A PLETHORA-auxin transcription module controls cell division plane rotation through MAP65 and CLASP.

Despite their pivotal role in plant development, control mechanisms for oriented cell divisions have remained elusive. Here, we describe how a precisely regulated cell division orientation switch in an Arabidopsis stem cell is controlled by upstream patterning factors. We show that the stem cell regulatory PLETHORA transcription factors induce division plane reorientation by local activation of auxin signaling, culminating in enhanced expression of the microtubule-associated MAP65 proteins. MAP65 upregulation is sufficient to reorient the cortical microtubular array through a CLASP microtubule-cell cortex interaction mediator-dependent mechanism. CLASP differentially localizes to cell faces in a microtubule- and MAP65-dependent manner. Computational simulations clarify how precise 90° switches in cell division planes can follow self-organizing properties of the microtubule array in combination with biases in CLASP localization. Our work demonstrates how transcription factor-mediated processes regulate the cellular machinery to control orientation of formative cell divisions in plants.

Live imaging of microtubule organization, cell expansion, and intercellular space formation in Arabidopsis leaf spongy mesophyll cells.

Leaf spongy mesophyll cells form an interconnected network of branched cells and intercellular spaces to maximize the surface area available for light capture and photosynthetic gas exchange. To investigate the morphogenetic events leading to cell separation and branching in Arabidopsis thaliana, we used mesophyll-specific promoters to facilitate imaging of mesophyll cell shape and microtubule (MT) organization over multiple spatiotemporal scales without interference from the overlying epidermal cells. We show that cells enlarge by selective expansion of cell wall regions in contact with intercellular spaces. Cell-cell contacts remain relatively fixed in size, forming the termini of interconnecting branches. Surprisingly, classic schizogeny (de-adhesion of neighboring cells) is relatively infrequent, being related to the local topology of cell junctions during early expansion. Intercellular spaces cue the position of stable MT bundles, which in turn promote efficient dilation of intercellular spaces and cell branching. Our data provide insights into mesophyll morphogenesis and MT organization and lay the groundwork for future investigations.

Clinical and economic burden of severe asthma among US patients treated with biologic therapies.

BACKGROUND: Patients with severe asthma may remain uncontrolled despite biologic therapy in addition to standard therapy, but this disease burden has not been quantified. OBJECTIVE: To estimate the clinical and economic burden in a US national sample. METHODS: Patients who have severe asthma with indicated biologic treatment (earliest use = index date) were selected from the MarketScan database between January 1, 2013, and June 30, 2018. Inclusion criteria were continuous enrollment for 12 months postindex with a minimum of 2 biologic fills, greater than or equal to 12 years of age, evidence of medium- to high-dose inhaled corticosteroids and long-acting ß-agonist combination before the index, and absence of other respiratory diagnoses and malignancies. Disease exacerbations (used to classify asthma control), health care costs, and treatment characteristics were reported during the 12-month postindex period. RESULTS: The sample included 3262 biologic patients; 88% with anti-immunoglobulin E therapy (omalizumab) and 12% non-anti-immunoglobulin E (reslizumab, mepolizumab, benralizumab). The mean age was 49 (±15) years; 64% were women. Prescriptions included inhaled corticosteroids and long-acting ß-agonist (82%), systemic corticosteroids (76%), and leukotriene receptor antagonists (68%). Notably, 63% of patients presented greater than or equal to 1 asthma exacerbation (mean 1.3 per patient/year). Furthermore, 35% of patients were categorized as having controlled asthma, whereas 28% were suboptimally controlled and 29% were uncontrolled. Patients with uncontrolled disease had higher all-cause and asthma-related costs ($69,206 and $45,693, respectively) than patients with suboptimally controlled ($59,407 and $40,793, respectively) or controlled disease ($53,083 and $38,393, respectively). Furthermore, 62% of newly treated patients were persistent with their index biologic. CONCLUSION: Biologic therapies are effective in reducing exacerbations, but a substantial proportion of patients with severe asthma treated with current biologics continue to experience uncontrolled disease, highlighting a remaining unmet need for patients with severe uncontrolled asthma.

Correction to: MeioCapture: an efficient method for staging and isolation of meiocytes in the prophase I sub-stages of meiosis in wheat.

Following publication of the original article [1], a reader spotted an incorrect citation of the reference 14 [2] in the 'Background'. The male meiocyte isolation work described in this article [2] was carried out in rice and not in Brassica as originally stated in the 'Background' [1]. Thus, the following amendment to the Background section should be noted.

MeioCapture: an efficient method for staging and isolation of meiocytes in the prophase I sub-stages of meiosis in wheat.

BACKGROUND: Molecular analysis of meiosis has been hindered by difficulties in isolating high purity subpopulations of sporogenous cells representing the succeeding stages of meiosis. Isolation of purified male meiocytes from defined meiotic stages is crucial in discovering meiosis specific genes and associated regulatory networks. RESULTS: We describe an optimized method termed MeioCapture for simultaneous isolation of uncontaminated male meiocytes from wheat (Triticum spp.), specifically from the pre-meiotic G2 and the five sub-stages of meiotic prophase I. The MeioCapture protocol builds on the traditional anther squash technique and the capillary collection method, and involves extrusion of intact sporogenous archesporial columns (SACs) containing meiocytes. This improved method exploits the natural meiotic synchrony between anthers of the same floret, the correlation between the length of anthers and meiotic stage, and the occurrence of meiocytes in intact SACs largely free of somatic cells. The main advantage of MeioCapture, compared to previous methods, is that it allows simultaneous collection of meiocytes from different sub-stages of prophase I at a very high level of purity, through correlation of stages with anther sizes. A detailed description is provided for all steps, including the collection of tissue, isolation and size sorting of anthers, extrusion of intact SACs, and staging of meiocytes. Precautions for individual steps throughout the procedure are also provided to facilitate efficient isolation of pure meiocytes. The proof-of-concept was successfully established in wheat, and a light microscopic atlas of meiosis, encompassing all stages from pre-meiosis to telophase II, was developed. CONCLUSION: The MeioCapture method provides an essential technique to study the molecular basis of chromosome pairing and exchange of genetic information in wheat, leading to strategies for manipulating meiotic recombination frequencies. The method also provides a foundation for similar studies in other crop species.

Microtubule encounter-based catastrophe in Arabidopsis cortical microtubule arrays.

BACKGROUND: The cortical microtubules (CMTs) that line the plasma membrane of interphase plant cells are extensively studied owing to their importance in forming cell walls, and their usefulness as a model system for the study of MT dynamic instability and acentrosomal MT organization. CMTs influence the orientation and structure of cellulose microfibrils in the cell wall by cooperatively forming arrays of varied patterns from parallel to netted. These CMT patterns are controlled by the combined activities of MT dynamic instability and MT-MT interactions. However, it is an open question as to how CMT patterns may feedback to influence CMT dynamics and interactions. RESULTS: To address this question, we investigated the effects of CMT array patterning on encounter-based CMT catastrophe, which occurs when one CMT grows into another and is unable to cross over. We hypothesized that the varied CMT angles present in disordered (mixed CMTs) arrays will create more opportunities for MT-MT interactions, and thus increase encounter-based catastrophe rates and distribution. Using live-cell imaging of Arabidopsis cotyledon and leaf epidermal cells, we found that roughly 87% of catastrophes occur via the encounter-based mechanism, with the remainder occurring without encounter (free). When comparing ordered (parallel) and disordered (mixed orientation) CMT arrays, we found that disordered configurations show higher proportions of encounter-based catastrophe relative to free. Similarly, disordered CMT arrays have more catastrophes in general than ordered arrays. Encounter-based catastrophes were associated with frequent and sustained periods of pause prior to depolymerization, and CMTs with tight anchoring to the plasma membrane were more prone to undergo encounter-based catastrophe than weakly-attached ones. This suggests that encounter-based catastrophe has a mechanical basis, wherein MTs form physical barriers to one another. Lastly, we show that the commonly used measure of catastrophe frequencies (Fcat) can also be influenced by CMT ordering and plasma membrane anchoring. CONCLUSIONS: Our observations add a new layer of complexity to our current understanding of MT organization in plants, showing that not only do individual CMT dynamics influence CMT array organization, but that CMT organization itself has a strong effect on the behavior of individual MTs.

Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women.

OBJECTIVE: Family studies and twin studies demonstrate that lower urinary tract symptoms and pelvic organ prolapse are heritable. This review aimed to identify genetic polymorphisms tested for an association with lower urinary tract symptoms or prolapse, and to assess the strength, consistency, and risk of bias among reported associations. STUDY DESIGN: PubMed and HuGE Navigator were searched up to May 1, 2014, using a combination of genetic and phenotype key words, including "nocturia," "incontinence," "overactive bladder," "prolapse," and "enuresis." Major genetics, urology, and gynecology conference abstracts were searched from 2005 through 2013. We screened 889 abstracts, and retrieved 78 full texts. In all, 27 published and 7 unpublished studies provided data on polymorphisms in or near 32 different genes. Fixed and random effects metaanalyses were conducted using codominant models of inheritance. We assessed the credibility of pooled associations using the interim Venice criteria. RESULTS: In pooled analysis, the rs4994 polymorphism of the ADRB3 gene was associated with overactive bladder (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.7-3.6; n = 419). The rs1800012 polymorphism of the COL1A1 gene was associated with prolapse (OR, 1.3; 95% CI, 1.0-1.7; n = 838) and stress urinary incontinence (OR, 2.1; 95% CI, 1.4-3.2; n = 190). Other metaanalyses, including those for polymorphisms of COL3A1,LAMC1,MMP1,MMP3, and MMP9 did not show significant effects. Many studies were at high risk of bias from genotyping error or population stratification. CONCLUSION: These metaanalyses provide moderate epidemiological credibility for associations of variation in ADRB3 with overactive bladder, and variation of COL1A1 with prolapse. Clinical testing for any of these polymorphisms cannot be recommended based on current evidence.

Microtubule initiation from the nuclear surface controls cortical microtubule growth polarity and orientation in Arabidopsis thaliana.

The nuclear envelope in plant cells has long been known to be a microtubule organizing center (MTOC), but its influence on microtubule organization in the cell cortex has been unclear. Here we show that nuclear MTOC activity favors the formation of longitudinal cortical microtubule (CMT) arrays. We used green fluorescent protein (GFP)-tagged gamma tubulin-complex protein 2 (GCP2) to identify nuclear MTOC activity and GFP-tagged End-Binding Protein 1b (EB1b) to track microtubule growth directions. We found that microtubules initiate from nuclei and enter the cortex in two directions along the long axis of the cell, creating bipolar longitudinal CMT arrays. Such arrays were observed in all cell types showing nuclear MTOC activity, including root hairs, recently divided cells in root tips, and the leaf epidermis. In order to confirm the causal nature of nuclei in bipolar array formation, we displaced nuclei by centrifugation, which generated a corresponding shift in the bipolarity split point. We also found that bipolar CMT arrays were associated with bidirectional trafficking of vesicular components to cell ends. Together, these findings reveal a conserved function of plant nuclear MTOCs and centrosomes/spindle pole bodies in animals and fungi, wherein all structures serve to establish polarities in microtubule growth.

Beauty is more than epidermis deep: How cell division and expansion sculpt the leaf spongy mesophyll.

As the main location of photosynthesis, leaf mesophyll cells are one of the most abundant and essential cell types on earth. Forming the bulk of the internal tissues of the leaf, their size, shape, and patterns of interconnectivity define the internal structure and surface area of the leaf, which in turn determines the efficiency of light capture and carbon fixation. Understanding how these cellular traits are controlled and translated into tissue- and organ-scale traits, and how they influence photosynthetic performance will be key to our ability to improve crop plants in the face of a changing climate. In contrast to the extensive literature on the anatomical and physiological aspects of mesophyll function, our understanding of the cell-level morphogenetic processes underpinning mesophyll cell growth and differentiation is scant. In this review, we focus on how cell division, expansion, and separation are coordinated to create the intricate architecture of the spongy mesophyll.

A randomized, placebo-controlled trial of long-acting dexamethasone viscous gel delivered by transforaminal injection for lumbosacral radicular pain.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03372161.

Increased incidence of Escherichia coli bacteremia post-Christchurch earthquake 2011: possible associations.

INTRODUCTION: Earthquakes are natural events that contribute to the transmission of infectious diseases. The aim of this research was to determine whether the observed increase in Escherichia coli (E. coli) bloodstream infections (BSI) during the period March-June 2011 was associated with the February 2011 Christchurch earthquake. METHODS: Descriptive statistics and spatial distributional analysis techniques were used to quantify patients with E. coli BSI in 2009-2011. RESULTS: E. coli BSI acquired from non-catheter related urinary tract infection (UTI) was the predominant infection type, with the greatest increase during March-June 2011. Bacteremia incidence was higher in females than in males for 2009-2011. In 2011, the median age of patients was 75 years, and an increase in males acquiring such infections was noted. Spatial distributional analysis failed to show direct association between bacteremia cases and liquefaction-related land damage or drinking water contamination. A higher incidence of E. coli BSI post-earthquake in the eastern suburbs, which tend towards a higher level of socioeconomic deprivation, was observed. CONCLUSION: A number of possible factors contributing to the observed increase in E. coli BSI acquired from UTI in 2011 were considered. Individuals with higher deprivation indices, males and the elderly may be particularly vulnerable to the effects of a major disaster with subsequent breakdown of infrastructure. These findings have important implications in natural disaster situations, and justify development of strategies to identify UTI and pyelonephritis risk factors and to manage E. coli bacteremia incidence rates.

CLASP balances two competing cell division plane cues during leaf development.

Starting as small, densely packed boxes, leaf mesophyll cells expand to form an intricate mesh of interconnected cells and air spaces, the organization of which dictates the internal surface area of the leaf for light capture and gas exchange during photosynthesis. Despite their importance, little is known about the basic patterns of mesophyll cell division, and how they contribute to cell and intercellular space organization. To address this, we tracked divisions within individual cell lineages in three dimensions over time in Arabidopsis spongy mesophyll. We found that early on, successive cell division planes switch their orientation such that each new cell wall intersects the previous at a right angle, creating a new multi-cell junction (the intersection of three or more cells). These junctions then open to create intercellular spaces. During subsequent enlargement of the spaces, the division planes of the surrounding cells show an increasing tendency to tilt in the direction of their adjacent intercellular spaces. This disrupts the alternating pattern, and by extension, halts the initiation of new multi-cell junctions and intercellular spaces, but allows the expansion of existing spaces. Both division patterns are specified before mitosis by the orientation of interphase cortical microtubules, which gradually narrow to form a preprophase band in the same orientation to establish the future plane of cell division. In the absence of the microtubule-associated protein CLASP, the early alternating division plane and microtubule patterns are compromised, whereas space-oriented divisions are exacerbated. This results in large distortions of the topological relations between cells and intercellular spaces, as well as changes in their relative abundance. Our data reveal the existence of two competing cell division mechanisms that are balanced by CLASP to specify the distribution of cells and intercellular spaces in spongy mesophyll tissue.

Clinical and economic burden of uncontrolled severe noneosinophilic asthma.

OBJECTIVES: To quantify the clinical and economic burden of patients with severe asthma with low blood eosinophil counts (BECs) untreated with biologics. STUDY DESIGN: Retrospective cohort study in IBM MarketScan claims database. METHODS: Patients 12 years and older with severe asthma with BEC data were selected between January 1, 2013, and June 30, 2018 (date of the most recent BEC was used as the index date). Inclusion criteria were (1) presence of BEC laboratory test result, (2) continuous enrollment for 12 months preceding and following the index date, (3) meeting the Healthcare Effectiveness Data and Information Set definition of persistent asthma, (4) meeting the Global Initiative for Asthma definition of severe asthma, and (5) an absence of biologic treatment, other respiratory diagnoses, and malignancies 12 months preceding and following the index date. Asthma exacerbations, levels of disease control, and all-cause and asthma-related health care costs were reported during the 12-month postindex period for patients with a BEC less than 300 cells/mcL. RESULTS: The sample included 8073 patients with severe asthma; 78% (n = 6260) presented with a BEC less than 300 cells/mcL. Mean (SD) age of the sample was 54.8 (14.2) years; 64% were female. Eighteen percent of patients had an asthma exacerbation; 19% had either uncontrolled or suboptimally controlled asthma based on the frequency of asthma-related hospital admissions, emergency department visits, or corticosteroid prescription fills. One-year all-cause and asthma-related total health care costs were $25,845 and $2802, respectively. Patients with suboptimally controlled and uncontrolled asthma spent $1471 and $3872 more, respectively, on asthma-related claims compared with patients with controlled asthma. CONCLUSIONS: Among patients with severe asthma with low eosinophils untreated with biologics, there is a high burden of disease among those who have suboptimal disease control, highlighting an unmet need in severe asthma treatment.

Localized growth and remodelling drives spongy mesophyll morphogenesis.

The spongy mesophyll is a complex, porous tissue found in plant leaves that enables carbon capture and provides mechanical stability. Unlike many other biological tissues, which remain confluent throughout development, the spongy mesophyll must develop from an initially confluent tissue into a tortuous network of cells with a large proportion of intercellular airspace. How the airspace in the spongy mesophyll develops while the tissue remains mechanically stable is unknown. Here, we use computer simulations of deformable polygons to develop a purely mechanical model for the development of the spongy mesophyll tissue. By stipulating that cell wall growth and remodelling occurs only near void space, our computational model is able to recapitulate spongy mesophyll development observed in Arabidopsis thaliana leaves. We find that robust generation of pore space in the spongy mesophyll requires a balance of cell growth, adhesion, stiffness and tissue pressure to ensure cell networks become porous yet maintain mechanical stability. The success of this mechanical model of morphogenesis suggests that simple physical principles can coordinate and drive the development of complex plant tissues like the spongy mesophyll.

Repeat Epidural Injections of SP-102 (Dexamethasone Sodium Phosphate Injectable Gel) in Subjects with Lumbosacral Radiculopathy.

PURPOSE: SP-102 is a novel epidural steroid injection (ESI) formulation of 10 mg dexamethasone sodium phosphate in a viscous gel solution. Repeat dosing of ESIs is possible if required for pain relief, but with consideration of hypothalamic-pituitary-adrenal (HPA) axis suppression from prolonged systemic exposure. This phase I/II study investigated the effect of initial and repeat SP-102 injections on HPA suppression and analgesia. METHODS: Subjects with lumbosacral radiculopathy received an initial epidural SP-102 injection (T1) on day 1, followed by a repeat injection (T2) on ≥28 days later. To determine HPA suppression, area under the effect curve over 28 days and maximum change from baseline were calculated for cortisol, glucose levels, and white blood cell (WBC) count. Equivalent effect on HPA suppression of T1 relative to T2 was determined if the 90% CIs for ratios of these measures were within 80%-125%. The effect of repeat injections on leg and back pain was also assessed. RESULTS: Based on the responder analysis, all subjects had achieved a cortisol response by day 3 after initial injection and by day 2 after repeat injection. The repeat injection had similar effects on glucose levels and WBC count to the initial injection. Pain scores decreased after each injection and remained low for the 28-day follow-up, with some evidence of improved analgesic effect of the second dose compared with the first. There were no serious adverse events or discontinuations due to adverse events. CONCLUSION: The lack of cumulative effect and rapid resolution of HPA suppression following repeated SP-102 dosing suggests that consideration of HPA pharmacodynamics is not clinically relevant when making decisions regarding repeat dosing. SP-102 ESIs provided prolonged pain relief, with preliminary evidence of greater efficacy after repeat injection. A phase III trial is ongoing. CLINICAL TRIAL IDENTIFIER: ClinicalTrials.gov: NCT03613662.

Wellbeing recovery inequity following the 2010/2011 Canterbury earthquake sequence: repeated cross-sectional studies.

OBJECTIVE: To track population mental wellbeing following the 2010/2011 Christchurch earthquakes and after-shocks. METHODS: The Canterbury Wellbeing Survey, a cross-sectional survey of randomly selected adults aged ≥18 years resident in Christchurch, was repeated biannually from April 2013 until June 2017 and annually thereafter. The self-reported 5-item World Health Organization Well-Being Index (WHO-5) has been elicited from April 2013. Regression analysis was employed to model WHO-5 score patterns over time and between important socio-demographic groups. RESULTS: Between 1,137 and 1,482 adults participated in each survey, totalling 14,100 overall. The mean WHO-5 significantly increased (p<0.001) from 52.4 (95% confidence interval [CI]: 51.1, 53.8) in the April 2013 survey to 60.8 (95%CI: 59.7, 61.9) in the June 2019 survey. A significant and sustained household income group disparity existed (p<0.001), even when adjusting for age, gender and ethnic differences. CONCLUSIONS: The disaster appeared to affect the mental wellbeing of all, and recovery was incremental and prolonged, taking a number of years. Those within the lowest household income group had lower mean WHO-5 scores than their wealthier counterparts at every measured time point. Implications for public health: Recovery takes time, and pre-existing inequities persist despite the implementation of recovery processes aimed at mitigating these risks.

CLASP promotes stable tethering of endoplasmic microtubules to the cell cortex to maintain cytoplasmic stability in Arabidopsis meristematic cells.

Following cytokinesis in plants, Endoplasmic MTs (EMTs) assemble on the nuclear surface, forming a radial network that extends out to the cell cortex, where they attach and incorporate into the cortical microtubule (CMT) array. We found that in these post-cytokinetic cells, the MT-associated protein CLASP is enriched at sites of EMT-cortex attachment, and is required for stable EMT tethering and growth into the cell cortex. Loss of EMT-cortex anchoring in clasp-1 mutants results in destabilized EMT arrays, and is accompanied by enhanced mobility of the cytoplasm, premature vacuolation, and precocious entry into cell elongation phase. Thus, EMTs appear to maintain cells in a meristematic state by providing a structural scaffold that stabilizes the cytoplasm to counteract actomyosin-based cytoplasmic streaming forces, thereby preventing premature establishment of a central vacuole and rapid cell elongation.

The Microtubule-Associated Protein CLASP Sustains Cell Proliferation through a Brassinosteroid Signaling Negative Feedback Loop.

The capacity for sustained cell division within the plant meristem is a critical determinant of organ structure and performance. This capacity is diminished in mutants lacking the microtubule-associated protein CLASP and when brassinosteroid signaling is increased. Here, we discovered that CLASP is both targeted by and promotes activity of the brassinosteroid pathway in Arabidopsis root apical meristems. We show that enhanced brassinosteroid signaling reduces CLASP transcript and protein levels, dramatically shifts microtubule organization, and reduces the number of cells in the meristem. In turn, CLASP, which tethers sorting nexin 1 vesicles to microtubules, sustains brassinosteroid signaling by fostering retrieval of endocytosed BRI1 receptors to the plasma membrane. clasp-1 null mutants have dampened brassinosteroid (BR)-mediated transcriptional activity and responses. Global transcript profiling confirmed the collapse of cell-cycle activity in clasp-1 and identified CLASP-mediated hormone crosstalk. Together, these findings reveal an unprecedented form of negative feedback supporting meristem homeostasis.

Microtubules in Plant Cells: Strategies and Methods for Immunofluorescence, Transmission Electron Microscopy, and Live Cell Imaging.

Microtubules (MTs) are required throughout plant development for a wide variety of processes, and different strategies have evolved to visualize and analyze them. This chapter provides specific methods that can be used to analyze microtubule organization and dynamic properties in plant systems and summarizes the advantages and limitations for each technique. We outline basic methods for preparing samples for immunofluorescence labeling, including an enzyme-based permeabilization method, and a freeze-shattering method, which generates microfractures in the cell wall to provide antibodies access to cells in cuticle-laden aerial organs such as leaves. We discuss current options for live cell imaging of MTs with fluorescently tagged proteins (FPs), and provide chemical fixation, high-pressure freezing/freeze substitution, and post-fixation staining protocols for preserving MTs for transmission electron microscopy and tomography.

Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men.

CONTEXT: Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS. OBJECTIVE: To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations. EVIDENCE ACQUISITION: A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies. EVIDENCE SYNTHESIS: We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes. CONCLUSIONS: Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses. PATIENT SUMMARY: Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations.