Probiotic Bacteria Survival and Shelf Life of High Fibre Plant Snack - Model Study.

The study aimed to develop plant-based model snacks that are high in fibre, contain probiotic bacteria and are convenient for long-term storage. The research focused on selecting a suitable form of probiotic bacteria (active biomass, microencapsulated, freeze-dried), inoculation method (in the base mass or in the filling of a snack) and appropriate storage conditions (4°Cor 20 °C). The potential synbiotic properties were evaluated. The microencapsulated bacteria had the highest survival rate at 4 °C, while the freeze-dried bacteria showed better survival rates at 20 °C. Probiotics had a higher survival rate when enclosed inside snacks with a low water activity (aw = 0.27) peanut butter filling than in snacks without filling (aw = 0.53). Enclosing the probiotics in a low aw filling ensures their survival at ambient temperature for 5 months at a count higher than 6 log CFU/g. The snacks exhibited high antioxidant capacity (average 300 mg ascorbic acid equivalent/100 g), polyphenol content (average 357 mg gallic acid equivalent/100 g) and high fibre content (average 10.2 g/100 g). The sensory analysis showed a high overall quality of the snacks (average 7.1/10 of the conventional units). Furthermore, after six months of storage, significant changes were observed in the antioxidant properties, polyphenol content and texture of the snacks, while their sensory quality remained unchanged. Moreover, a potential synbiotic effect was observed. The method used to assess bacterial growth indicated significantly higher values in the model snacks compared to a control sample. Therefore, this study has effectively addressed the gap in knowledge regarding the survival of probiotics in snacks of this nature.

Investigating the Probiotic Potential of Vegan Puree Mixture: Viability during Simulated Digestion and Bioactive Compound Bioaccessibility.

This study aimed to develop a fermented puree mixture containing plant-based ingredients and potential probiotic strains Lacticaseibacillus rhamnosusK3 and Lactobacillus johnsonii K4. The survival of potential probiotic strains, changes in sugar and organic acid concentrations, bioaccessibility of polyphenols, and antioxidant capacity after simulated digestion were examined with sensory quality. The mixture of apple puree, chia seeds, and oat bran or oat flakes was fermented. The sensory quality of the puree mixture was assessed by the quantitative descriptive profile (QDP) method. In vitro digestion was simulated using a static gastrointestinal model. Antioxidant capacity and total polyphenol content were analyzed before and after the digestion phases. All samples changed sensory profiles after fermentation. The overall quality was above six out of ten for every product. Fermentation also changed the organic acid composition, with significant increases in lactic, succinic, and acetic acids. After the digestion process, the survival rate remained above 5.8 log10 CFU/g. As a result of fermentation with potential probiotics, the bioaccessibility of the total phenolics and antioxidant activity increased. These results showed that the addition of potential probiotic strains increases nutritional value and could help with healthy nourishment habits. This knowledge can guide the development of consumer-satisfying products in the food industry, expanding the probiotic food market with innovative alternatives.

Treatment patterns in women of childbearing age and pregnant women with epilepsy in Poland between the years 2019 and 2022-A nationwide population-based cohort study.

AIM: To describe the antiseizure medications (ASMs) prescription pattern in women of childbearing age (WOCA) and pregnant women with epilepsy in the 2019-2022 period in Poland MATERIALS AND METHODS: The National Health Fund (NHF) databases were analyzed. Women aged 15-49 years were considered as being of childbearing age, while exposure during pregnancy was estimated taking into account 15 months before delivery. ASMs belonging to the N03A subgroup of the Anatomical Therapeutic Chemical Classification System, reimbursed by NHF were analyzed. RESULTS: During 2019, 36 784 WOCA and 921 pregnant women filled at least 1 ASM prescription. In 2022, these numbers were 32 304 and 594, respectively. Valproate was the most widely used ASM in WOCA (38.4 %) in 2019, followed by levetiracetam (35.6 %), lamotrigine (30.1 %), and carbamazepine (20.0 %). The percentage of ASM users decreased in 2022 for valproate (32.1 %; p < 0.001) and carbamazepine (17 %; p < 0.001) and increased for levetiracetam (40.8 %; p < 0.001) and lamotrigine (32.7 %; p < 0.001). In 2019 lamotrigine (42.1 %) and levetiracetam (41.5 %) were the most frequently prescribed ASMs to pregnant women. During the study period, a significant increase in prescriptions for levetiracetam was observed (49.5 %; p = 0.003). The proportion of ASMs exposed pregnancies declined for valproate (from 24.7 to 16 %; p < 0.001) and topiramate (from 6.6 to 3.2 %; p = 0.005). The percentage of polytherapy regimens remained stable over the years, both for WOCA (39 %) and pregnant women (32 %). CONCLUSION: Despite the decline in valproate usage, the drug was still among the most commonly prescribed ASMs in women of childbearing age and pregnant women with epilepsy. The awareness of teratogenic risks and new treatment guidelines should be improved in Poland.

Reduction of Nitrite in Canned Pork through the Application of Black Currant (Ribes nigrum L.) Leaves Extract.

Sodium nitrite is a multifunctional additive commonly used in the meat industry. However, this compound has carcinogenic potential, and its use should be limited. Therefore, in this study the possibility of reducing the amount of sodium(III) nitrite added to canned meat from 100 to 50 mg/kg, while enriching it with freeze-dried blackcurrant leaf extract, was analyzed. The possibility of fortification of canned meat with blackcurrant leaf extract was confirmed. It contained significant amounts of phenolic acids and flavonoid derivatives. These compounds contributed to their antioxidant activity and their ability to inhibit the growth of selected Gram-positive bacteria. In addition, it was observed that among the three different tested doses (50, 100, and 150 mg/kg) of the blackcurrant leaf extract, the addition of the highest dose allowed the preservation of the antioxidant properties of canned meat during 180 days of storage (4 °C). At the end of the storage period, this variant was characterized by antiradical activity against ABTS (at the level of 4.04 mgTrolox/mL) and the highest reducing capacity. The addition of 150 mg/kg of blackcurrant leaf extract caused a reduction in oxidative transformations of fat in meat products during the entire storage period, reaching a level of TBARS almost two times less than in the control sample. In addition, these products were generally characterized by stability (or slight fluctuations) of color parameters and good microbiological quality and did not contain N-nitrosamines.

Sex differences in incidence, management, and outcomes in adult patients aged over 20 years with clinically diagnosed myocarditis in the last 10 years: data from the MYO­PL nationwide database.

INTRODUCTION: Comprehensive epidemiological data about the course of myocarditis and sex differ-ences are lacking. OBJECTIVES: We aimed to investigate the current differences in the incidence, clinical characteristics, management, and outcomes of men and women with a clinical diagnosis of myocarditis in Poland in the last 10 years. PATIENTS AND METHODS: The nationwide MYO­PL (Occurrence, Trends, Management, and Outcomes of Patients with Myocarditis in Poland) database identified hospitalization records with a primary diag-nosis of myocarditis following the International Classification of Diseases and Related Health Problems, 10th Revision (ICD­10), derived from the database of the national health care insurer; ClinicalTrials.gov identifier: NCT04827706. RESULTS: A total of 16 319 patients (4208 [25.8%] women and 12 111 [74.2%] men) aged over 20 years with a hospital­based clinical diagnosis of myocarditis were included in the study. The women were older than the men (median age, 54 (36-70) and 35 (28-47) years, respectively). The incidence of myocarditis was age-, sex-, and season­dependent. The incidence rate of myocarditis increased over time only in men. Although women were more symptomatic and demonstrated more comorbidities than men, they were less likely to be admitted to a cardiology ward or undergo diagnostic tests. Regardless of the age and sex, the patients with myocarditis had a poorer prognosis than the general population. The women aged 21-40 years had a poorer prognosis than the men of the same age. CONCLUSIONS: The incidence of myocarditis was age-, sex-, and season­dependent. Significant improve-ment is required in the management of myocarditis, including the initial diagnostic process, as well as short-and long­term therapy, particularly in women.

Sex Differences in Incidence, Clinical Characteristics and Outcomes in Children and Young Adults Hospitalized for Clinically Suspected Myocarditis in the Last Ten Years-Data from the MYO-PL Nationwide Database.

There is a widespread lack of systematic knowledge about myocarditis in children and young adults in European populations. The MYO-PL nationwide study aimed to evaluate sex differences in the incidence, clinical characteristics, management and outcomes of all young patients with a clinical diagnosis of myocarditis, hospitalized in the last ten years. The study involved data (from the only public healthcare insurer in Poland) of all (n = 3659) patients aged 0-20 years hospitalized for myocarditis in the years 2011-2019. We assessed clinical characteristics, management and five-year outcomes. Males comprised 75.4% of the study population. The standardized incidence rate of myocarditis increased over the last ten years and was, on average, 7.8 and 2.5 (in males and females, respectively). It was the highest (19.5) in males aged 16-20 years. The highest rates of hospital admissions occurred from late autumn to early spring. Most myocarditis-directed diagnostic procedures, including laboratory tests, echocardiography, coronary angiography, cardiac magnetic resonance and endomyocardial biopsy, were performed in a low number of patients, particularly in females. Most patients required rehospitalization for cardiovascular reasons. The results of this large epidemiological study showed an increasing incidence of myocarditis hospitalizations in young patients over last ten years and that it was sex-, age- and season-dependent. Survival in young patients with myocarditis was age- and sex-related and usually it was worse than in the national population. The general management of myocarditis requires significant improvement.

Occurrence, Trends, Management and Outcomes of Patients Hospitalized with Clinically Suspected Myocarditis-Ten-Year Perspectives from the MYO-PL Nationwide Database.

The epidemiology of myocarditis is unknown and based mainly on small single-centre studies. The study aimed to evaluate the current incidence, clinical characteristics, management and outcomes of patients hospitalized due to myocarditis in a general population. The study was registered in ClinicalTrials.gov (NCT04827706). The nationwide MYO-PL (the occurrence, trends, management and outcomes of patients with myocarditis in Poland) database (years 2009-2020) was created to identify hospitalization records with a primary diagnosis of myocarditis according to the International Classification of Diseases and Related Health Problems, 10th Revision (ICD 10), derived from the database of the national healthcare insurer. We identified 19,978 patients who were hospitalized with suspected myocarditis for the first time, of whom 74% were male. The standardized incidence rate of myocarditis ranged from 1.15 to 14 per 100,000 people depending on the age group and was the highest in patients aged 16-20 years. The overall incidence increased with time. The performance of the recommended diagnostic tests (in particular, endomyocardial biopsy) was low. Relative five-year survival ranged from 0.99 to 0.56-worse in younger females and older males. During a five-year follow-up, 6% of patients (3.7% and 6.9% in females and males, respectively) were re-hospitalized for myocarditis. Surprisingly, females more frequently required hospitalization due to heart failure/cardiomyopathy (10.5%) and atrial fibrillation (5%) than compared to males (7.3% and 2.2%, respectively) in the five-year follow up. In the last ten years, the incidence of suspected myocarditis increased, particularly in males. Survival rates for patients with myocarditis were worse than in the general population. Management of myocarditis requires significant improvement.

Analysis of Biofilm Formation on the Surface of Organic Mung Bean Seeds, Sprouts and in the Germination Environment.

This study aimed to analyse the impact of sanitation methods on the formation of bacterial biofilms after disinfection and during the germination process of mung bean on seeds and in the germination environment. Moreover, the influence of Lactobacillus plantarum 299v on the growth of the tested pathogenic bacteria was evaluated. Three strains of Salmonella and E. coli were used for the study. The colony forming units (CFU), the crystal violet (CV), the LIVE/DEAD and the gram fluorescent staining, the light and the scanning electron microscopy (SEM) methods were used. The tested microorganisms survive in a small number. During germination after disinfection D2 (20 min H2O at 60 °C, then 15 min in a disinfecting mixture consisting of H2O, H2O2 and CH3COOH), the biofilms grew most after day 2, but with the DP2 method (D2 + L. plantarum 299v during germination) after the fourth day. Depending on the method used, the second or fourth day could be a time for the introduction of an additional growth-limiting factor. Moreover, despite the use of seed disinfection, their germination environment could be favourable for the development of bacteria and, consequently, the formation of biofilms. The appropriate combination of seed disinfection methods and growth inhibition methods at the germination stage will lead to the complete elimination of the development of unwanted microflora and their biofilms.

Application of the "SCOBY" and Kombucha Tea for the Production of Fermented Milk Drinks.

For the production of fermented milk drinks, cultures of microorganisms other than traditionally applied can be used. Such possibilities are created by the symbiotic culture of bacteria and yeast (SCOBY), which is used to produce kombucha. The aim of the study was to evaluate the possibility of using kombucha and the SCOBY for fermented milk drink products. The drinks were developed with a lactose-free variant and traditional milk. For the analysis of the obtained beverages, microbiological methods (CFU method), chemical methods (pH method and HPLC method) and the quantitative descriptive analysis (QDA) sensory method were used. As a result of the research, a recipe and the fermentation parameters for fermented milk drinks were developed. In the developed lactose milk drinks, the average lactose content was 4.25 g/100 g. In lactose-free milk drinks, the average glucose content was 2.26 g/100 g. Lactic acid in both types of products was at the highest average level of 0.68 g/100 g. The products had a characteristic pH value for fermented milk drinks and a very good microbiological quality, which followed the FAO/WHO guidelines. Drinks also had a typical sensory profile for this products group. However, slight sensory defects were detected. The developed fermented milk drinks have a potential health-promoting value, thanks to the content of active microflora and organic acids, which have a confirmed positive effect on the human body. The drinks produced require further testing to optimize their cost of production, possible health benefits and sensory quality.

10 year trends in hospitalization rates due to heart failure and related in-hospital mortality in Poland (2010-2019).

AIMS: Heart failure (HF) remains a major public health challenge worldwide. Contemporary epidemiological data on HF hospitalization rates and related in-hospital mortality are scarce also in Poland. The aim of the study was to determine the trends in hospitalization rates due to HF and related in-hospital mortality in Poland in the recent decade. METHODS AND RESULTS: Data on HF hospitalizations and in-hospital mortality in patients aged >17 years in Poland between 2010 and 2019 were obtained from the central database of the Polish National Health Fund. Hospitalizations with either primary or secondary diagnosis of HF were identified using the 10th revision of the International Statistical Classification of Diseases and Related Health Problems codes (I50, I42, J81 with extensions, and R57.0). There were 4 259 698 HF hospitalizations and 608 577 in-hospital deaths (14% in-hospital mortality) reported during 2010-2019 in Poland. During this period, there was a steady increase in the number of HF hospitalizations per 1000 inhabitants in subsequent years, being more pronounced in men than in women (in 2019: 16 and 13 HF hospitalizations per 1000 inhabitants in men and women, respectively). The relative risk of HF hospitalization was higher in men than in women, and this gender-related difference steadily increased from 9% in 2010 to 25% in 2019. During 2010-2019, there was an increase in the number of HF hospitalizations per 1000 inhabitants in subsequent age groups, with a trend being more pronounced in men than in women (129 and 99 HF hospitalizations per 1000 inhabitants in men and women aged ≥80 years, respectively). During this period, there was a slight increase in in-hospital mortality during HF hospitalization in subsequent years, being more pronounced in women than in men (in 2019: 16% and 14% of in-hospital mortality in women and men, respectively). The relative risk of in-hospital mortality during HF hospitalization was higher in women than in men, and this gender-related difference steadily increased from 8% in 2010 to 18% in 2019. During this period, in-hospital mortality during HF hospitalization was ~12% for women and men aged 18-29 years, whereas the highest values of in-hospital mortality reached ~19% for patients aged ≥80 years. CONCLUSIONS: We have observed steady growing trends in HF hospitalization rates and related in-hospital mortality in Poland over the last decade. Both age and gender have differentiated the reported epidemiological patterns.

Genetic determinants of heel bone properties: genome-wide association meta-analysis and replication in the GEFOS/GENOMOS consortium.

Quantitative ultrasound of the heel captures heel bone properties that independently predict fracture risk and, with bone mineral density (BMD) assessed by X-ray (DXA), may be convenient alternatives for evaluating osteoporosis and fracture risk. We performed a meta-analysis of genome-wide association (GWA) studies to assess the genetic determinants of heel broadband ultrasound attenuation (BUA; n = 14 260), velocity of sound (VOS; n = 15 514) and BMD (n = 4566) in 13 discovery cohorts. Independent replication involved seven cohorts with GWA data (in silico n = 11 452) and new genotyping in 15 cohorts (de novo n = 24 902). In combined random effects, meta-analysis of the discovery and replication cohorts, nine single nucleotide polymorphisms (SNPs) had genome-wide significant (P < 5 × 10(-8)) associations with heel bone properties. Alongside SNPs within or near previously identified osteoporosis susceptibility genes including ESR1 (6q25.1: rs4869739, rs3020331, rs2982552), SPTBN1 (2p16.2: rs11898505), RSPO3 (6q22.33: rs7741021), WNT16 (7q31.31: rs2908007), DKK1 (10q21.1: rs7902708) and GPATCH1 (19q13.11: rs10416265), we identified a new locus on chromosome 11q14.2 (rs597319 close to TMEM135, a gene recently linked to osteoblastogenesis and longevity) significantly associated with both BUA and VOS (P < 8.23 × 10(-14)). In meta-analyses involving 25 cohorts with up to 14 985 fracture cases, six of 10 SNPs associated with heel bone properties at P < 5 × 10(-6) also had the expected direction of association with any fracture (P < 0.05), including three SNPs with P < 0.005: 6q22.33 (rs7741021), 7q31.31 (rs2908007) and 10q21.1 (rs7902708). In conclusion, this GWA study reveals the effect of several genes common to central DXA-derived BMD and heel ultrasound/DXA measures and points to a new genetic locus with potential implications for better understanding of osteoporosis pathophysiology.

A genome-wide copy number association study of osteoporotic fractures points to the 6p25.1 locus.

BACKGROUND: Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density and increased susceptibility to fracture; these traits are highly heritable. Both common and rare copy number variants (CNVs) potentially affect the function of genes and may influence disease risk. AIM: To identify CNVs associated with osteoporotic bone fracture risk. METHOD: We performed a genome-wide CNV association study in 5178 individuals from a prospective cohort in the Netherlands, including 809 osteoporotic fracture cases, and performed in silico lookups and de novo genotyping to replicate in several independent studies. RESULTS: A rare (population prevalence 0.14%, 95% CI 0.03% to 0.24%) 210 kb deletion located on chromosome 6p25.1 was associated with the risk of fracture (OR 32.58, 95% CI 3.95 to 1488.89; p = 8.69 × 10(-5)). We performed an in silico meta-analysis in four studies with CNV microarray data and the association with fracture risk was replicated (OR 3.11, 95% CI 1.01 to 8.22; p = 0.02). The prevalence of this deletion showed geographic diversity, being absent in additional samples from Australia, Canada, Poland, Iceland, Denmark, and Sweden, but present in the Netherlands (0.34%), Spain (0.33%), USA (0.23%), England (0.15%), Scotland (0.10%), and Ireland (0.06%), with insufficient evidence for association with fracture risk. CONCLUSIONS: These results suggest that deletions in the 6p25.1 locus may predispose to higher risk of fracture in a subset of populations of European origin; larger and geographically restricted studies will be needed to confirm this regional association. This is a first step towards the evaluation of the role of rare CNVs in osteoporosis.

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10(-4), Bonferroni corrected), of which six reached P < 5 × 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

LRP5 Polymorphisms and response to risedronate treatment in osteoporotic men.

Genetic factors are important in the pathogenesis of osteoporosis, but little is known about the genetic determinants of treatment response. Previous studies have shown that polymorphisms of the LRP5 gene are associated with bone mineral density (BMD), but the relationship between LRP5 polymorphisms and response to bisphosphonate treatment in osteoporosis has not been studied. In this study we investigated LRP5 polymorphisms in relation to treatment response in a group of 249 osteoporotic or osteopenic men who participated in a 24-month randomized double blind placebo-controlled trial of risedronate treatment. BMD and biochemical markers of bone turnover were measured at baseline and after 6, 12, and 24 months of follow-up. We analyzed two coding polymorphisms of LRP5, which have previously been associated with BMD, V667M (rs4988321) and A1330V (rs3736228), and found a significant association between the A1330V polymorphism and hip BMD at baseline. Subjects with the 1330 Val/Val genotype had 8.4% higher total-hip BMD compared with the other genotype groups (P = 0.009), and similar associations were observed at the femoral neck (P = 0.01) and trochanter (P = 0.002). There was no association between A1330V and spine BMD, however, or between the V667M polymorphism and BMD at any site. The difference in hip BMD between A1330V genotype groups remained significant throughout the study, but there was no evidence of a genotype-treatment interaction in either risedronate- or placebo-treated patients. In conclusion, the LRP5 A1330V polymorphism is associated with hip BMD in osteoporotic men, but allelic variations in LRP5 do not appear to be associated with response to bisphosphonate treatment.

Large-scale analysis of association between LRP5 and LRP6 variants and osteoporosis.

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 x 10(-8)), as was the Val1330 allele (n = 24,812; 14-mg/cm2 lower BMD per Val1330 copy; P = 2.6 x 10(-9)). Similar effects were observed for femoral neck BMD, with a decrease of 11 mg/cm2 (P = 3.8 x 10(-5)) and 8 mg/cm2 (P = 5.0 x 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.

Large-scale analysis of association between polymorphisms in the transforming growth factor beta 1 gene (TGFB1) and osteoporosis: the GENOMOS study.

INTRODUCTION: The TGFB1 gene which encodes transforming growth factor beta 1, is a strong candidate for susceptibility to osteoporosis and several studies have reported associations between bone mineral density (BMD), osteoporotic fractures and polymorphisms of TGFB1, although these studies have yielded conflicting results. METHODS: We investigated associations between TGFB1 polymorphisms and BMD and fracture in the GENOMOS study: a prospective multicenter study involving 10 European research studies including a total of 28,924 participants. Genotyping was conducted for known TGFB1 polymorphisms at the following sites: G-1639-A (G-800-A, rs1800468), C-1348-T (C-509-T, rs1800469), T29-C (Leu10Pro, rs1982073), G74-C (Arg25Pro, rs1800471) and C788-T (Thr263Ile, rs1800472). These polymorphisms were genotyped prospectively and methodology was standardized across research centers. Genotypes and haplotypes were related to BMD at the lumbar sine and femoral neck and fractures. RESULTS: There were no significant differences in either women or men at either skeletal site for any of the examined polymorphisms with the possible exception of a weak association with reduced BMD (-12 mg/cm2) in men with the T-1348 allele (p<0.05). None of the haplotypes was associated with BMD and none of the polymorphisms or haplotypes significantly affected overall risk of fractures, however, the odds ratio for incident vertebral fracture in carriers of the rare T788 allele was 1.64 (95% CI: 1.09-2.64), p<0.05. CONCLUSIONS: This study indicates that polymorphic variation in the TGFB1 gene does not play a major role in regulating BMD or susceptibility to fractures. The weak associations we observed between the C-1348-T and lumbar spine BMD in men and between C788-T and risk of incident vertebral fractures are of interest but could be chance findings and will need replication in future studies.

The association between common vitamin D receptor gene variations and osteoporosis: a participant-level meta-analysis.

BACKGROUND: Polymorphisms of the vitamin D receptor (VDR) gene have been implicated in the genetic regulation of bone mineral density (BMD). However, the clinical impact of these variants remains unclear. OBJECTIVE: To evaluate the relation between VDR polymorphisms, BMD, and fractures. DESIGN: Prospective multicenter large-scale association study. SETTING: The Genetic Markers for Osteoporosis consortium, involving 9 European research teams. PARTICIPANTS: 26,242 participants (18,405 women). MEASUREMENTS: Cdx2 promoter, FokI, BsmI, ApaI, and TaqI polymorphisms; BMD at the femoral neck and the lumbar spine by dual x-ray absorptiometry; and fractures. RESULTS: Comparisons of BMD at the lumbar spine and femoral neck showed nonsignificant differences less than 0.011 g/cm2 for any genotype with or without adjustments. A total of 6067 participants reported a history of fracture, and 2088 had vertebral fractures. For all VDR alleles, odds ratios for fractures were very close to 1.00 (range, 0.98 to 1.02) and collectively the 95% CIs ranged from 0.94 (lowest) to 1.07 (highest). For vertebral fractures, we observed a 9% (95% CI, 0% to 18%; P = 0.039) risk reduction for the Cdx2 A-allele (13% risk reduction in a dominant model). LIMITATIONS: The authors analyzed only selected VDR polymorphisms. Heterogeneity was detected in some analyses and may reflect some differences in collection of fracture data across cohorts. Not all fractures were related to osteoporosis. CONCLUSIONS: The FokI, BsmI, ApaI, and TaqI VDR polymorphisms are not associated with BMD or with fractures, but the Cdx2 polymorphism may be associated with risk for vertebral fractures.

Large-scale evidence for the effect of the COLIA1 Sp1 polymorphism on osteoporosis outcomes: the GENOMOS study.

BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm2 (CI, 16 to 34 mg/cm2) lower in TT homozygotes than the other genotype groups (p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm2 (CI, 1 to 42 mg/cm2), (p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study-which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene-demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases.