Nonchromosomal birth defects and risk of childhood acute leukemia: An assessment in 15 000 leukemia cases and 46 000 controls from the Childhood Cancer and Leukemia International Consortium.

Although recent studies have demonstrated associations between nonchromosomal birth defects and several pediatric cancers, less is known about their role on childhood leukemia susceptibility. Using data from the Childhood Cancer and Leukemia International Consortium, we evaluated associations between nonchromosomal birth defects and childhood leukemia. Pooling consortium data from 18 questionnaire-based and three registry-based case-control studies across 13 countries, we used multivariable logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association between a spectrum of birth defects and leukemia. Our analyses included acute lymphoblastic leukemia (ALL, n = 13 115) and acute myeloid leukemia (AML, n = 2120) cases, along with 46 172 controls. We used the false discovery rate to account for multiple comparisons. In the questionnaire-based studies, the prevalence of birth defects was 5% among cases vs 4% in controls, whereas, in the registry-based studies, the prevalence was 11% among cases vs 7% in controls. In pooled adjusted analyses, there were several notable associations, including (1) digestive system defects and ALL (OR = 2.70, 95% CI: 1.46-4.98); (2) congenital anomalies of the heart and circulatory system and AML (OR = 2.86, 95% CI: 1.81-4.52) and (3) nervous system defects and AML (OR = 4.23, 95% CI: 1.50-11.89). Effect sizes were generally larger in registry-based studies. Overall, our results could point to novel genetic and environmental factors associated with birth defects that could also increase leukemia susceptibility. Additionally, differences between questionnaire- and registry-based studies point to the importance of complementary sources of birth defect phenotype data when exploring these associations.

Breastfeeding and risk of childhood brain tumors: a report from the Childhood Cancer and Leukemia International Consortium.

PURPOSE: Studies report mixed findings regarding the association of breastfeeding with childhood brain tumors (CBT), the leading causes of cancer-related mortality in young people. Our objective was to determine whether breastfeeding is associated with CBT incidence. METHODS: We pooled data on N = 2610 cases with CBT (including 697 cases with astrocytoma, 447 cases with medulloblastoma/primitive neuroectodermal tumor [PNET], 167 cases with ependymoma) and N = 8128 age- and sex-matched controls in the Childhood Cancer and Leukemia International Consortium. We computed unconditional logistic regression models to estimate the odds ratio (OR) and 95% confidence interval (CI) of CBT, astrocytoma, medulloblastoma/PNET, and ependymoma according to breastfeeding status, adjusting for study, sex, mode of delivery, birthweight, age at diagnosis/interview, maternal age at delivery, maternal educational attainment, and maternal race/ethnicity. We evaluated any breastfeeding versus none and breastfeeding ≥ 6 months versus none. We subsequently performed random effects meta-analysis to confirm our findings, identify potential sources of heterogeneity, and evaluate for outliers or influential studies. RESULTS: Breastfeeding was reported by 64.8% of control mothers and 64.5% of case mothers and was not associated with CBT (OR 1.04, 95% CI 0.94-1.15), astrocytoma (OR 1.01, 95% CI 0.87-1.17), medulloblastoma/PNET (OR 1.11, 95% CI 0.93-1.32), or ependymoma (OR 1.06, 95% CI 0.81-1.40). Results were similar when we restricted to breastfeeding ≥ 6 months and in meta-analyses. CONCLUSION: Our data suggest that breastfeeding does not protect against CBT.

Orchidopexy for congenital cryptorchidism in childhood and adolescence and testicular cancer in adults: an updated systematic review and meta-analysis of observational studies.

Congenital cryptorchidism is a well-established risk factor of testicular malignancies. However, there is still remarkable variability in the measures of associations between of these two clinical entities. The current meta-analysis investigates the up-to-date risk of testicular cancer in adults with a history of surgically corrected congenital cryptorchidism until adolescence. The meta-analysis was conducted with strict criteria for the identification of the congenital cryptorchidism cases that underwent surgery before adulthood. The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of the PubMed and the Scopus databases was conducted, using a defined strategy, from inception to February 2023. Two independent authors screened the literature and extracted the data, using inclusion and exclusion criteria. Of the 2176 articles identified, 93 articles were fully retrieved, and 6 articles met all the inclusion criteria. The Newcastle-Ottawa scale was applied for the studies' quality assessment. The random-effects model in RevMan 5.4 program was used for the meta-analysis. Three case-control studies and three cohort studies were selected. They included 371,681 patients and 1786 incidents of testicular cancer. The pooled odds ratio (OR) was 3.99 (95% confidence intervals (CI): 2.80-5.71). The heterogeneity was moderate and estimated at 51% with the I-squared statistic. A forest plot and a funnel plot were produced to evaluate the ORs and the probable publication bias, respectively. The mean Newcastle-Ottawa score was 8/9 for all the included reports.  Conclusion: This systematic review and meta-analysis verifies, with an updated estimate, the increased risk of testicular cancer in adults with an orchidopexy history. New evidence on the maldescent laterality supports that the cancer risk remains increased and for the contralateral, unaffected testicle, although to a lesser extent. The orchidopexy in the first year of life prevents the testicular damage and decreases the overall cancer risk. What is Known: • Congenital cryptorchidism is the commonest genitourinary abnormality and a risk factor for testicular cancer. • The most recent meta-analysis reporting this association was in 2013. What is New: • After reviewing literature until February 2023, the association of congenital cryptorchidism with testicular cancer risk in adulthood was verified: odds ratio=3.99 [2.80-5.71], 95% CI. • The meta-analysis highlights the protective role of early orchidopexy and the controversial data about maldescent and testicular cancer laterality.

Infant feeding practices and childhood acute leukemia: Findings from the Childhood Cancer & Leukemia International Consortium.

Increasing evidence suggests that breastfeeding may protect from childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). However, most studies have limited their analyses to any breastfeeding, and only a few data have examined exclusive breastfeeding, or other exposures such as formula milk. We performed pooled analyses and individual participant data metaanalyses of data from 16 studies (N = 17 189 controls; N = 10 782 ALL and N = 1690 AML cases) from the Childhood Leukemia International Consortium (CLIC) to characterize the associations of breastfeeding duration with ALL and AML, as well as exclusive breastfeeding duration and age at introduction to formula with ALL. In unconditional multivariable logistic regression analyses of pooled data, we observed decreased odds of ALL among children breastfed 4 to 6 months (0.88, 95% CI 0.81-0.96) or 7 to 12 months (OR 0.85, 0.79-0.92). We observed a similar inverse association between breastfeeding ≥4 months and AML (0.82, 95% CI 0.71-0.95). Odds of ALL were reduced among children exclusively breastfed 4 to 6 months (OR 0.73, 95% CI 0.63-0.85) or 7 to 12 months (OR 0.70, 95% CI 0.53-0.92). Random effects metaanalyses produced similar estimates, and findings were unchanged in sensitivity analyses adjusted for race/ethnicity or mode of delivery, restricted to children diagnosed ≥1 year of age or diagnosed with B-ALL. Our pooled analyses indicate that longer breastfeeding is associated with decreased odds of ALL and AML. Few risk factors for ALL and AML have been described, therefore our findings highlight the need to promote breastfeeding for leukemia prevention.

Treatment With Dupilumab in Patients With Atopic Dermatitis: Systematic Review and Meta-Analysis.

Atopic dermatitis (AD) is a type 2 chronic skin disorder associated with systemic and psychosocial comorbidities decreasing the quality of life for many patients. Dupilumab, a human monoclonal antibody that blocks interleukins IL-4 and IL-13, is a recently added systematic treatment option with an emerging evidence base. Here, we assessed the safety and efficacy of dupilumab in patients with AD. We conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials evaluating the safety and efficacy of dupilumab on AD-related outcomes including clinical symptoms, quality of life and adverse events (AE). Subgroup analysis was further performed in adults and children/adolescents. Fourteen trials were included: twelve in adults (n = 3,817) and two in children/adolescents (n = 618). Dupilumab decreased the Eczema Area Severity Index (EASI) score [standardized mean difference (SMD) = -0.98; 95% confidence interval (95% CI) = (-1.09, -0.88)], the percent change difference in Scoring Atopic Dermatitis (SCORAD) [mean difference (MD) = -31.56, 95% CI = (-33.75, -29.36)], and in pruritus Numeric Rating Scale (pNRS) [MD = -29.24, 95% CI = (-32.11, -26.37)]. It also achieved a reduction of at least ≥75% in the EASI score [Risk Ratio (RR) = 2.89, 95% CI = (2.47, 3.38)], the Investigator's Global Assessment (IGA) score ≤1 [RR = 3.47, 95% CI = (2.96, 4.06)] and eight additional endpoints with no signs of increased AE compared to placebo. In subgroup analysis, the results were concordant for both groups. Dupilumab improved clinical symptoms and quality of life in adults and children/adolescents with a safety profile comparable to placebo.

Association between childhood asthma and history of assisted reproduction techniques: a systematic review and meta-analysis.

Genetic and environmental factors during early development may influence lung growth and impact lung function. We performed a meta-analysis of epidemiological studies examining the association between conception history of assisted reproduction techniques (ART) and childhood asthma. We searched PubMed and Embase up to November 2020 for relevant observational studies and synthesized data data under a fixed or random effects model as appropriate. Heterogeneity was assessed using the I2 metric. We identified 13 individual studies including 3,226,386 participants. We did not observe a statistically significant association between ART and physician-diagnosed asthma (n = 9, random OR 1.16; 95% CI 0.94-1.43; I2 61%). We observed a statistically significant association between ART and prescription of asthma medications (n = 6, fixed OR 1.27; 95% CI 1.23-1.32; I2 0%). Wheezing was also associated with ART (n = 4, fixed OR 1.71; 95% CI 1.08-2.72; I2 0%). When we combined studies using any asthma definition, a statistically significant association was observed (random OR 1.19; 95% CI 1.05-1.34; I2 80%).Conclusion: The available observational evidence suggests that the risk of asthma is higher among children born after ART. The mechanism and potential sources of bias behind this association are under scrutiny, and further work is needed to establish causality. What is Known: • "Positive" epidemiological signals for the association between assisted reproduction techniques and asthma stemming from large studies were not replicated by subsequent research. • Any available research synthesis effort so far bears no quantitative aspect. What is New: • The available observational evidence suggests that the risk of asthma is higher among children born after ART. • The mechanism and potential sources of bias behind this association are under scrutiny.

Awareness, knowledge and trust in the Greek authorities towards COVID-19 pandemic: results from the Epirus Health Study cohort.

BACKGROUND: To assess the level of knowledge and trust in the policy decisions taken regarding the coronavirus disease (COVID-19) pandemic among Epirus Health Study (EHS) participants. METHODS: The EHS is an ongoing and deeply-phenotyped prospective cohort study that has recruited 667 participants in northwest Greece until August 31st, 2020. Level of knowledge on coronavirus (SARS-CoV-2) transmission and COVID-19 severity was labeled as poor, moderate or good. Variables assessing knowledge and beliefs towards the pandemic were summarized overall and by sex, age group (25-39, 40-49, 50-59, ≥60 years) and period of report (before the lifting of lockdown measures in Greece: March 30th to May 3rd, and two post-lockdown time periods: May 4th to June 31st, July 1st to August 31st). A hypothesis generating exposure-wide association analysis was conducted to evaluate the associations between 153 agnostically-selected explanatory variables and participants' knowledge. Correction for multiple comparisons was applied using a false discovery rate (FDR) threshold of 5%. RESULTS: A total of 563 participants (49 years mean age; 60% women) had available information on the standard EHS questionnaire, the clinical and biochemical measurements, and the COVID-19-related questionnaire. Percentages of poor, moderate and good knowledge status regarding COVID-19 were 4.5, 10.0 and 85.6%, respectively. The majority of participants showed absolute or moderate trust in the Greek health authorities for the management of the epidemic (90.1%), as well as in the Greek Government (84.7%) and the official national sources of information (87.4%). Trust in the authorities was weaker in younger participants and those who joined the study after the lifting of lockdown measures (p-value≤0.001). None of the factors examined was associated with participants' level of knowledge after correction for multiple testing. CONCLUSIONS: High level of knowledge about the COVID-19 pandemic and trust in the Greek authorities was observed, possibly due to the plethora of good quality publicly available information and the timely management of the pandemic at its early stages in Greece. Information campaigns for the COVID-19 pandemic should be encouraged even after the lifting of lockdown measures to increase public awareness.

Birth seasonality of childhood central nervous system tumors: Analysis of primary data from 16 Southern-Eastern European population-based registries.

Season of birth, a surrogate of seasonal variation of environmental exposures, has been associated with increased risk of several cancers. In the context of a Southern-Eastern Europe (SEE) consortium, we explored the potential association of birth seasonality with childhood (0-14 years) central nervous system (CNS) tumors. Primary CNS tumor cases (n = 6,014) were retrieved from 16 population-based SEE registries (1983-2015). Poisson regression and meta-analyses on birth season were performed in nine countries with available live birth data (n = 4,987). Subanalyses by birth month, age, gender and principal histology were also conducted. Children born during winter were at a slightly increased risk of developing a CNS tumor overall [incidence rate ratio (IRR): 1.06, 95% confidence intervals (CI): 0.99-1.14], and of embryonal histology specifically (IRR: 1.13, 95% CI: 1.01-1.27). The winter peak of embryonal tumors was higher among boys (IRR: 1.24, 95% CI: 1.05-1.46), especially during the first 4 years of life (IRR: 1.33, 95% CI: 1.03-1.71). In contrast, boys <5 years born during summer seemed to be at a lower risk of embryonal tumors (IRR: 0.73, 95% CI: 0.54-0.99). A clustering of astrocytomas was also found among girls (0-14 years) born during spring (IRR: 1.23, 95% CI: 1.03-1.46). Although the present exploratory results are by no means definitive, they provide some indications for age-, gender- and histology-related seasonal variations of CNS tumors. Expansion of registration and linkage with cytogenetic reports could refine if birth seasonality is causally associated with CNS tumors and shed light into the complex pathophysiology of this lethal disease.

Is brucellosis a great mimic of tuberculosis? A case report.

Tuberculosis (TB) can manifest prolonged fever or fever of unknown origin, especially when it is located extrapulmonary. We report a case of disseminated TB complicated by iliac bone osteolysis and a gluteal abscess in a 75-year-old female patient with fever and bone marrow dysplasia. Diagnosis of TB was made despite transient false-positive high-titer agglutination tests and ELISA antibodies to Brucella. The case presented shows that in a highly suggestive case of TB, positive agglutination tests or ELISA antibodies to Brucella should be interpreted with caution, and repeated testing should be performed to assess their persistence and fluctuation over time.

Repeated leftover serosurvey of SARS-CoV-2 IgG antibodies, Greece, March and April 2020.

A serosurvey of IgG antibodies against severe acute respiratory coronavirus 2 (SARS-CoV-2) was performed during March and April 2020. Among 6,586 leftover sera, 24 (0.36%) were positive, with higher prevalence in females, older individuals and residents of large urban areas. Seroprevalence was estimated at 0.02% and 0.25%, respectively, in March and April, infection fatality rate at 2.66% and 0.54%. Our findings confirm low COVID-19 incidence in Greece and possibly the effectiveness of early measures.

Searching for published protocols of randomized controlled trials in primary health care: an empirical systematic approach.

INTRODUCTION: Electronic search filters on family medicine or general practice studies have been developed and validated in previous work. However, there has been no systematic effort to specifically identify and record protocols of randomized controlled trials (RCT) protocols in primary health care (PHC). The aim of the present study was to systematically identify published RCT protocols in PHC and capture information about specific protocol characteristics that may describe this field. METHODS: PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus from inception to December 2014 were systematically searched. Protocols of RCTs that were published in English and were relevant to PHC were considered as eligible. Protocols referred either to a mixed population, or to an intervention including a specialized part as well as pilot or feasibility trial protocols, were excluded. Specific protocol characteristics including publication year, country, prospective registration, funding, and publication sources were extracted. RESULTS: The final database included 628 published RCT protocols (median publication year 2011; interquartile range 2009-2013). The majority of protocols were designed in the UK (n=141, 22.5%), the Netherlands (n=105, 16.7%), and USA (n=93, 14.8%). Research was mainly funded by the government (n=408, 65.0%) while 45 protocols (7.2%) included industry as the funding source. Two registries - International Standard Randomised Controlled Trials Number Registry (245 (42.9%)) and ClinicalTrials.gov (209 (36.6%)) - indexed most of the protocols. Journals from several scientific fields published the articles; the field of 'Primary Health Care Medicine, General and Internal' included 69 (11.0%) articles. CONCLUSION: A compilation of published RCT protocols on PHC was feasible. The majority of protocols on PHC were published over the past 10 years, funded by the government and designed in three main countries.

Effects of economic crisis on air quality in Ioannina, Greece.

The aim of this study was to investigate the regime of air pollution in Ioannina, NW Greece during the years of Greek financial crisis. Annual, weekly and daily patterns for PM10, PM2.5, NO2, O3 and Benzene were defined in order to reveal the sources of air pollutants in Ioannina and the time periods of probable episodes. The quality of air was characterized according to the European Environment Agency's European Air Quality Index, separately for winter and summer, while it was examined if and in what extend the thresholds of European Directives for each pollutant have been exceeded. The air quality in Ioannina was found to be "Good" as far as NO2 and O3 were concerned. In contrast, there were many cases with "Poor" and "Very Poor" conditions related to PM10 and PM2.5 levels, mainly during winter and autumn, caused by wood burning for residential heating. The mean annual concentrations of all pollutants did not exceed EU's standards, but from 2011 onwards, the number of cases with PM10 mean daily concentration above threshold surpassed the number of permitted exceedences of EU directives.

Identification of a novel locus on chromosome 2q13, which predisposes to clinical vertebral fractures independently of bone density.

OBJECTIVES: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis. METHODS: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies. RESULTS: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10-9) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures. CONCLUSION: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism.

Educational strategies to train health care professionals across the education continuum on the process of frailty prevention and frailty management: a systematic review.

BACKGROUND: In addition to the normal process of ageing, frailty, defined as a geriatric syndrome, is becoming more prevalent. Around 10% of people over 65 years and 25-50% of those aged over 85 years are frail. Frail elderly are more vulnerable to external stressors and have an increased risk of adverse health outcomes. To tackle these challenges, European Union (EU) member states need to develop a health work force capable of the right skills mix. A goal-centred education and training of professionals is crucial for effective and efficient health care delivery for Europe's greying population. AIMS: The aim of this study was to systematically collect, review and critically appraise studies carried out to investigate the efficacy and effectiveness of comprehensive educational programmes for health professionals related to frailty prevention and/or frailty management. METHODS: A systematic review was carried out searching the databases PubMed, CINAHL, Cochrane CENTRAL, Medline, Up to date and Embase. Additionally, a manual search of the reference lists and searches via Google Scholar and greylit.org was done. RESULTS: No relevant publications addressing the evidence and sustainability of educational/training programmes for frailty prevention and/or frailty management were identified. DISCUSSION: The result of an empty review is surprising because several educational programmes in different countries are currently run. CONCLUSIONS: A significant knowledge gap exists in the scientific literature regarding education and training of health care workers regarding prevention and management of frailty. Further research is needed to identify effective educational strategies for health professionals to prevent and manage frailty.

Who benefits from a dietary online intervention? Evidence from Italy, Spain and Greece.

OBJECTIVE: The traditional Mediterranean diet includes high consumption of fruits, vegetables, olive oil, legumes, cereals and nuts, moderate to high intake of fish and dairy products, and low consumption of meat products. Intervention effects to improve adoption of this diet may vary in terms of individuals' motivational or volitional prerequisites. In the context of a three-country research collaboration, intervention effects on these psychological constructs for increasing adoption of the Mediterranean diet were examined. DESIGN: An intervention was conducted to improve Mediterranean diet consumption with a two-month follow-up. Linear multiple-level models examined which psychological constructs (outcome expectancies, planning, action control and stage of change) were associated with changes in diet scores. SETTING: Web-based intervention in Italy, Spain and Greece. SUBJECTS: Adults (n 454; mean age 42·2 (sd 10·4) years, range 18-65 years; n 112 at follow-up). RESULTS: Analyses yielded an overall increase in the Mediterranean diet scores. Moreover, there were interactions between time and all four psychological constructs on these changes. Participants with lower levels of baseline outcome expectancies, planning, action control and stage of change were found to show steeper slopes, thus greater behavioural adoption, than those who started out with higher levels. CONCLUSIONS: The intervention produced overall improvements in Mediterranean diet consumption, with outcome expectancies, planning, action control and stage of change operating as moderators, indicating that those with lower motivational or volitional prerequisites gained more from the online intervention. Individual differences in participants' readiness for change need to be taken into account to gauge who would benefit most from the given treatment.

Evidence Suggesting the End of Universal Domestic Asbestos Exposure in Metsovo, NW Greece.

BACKGROUND: Inhabitants of Metsovo, NW Greece, had been domestically exposed to asbestos from a gradually abandoned whitewash ("luto") that resulted in a declining epidemic of malignant mesothelioma. OBJECTIVES: We aimed to evaluate whether other sources of asbestos exposure exist following "luto" abandonment. METHODS: Chest computed tomography (CT) and bronchoalveolar lavage (BAL) were used to evaluate residual asbestos exposure in younger Metsovites through the identification of pleural calcifications and asbestos bodies, respectively. In order to provide a historical universally exposed group for comparison, we used the accumulated chest CTs and chest roentgenograms of our previous studies, performed in Metsovites with confirmed exposure but negative chest roentgenogram. As an additional external comparison group, we also assessed CT scans and chest roentgenograms of Metsovites being older than our target group obtained from the records of the Radiology Department between 2009 and 2011. In order to be able to compare our BAL findings, we sought historical controls among BAL studies performed in Metsovites with known exposure to "luto," in the 1980s-1990s, mainly to evaluate alveolitis. Those belonging to individuals of the same age range were used for further comparison. RESULTS: Twenty-two Metsovites born between 1960 and 1980 consented to undergo a chest CT scan, while another 14 CTs were retrieved from the records of the Radiology Department (among 86 of all ages), thus increasing the number of individuals studied to 36. Five of the 36 Metsovites studied were former "luto" users for a short period of time. Minimal pleural calcifications were present in 2 of them, while all chest CTs of nonusers were negative. All 8 BAL studies were negative for asbestos bodies. CONCLUSION: "Luto" use seems to have been the only source of considerable asbestos exposure in Metsovo.

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.

CER1 gene variations associated with bone mineral density, bone markers, and early menopause in postmenopausal women.

BACKGROUND: Osteoporosis has a multifactorial pathogenesis characterized by a combination of low bone mass and increased fragility. In our study, we focused on the effects of polymorphisms in CER1 and DKK1 genes, recently reported as important susceptibility genes for osteoporosis, on bone mineral density (BMD) and bone markers in osteoporotic women. Our objective was to evaluate the effect of CER1 and DKK1 variations in 607 postmenopausal women. The entire DKK1 gene sequence and five selected CER1 SNPs were amplified and resequenced to assess whether there is a correlation between these genes and BMD, early menopause, and bone turnover markers in osteoporotic patients. RESULTS: Osteoporotic women seem to suffer menopause 2 years earlier than the control group. The entire DKK1 gene sequence analysis revealed six variations. There was no correlation between the six DKK1 variations and osteoporosis, in contrast to the five common CER1 variations that were significantly associated with BMD. Additionally, osteoporotic patients with rs3747532 and rs7022304 CER1 variations had significantly higher serum levels of parathyroid hormone and calcitonin and lower serum levels of osteocalcin and IGF-1. CONCLUSIONS: No significant association between the studied DKK1 variations and osteoporosis was found, while CER1 variations seem to play a significant role in the determination of osteoporosis and a potential predictive role, combined with bone markers, in postmenopausal osteoporotic women.