later. RESULTS: The prevalence of having at least one joint replacement operation due to OA was 13.6% and the yearly incidence was 1.4%/year during the five-year follow-up. Factors positively associated with late life prevalence of TJR included BMI, hand OA severity, female gender, finger length ratio and spine BMD. Risk factors for TJRs in the incidence group were symptoms at initial visit, prior TJR in the contralateral joint and BMI. Much stronger associations were seen for TKR than for THR with discriminatory analysis showing an AUC 0.71 for late life prevalence and 0.84 for the incidence. CONCLUSIONS: This study illustrates the importance of the different information expressed by late life prevalence vs. incidence on the factors associated with severe osteoarthritis of the knee and hip. The observation that prior TJR is a risk factor for subsequent TJR in the contralateral joint has not been described previously. The high power predictions for TKR suggest that a predictive model may be feasible, particularly if it can be extended by the addition of further predictive variables, perhaps through genetic, biomarker or imaging data.

Sex-specific predictors of hearing-aid use in older persons: The age, gene/environment susceptibility - Reykjavik study.

OBJECTIVE: We estimate the prevalence of hearing-aid use in Iceland and identify sex-specific factors associated with use. DESIGN: Population-based cohort study. STUDY SAMPLE: A total of 5172 age, gene/environment susceptibility - Reykjavik study (AGES-RS) participants, aged 67 to 96 years (mean age 76.5 years), who completed air-conduction and pure-tone audiometry. RESULTS: Hearing-aid use was reported by 23.0% of men and 15.9% of women in the cohort, although among participants with at least moderate hearing loss in the better ear (pure-tone average [PTA] of thresholds at 0.5, 1, 2, and 4 kHz ≥ 35 dB hearing level [HL]) it was 49.9% and did not differ by sex. Self-reported hearing loss was the strongest predictor of hearing-aid use in men [OR: 2.68 (95% CI: 1.77, 4.08)] and women [OR: 3.07 (95% CI: 1.94, 4.86)], followed by hearing loss severity based on audiometry. Having diabetes or osteoarthritis were significant positive predictors of use in men, whereas greater physical activity and unimpaired cognitive status were important in women. CONCLUSIONS: Hearing-aid use was comparable in Icelandic men and women with moderate or greater hearing loss. Self-recognition of hearing loss was the factor most predictive of hearing-aid use; other influential factors differed for men and women.

A variant in MCF2L is associated with osteoarthritis.

Osteoarthritis (OA) is a prevalent, heritable degenerative joint disease with a substantial public health impact. We used a 1000-Genomes-Project-based imputation in a genome-wide association scan for osteoarthritis (3177 OA cases and 4894 controls) to detect a previously unidentified risk locus. We discovered a small disease-associated set of variants on chromosome 13. Through large-scale replication, we establish a robust association with SNPs in MCF2L (rs11842874, combined odds ratio [95% confidence interval] 1.17 [1.11-1.23], p = 2.1 × 10(-8)) across a total of 19,041 OA cases and 24,504 controls of European descent. This risk locus represents the third established signal for OA overall. MCF2L regulates a nerve growth factor (NGF), and treatment with a humanized monoclonal antibody against NGF is associated with reduction in pain and improvement in function for knee OA patients.

A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip.

OBJECTIVES: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. METHODS: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. RESULTS: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). CONCLUSIONS: Novel genetic loci for hip OA were found in this meta-analysis of GWAS.

Type 3 finger length pattern is associated with total knee replacements due to osteoarthritis but not with hip replacements or hand osteoarthritis in the elderly: the AGES-Reykjavik study.

BACKGROUND: Recent case-control studies have shown an association between type 3 finger length pattern (longer ring finger than index finger) and knee osteoarthritis. This large cross-sectional study tests the hypothesis that the type 3 pattern is associated with total joint replacements due to osteoarthritis in a large population based study. METHODS: Finger length ratios were assessed visually on 5170 hand photographs (2975 females, 2195 males, mean age 76). In this population-based multidisciplinary study of aging in Reykjavik, Iceland, the prevalence of osteoarthritis associated total knee replacements was 223(4.3%) and total hip replacements 316(6.1%). We then performed a binary logistic regression analysis for total knee replacements and total hip replacements, including finger length patterns, osteoarthritis at other sites and other variables with possible association to osteoarthritis such as age, BMI and bone mineral density of the spine. RESULTS: The prevalence of the type 3 pattern was 50% (43% in females, 58% in males). The regression analysis revealed an odds ratio for total knee replacements of 1.65 (1.24-2.2) p = 0.0007, in the type 3 finger pattern group, similar in both genders. This association was independent of the associations we have previously reported between total knee replacements and BMI and the presence of hand osteoarthritis. No association was seen between finger length patterns and total hip replacements. CONCLUSION: Finger length patterns read from digital photographs in this large study confirm previous radiographic observations with significant associations between the type 3 pattern and total knee replacements but not total hip replacements in both genders in this elderly group.