Cis- and trans-eQTL TWASs of breast and ovarian cancer identify more than 100 susceptibility genes in the BCAC and OCAC consortia.

Transcriptome-wide association studies (TWASs) have investigated the role of genetically regulated transcriptional activity in the etiologies of breast and ovarian cancer. However, methods performed to date have focused on the regulatory effects of risk-associated SNPs thought to act in cis on a nearby target gene. With growing evidence for distal (trans) regulatory effects of variants on gene expression, we performed TWASs of breast and ovarian cancer using a Bayesian genome-wide TWAS method (BGW-TWAS) that considers effects of both cis- and trans-expression quantitative trait loci (eQTLs). We applied BGW-TWAS to whole-genome and RNA sequencing data in breast and ovarian tissues from the Genotype-Tissue Expression project to train expression imputation models. We applied these models to large-scale GWAS summary statistic data from the Breast Cancer and Ovarian Cancer Association Consortia to identify genes associated with risk of overall breast cancer, non-mucinous epithelial ovarian cancer, and 10 cancer subtypes. We identified 101 genes significantly associated with risk with breast cancer phenotypes and 8 with ovarian phenotypes. These loci include established risk genes and several novel candidate risk loci, such as ACAP3, whose associations are predominantly driven by trans-eQTLs. We replicated several associations using summary statistics from an independent GWAS of these cancer phenotypes. We further used genotype and expression data in normal and tumor breast tissue from the Cancer Genome Atlas to examine the performance of our trained expression imputation models. This work represents an in-depth look into the role of trans eQTLs in the complex molecular mechanisms underlying these diseases.

Legacy of a magic gene-CCR5-∆32: From discovery to clinical benefit in a generation.

The discovery of the 32-bp deletion allele of the chemokine receptor gene CCR5 showed that homozygous carriers display near-complete resistance to HIV infection, irrespective of exposure. Algorithms of molecular evolutionary theory suggested that the CCR5-∆32 mutation occurred but once in the last millennium and rose by strong selective pressure relatively recently to a ~10% allele frequency in Europeans. Several lines of evidence support the hypothesis that CCR5-∆32 was selected due to its protective influence to resist Yersinia pestis, the agent of the Black Death/bubonic plague of the 14th century. Powerful anti-AIDS entry inhibitors targeting CCR5 were developed as a treatment for HIV patients, particularly those whose systems had developed resistance to powerful anti-retroviral therapies. Homozygous CCR5-∆32/∆32 stem cell transplant donors were used to produce HIV-cleared AIDS patients in at least five "cures" of HIV infection. CCR5 has also been implicated in regulating infection with Staphylococcus aureus, in recovery from stroke, and in ablation of the fatal graft versus host disease (GVHD) in cancer transplant patients. While homozygous CCR5-∆32/32 carriers block HIV infection, alternatively they display an increased risk for encephalomyelitis and death when infected with the West Nile virus.

Precision Approaches to Chronic Obstructive Pulmonary Disease Management.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. COPD heterogeneity has hampered progress in developing pharmacotherapies that affect disease progression. This issue can be addressed by precision medicine approaches, which focus on understanding an individual's disease risk, and tailoring management based on pathobiology, environmental exposures, and psychosocial issues. There is an urgent need to identify COPD patients at high risk for poor outcomes and to understand at a mechanistic level why certain individuals are at high risk. Genetics, omics, and network analytic techniques have started to dissect COPD heterogeneity and identify patients with specific pathobiology. Drug repurposing approaches based on biomarkers of specific inflammatory processes (i.e., type 2 inflammation) are promising. As larger data sets, additional omics, and new analytical approaches become available, there will be enormous opportunities to identify high-risk individuals and treat COPD patients based on their specific pathophysiological derangements. These approaches show great promise for risk stratification, early intervention, drug repurposing, and developing novel therapeutic approaches for COPD.

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects.

Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.

Using genetic association data to guide drug discovery and development: Review of methods and applications.

Evidence on the validity of drug targets from randomized trials is reliable but typically expensive and slow to obtain. In contrast, evidence from conventional observational epidemiological studies is less reliable because of the potential for bias from confounding and reverse causation. Mendelian randomization is a quasi-experimental approach analogous to a randomized trial that exploits naturally occurring randomization in the transmission of genetic variants. In Mendelian randomization, genetic variants that can be regarded as proxies for an intervention on the proposed drug target are leveraged as instrumental variables to investigate potential effects on biomarkers and disease outcomes in large-scale observational datasets. This approach can be implemented rapidly for a range of drug targets to provide evidence on their effects and thus inform on their priority for further investigation. In this review, we present statistical methods and their applications to showcase the diverse opportunities for applying Mendelian randomization in guiding clinical development efforts, thus enabling interventions to target the right mechanism in the right population group at the right time. These methods can inform investigators on the mechanisms underlying drug effects, their related biomarkers, implications for the timing of interventions, and the population subgroups that stand to gain the most benefit. Most methods can be implemented with publicly available data on summarized genetic associations with traits and diseases, meaning that the only major limitations to their usage are the availability of appropriately powered studies for the exposure and outcome and the existence of a suitable genetic proxy for the proposed intervention.

A joint transcriptome-wide association study across multiple tissues identifies candidate breast cancer susceptibility genes.

Genome-wide association studies (GWASs) have identified more than 200 genomic loci for breast cancer risk, but specific causal genes in most of these loci have not been identified. In fact, transcriptome-wide association studies (TWASs) of breast cancer performed using gene expression prediction models trained in breast tissue have yet to clearly identify most target genes. To identify candidate genes, we performed a GWAS analysis in a breast cancer dataset from UK Biobank (UKB) and combined the results with the GWAS results of the Breast Cancer Association Consortium (BCAC) by a meta-analysis. Using the summary statistics from the meta-analysis, we performed a joint TWAS analysis that combined TWAS signals from multiple tissues. We used expression prediction models trained in 11 tissues that are potentially relevant to breast cancer from the Genotype-Tissue Expression (GTEx) data. In the GWAS analysis, we identified eight loci distinct from those reported previously. In the TWAS analysis, we identified 309 genes at 108 genomic loci to be significantly associated with breast cancer at the Bonferroni threshold. Of these, 17 genes were located in eight regions that were at least 1 Mb away from published GWAS hits. The remaining TWAS-significant genes were located in 100 known genomic loci from previous GWASs of breast cancer. We found that 21 genes located in known GWAS loci remained statistically significant after conditioning on previous GWAS index variants. Our study provides insights into breast cancer genetics through mapping candidate target genes in a large proportion of known GWAS loci and discovering multiple new loci.

Combining evidence from Mendelian randomization and colocalization: Review and comparison of approaches.

Mendelian randomization and colocalization are two statistical approaches that can be applied to summarized data from genome-wide association studies (GWASs) to understand relationships between traits and diseases. However, despite similarities in scope, they are different in their objectives, implementation, and interpretation, in part because they were developed to serve different scientific communities. Mendelian randomization assesses whether genetic predictors of an exposure are associated with the outcome and interprets an association as evidence that the exposure has a causal effect on the outcome, whereas colocalization assesses whether two traits are affected by the same or distinct causal variants. When considering genetic variants in a single genetic region, both approaches can be performed. While a positive colocalization finding typically implies a non-zero Mendelian randomization estimate, the reverse is not generally true: there are several scenarios which would lead to a non-zero Mendelian randomization estimate but lack evidence for colocalization. These include the existence of distinct but correlated causal variants for the exposure and outcome, which would violate the Mendelian randomization assumptions, and a lack of strong associations with the outcome. As colocalization was developed in the GWAS tradition, typically evidence for colocalization is concluded only when there is strong evidence for associations with both traits. In contrast, a non-zero estimate from Mendelian randomization can be obtained despite only nominally significant genetic associations with the outcome at the locus. In this review, we discuss how the two approaches can provide complementary information on potential therapeutic targets.

Harnessing tissue-specific genetic variation to dissect putative causal pathways between body mass index and cardiometabolic phenotypes.

Body mass index (BMI) is a complex disease risk factor known to be influenced by genes acting via both metabolic pathways and appetite regulation. In this study, we aimed to gain insight into the phenotypic consequences of BMI-associated genetic variants, which may be mediated by their expression in different tissues. First, we harnessed meta-analyzed gene expression datasets derived from subcutaneous adipose (n = 1257) and brain (n = 1194) tissue to identify 86 and 140 loci, respectively, which provided evidence of genetic colocalization with BMI. These two sets of tissue-partitioned loci had differential effects with respect to waist-to-hip ratio, suggesting that the way they influence fat distribution might vary despite their having very similar average magnitudes of effect on BMI itself (adipose = 0.0148 and brain = 0.0149 standard deviation change in BMI per effect allele). For instance, BMI-associated variants colocalized with TBX15 expression in adipose tissue (posterior probability [PPA] = 0.97), but not when we used TBX15 expression data derived from brain tissue (PPA = 0.04) This gene putatively influences BMI via its role in skeletal development. Conversely, there were loci where BMI-associated variants provided evidence of colocalization with gene expression in brain tissue (e.g., NEGR1, PPA = 0.93), but not when we used data derived from adipose tissue, suggesting that these genes might be more likely to influence BMI via energy balance. Leveraging these tissue-partitioned variant sets through a multivariable Mendelian randomization framework provided strong evidence that the brain-tissue-derived variants are predominantly responsible for driving the genetically predicted effects of BMI on cardiovascular-disease endpoints (e.g., coronary artery disease: odds ratio = 1.05, 95% confidence interval = 1.04-1.07, p = 4.67 × 10-14). In contrast, our analyses suggested that the adipose tissue variants might predominantly be responsible for the underlying relationship between BMI and measures of cardiac function, such as left ventricular stroke volume (beta = 0.21, 95% confidence interval = 0.09-0.32, p = 6.43 × 10-4).

Shared genetic effect of kidney function on bipolar and major depressive disorders: a large-scale genome-wide cross-trait analysis.

BACKGROUND: Epidemiological studies have revealed a significant association between impaired kidney function and certain mental disorders, particularly bipolar disorder (BIP) and major depressive disorder (MDD). However, the evidence regarding shared genetics and causality is limited due to residual confounding and reverse causation. METHODS: In this study, we conducted a large-scale genome-wide cross-trait association study to investigate the genetic overlap between 5 kidney function biomarkers (eGFRcrea, eGFRcys, blood urea nitrogen (BUN), serum urate, and UACR) and 2 mental disorders (MDD, BIP). Summary-level data of European ancestry were extracted from UK Biobank, Chronic Kidney Disease Genetics Consortium, and Psychiatric Genomics Consortium. RESULTS: Using LD score regression, we found moderate but significant genetic correlations between kidney function biomarker traits on BIP and MDD. Cross-trait meta-analysis identified 1 to 19 independent significant loci that were found shared among 10 pairs of 5 kidney function biomarkers traits and 2 mental disorders. Among them, 3 novel genes: SUFU, IBSP, and PTPRJ, were also identified in transcriptome-wide association study analysis (TWAS), most of which were observed in the nervous and digestive systems (FDR < 0.05). Pathway analysis showed the immune system could play a role between kidney function biomarkers and mental disorders. Bidirectional mendelian randomization analysis suggested a potential causal relationship of kidney function biomarkers on BIP and MDD. CONCLUSIONS: In conclusion, the study demonstrated that both BIP and MDD shared genetic architecture with kidney function biomarkers, providing new insights into their genetic architectures and suggesting that larger GWASs are warranted.

Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades.

Hearing loss is a clinically and genetically heterogeneous disorder, with over 148 genes and 170 loci associated with its pathogenesis. The spectrum and frequency of causal variants vary across different genetic ancestries and are more prevalent in populations that practice consanguineous marriages. Pakistan has a rich history of autosomal recessive gene discovery related to non-syndromic hearing loss. Since the first linkage analysis with a Pakistani family that led to the mapping of the DFNB1 locus on chromosome 13, 51 genes associated with this disorder have been identified in this population. Among these, 13 of the most prevalent genes, namely CDH23, CIB2, CLDN14, GJB2, HGF, MARVELD2, MYO7A, MYO15A, MSRB3, OTOF, SLC26A4, TMC1 and TMPRSS3, account for more than half of all cases of profound hearing loss, while the prevalence of other genes is less than 2% individually. In this review, we discuss the most common autosomal recessive non-syndromic hearing loss genes in Pakistani individuals as well as the genetic mapping and sequencing approaches used to discover them. Furthermore, we identified enriched gene ontology terms and common pathways involved in these 51 autosomal recessive non-syndromic hearing loss genes to gain a better understanding of the underlying mechanisms. Establishing a molecular understanding of the disorder may aid in reducing its future prevalence by enabling timely diagnostics and genetic counselling, leading to more effective clinical management and treatments of hearing loss.

Comparison of caffeine consumption behavior with plasma caffeine levels as exposure measures in drug-target Mendelian randomization.

Mendelian randomization is an epidemiological technique that can explore the potential effect of perturbing a pharmacological target. Plasma caffeine levels can be used as a biomarker to measure the pharmacological effects of caffeine. Alternatively, this can be assessed using a behavioral proxy, such as average number of caffeinated drinks consumed per day. Either variable can be used as the exposure in a Mendelian randomization investigation, and to select which genetic variants to use as instrumental variables. Another possibility is to choose variants in gene regions with known biological relevance to caffeine level regulation. These choices affect the causal question that is being addressed by the analysis, and the validity of the analysis assumptions. Further, even when using the same genetic variants, the sign of Mendelian randomization estimates (positive or negative) can change depending on the choice of exposure. Some genetic variants that decrease caffeine metabolism associate with higher levels of plasma caffeine, but lower levels of caffeine consumption, as individuals with these variants require less caffeine consumption for the same physiological effect. We explore Mendelian randomization estimates for the effect of caffeine on body mass index, and discuss implications for variant and exposure choice in drug target Mendelian randomization investigations.

A current guide to candidate gene association studies.

Important factors contribute to a gained momentum in candidate gene association studies (CGASs), including the generalized use of next-generation sequencing (NGS), growing opportunities for hospital-based research, and the availability of open-source databases and bioinformatics tools. This article summarizes the general principles and analytical methods as a guide to CGASs in today's favorable context.

Heritability and genetic correlations of obesity indices and cardiometabolic traits in the Northern Chinese families.

OBJECTIVE: This study aimed to investigate the heritability of various obesity indices and their shared genetic factors with cardiometabolic traits in the Chinese nuclear family. METHODS: A total of 1270 individuals from 538 nuclear families were included in this cross-sectional study. Different indices were used to quantify fat mass and distribution, including body index mass (BMI), visceral fat index (VFI), and body fat percent (BFP). Heritability and genetic correlations for all quantitative traits were estimated using variance component models. The susceptibility-threshold model was utilized to estimate the heritability for binary traits. RESULTS: Heritability estimates for obesity indices were highest for BMI (59%), followed by BFP (49%), and VFI (40%). Heritability estimates for continuous cardiometabolic traits varied from 24% to 50%. All obesity measures exhibited consistently significant positive genetic correlations with blood pressure, fasting blood glucose, and uric acid (rG range: 0.26-0.57). However, diverse genetic correlations between various obesity indices and lipid profiles were observed. Significant genetic correlations were limited to specific pairs: BFP and total cholesterol (rG = 0.24), BFP and low-density lipoprotein cholesterol (rG = 0.25), and VFI and triglyceride (rG = 0.33). CONCLUSION: The genetic overlap between various obesity indices and cardiometabolic traits underscores the importance of pleiotropic genes. Further studies are warranted to investigate specific shared genetic and environmental factors between obesity and cardiometabolic diseases.

Addressing the credibility crisis in Mendelian randomization.

BACKGROUND: Genome-wide association studies have enabled Mendelian randomization analyses to be performed at an industrial scale. Two-sample summary data Mendelian randomization analyses can be performed using publicly available data by anyone who has access to the internet. While this has led to many insightful papers, it has also fuelled an explosion of poor-quality Mendelian randomization publications, which threatens to undermine the credibility of the whole approach. FINDINGS: We detail five pitfalls in conducting a reliable Mendelian randomization investigation: (1) inappropriate research question, (2) inappropriate choice of variants as instruments, (3) insufficient interrogation of findings, (4) inappropriate interpretation of findings, and (5) lack of engagement with previous work. We have provided a brief checklist of key points to consider when performing a Mendelian randomization investigation; this does not replace previous guidance, but highlights critical analysis choices. Journal editors should be able to identify many low-quality submissions and reject papers without requiring peer review. Peer reviewers should focus initially on key indicators of validity; if a paper does not satisfy these, then the paper may be meaningless even if it is technically flawless. CONCLUSIONS: Performing an informative Mendelian randomization investigation requires critical thought and collaboration between different specialties and fields of research.

Genetic evidence for the causal association between type 1 diabetes and the risk of polycystic ovary syndrome.

BACKGROUND: Accumulating observational studies have identified associations between type 1 diabetes (T1D) and polycystic ovary syndrome (PCOS). Still, the evidence about the causal effect of this association is uncertain. METHODS: We performed a two-sample Mendelian randomization (MR) analysis to test for the causal association between T1D and PCOS using data from a large-scale biopsy-confirmed genome-wide association study (GWAS) in European ancestries. We innovatively divided T1D into nine subgroups to be analyzed separately, including: type1 diabetes wide definition, type1 diabetes early onset, type 1 diabetes with coma, type 1 diabetes with ketoacidosis, type 1 diabetes with neurological complications, type 1 diabetes with ophthalmic complications, type 1 diabetes with peripheral circulatory complications, type 1 diabetes with renal complications, and type 1 diabetes with other specified/multiple/unspecified complications. GWAS data for PCOS were obtained from a large-scale GWAS (10,074 cases and 103,164 controls) for primary analysis and the IEU consortium for replication and meta-analysis. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. RESULTS: Following rigorous instrument selection steps, the number of SNPs finally used for T1D nine subgroups varying from 6 to 36 was retained in MR estimation. However, we did not observe evidence of causal association between type 1 diabetes nine subgroups and PCOS using the IVW analysis, MR-Egger regression, and weighted median approaches, and all P values were > 0.05 with ORs near 1. Subsequent replicates and meta-analyses also yielded consistent results. A number of sensitivity analyses also did not reveal heterogeneity and pleiotropy, including Cochran's Q test, MR-Egger intercept test, MR-PRESSO global test, leave-one-out analysis, and funnel plot analysis. CONCLUSION: This is the first MR study to investigate the causal relationship between type 1 diabetes and PCOS. Our findings failed to find substantial causal effect of type 1 diabetes on risk of PCOS. Further randomized controlled studies and MR studies are necessary.

Mendelian randomization analysis of maternal coffee consumption during pregnancy on offspring neurodevelopmental difficulties in the Norwegian Mother, Father and Child Cohort Study (MoBa).

BACKGROUND: Previous observational epidemiological studies have suggested that coffee consumption during pregnancy may affect fetal neurodevelopment. However, results are inconsistent and may represent correlational rather than causal relationships. The present study investigated whether maternal coffee consumption was observationally associated and causally related to offspring childhood neurodevelopmental difficulties (NDs) in the Norwegian Mother, Father and Child Cohort Study. METHODS: The observational relationships between maternal/paternal coffee consumption (before and during pregnancy) and offspring NDs were assessed using linear regression analyses (N = 58694 mother-child duos; N = 22 576 father-child duos). To investigate potential causal relationships, individual-level (N = 46 245 mother-child duos) and two-sample Mendelian randomization (MR) analyses were conducted using genetic variants previously associated with coffee consumption as instrumental variables. RESULTS: We observed positive associations between maternal coffee consumption and offspring difficulties with social-communication/behavioral flexibility, and inattention/hyperactive-impulsive behavior (multiple testing corrected p < 0.005). Paternal coffee consumption (negative control) was not observationally associated with the outcomes. After adjusting for potential confounders (smoking, alcohol, education and income), the maternal associations attenuated to the null. MR analyses suggested that increased maternal coffee consumption was causally associated with social-communication difficulties (individual-level: beta = 0.128, se = 0.043, p = 0.003; two-sample: beta = 0.348, se = 0.141, p = 0.010). However, individual-level MR analyses that modelled potential pleiotropic pathways found the effect diminished (beta = 0.088, se = 0.049, p = 0.071). Individual-level MR analyses yielded similar estimates (heterogeneity p = 0.619) for the causal effect of coffee consumption on social communication difficulties in maternal coffee consumers (beta = 0.153, se = 0.071, p = 0.032) and non-consumers (beta = 0.107, se = 0.134, p = 0.424). CONCLUSIONS: Together, our results provide little evidence for a causal effect of maternal coffee consumption on offspring NDs.

Does Gastroesophageal Reflux Disease Increase the Risk of Sepsis and Its 28-day Mortality? A Causal Study Using a Mendelian Randomization Approach.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a prevalent gastrointestinal disorder. Recent studies indicate that GERD may exert systemic effects, potentially elevating the risk of severe infections, including sepsis. Nevertheless, the causal relationship between GERD and sepsis, as well as sepsis-related 28-day mortality, remains uncertain. AIM: The aim of this study is to investigate the causal relationship between GERD and the risk of sepsis, including 28-day mortality of sepsis. METHODS: This study utilized a two-sample Mendelian Randomization (MR) approach to analyze data from publicly available genome-wide association studies (GWAS) databases ( https://gwas.mrcieu.ac.uk/ ). The analysis comprised 129,080 cases and 473,524 controls for GERD; 11,643 patients and 474,841 controls for sepsis; and 1,896 patients and 484,588 controls for 28-day mortality from sepsis. The objective was to evaluate the causal impact of GERD on the risk of sepsis and 28-day sepsis mortality. Genetic variation data pertinent to GERD were obtained from the most recent genome-wide association studies (GWAS). The primary analysis employed the Inverse Variance Weighted (IVW) method. Sensitivity and pleiotropy analyses were performed to validate the robustness of the findings. RESULTS: MR analysis revealed a notable link between genetically predicted GERD and increased sepsis risk (odds ratio [OR] 1.37, 95% confidence interval [CI] 1.24-1.52; p = 2.79 × 10-9). Moreover, GERD correlated with elevated 28-day mortality of sepsis (OR 1.44, 95% CI 1.11-1.85; p = 5.34 × 10-3). These results remained consistent throughout various sensitivity analyses, indicating their resilience against potential pleiotropy and other biases. CONCLUSION: This study indicates that genetic predisposition to GERD may be linked to an elevated risk of sepsis and its associated 28-day mortality. However, the study does not establish a direct causal relationship for GERD itself, nor does it assess the impact of GERD treatment. Further research is needed to explore the underlying mechanisms and potential therapeutic interventions involved.

SNP-based heritability and selection analyses: Improved models and new results.

Complex-trait genetics has advanced dramatically through methods to estimate the heritability tagged by SNPs, both genome-wide and in genomic regions of interest such as those defined by functional annotations. The models underlying many of these analyses are inadequate, and consequently many SNP-heritability results published to date are inaccurate. Here, we review the modelling issues, both for analyses based on individual genotype data and association test statistics, highlighting the role of a low-dimensional model for the heritability of each SNP. We use state-of-art models to present updated results about how heritability is distributed with respect to functional annotations in the human genome, and how it varies with allele frequency, which can reflect purifying selection. Our results give finer detail to the picture that has emerged in recent years of complex trait heritability widely dispersed across the genome. Confounding due to population structure remains a problem that summary statistic analyses cannot reliably overcome. Also see the video abstract here: https://youtu.be/WC2u03V65MQ.

Genetic Epidemiology of Alpha-1 Antitrypsin Deficiency in Macaronesia.

INTRODUCTION: The prevalence of alpha-1 antitrypsin deficiency (AATD) in Macaronesia (i.e., Azores, Madeira, Canary Islands, and Cape Verde archipelagos) is poorly known. Our goal was to update it by selecting the most reliable available articles. METHOD: Literature search using MEDLINE, Embase (via Ovid), and Google Scholar, until December 2023, for studies on prevalence of AATD in the general population and in screenings, published in peer-reviewed journals. RESULTS: Three studies carried out in the general population of Madeira, La Palma, and Cape Verde, and three screenings carried out in La Palma (2) and Gran Canaria (1) were selected. The frequencies of PI*S in the general population showed an ascending gradient, from South to North, with values (per thousand) of 35 in Cape Verde, 82 in La Palma, and 180 in Madeira. The PI*Z frequencies showed this same gradient, with values of 2 × 1,000 in Cape Verde, 21 in La Palma, and 25 in Madeira. Screenings detected high percentages of defective alleles, including several rare and null alleles, some unique to these islands. CONCLUSION: The frequencies of PI*S and PI*Z in Madeira are comparable to the highest in the world. Those of the Canary Islands are similar to those of the peninsular population of Spain, and contrast with the low rates of Cape Verde. Screenings detected high numbers of deficient alleles. These results support the systematic investigation of AATD in clinically suspected patients and in relatives of index cases, to reduce underdiagnosis and apply early preventive and therapeutic measures in those affected.

Mendelian randomization study of urolithiasis: exploration of risk factors using human blood metabolites.

BACKGROUND: Urolithiasis is a highly prevalent global disease closely associated with metabolic factors; however, the causal relationship between blood metabolites and urolithiasis remains poorly understood. METHOD: In our study, we employed a bi-directional two-sample Mendelian randomization (MR) analysis to investigate the causal associations between urolithiasis and metabolites. The random-effects inverse-variance weighted (IVW) estimation method was utilized as the primary approach, complemented by several other estimators including MR-Egger, weighted median, colocalization and MR-PRESSO. Furthermore, the study included replication and meta-analysis. Finally, we conducted metabolic pathway analysis to elucidate potential metabolic pathways. RESULTS: After conducting multiple tests for correction, glycerol might contribute to the urolithiasis and dehydroisoandrosterone sulfate (DHEA-S) might inhibit this process. Furthermore, several blood metabolites had shown potential associations with a causal relationship. Among the protective metabolites were lipids (dehydroisoandrosterone sulfate and 1-stearoylglycerol (1-monostearin)), amino acids (isobutyrylcarnitine and 2-aminobutyrate), a keto acid (acetoacetate) and a carbohydrate (mannose). The risk metabolites included lipids (1-palmitoylglycerophosphoethanolamine, glycerol and cortisone), a carbohydrate (erythronate), a peptide (pro-hydroxy-pro) and a fatty acid (eicosenoate). In reverse MR analysis, urolithiasis demonstrated a statistically significant causal relationship with butyrylcarnitine, 3-methyl-2-oxobutyrate, scyllo-inositol, leucylleucine and leucylalanine. However, it was worth noting that none of the blood metabolites exhibited statistical significance after multiple corrections. Additionally, we identified one metabolic pathway associated with urolithiasis. CONCLUSION: The results we obtained demonstrate the causal relevance between two metabolites and urolithiasis, as well as identify one metabolic pathway potentially associated with its development. Given the high prevalence of urolithiasis, further investigations are encouraged to elucidate the mechanisms of these metabolites and explore novel therapeutic strategies.