A new test for trait mean and variance detects unreported loci for blood-pressure variation.

Variability in quantitative traits has clinical, ecological, and evolutionary significance. Most genetic variants identified for complex quantitative traits have only a detectable effect on the mean of trait. We have developed the mean-variance test (MVtest) to simultaneously model the mean and log-variance of a quantitative trait as functions of genotypes and covariates by using estimating equations. The advantages of MVtest include the facts that it can detect effect modification, that multiple testing can follow conventional thresholds, that it is robust to non-normal outcomes, and that association statistics can be meta-analyzed. In simulations, we show control of type I error of MVtest over several alternatives. We identified 51 and 37 previously unreported associations for effects on blood-pressure variance and mean, respectively, in the UK Biobank. Transcriptome-wide association studies revealed 633 significant unique gene associations with blood-pressure mean variance. MVtest is broadly applicable to studies of complex quantitative traits and provides an important opportunity to detect novel loci.

Incidental urinary tract injury and the formation of vesicovaginal fistula at the time of hysterectomy for benign indications.

INTRODUCTION AND HYPOTHESIS: The association between hysterectomy type, laparoscopy use and vesicovaginal fistula (VVF) is currently unclear and would be useful to determine route of surgery and provide adequate patient counseling. The objective of this study was to evaluate the magnitude of association between the use of laparoscopic assistance, recognized intraoperative urinary tract injury and subsequent VVF repair and to quantify any differences in fistula repair and injury detection by hysterectomy type. Lastly, we sought to determine whether the type of hysterectomy is a risk factor for VVF repair independent of injury identification. METHODS: We performed a retrospective cohort study utilizing the Healthcare Cost and Utilization Project database examining benign hysterectomies performed in California, New York and Florida from 2005-2011. Multivariable logistic regression models were used to evaluate associations among hysterectomy type, reported injury and VVF. RESULTS: Of 581,395 eligible hysterectomies, urinary tract injuries occurred in 6702 patients (1.15%) and 640 patients developed VVF (0.11%). Patients with reported injury were 20-fold more likely to develop VVF than those without (OR = 20.6; 1.96% vs. 0.089% respectively). The association between reported injury and VVF development was stronger if laparoscopy was involved (OR = 30) than if it was not (OR = 17). Patients undergoing laparoscopic procedures were less likely to have injury reported (OR = 0.6) but more likely to undergo VVF repair (OR = 1.5). This association with VVF repair was independent of injury identification. Patients developing VVF were more likely to have undergone total abdominal hysterectomy compared to other hysterectomy types. CONCLUSIONS: Laparoscopy is an independent risk factor for the need for subsequent VVF repair, independent of hysterectomy type and presence of intraoperatively recognized urinary tract injury.

Risk factors for degenerative, symptomatic rotator cuff tears: a case-control study.

BACKGROUND: Despite the considerable public health burden of rotator cuff tears, there is no consensus on risk factors associated with symptomatic rotator cuff tears. In this study, a large data source was used to identify factors associated with symptomatic rotator cuff tears. We defined cases of rotator cuff tears as those verified by imaging or operative reports and controls as symptomatic shoulders without rotator cuff tears as verified by imaging or operative reports. METHODS: We performed a case-control study of patients with and without symptomatic rotator cuff tears by use of the Vanderbilt University Medical Center de-identified electronic medical record system, the Synthetic Derivative, with records on >2.5 million patients from 1998 to 2017. Cases and controls were confirmed by individual chart review and review of imaging and/or operative notes. A final set of 11 variables were analyzed as potential risk factors for cuff tears: age, sex, body mass index (BMI), race, smoking history, hypertension, depression/anxiety, dyslipidemia, carpal tunnel syndrome, overhead activity, and affected side. Multivariable logistic regression was used to estimate the association between predictor variables and the risk of having a rotator cuff tear. RESULTS: A total of 2738 patients were selected from the Synthetic Derivative, which included 1731 patients with rotator cuff tears and 1007 patients without rotator cuff tears. Compared with individuals without tears, those with rotator cuff tears were more likely to be older (odds ratio [OR], 2.44; 95% confidence interval [CI], 2.12-2.89), to have a higher BMI (OR, 1.45; 95% CI, 1.24-1.69), to be of male sex (OR, 1.56; 95% CI, 1.32-1.85), and to have carpal tunnel syndrome (OR, 1.41; 95% CI, 1.03-1.93). Patients with rotator cuff tears were less likely to have left shoulder symptoms (OR, 0.68; 95% CI, 0.57-0.82) and to have depression/anxiety (OR, 0.77; 95% CI, 0.62-0.95) compared with the control group, which had symptomatic shoulder pain without rotator cuff tears. CONCLUSIONS: In a large imaging and operative report-verified case-control study, we identified advancing age, male sex, higher BMI, and diagnosis of carpal tunnel syndrome as risk factors significantly associated with an increased risk of rotator cuff tears. Left shoulder symptoms and depression/anxiety were less likely to be associated with rotator cuff tears compared with symptomatic shoulders without rotator cuff tears. Contrary to some prior reports in the literature, smoking was not associated with rotator cuff tears.

Obesity and sex influence fatty infiltration of the rotator cuff: the Rotator Cuff Outcomes Workgroup (ROW) and Multicenter Orthopaedic Outcomes Network (MOON) cohorts.

BACKGROUND: Fatty infiltration (FI) is one of the most important prognostic factors for outcomes after rotator cuff surgery. Established risk factors include advancing age, larger tear size, and increased tear chronicity. A growing body of evidence suggests that sex and obesity are associated with FI; however, data are limited. METHODS: We recruited 2 well-characterized multicenter cohorts of patients with rotator cuff tears (Multicenter Orthopaedic Outcomes Network [MOON] cohort [n = 80] and Rotator Cuff Outcomes Workgroup [ROW] cohort [n = 158]). We used multivariable logistic regression to evaluate the relationship between body mass index (BMI) and the presence of FI while adjusting for the participant's age at magnetic resonance imaging, sex, and duration of shoulder symptoms, as well as the cross-sectional area of the tear. We analyzed the 2 cohorts separately and performed a meta-analysis to combine estimates. RESULTS: A total of 27 patients (33.8%) in the Multicenter Orthopaedic Outcomes Network (MOON) cohort and 57 patients (36.1%) in the Rotator Cuff Outcomes Workgroup (ROW) cohort had FI. When BMI < 25 kg/m2 was used as the reference category, being overweight was associated with a 2.37-fold (95% confidence interval [CI], 0.77-7.29) increased odds of FI and being obese was associated with a 3.28-fold (95% CI, 1.16-9.25) increased odds of FI. Women were 4.9 times (95% CI, 2.06-11.69) as likely to have FI as men. CONCLUSIONS: Among patients with rotator cuff tears, obese patients had a substantially higher likelihood of FI. Further research is needed to assess whether modifying BMI can alter FI in patients with rotator cuff tears. This may have significant clinical implications for presurgical surgical management of rotator cuff tears. Sex was also significantly associated with FI, with women having higher odds of FI than men. Higher odds of FI in female patients may also explain previously reported early suboptimal outcomes of rotator cuff surgery and higher pain levels in female patients as compared with male patients.

Family history and pelvic organ prolapse: a systematic review and meta-analysis.

INTRODUCTION AND HYPOTHESIS: Numerous analytic observational studies assess family history as a risk factor for POP and report a wide range of associations. This review aims to systematically evaluate the role of family history of POP in relation to POP risk and its recurrence. METHODS: A review was performed of the PubMed/MEDLINE database with search criteria specifying family history, risk factors, POP, and their synonyms as title/abstract keywords, as well as MESH terms, up to March 2020. We aggregated evidence across studies with fixed effects (FE) and random effects (RE) meta-analysis. RESULTS: Forty-three articles underwent full-text review. Eighteen independent studies evaluating the relationship between family history of POP and POP risk in 3639 POP cases and 10,912 controls were eligible for meta-analysis. Four studies evaluating family history and POP recurrence in 224 recurrent cases and 400 non-recurrent cases were eligible for inclusion into another meta-analyses. A positive family history of POP is on average associated with 2.3- to 2.7-fold increased risk for POP (RE OR = 2.64; 95% CI = 2.07, 3.35) as well as a 1.4-fold increased risk for POP recurrence (FE OR = 1.44; 95% CI = 1.00, 2.08). Meta-analysis estimates of POP risk varied by study design, definition of family history, and model adjustment status. We found evidence that publication bias and recall bias are a possibility. CONCLUSIONS: Family history of POP is a risk factor for both POP presence and recurrence. However, reported magnitudes may be overestimates due to confounding, recall bias, and publication bias.

Association of APOL1 Risk Alleles With Cardiovascular Disease in Blacks in the Million Veteran Program.

BACKGROUND: Approximately 13% of black individuals carry 2 copies of the apolipoprotein L1 (APOL1) risk alleles G1 or G2, which are associated with 1.5- to 2.5-fold increased risk of chronic kidney disease. There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease (CVD) that is independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease, peripheral artery disease, and stroke among black individuals in the Million Veteran Program. METHODS: We performed a time-to-event analysis of retrospective electronic health record data using Cox proportional hazard and competing-risks Fine and Gray subdistribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident coronary artery disease among individuals without chronic kidney disease during the 12.5-year follow-up period. We separately analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association. RESULTS: Among 30 903 black Million Veteran Program participants, 3941 (13%) carried the 2 APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with 2 risk alleles had slightly higher risk of developing coronary artery disease compared with those with no risk alleles (hazard ratio, 1.11 [95% CI, 1.01-1.21]; P=0.039). Similarly, modest associations were identified with incident stroke (hazard ratio, 1.20 [95% CI, 1.05-1.36; P=0.007) and peripheral artery disease (hazard ratio, 1.15 [95% CI, 1.01-1.29l; P=0.031). When both cardiovascular and renal outcomes were modeled, APOL1 was strongly associated with incident renal disease, whereas no significant association with the CVD end points could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with CVD subsets. CONCLUSIONS: APOL1 risk variants display a modest association with CVD, and this association is likely mediated by the known APOL1 association with chronic kidney disease.

African genetic ancestry interacts with body mass index to modify risk for uterine fibroids.

Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between categories of body mass index (BMI) and reported-race in relation to uterine fibroids. We then investigate whether the association between inferred local European ancestry and fibroid risk is modified by BMI in African American (AA) women in the Vanderbilt University Medical Center bio-repository (BioVU) (539 cases and 794 controls) and the Coronary Artery Risk Development in Young Adults study (CARDIA, 264 cases and 173 controls). We used multiple logistic regression to evaluate interactions between local European ancestry and BMI in relation to fibroid risk, then performed fixed effects meta-analysis. Statistical significance threshold for local-ancestry and BMI interactions was empirically estimated with 10,000 permutations (p-value = 1.18x10-4). Admixture mapping detected an association between European ancestry and fibroid risk which was modified by BMI (continuous-interaction p-value = 3.75x10-5) around ADTRP (chromosome 6p24); the strongest association was found in the obese category (ancestry odds ratio (AOR) = 0.51, p-value = 2.23x10-5). Evaluation of interaction between genotyped/imputed variants and BMI in this targeted region suggested race-specific interaction, present in AAs only; strongest evidence was found for insertion/deletion variant (6:11946435), again in the obese category (OR = 1.66, p-value = 1.72x10-6). We found nominal evidence for interaction between local ancestry and BMI at a previously reported region in chromosome 2q31-32, which includes COL5A2, and TFPI, an immediate downstream target of ADTRP. Interactions between BMI and SNPs (single nucleotide polymorphisms) found in this region in AA women were also detected in an independent European American population of 1,195 cases and 1,164 controls. Findings from our study provide an example of how modifiable and non-modifiable factors may interact to influence fibroid risk and suggest a biological role for BMI in fibroid etiology.

Rare variants in fox-1 homolog A (RBFOX1) are associated with lower blood pressure.

Many large genome-wide association studies (GWAS) have identified common blood pressure (BP) variants. However, most of the identified BP variants do not overlap with the linkage evidence observed from family studies. We thus hypothesize that multiple rare variants contribute to the observed linkage evidence. We performed linkage analysis using 517 individuals in 130 European families from the Cleveland Family Study (CFS) who have been genotyped on the Illumina OmniExpress Exome array. The largest linkage peak was observed on chromosome 16p13 (MLOD = 2.81) for systolic blood pressure (SBP). Follow-up conditional linkage and association analyses in the linkage region identified multiple rare, coding variants in RBFOX1 associated with reduced SBP. In a 17-member CFS family, carriers of the missense variant rs149974858 are normotensive despite being obese (average BMI = 60 kg/m2). Gene-based association test of rare variants using SKAT-O showed significant association with SBP (p-value = 0.00403) and DBP (p-value = 0.0258) in the CFS participants and the association was replicated in large independent replication studies (N = 57,234, p-value = 0.013 for SBP, 0.0023 for PP). RBFOX1 is expressed in brain tissues, the atrial appendage and left ventricle in the heart, and in skeletal muscle tissues, organs/tissues which are potentially related to blood pressure. Our study showed that associations of rare variants could be efficiently detected using family information.

Calcium: magnesium intake ratio and colorectal carcinogenesis, results from the prostate, lung, colorectal, and ovarian cancer screening trial.

BACKGROUND: We aimed to evaluate the associations between calcium and various stages of colorectal carcinogenesis and whether these associations are modified by the calcium to magnesium (Ca:Mg) ratio. METHODS: We tested our hypotheses in the prostate lung, colorectal and ovarian cancer screening trial. RESULTS: Calcium intake did not show a dose-response association with incident adenoma of any size/stage (P-trend = 0.17), but followed an inverse trend when restricted to synchronous/advanced adenoma cases (P-trend = 0.05). This inverse trend was mainly in participants with Ca:Mg ratios between 1.7 and 2.5 (P-trend = 0.05). No significant associations were observed for metachronous adenoma. Calcium intake was inversely associated with CRC (P-trend = 0.03); the association was primarily present for distal CRC (P-trend = 0.01). The inverse association between calcium and distal CRC was further modified by the Ca:Mg ratio (P-interaction < 0.01); significant dose-response associations were found only in participants with a Ca:Mg ratio between 1.7 and 2.5 (P-trend = 0.04). No associations for calcium were found in the Ca:Mg ratio above 2.5 or below 1.7. CONCLUSION: Higher calcium intake may be related to reduced risks of incident advanced and/or synchronous adenoma and incident distal CRC among subjects with Ca:Mg intake ratios between 1.7 and 2.5.

Platelet-Related Variants Identified by Exomechip Meta-analysis in 157,293 Individuals.

Platelet production, maintenance, and clearance are tightly controlled processes indicative of platelets' important roles in hemostasis and thrombosis. Platelets are common targets for primary and secondary prevention of several conditions. They are monitored clinically by complete blood counts, specifically with measurements of platelet count (PLT) and mean platelet volume (MPV). Identifying genetic effects on PLT and MPV can provide mechanistic insights into platelet biology and their role in disease. Therefore, we formed the Blood Cell Consortium (BCX) to perform a large-scale meta-analysis of Exomechip association results for PLT and MPV in 157,293 and 57,617 individuals, respectively. Using the low-frequency/rare coding variant-enriched Exomechip genotyping array, we sought to identify genetic variants associated with PLT and MPV. In addition to confirming 47 known PLT and 20 known MPV associations, we identified 32 PLT and 18 MPV associations not previously observed in the literature across the allele frequency spectrum, including rare large effect (FCER1A), low-frequency (IQGAP2, MAP1A, LY75), and common (ZMIZ2, SMG6, PEAR1, ARFGAP3/PACSIN2) variants. Several variants associated with PLT/MPV (PEAR1, MRVI1, PTGES3) were also associated with platelet reactivity. In concurrent BCX analyses, there was overlap of platelet-associated variants with red (MAP1A, TMPRSS6, ZMIZ2) and white (PEAR1, ZMIZ2, LY75) blood cell traits, suggesting common regulatory pathways with shared genetic architecture among these hematopoietic lineages. Our large-scale Exomechip analyses identified previously undocumented associations with platelet traits and further indicate that several complex quantitative hematological, lipid, and cardiovascular traits share genetic factors.

Exome Genotyping Identifies Pleiotropic Variants Associated with Red Blood Cell Traits.

Red blood cell (RBC) traits are important heritable clinical biomarkers and modifiers of disease severity. To identify coding genetic variants associated with these traits, we conducted meta-analyses of seven RBC phenotypes in 130,273 multi-ethnic individuals from studies genotyped on an exome array. After conditional analyses and replication in 27,480 independent individuals, we identified 16 new RBC variants. We found low-frequency missense variants in MAP1A (rs55707100, minor allele frequency [MAF] = 3.3%, p = 2 × 10(-10) for hemoglobin [HGB]) and HNF4A (rs1800961, MAF = 2.4%, p < 3 × 10(-8) for hematocrit [HCT] and HGB). In African Americans, we identified a nonsense variant in CD36 associated with higher RBC distribution width (rs3211938, MAF = 8.7%, p = 7 × 10(-11)) and showed that it is associated with lower CD36 expression and strong allelic imbalance in ex vivo differentiated human erythroblasts. We also identified a rare missense variant in ALAS2 (rs201062903, MAF = 0.2%) associated with lower mean corpuscular volume and mean corpuscular hemoglobin (p < 8 × 10(-9)). Mendelian mutations in ALAS2 are a cause of sideroblastic anemia and erythropoietic protoporphyria. Gene-based testing highlighted three rare missense variants in PKLR, a gene mutated in Mendelian non-spherocytic hemolytic anemia, associated with HGB and HCT (SKAT p < 8 × 10(-7)). These rare, low-frequency, and common RBC variants showed pleiotropy, being also associated with platelet, white blood cell, and lipid traits. Our association results and functional annotation suggest the involvement of new genes in human erythropoiesis. We also confirm that rare and low-frequency variants play a role in the architecture of complex human traits, although their phenotypic effect is generally smaller than originally anticipated.

Large-Scale Exome-wide Association Analysis Identifies Loci for White Blood Cell Traits and Pleiotropy with Immune-Mediated Diseases.

White blood cells play diverse roles in innate and adaptive immunity. Genetic association analyses of phenotypic variation in circulating white blood cell (WBC) counts from large samples of otherwise healthy individuals can provide insights into genes and biologic pathways involved in production, differentiation, or clearance of particular WBC lineages (myeloid, lymphoid) and also potentially inform the genetic basis of autoimmune, allergic, and blood diseases. We performed an exome array-based meta-analysis of total WBC and subtype counts (neutrophils, monocytes, lymphocytes, basophils, and eosinophils) in a multi-ancestry discovery and replication sample of âˆ¼157,622 individuals from 25 studies. We identified 16 common variants (8 of which were coding variants) associated with one or more WBC traits, the majority of which are pleiotropically associated with autoimmune diseases. Based on functional annotation, these loci included genes encoding surface markers of myeloid, lymphoid, or hematopoietic stem cell differentiation (CD69, CD33, CD87), transcription factors regulating lineage specification during hematopoiesis (ASXL1, IRF8, IKZF1, JMJD1C, ETS2-PSMG1), and molecules involved in neutrophil clearance/apoptosis (C10orf54, LTA), adhesion (TNXB), or centrosome and microtubule structure/function (KIF9, TUBD1). Together with recent reports of somatic ASXL1 mutations among individuals with idiopathic cytopenias or clonal hematopoiesis of undetermined significance, the identification of a common regulatory 3' UTR variant of ASXL1 suggests that both germline and somatic ASXL1 mutations contribute to lower blood counts in otherwise asymptomatic individuals. These association results shed light on genetic mechanisms that regulate circulating WBC counts and suggest a prominent shared genetic architecture with inflammatory and autoimmune diseases.

Miniature Diamond-Based Fiber Optic Pressure Sensor with Dual Polymer-Ceramic Adhesives.

Diamond is a good candidate for harsh environment sensing due to its high melting temperature, Young's modulus, and thermal conductivity. A sensor made of diamond will be even more promising when combined with some advantages of optical sensing (i.e., EMI inertness, high temperature operation, and miniaturization). We present a miniature diamond-based fiber optic pressure sensor fabricated using dual polymer-ceramic adhesives. The UV curable polymer and the heat-curing ceramic adhesive are employed for easy and reliable optical fiber mounting. The usage of the two different adhesives considerably improves the manufacturability and linearity of the sensor, while significantly decreasing the error from the temperature cross-sensitivity. Experimental study shows that the sensor exhibits good linearity over a pressure range of 2.0-9.5 psi with a sensitivity of 18.5 nm/psi (R2 = 0.9979). Around 275 °C of working temperature was achieved by using polymer/ceramic dual adhesives. The sensor can benefit many fronts that require miniature, low-cost, and high-accuracy sensors including biomedical and industrial applications. With an added antioxidation layer on the diamond diaphragm, the sensor can also be applied for harsh environment applications due to the high melting temperature and Young's modulus of the material.

Testing the role of predicted gene knockouts in human anthropometric trait variation.

Although the role of complete gene inactivation by two loss-of-function mutations inherited in trans is well-established in recessive Mendelian diseases, we have not yet explored how such gene knockouts (KOs) could influence complex human phenotypes. Here, we developed a statistical framework to test the association between gene KOs and quantitative human traits. Our method is flexible, publicly available, and compatible with common genotype format files (e.g. PLINK and vcf). We characterized gene KOs in 4498 participants from the NHLBI Exome Sequence Project (ESP) sequenced at high coverage (>100×), 1976 French Canadians from the Montreal Heart Institute Biobank sequenced at low coverage (5.7×), and >100 000 participants from the Genetic Investigation of ANthropometric Traits (GIANT) Consortium genotyped on an exome array. We tested associations between gene KOs and three anthropometric traits: body mass index (BMI), height and BMI-adjusted waist-to-hip ratio (WHR). Despite our large sample size and multiple datasets available, we could not detect robust associations between specific gene KOs and quantitative anthropometric traits. Our results highlight several limitations and challenges for future gene KO studies in humans, in particular when there is no prior knowledge on the phenotypes that might be affected by the tested gene KOs. They also suggest that gene KOs identified with current DNA sequencing methodologies probably do not strongly influence normal variation in BMI, height, and WHR in the general human population.

Obesity and pelvic organ prolapse: a systematic review and meta-analysis of observational studies.

BACKGROUND: Studies evaluating the association between obesity and pelvic organ prolapse report estimates that range from negative to positive associations. Heterogeneous definitions for pelvic organ prolapse and variable choices for categorizing obesity measures have made it challenging to conduct meta-analysis. OBJECTIVE: We systematically evaluated evidence to provide quantitative summaries of association between degrees of obesity and pelvic organ prolapse, and identify sources of heterogeneity. STUDY DESIGN: We searched for all indexed publications relevant to pelvic organ prolapse up until June 18, 2015, in PubMed/MEDLINE to identify analytical observational studies published in English that reported risk ratios (relative risk, odds ratio, or hazard ratio) for body mass index categories in relation to pelvic organ prolapse. Random effects meta-analyses were conducted to report associations with pelvic organ prolapse for overweight and obese body mass index categories compared with women in the normal-weight category (referent: body mass index <25 kg/m2). RESULTS: Of the 70 studies that reported evidence on obesity and pelvic organ prolapse, 22 eligible studies provided effect estimates for meta-analysis of the overweight and obese body mass index categories. Compared with the referent category, women in the overweight and obese categories had meta-analysis risk ratios of at least 1.36 (95% confidence interval, 1.20-1.53) and at least 1.47 (95% confidence interval, 1.35-1.59), respectively. Subgroup analyses showed effect estimates for objectively measured clinically significant pelvic organ prolapse were higher than for self-reported pelvic organ prolapse. Other potential sources of heterogeneity included proportion of postmenopausal women in study and reported study design. CONCLUSION: Overweight and obese women are more likely to have pelvic organ prolapse compared with women with body mass index in the normal range. The finding that the associations for obesity measures were strongest for objectively measured, clinically significant pelvic organ prolapse further strengthens this evidence. However, prospective investigations evaluating obesity and pelvic organ prolapse are few.

Genetic epidemiology of pelvic organ prolapse: a systematic review.

Given current evidence supporting a genetic predisposition for pelvic organ prolapse, we conducted a systematic review of published literature on the genetic epidemiology of pelvic organ prolapse. Inclusion criteria were linkage studies, candidate gene association and genome-wide association studies in adult women published in English and indexed in PubMed through Dec. 2012, with no limit on date of publication. Methodology adhered to the PRISMA guidelines. Data were systematically extracted by 2 reviewers and graded by the Venice criteria for studies of genetic associations. A metaanalysis was performed on all single nucleotide polymorphisms evaluated by 2 or more studies with similar methodology. The metaanalysis suggests that collagen type 3 alpha 1 (COL3A1) rs1800255 genotype AA is associated with pelvic organ prolapse (odds ratio, 4.79; 95% confidence interval, 1.91-11.98; P = .001) compared with the reference genotype GG in populations of Asian and Dutch women. There was little evidence of heterogeneity for rs1800255 (P value for heterogeneity = .94; proportion of variance because of heterogeneity, I(2) = 0.00%). There was insufficient evidence to determine whether other single nucleotide polymorphisms evaluated by 2 or more papers were associated with pelvic organ prolapse. An association with pelvic organ prolapse was seen in individual studies for estrogen receptor alpha (ER-α) rs2228480 GA, COL3A1 exon 31, chromosome 9q21 (heterogeneity logarithm of the odds score 3.41) as well as 6 single nucleotide polymorphisms identified by a genome-wide association study. Overall, individual studies were of small sample size and often of poor quality. Future studies would benefit from more rigorous study design as outlined in the Venice recommendations.

Elevated Body Mass Index Is Associated With Rotator Cuff Disease: A Systematic Review and Meta-analysis.

Purpose: To analyze the literature regarding obesity, body mass index (BMI), and rotator cuff disease (RCD). Methods: In this Systematic Review and Meta-analysis, we queried PubMed, Embase, Cochrane, Cumulative Index to Nursing & Allied Health, and Science Direct using key words (August 25, 2023). Analytic observational studies (cohort, case-control, and cross-sectional studies) with more than 30 participants per comparison group, evaluating the association between obesity and rotator cuff pathology, were eligible for inclusion. Meta-analysis was performed to quantitatively summarize associations between BMI and RCD to report odds ratios and corresponding 95% confidence intervals (CIs) for regression-based models and BMI mean differences between cases and controls. Risk Of Bias In Non-randomised Studies - of Interventions tool was used to evaluate risk of bias across all studies in the systematic review. Results: After full-text review of 248 articles, 27 presented data on obesity and RCD, and 17 qualified for meta-analysis. Individuals with RCD were 1.21 times (95% CI 1.10-1.34) as likely to have overweight and 1.44 times (95% CI 1.32-1.59) as likely to have obesity compared with those without RCD. Each 5-unit increase in BMI was associated with 35% greater odds of having rotator cuff tear (95% CI 1.06-1.71). In-depth assessment for risk of bias shows quality of studies varies greatly and highlights outcome heterogeneity, lack of temporality, confounding and selection bias as major concerns for individual studies. Conclusions: In this study, we found a positive association between elevated BMI and RCD. Level of Evidence: Level III, systematic review and meta-analysis of Level II-III studies.

Palmitate and group B Streptococcus synergistically and differentially induce IL-1ß from human gestational membranes.

Introduction: Rupture of the gestational membranes often precedes major pregnancy complications, including preterm labor and preterm birth. One major cause of inflammation in the gestational membranes, chorioamnionitis (CAM) is often a result of bacterial infection. The commensal bacterium Streptococcus agalactiae, or Group B Streptococcus (GBS) is a leading infectious cause of CAM. Obesity is on the rise worldwide and roughly 1 in 4 pregnancy complications is related to obesity, and individuals with obesity are also more likely to be colonized by GBS. The gestational membranes are comprised of several distinct cell layers which are, from outermost to innermost: maternally-derived decidual stromal cells (DSCs), fetal cytotrophoblasts (CTBs), fetal mesenchymal cells, and fetal amnion epithelial cells (AECs). In addition, the gestational membranes have several immune cell populations; macrophages are the most common phagocyte. Here we characterize the effects of palmitate, the most common long-chain saturated fatty acid, on the inflammatory response of each layer of the gestational membranes when infected with GBS, using human cell lines and primary human tissue. Results: Palmitate itself slightly but significantly augments GBS proliferation. Palmitate and GBS co-stimulation synergized to induce many inflammatory proteins and cytokines, particularly IL-1ß and matrix metalloproteinase 9 from DSCs, CTBs, and macrophages, but not from AECs. Many of these findings are recapitulated when treating cells with palmitate and a TLR2 or TLR4 agonist, suggesting broad applicability of palmitate-pathogen synergy. Co-culture of macrophages with DSCs or CTBs, upon co-stimulation with GBS and palmitate, resulted in increased inflammatory responses, contrary to previous work in the absence of palmitate. In whole gestational membrane biopsies, the amnion layer appeared to dampen immune responses from the DSC and CTB layers (the choriodecidua) to GBS and palmitate co-stimulation. Addition of the monounsaturated fatty acid oleate, the most abundant monounsaturated fatty acid in circulation, dampened the proinflammatory effect of palmitate. Discussion: These studies reveal a complex interplay between the immunological response of the distinct layers of the gestational membrane to GBS infection and that such responses can be altered by exposure to long-chain saturated fatty acids. These data provide insight into how metabolic syndromes such as obesity might contribute to an increased risk for GBS disease during pregnancy.

GLP1R Gene Expression and Kidney Disease Progression.

Importance: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) may have nephroprotective properties beyond those related to weight loss and glycemic control. Objective: To investigate the association of genetically proxied GLP-1RAs with kidney disease progression. Design, Setting, and Participants: This genetic association study assembled a national retrospective cohort of veterans aged 18 years or older from the US Department of Veterans Affairs Million Veteran Program between January 10, 2011, and December 31, 2021. Data were analyzed from November 2023 to February 2024. Exposures: Genetic risk score for systemic GLP1R gene expression that was calculated for each study participant based on genetic variants associated with GLP1R mRNA levels across all tissue samples within the Genotype-Tissue Expression project. Main Outcomes and Measures: The primary composite outcome was incident end-stage kidney disease or a 40% decline in estimated glomerular filtration rate. Cox proportional hazards regression survival analysis assessed the association between genetically proxied GLP-1RAs and kidney disease progression. Results: Among 353 153 individuals (92.5% men), median age was 66 years (IQR, 58.0-72.0 years) and median follow-up was 5.1 years (IQR, 3.1-7.2 years). Overall, 25.7% had diabetes, and 45.0% had obesity. A total of 4.6% experienced kidney disease progression. Overall, higher genetic GLP1R gene expression was associated with a lower risk of kidney disease progression in the unadjusted model (hazard ratio [HR], 0.96; 95% CI, 0.92-0.99; P = .02) and in the fully adjusted model accounting for baseline patient characteristics, body mass index, and the presence or absence of diabetes (HR, 0.96; 95% CI, 0.92-1.00; P = .04). The results were similar in sensitivity analyses stratified by diabetes or obesity status. Conclusions and Relevance: In this genetic association study, higher GLP1R gene expression was associated with a small reduction in risk of kidney disease progression. These findings support pleiotropic nephroprotective mechanisms of GLP-1RAs independent of their effects on body weight and glycemic control.

Obesity is associated with muscle atrophy in rotator cuff tear.

Objective: The primary goal of this study is to evaluate the relationship between Body Mass Index (BMI) and muscle atrophy in individuals with rotator cuff tears. Methods: This study consists of patients with rotator cuff tears identified by MRI from two independent cohorts, the Rotator Cuff Outcomes Workgroup (ROW) and the Multicenter Orthopaedic Outcomes Network (MOON). Presence of atrophy (yes/no) and severity of atrophy (as an ordinal variable) were assessed on MRI by expert physicians. We used multivariable regression models to evaluate the relationship between BMI and muscle atrophy while adjusting for age and sex in each study, conducted sensitivity analyses for full-thickness tear and combined results using inverse variance-weighted meta-analysis. Results: A total of 539 patients (MOON=395, ROW=144) from the combined cohorts had MRI data available on muscle atrophy. Among these patients, 246 (46%) had atrophy of at least one of the muscles of the rotator cuff and 282 (52%) had full-thickness tears. In meta-analysis across both cohorts, each 5 kg/m2 increase in BMI was associated with a 21% (aOR=1.21, 95% CI=1.02, 1.43) increased odds of having muscle atrophy among individuals with any tear size, and 36% (aOR=1.36, 95% CI=1.01-1.81) increased odds among individuals with full-thickness tear. Conclusions: Higher BMI was associated with significantly higher odds of muscle atrophy in patiens with rotator cuff tears. More study is needed to unders1tand why and how this relationship exists, as well as whether interventions to reduce BMI may help improve outcomes for these patients. Level of Evidence: III.