Inverse-variance Weighted Mendelian Randomization Research Articles

Genetic proxy of lipid-lowering drugs and calcific aortic valve stenosis: A Mendelian randomization study

BackgroundLipid metabolism plays an important role in the pathogenesis and development of calcific aortic valve stenosis. Our aim was to evaluate the causal effect of lipid-lowering drugs, such as low-density lipoprotein cholesterol (LDL-C) lowering and triglyceride lowering drugs, on the outcome of aortic valve stenosis using a two-sample Mendelian randomization (MR) study. MethodsWe used two genetic tools to represent the exposure of lipid-lowering drugs, including expression quantitative trait loci for the expression of drug target genes, and genetic variants within or near drug target genes that are associated with LDL-C and triglyceride concentrations from Genome-Wide Association Studies (GWAS). Effect estimates were calculated using summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis. ResultsBased on the results of SMR and IVW-MR analysis, LDL-C-lowering PCSK9 inhibitors have potential in reducing the risk of aortic valve stenosis (for SMR, OR: 1.044; 95%CI: 1.002–1.404; P = 0.047; for IVW-MR, OR: 1.647, 95%CI: 1.316–2.062, P < 0.001). However, no significant association was observed between triglyceride target gene expression, as well as triglyceride-lowering drugs, and aortic valve stenosis. ConclusionThis two-sample drug-targeted MR study suggests a potential causal relationship between PCSK9 inhibitors and the reduction of calcific aortic valve stenosis risk.

Association of lipid-lowering drug targets with risk of cutaneous melanoma: a mendelian randomization study

BackgroundMelanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies.MethodThis study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs.ResultsOur findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08–1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10–2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses.ConclusionThe study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.

Genetic Association between Lipid-Regulating Drug Targets and Diabetic Retinopathy: A Drug Target Mendelian Randomization Study.

Diabetic retinopathy (DR) is a diabetic microvascular complication and a leading cause of vision loss. However, there is a lack of effective strategies to reduce the risk of DR currently. The present study is aimed at assessing the causal effect of lipid-regulating targets on DR risk using a two-sample Mendelian randomization (MR) study. Genetic variants within or near drug target genes, including eight lipid-regulating targets for LDL-C (HMGCR, PCSK9, and NPC1L1), HDL-C (CETP, SCARB1, and PPARG), and TG (PPARA and LPL), were selected as exposures. The exposure data were obtained from the IEU OpenGWAS project. The outcome dataset related to DR was obtained from the FinnGen research project. Inverse-variance-weighted MR (IVW-MR) was used to calculate the effect estimates by each target. Sensitivity analyses were performed to verify the robustness of the results. There was suggestive evidence that PCSK9-mediated LDL-C levels were positively associated with DR, with OR (95% CI) of 1.34 (1.02-1.77). No significant association was found between the expression of HMGCR- and NPC1L1-mediated LDL-C levels; CETP-, SCARB1-, and PPARG-mediated HDL-C levels; PPARA- and LPL-mediated TG levels; and DR risk. This is the first study to reveal a genetically causal relationship between lipid-regulating drug targets and DR risk. PCSK9-mediated LDL-C levels maybe positively associated with DR risk at the genetic level. This study provides suggestive evidence that PCSK9 inhibition may reduce the risk of DR.

Statins as a risk factor for diabetic retinopathy: a Mendelian randomization and cross-sectional observational study

BackgroundDiabetic retinopathy (DR) is the foremost cause of vision loss among the global working-age population, and statins are among the most frequently prescribed drugs for lipid management in patients with DR. The exact relationship between statins and DR has not been determined. This study sought to validate the causal association between statins usage and diabetic retinopathy.MethodsThe summary-data-based Mendelian randomization (SMR) method and inverse-variance-weighted Mendelian randomization (IVW-MR) were used to identify the causal relationship between statins and DR via the use of expression quantitative trait loci (eQTL) data for 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) (31,684 blood samples), low density lipoprotein cholesterol-related GWAS data (sample size: 440,546), and DR-related GWAS data (14,584 cases and 176,010 controls). Additionally, a cross-sectional observational study based on the data from the National Health and Nutrition Examination Survey (NHANES) was conducted to supplement the association between DR and statins (sample size: 106,911). The odds ratios (ORs) with corresponding 95% confidence intervals (CIs) was employed to evaluate the results.ResultsBased on the results of the MR analysis, HMGCR inhibitors were causally connected with a noticeably greater incidence of DR (IVW: OR = 0.54, 95% CI [0.42, 0.69], p = 0.000002; SMR: OR = 0.66, 95% CI [0.52, 0.84], p = 0.00073). Subgroup analysis revealed that the results were not affected by the severity of DR. The sensitivity analysis revealed the stability and reliability of the MR analysis results. The results from the cross-sectional study based on NHANES also support the association between not taking statins and a decreased risk of DR (OR = 0.54, 95% CI [0.37, 0.79], p = 0.001).ConclusionsThis study revealed that a significant increase in DR risk was causally related to statins use, providing novel insights into the role of statins in DR. However, further investigations are needed to verify these findings.

Association between oxidative stress and chronic orofacial pain and potential druggable targets: Evidence from a Mendelian randomization study.

Oxidative stress indicators affect chronic orofacial pain (COFP), but how to reduce these effects is uncertain. 11 oxidative stress biomarkers were collected as exposures, while four forms of COFP were chosen as outcomes for Mendelian randomization (MR) study. The effect estimates between oxidative stress and COFP were calculated using inverse variance-weighted MR (IVW-MR). Then, functional mapping and annotation (FUMA) was utilized in order to carry out SNP-based functional enrichment analyses. In addition, the IVW-MR method was applied to combine effect estimates when using genetic variants associated with oxidative stress biomarkers as an instrument for exploring potential druggable targets. The results indicated that oxidative stress biomarkers (causal OR of uric acid (UA), 0.998 for myofascial pain, 95% CI 0.996-1.000, p < .05; and OR of glutathione transferase (GST), 1.002 for dentoalveolar pain, 95% CI 1.000-1.003, p < .05) were significantly linked with the probability of COFP. Functional analysis also demonstrated that UA and myofascial pain genes were prominent in nitrogen and uracil metabolism, while GST and dentoalveolar pain genes were enriched in glutathione metabolism. Also, the study provided evidence that solute carrier family 2 member 9 (SLC2A9) and glutathione S-transferase alpha 2 (GSTA2) cause discomfort in the myofascial pain (OR = 1.003, 95% CI 1.000-1.006; p < .05) and dentoalveolar region (OR = 1.001, 95% CI 1.000-1.002; p < .05), respectively. In conclusion, this MR study indicates that genetically predicted myofascial pain was significantly associated with decreased UA and dentoalveolar pain was significantly associated with increased GST level. SLC2A9 inhibitor and GSTA2 inhibitor were novel chronic orofacial pain therapies and biomarkers, but clinical trials are called to examine if these oxidative biomarkers have the protective effect against orofacial pain, and further research are needed to explore the underlying mechanisms.

Genetic insights into repurposing statins for hyperthyroidism prevention: a drug-target Mendelian randomization study.

Current therapeutic measures for thyroid dysfunction are limited and often accompanied by adverse effects. The use of lipid-lowering drugs like statins has recently been associated with lower thyroid eye diseases risk. To investigate the implications of genetically proxied lipid-lowering drugs on thyroid dysfunction. In this drug-target Mendelian randomization (MR) study, we utilized genetic variants within drug target genes associated with low-density lipoprotein (LDL) or triglyceride (TG), derived from a genome-wide association study (GWAS) meta-analysis (N ≤ 188,577), to simulate lifelong drug interventions. Genetic summary statistics for thyroid dysfunction outcomes were retrieved from GWAS datasets of Thyroid Omics Consortium (N ≤ 54,288) and UK Biobank (N = 484,598). Inverse-variance-weighted MR (IVW-MR) method was performed as primary analysis, followed by validation in colocalization analysis. A subsequent two-step MR analysis was conducted to identify biomarkers mediating the identified drug-outcome association. In IVW-MR analysis, genetic mimicry of 3-hydroxy-3-methylglutarylcoenzyme reductase (HMGCR) inhibitors (e.g. statins) was significantly associated with lower risk of hyperthyroidism in two independent datasets (OR1, 0.417 per 1-mmol/L lower in LDL-C; 95% CI 0.262 to 0.664; P1=2.262 × 10-4; OR2 0.996; 95% CI 0.993-0.998; P2=0.002). Two-step MR analysis revealed eighteen biomarkers linked to genetic mimicry of HMGCR inhibition, and identified insulin-like growth factor 1 (IGF-1) levels mediating 2.108% of the negative causal relationship between HMGCR inhibition and hyperthyroidism. This study supports HMGCR inhibition as a promising therapeutic strategy for hyperthyroidism and suggests its underlying mechanisms may extend beyond lipid metabolism. Further investigations through laboratory studies and clinical trials are necessary to confirm and elucidate these findings.

Circadian clock-related genome-wide mendelian randomization identifies putatively genes for ulcerative colitis and its comorbidity

BackgroundCircadian rhythm is crucial to the function of the immune system. Disorders of the circadian rhythm can contribute to inflammatory diseases such as Ulcerative colitis (UC). This Mendelian Randomization (MR) analysis applies genetic tools to represent the aggregated statistical results of exposure to circadian rhythm disorders and UC and its comorbidities, allowing for causal inferences.MethodsSummary statistics of protein, DNA methylation and gene expression quantitative trait loci in individuals of European ancestry (pQTL, mQTL, and eQTL, respectively) were used. Genetic variants located within or near 152 circadian clock-related genes and closely related to circadian rhythm disorders were selected as instrumental variables. Causal relationships with UC and its comorbidities were then estimated through employed Summary data-based Mendelian Randomization (SMR) and Inverse-Variance-Weighted MR (IVW-MR).ResultsThrough preliminary SMR analysis, we identified a potential causal relationship between circadian clock-related genes and UC along with its comorbidities, which was further confirmed by IVW-MR analysis. Our study identified strong evidence of positive correlation involving seven overlapping genes (CSNK1E, OPRL1, PIWIL2, RORC, MAX, PPP5C, and AANAT) through MWAS and TWAS in UC, four overlapping genes (OPRL1, CHRNB2, FBXL17, and SIRT1) in UC with PSC, and three overlapping genes (ARNTL, USP7, and KRAS) in UC with arthropathy.ConclusionsThis SMR study demonstrates the causal effect of circadian rhythm disorders in UC and its comorbidities. Furthermore, our investigation pinpointed candidate genes that could potentially serve as drug targets.

The Causal Association Between Medication Intake and Increased Risk of Psoriasis.

Psoriasis is a chronic, inflammatory, and papulo-squamous skin disorder without a radical cure. Although previous observational analyses have discovered a relationship between medication intake and increased risk of psoriasis, they are susceptible to confounders. We intend to ascertain if there is a causal association between specific medication intake and increased risk of psoriasis by utilizing the Mendelian randomization (MR) method. We obtained the genome-wide association study (GWAS) data for medication intake (23 types, N = 1809) from UK Biobank samples. And we sourced the GWAS data for psoriasis from the 8th release of the FinnGen database, which included 8,075 psoriasis cases and 330,975 healthy control cases. Then a two-sample MR study was performed to determine their causal association, and inverse-variance-weighted MR (IVW-MR) was applied to calculate the effect estimates. The IVW-MR analysis uncovered a positive correlation between the intake of HMG CoA reductase inhibitors and the increased risk of psoriasis (odds ratio [OR] = 1.167, 95% confidence interval [CI] = 1.084-1.257). Similarly, the use of thyroid preparations (OR=1.080, 95% CI=1.026-1.138), nonsteroidal anti-inflammatory and antirheumatic products (OR=1.406, 95% CI=1.037-1.908), anilides (OR=1.379, 95% CI=1.004-1.894), antihistamines for systemic use (OR=1.341, 95% CI=1.104-1.630), and antihypertensives (OR=1.099, 95% CI=1.016-1.190) were associated with an increased risk of psoriasis. We did not find evidence from IVW-MR for other associations. Our study offers a causal testimony that the intake of HMG CoA reductase inhibitors, thyroid preparations, nonsteroidal anti-inflammatory and antirheumatic products, anilides, antihistamines for systemic use, and antihypertensives will potentially increase the risk of psoriasis.

Genetic Association of Lipids and Lipid-Lowering Drug Target Genes With Attention Deficit Hyperactivity Disorder.

Lipid metabolism plays an essential role in nervous system development. Cholesterol deficiency leads to a variety of neurodevelopmental disorders, such as autism spectrum disorder and fragile X syndrome. There have been a lot of efforts to search for biological markers associated with and causal to ADHD, among which lipid is one possible etiological factor that is quite widely studied. We aimed to evaluate the causal relationship between lipids traits, lipid-lowering drugs, and attention deficit hyperactivity disorder (ADHD) outcomes using Mendelian randomization (MR) studies. We used summary data from genome-wide association studies to explore the causal relationships between circulating lipid-related traits and ADHD. Then, quantitative trait loci for the expression of lipid-lowering drug target genes and genetic variants associated with lipid traits were extracted. Summary-data-based MR and inverse-variance-weighted MR (IVW-MR) were used to investigate the correlation between the expression of these drug-target genes and ADHD. After rigorous screening, 939 instrumental variables were finally included for univariable mendelian randomization analysis. However, there is no correlation between lipid profile and ADHD risk. Drug target analysis by IVW-MR method observed that APOB-mediated low-density lipoprotein cholesterol was associated with lower ADHD risk (odds ratio [OR] = 0.90, 95% confidence interval [CI] [0.84, 0.97]; p = .007), whereas LPL-mediated triglycerides levels were associated with a higher risk of ADHD (OR = 1.13, 95% CI [1.06, 1.21]; p < .001). Our results suggest that APOB gene and LPL gene may be candidate drug target genes for the treatment of ADHD.

Association of high LDL concentrations with erectile dysfunction from a Mendelian randomization study

Lipid metabolism plays a key role in erectile dysfunction. Our purpose was to evaluate the influence of lipid-lowering drugs on erectile dysfunction employing a two-sample Mendelian randomization (MR) study. Genetic instruments were employed to represent the exposure of lipid-lowering drugs. Inverse variance-weighted MR (IVWMR) was employed to calculate the estimation of effects. IVW-MR analysis showed that the positive relationship between the expression of HMGCR and the risk of erectile dysfunction (odds ratio [OR] = 1.27, 95% confidence interval [CI] 1.03–1.57; p = 0.028). No significant relationship was detected between NPC1L1, PSK9 expression and erectile dysfunction. This MR study suggested that HMGCR inhibitors are a more desirable treatment modality for patients with ED.

Association between antihypertensive drugs and oral cancer: a drug target Mendelian randomization study

Background: Recent reports have suggested that antihypertensive drugs may play an oncogenic role in common cancers, but it is still uncertain whether this could influence the risk of oral cancer. Through two-sample Mendelian randomization (MR), we sought to assess the causal effect of antihypertensive drugs on oral cancer outcomes.Methods: To proxy the exposure of antihypertensive drugs, we utilized two genetic instruments, including expression quantitative trait loci of drug target genes and genetic variants within or around drug target genes related to blood pressure from genome-wide association studies. Inverse-variance-weighted MR (IVW-MR) and summary-data-based MR (SMR) were employed to compute the instrument effect estimates.Results: It was observed through IVW-MR analysis that there is a positive relationship between KCNH2 (target of beta-adrenoceptor blockers)–mediated blood pressure and oral cancer (odds ratio [OR] = 1.197, 95% confidence interval [CI] = 1.028–1.394). Similarly, SMR analysis demonstrated that a higher expression of KCNH2 (target of beta-adrenoceptor blockers) was linked to a greater risk of oral cancer (OR = 2.223, 95% CI = 1.094–4.516). Both analyses yielded no consistent evidence of other associations.Conclusion: This two-sample MR study proposed a latent causal association between KCNH2 (target of beta-adrenoceptor blockers) inhibition and diminished risk of oral cancer.

Abstract 12098: Evaluation of Inflammatory Biomarkers and Causal Association With Abdominal Aortic Aneurysm Development

Introduction: Observational analyses have linked circulating inflammatory biomarkers with an increased risk of abdominal aortic aneurysms (AAA). Although observational studies implicate inflammatory biomarkers in AAA, whether these are a cause or consequence of the disease is unknown. A limited number of trials have explored agents that reduce inflammation in slowing the progression of AAA. Observational study quality may be limited by residual confounding and reverse causality. We sought to leverage genetic instruments and Mendelian Randomization (MR) to evaluate the human genetic evidence supporting inflammatory biomarkers in the pathogenesis of AAA. Methods: We leveraged a meta-analysis of 6 genome-wide association studies (GWAS) of 66 circulating inflammatory markers including up to 59,969 participants of European ancestry. We tested the association for each biomarker with AAA using summary statistics from a meta-analysis of 17 individual GWAS from 14 discovery cohorts in the AAAgen consortium comprising 39,221 individuals with AAA. We employed Wald ratio or inverse-variance weighted MR; weighted median and weighted mode methods were applied as sensitivity analyses. Results: After accounting for multiple testing by controlling the false discovery rate (q &lt; 0.05), we identified a total of 6/66 (9.1%) inflammatory biomarkers that had a significant association with AAA: sIL6R, CCL8, CCL7, ILRN, F2, and PIGF. These results were consistent across a range of linkage-disequilibrium thresholds to identify independent genetic instruments. Some of these biomarkers have been previously implicated in the development of AAA but have not been validated in human RCTs of aneurysm development, growth, or rupture. Conclusions: This analysis highlights the role of several circulating inflammatory markers in the development of AAA. These findings represent potential therapeutic targets for further investigation in mechanistic trials.

Genetic variation in targets of lipid-lowering drugs and amyotrophic lateral sclerosis risk: a Mendelian randomization study

Background The use of lipid-lowering drugs is still highly controversial in patients with amyotrophic lateral sclerosis (ALS). We performed a drug-target Mendelian randomization (MR) analysis to investigate the effect of targeted lipid-lowering drugs on the risk of ALS. Methods First, we evaluated the causal relationship between HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase (HMGCR) inhibitors-taking trait and ALS using a bidirectional two-sample MR study. Second, we investigated the causal relationship between lipid-lowering drugs and ALS through a drug-target MR approach. The summary data for HMGCR inhibitors-taking traits were extracted from a genome-wide association study (GWAS) of medication use and associated disease in the UK Biobank. The summary data for low-density lipoprotein cholesterol and apolipoprotein B (apoB) were extracted from a meta-analysis of GWAS in individuals of European ancestry in the UKB. The GWAS summary data of ALS were obtained from the Project MinE. Results Our bidirectional two-sample MR showed that genetically determined increased HMGCR inhibitors-taking trait was an independent risk factor for ALS (odds ratio [OR] = 1.090, 95% confidence interval [CI] = 1.035–1.150, p = 0.001). The results of drug-target MR showed that the increased expression of the HMGCR gene in blood with the higher risk of ALS (OR = 1.21, 95% CI = 1.01–1.46; p = 0.042) through SMR method and the apoB level mediated by the APOB gene increased the risk of ALS (OR = 1.15; 95% CI =1.05–1.25; p = 0.001) through inverse-variance weighted MR method. Conclusion This present study provides genetic support for a positive causal effect of HMGCR inhibitors-taking trait and ALS. The reason for this may be due to the underlying disease condition behind the medication, rather than the medication itself. Our findings also suggested that HMGCR and apoB inhibitors may have potential protective effects on ALS.

TNF inhibitors associated with cardiovascular diseases and cardiometabolic risk factors: a Mendelian randomization study.

There is still disagreement about whether anti-tumor necrosis factor (TNF) therapy is beneficial or detrimental to cardiovascular conditions. This two-sample Mendelian randomization (MR) study aimed to evaluate the effects of long-term tumor necrosis factor (TNF) inhibition on cardiovascular diseases (CVDs) and cardiometabolic risk factors via genetically proxied inhibition of tumor necrosis factor receptor 1 (TNFR1) and TNF. Two genetic instruments were examined to mimic the long-term effect of TNF inhibitors. The first were single-nucleotide polymorphisms (SNPs) within or nearby drug-target genes TNFRSF1A and TNF (encoding TNFR1 and TNF) associated with circulating CRP levels. The other instruments were the expression quantitative trait loci (eQTLs) near the genes. Inverse variance-weighted MR (IVW-MR) and summary-based MR (SMR) methods were employed to estimate causal effects. In IVW-MR analysis, TNF-mediated circulating CRP levels were significantly associated with 4 out of 12 CVDs, including hypertension [odds ratio (OR) = 1.13; 95% CI, 1.09-1.18], coronary artery disease (OR = 3.18; 95% CI, 1.77-5.71), coronary atherosclerosis (OR = 1.05; 95% CI, 1.02-1.08) and type 2 diabetes (OR = 3.48; 95% CI, 1.98-6.10). These findings were also validated in the FinnGen study. Moreover, TNF inhibition was also associated with total cholesterol, triglycerides, apolipoprotein B, systolic blood pressure, serum cystatin C, height, weight, and body mass index. In this study, the decrease in several CVDs and cardiometabolic risk factors has been found to be causally associated with genetically proxied TNF inhibitors.

Associations of lipids and lipid-lowering drugs with risk of stroke: a Mendelian randomization study.

Stroke is a leading cause of death worldwide, but it is unclear whether circulating lipids and lipid-lowering drugs are causally associated with stroke and its subtypes. We used two-sample Mendelian randomization (MR) to examine the effects of blood lipids and lipid-lowering drugs on stroke and its subtypes. The inverse variance weighted Mendelian randomization (IVW-MR) revealed the low-density lipoprotein cholesterol (LDL-C) (OR, 1.46; 95% CI, 1.17-1.83; p = 0.0008) and apolipoprotein B (apoB) (OR, 1.46; 95% CI, 1.21-1.77; p = 0.0001) was positively correlated with large artery stroke (LAS). However, no causal effect was found in LDL-C and apoB on LAS risk when we conducted mvMR. The IVW-MR also found a suggestive evidence that decreased LDL-C levels mediated by the PCSK9 (proprotein convertase subtilisin-kexin type 9) gene were associated with a reduced risk of any stroke (AS) (OR, 1.31; 95% CI, 1.13-1.52; p = 0.0003), any ischemic stroke (AIS) (OR, 1.29; 95% CI, 1.10-1.51; p = 0.001), and LAS (OR, 1.73; 95% CI, 1.15-2.59; p = 0.008), while NPC1L1 (Niemann-Pick C1-like protein)-mediated LDL-C levels were associated with a higher risk of small vessel stroke (SVS) (OR, 6.10; 95% CI, 2.13-17.43; p = 0.0008). The SMR revealed that expression of PCSK9 was associated with risk of AS (OR, 1.15; 95% CI, 1.03-1.28; p = 0.01), AIS (OR, 1.02; 95% CI, 1.14-1.29; p = 0.03), cardioembolic stroke (CES) (OR, 1.28; 95% CI, 1.01-1.61; p = 0.04). And, a significant association was found between the expression of NPC1L1 and the risk of SVS (OR, 1.15; 95% CI, 1.00-1.32; p = 0.04). We cautiously find that LDL-C and apoB was positively correlated with LAS. These findings suggest that the reducing LDL-C levels could be an effective prevention strategy for reducing the risk of stroke.

Proteome-Wide Mendelian Randomization Identifies Causal Links Between Blood Proteins and Acute Pancreatitis

Acute pancreatitis (AP) is a complex disease and the leading cause of gastrointestinal disease-related hospital admissions. Few therapeutic options exist for AP prevention. Blood proteins with causal evidence may represent promising drug targets, but few have been causally linked with AP. Our objective was to identify blood proteins linked with AP by combining genome-wide association meta-analysis and proteome-wide Mendelian randomization (MR) studies. We performed a genome-wide association meta-analysis totalling 10,630 patients with AP and 844,679 controls and a series of inverse-variance weighted MR analyses using cis-acting variants on 4719 blood proteins from the deCODE study (N= 35,559) and 4979 blood proteins from the Fenland study (N= 10,708). The meta-analysis identified genome-wide significant variants (P <5× 10-8) at 5 loci (ABCG5/8, TWIST2, SPINK1, PRSS2 and MORC4). The proteome-wide MR analyses identified 68 unique blood proteins that may causally be associated with AP, including 29 proteins validated in both data sets. Functional annotation of these proteins confirmed expression of many proteins in metabolic tissues responsible for digestion and energy metabolism, such as the esophagus, adipose tissue, and liver as well as acinar cells of the pancreas. Genetic colocalization and investigations into the druggable genome also identified potential drug targets for AP. This large genome-wide association study meta-analysis for AP identified new variants linked with AP as well as several blood proteins that may be causally associated with AP. This study provides new information on the genetic architecture of this disease and identified pathways related to AP, which may be further explored as possible therapeutic targets forAP.

Association Between Obesity and Chronic Kidney Disease: Multivariable Mendelian Randomization Analysis and Observational Data From a Bariatric Surgery Cohort.

Obesity is postulated to independently increase chronic kidney disease (CKD), even after adjusting for type 2 diabetes (T2D) and hypertension. Dysglycemia below T2D thresholds, frequently seen with obesity, also increases CKD risk. Whether obesity increases CKD independent of dysglycemia and hypertension is unknown and likely influences the optimal weight loss (WL) needed to reduce CKD. T2D remission rates plateaus with 20-25%WL postbariatric surgery (BS) but further WL increases normoglycemia/normotension. We undertook bidirectional inverse variance weighted Mendelian randomization (IVMR) to investigate potential independent causal associations between increased BMI and CKDeGFR (estimated glomerular filtration rate, eGFR < 60 ml/min1.73m2) and microalbuminuria (MA). In 5337 BS patients, we assessed whether WL influences >50% decline in eGFR (primary outcome) or CKD hospitalization (secondary outcome) using <20% WL as a comparator. IVWMR suggests increased BMI increases CKDeGFR (beta=0.13, p=1.64x10-4), Odds ratio, OR (95% confidence interval, CI)=1.14(1.07-1.23) and MA (b=0.25, p=2.14 x 10-4,OR(95%CI)=1.29(1.13-1.48). After adjusting for hypertension and fasting glucose, increased BMI did not significantly increase CKDeGFR (b=-0.02, p=0.72), OR(95%CI)=0.98(0.87-1.1) or MA (b=0.19, p=0.08, OR (95%CI)=1.21 (0.98, 1.51). Post-BS WL significantly reduced the primary outcome with 30-<40%WL (Hazard ratio HR=0.53, 95%CI=0.32-0.87), but not 20-<30%WL (HR=0.72, 95%CI=0.44-1.2) and ≥40%WL (HR=0.73, 95%CI=0.41-1.30). For CKD hospitalization, progressive reduction was seen with increased WL which was significant for 30-<40%WL (HR=0.37, 95%CI=0.17-0.82) and ≥40%WL (HR=0.24, 95%CI=0.07-0.89), but not 20-30%WL (HR=0.60, 95%CI=0.29-1.23). The data suggests obesity is likely not an independent cause of CKD. WL thresholds previously associated with normotension and normoglycemia, likely causal mediators, may reduce CKD post-BS.

Genetically Predicted Smoking and Alcohol Consumption and Functional Outcome After Ischemic Stroke.

Smoking and alcohol consumption have been adversely associated with poststroke outcome in traditional epidemiologic studies. The present study explored the association of genetically predicted smoking and alcohol consumption on poststroke outcomes using the mendelian randomization (MR) framework. Instrumental variables for smoking initiation and alcohol consumption were selected from a genome-wide association study data of European ancestry individuals. Summary-level data for functional outcome after ischemic stroke were obtained from the Genetics of Ischemic Stroke Functional Outcome network study of European ancestry patients. The univariable and multivariable inverse-variance weighted MR methods were performed to obtain the causal estimates. The weighted median, MR-robust adjusted profile score, and MR-Egger regression approaches were adopted as sensitivity analyses. Q and I 2 statistics were used to evaluate heterogeneity in MR estimates across variants. Genetic predisposition to smoking initiation was associated with worse functional outcome after ischemic stroke in univariable inverse-variance weighted MR analysis (odds ratio [OR] 1.48; 95% CI 1.08-2.01, p = 0.013). This association remained significant when adjusting for genetically predicted alcohol consumption in multivariable MR analyses (OR 1.56; 95% CI 1.05-2.32, p = 0.027). Genetically predicted alcohol consumption was not associated with functional outcome after ischemic stroke (p > 0.05). Sensitivity analyses with other approaches and in analyses restricted to models without adjustment for baseline stroke severity produced similar results, and no evidence of heterogeneity in MR estimates between variants was detected (p > 0.05). Our results provide genetic support for a causal association of smoking with worse functional outcome after ischemic stroke and have important implications for poststroke recovery. Smoking cessation and avoidance should be promoted in patients with ischemic stroke.

Rheumatoid arthritis and the risk of major cardiometabolic diseases: a Mendelian randomization study

Objective Rheumatoid arthritis (RA) is suggested to be implicated in the development of cardiometabolic diseases. We conducted a Mendelian randomization (MR) study to assess potential causality for associations of RA with the risk of cardiometabolic diseases, including type 2 diabetes (T2D), coronary artery disease (CAD), and ischaemic stroke. Method Seventy independent single-nucleotide polymorphisms (SNPs) associated with RA were identified as instrumental variables from a genome-wide association study (GWAS) of 58 284 European subjects. Summary-level data for the associations of the 70 genetic variants with T2D, CAD, and ischaemic stroke were taken from three GWASs with a total of 1 529 131 participants. Inverse-variance weighted (IVW) MR was used in the main analyses. Results The main IVW MR analysis showed that genetically determined RA was associated with higher risks of T2D [odds ratio (OR): 1.04, 95% confidence interval (CI) 1.02–1.05; p < 0.001] and CAD (OR: 1.02, 95% CI 1.00–1.03; p = 0.012), but not ischaemic stroke (OR: 1.00, 95% CI 0.99–1.02; p = 0.961). Sensitivity analyses with multiple MR methods confirmed these associations. MR-Egger regression showed no evidence of pleiotropy in the association between genetically determined RA and the risk of T2D, CAD, and ischaemic stroke. Leave-one-out sensitivity analysis showed that the association between genetically determined RA and the risk of T2D, CAD, and ischaemic stroke was not driven by any individual SNP. Conclusion Genetically determined RA was associated with increased risks of T2D and CAD, suggesting that RA plays a crucial role in the pathogenesis of T2D and CAD.

Abstract 297: Systematic Review And Mendelian Randomization Of Plasma Biomarkers To Predict Their Causal Role In Peripheral Artery Disease Pathophysiology

Introduction: Observational analyses have described hundreds of biomarkers for Peripheral artery disease (PAD). These studies can be limited by sample size, lack of replication, residual confounding, and reverse causality. To assess this we performed a systematic review of the literature and leveraged genetic approaches to causal inference. Methods: We performed a systematic literature review for terms related to PAD and/or biomarkers using Pubmed, Cochrane, and Embase, followed by manual review to extract biomarkers and their direction of effect. To test for evidence of causality we employed 2 sample Mendelian randomization (MR). We developed genetic instruments for the biomarkers by mapping them to genome wide association studies (GWAS) of circulating biomolecules agglomerated in the IEU Open GWAS project. We tested the association of the genetic instruments with PAD using summary statistics from a GWAS of 31,307 individuals with and 211,753 individuals without PAD in the VA Million Veteran Program. We employed Wald ratio or inverse-variance weighted MR; weighted median and weighted mode methods were applied as sensitivity analyses. Results: After manual review, we identified 159 unique papers mentioning 268 unique PAD biomarkers. We mapped 76 biomarkers to genetic data, 19 of which were nominally associated with PAD (p &lt; 0.05). After accounting for multiple testing (FDR &lt; 0.05) 12 remained significant, of which only 7 had concordant directions of effect with published reports: ApoB, ApoA1, HDL, triglycerides, Von-Willebrand factor, cadherin-5, and b2-microglobulin. Conclusion: This systematic review paired with genetic causal inference illuminates key biomarkers causally relevant to PAD, and highlights discrepancies between observational and genetic findings. This highlights the importance of rigorous analysis of observational biomarker data and the opportunity to leverage human genetics to inform these studies.