Large-scale cross-ancestry genome-wide meta-analysis of serum urate.

Hyperuricemia is an essential causal risk factor for gout and is associated with cardiometabolic diseases. Given the limited contribution of East Asian ancestry to genome-wide association studies of serum urate, the genetic architecture of serum urate requires exploration. A large-scale cross-ancestry genome-wide association meta-analysis of 1,029,323 individuals and ancestry-specific meta-analysis identifies a total of 351 loci, including 17 previously unreported loci. The genetic architecture of serum urate control is similar between European and East Asian populations. A transcriptome-wide association study, enrichment analysis, and colocalization analysis in relevant tissues identify candidate serum urate-associated genes, including CTBP1, SKIV2L, and WWP2. A phenome-wide association study using polygenic risk scores identifies serum urate-correlated diseases including heart failure and hypertension. Mendelian randomization and mediation analyses show that serum urate-associated genes might have a causal relationship with serum urate-correlated diseases via mediation effects. This study elucidates our understanding of the genetic architecture of serum urate control.

An atlas of associations between 14 micronutrients and 22 cancer outcomes: Mendelian randomization analyses.

BACKGROUND: Micronutrients, namely vitamins and minerals, are associated with cancer outcomes; however, their reported effects have been inconsistent across studies. We aimed to identify the causally estimated effects of micronutrients on cancer by applying the Mendelian randomization (MR) method, using single-nucleotide polymorphisms associated with micronutrient levels as instrumental variables. METHODS: We obtained instrumental variables of 14 genetically predicted micronutrient levels and applied two-sample MR to estimate their causal effects on 22 cancer outcomes from a meta-analysis of the UK Biobank (UKB) and FinnGen cohorts (overall cancer and 21 site-specific cancers, including breast, colorectal, lung, and prostate cancer), in addition to six major cancer outcomes and 20 cancer subset outcomes from cancer consortia. We used sensitivity MR methods, including weighted median, MR-Egger, and MR-PRESSO, to assess potential horizontal pleiotropy or heterogeneity. Genome-wide association summary statistical data of European descent were used for both exposure and outcome data, including up to 940,633 participants of European descent with 133,384 cancer cases. RESULTS: In total, 672 MR tests (14 micronutrients × 48 cancer outcomes) were performed. The following two associations met Bonferroni significance by the number of associations (P < 0.00016) in the UKB plus FinnGen cohorts: increased risk of breast cancer with magnesium levels (odds ratio [OR] = 1.281 per 1 standard deviation [SD] higher magnesium level, 95% confidence interval [CI] = 1.151 to 1.426, P < 0.0001) and increased risk of colorectal cancer with vitamin B12 level (OR = 1.22 per 1 SD higher vitamin B12 level, 95% CI = 1.107 to 1.345, P < 0.0001). These two associations remained significant in the analysis of the cancer consortia. No significant heterogeneity or horizontal pleiotropy was observed. Micronutrient levels were not associated with overall cancer risk. CONCLUSIONS: Our results may aid clinicians in deciding whether to regulate the intake of certain micronutrients, particularly in high-risk groups without nutritional deficiencies, and may help in the design of future clinical trials.

Prioritization of therapeutic targets for dyslipidemia using integrative multi-omics and multi-trait analysis.

Drug targets with genetic support are several-fold more likely to succeed in clinical trials. We introduce a genetic-driven approach based on causal inferences that can inform drug target prioritization, repurposing, and adverse effects of using lipid-lowering agents. Given that a multi-trait approach increases the power to detect meaningful variants/genes, we conduct multi-omics and multi-trait analyses, followed by network connectivity investigations, and prioritize 30 potential therapeutic targets for dyslipidemia, including SORT1, PSRC1, CELSR2, PCSK9, HMGCR, APOB, GRN, HFE2, FJX1, C1QTNF1, and SLC5A8. 20% (6/30) of prioritized targets from our hypothesis-free drug target search are either approved or under investigation for dyslipidemia. The prioritized targets are 22-fold higher in likelihood of being approved or under investigation in clinical trials than genome-wide association study (GWAS)-curated targets. Our results demonstrate that the genetic-driven approach used in this study is a promising strategy for prioritizing targets while informing about the potential adverse effects and repurposing opportunities.

ICD2Vec: Mathematical representation of diseases.

BACKGROUND: The International Classification of Diseases (ICD) codes represent the global standard for reporting disease conditions. The current ICD codes connote direct human-defined relationships among diseases in a hierarchical tree structure. Representing the ICD codes as mathematical vectors helps to capture nonlinear relationships in medical ontologies across diseases. METHODS: We propose a universally applicable framework called "ICD2Vec" designed to provide mathematical representations of diseases by encoding corresponding information. First, we present the arithmetical and semantic relationships between diseases by mapping composite vectors for symptoms or diseases to the most similar ICD codes. Second, we investigated the validity of ICD2Vec by comparing the biological relationships and cosine similarities among the vectorized ICD codes. Third, we propose a new risk score called IRIS, derived from ICD2Vec, and demonstrate its clinical utility with large cohorts from the UK and South Korea. RESULTS: Semantic compositionality was qualitatively confirmed between descriptions of symptoms and ICD2Vec. For example, the diseases most similar to COVID-19 were found to be the common cold (ICD-10: J00), unspecified viral hemorrhagic fever (ICD-10: A99), and smallpox (ICD-10: B03). We show the significant associations between the cosine similarities derived from ICD2Vec and the biological relationships using disease-to-disease pairs. Furthermore, we observed significant adjusted hazard ratios (HR) and area under the receiver operating characteristics (AUROC) between IRIS and risks for eight diseases. For instance, the higher IRIS for coronary artery disease (CAD) can be the higher probability for the incidence of CAD (HR: 2.15 [95% CI 2.02-2.28] and AUROC: 0.587 [95% CI 0.583-0.591]). We identified individuals at substantially increased risk of CAD using IRIS and 10-year atherosclerotic cardiovascular disease risk (adjusted HR: 4.26 [95% CI 3.59-5.05]). CONCLUSIONS: ICD2Vec, a proposed universal framework for converting qualitatively measured ICD codes into quantitative vectors containing semantic relationships between diseases, exhibited a significant correlation with actual biological significance. In addition, the IRIS was a significant predictor of major diseases in a prospective study using two large-scale datasets. Based on this clinical validity and utility evidence, we suggest that publicly available ICD2Vec can be used in diverse research and clinical practices and has important clinical implications.

Causal effect of adiposity on the risk of 19 gastrointestinal diseases: a Mendelian randomization study.

OBJECTIVE: Although the association between adiposity and gastrointestinal (GI) diseases has been explored, the causal effects of adiposity on GI diseases are largely unknown. METHODS: Mendelian randomization was conducted using single-nucleotide polymorphisms associated with BMI and waist circumference (WC) as instrumental variables, and the causal associations of BMI or WC with GI conditions were estimated among >400,000 UK Biobank participants, >170,000 Finnish-descent participants, and numerous consortia participants of predominantly European ancestry. RESULTS: Genetically predicted BMI was robustly associated with increased risk of nonalcoholic fatty liver disease (NAFLD), cholecystitis, cholelithiasis, and primary biliary cholangitis. For the diseases, the odds ratio per 1-SD increase in genetically predicted BMI (4.77 kg/m2 ) ranged from 1.22 (95% CI: 1.12-1.34; p < 0.0001) for NAFLD to 1.65 (95% CI: 1.31-2.06; p < 0.0001) for cholecystitis. Genetically predicted WC was robustly associated with increased risk of NAFLD, alcoholic liver disease, cholecystitis, cholelithiasis, colon cancer, and gastric cancer. Alcoholic liver disease was consistently associated with WC even after adjusting for alcohol consumption in a multivariable Mendelian randomization analysis. The odds ratio per 1-SD increase in genetically predicted WC (12.52 cm) for such associations ranged from 1.41 (95% CI: 1.17-1.70; p = 0.0015) for gastric cancer to 1.74 (95% CI: 1.21-1.78; p < 0.0001) for cholelithiasis. CONCLUSIONS: High genetically predicted adiposity was causally associated with an increased risk of GI abnormalities, particularly of hepatobiliary organs (liver, biliary tract, and gallbladder) that are functionally related to fat metabolism.

Outcomes of Endoscopic Resection for Early Gastric Cancer in Very Elderly Patients: A Nationwide Population-Based Study.

Background/Aims: Few studies have investigated the long-term outcomes of endoscopic resection for early gastric cancer (EGC) in very elderly patients. The aim of this study was to determine the appropriate treatment strategy and identify the risk factors for mortality in these patients. Methods: Patients with EGC who underwent endoscopic resection from 2006 to 2017 were identified using National Health Insurance Data and divided into three age groups: very elderly (≥85 years), elderly (65 to 84 years), and non-elderly (≤64 years). Their long- and short-term outcomes were compared in the three age groups, and the survival in the groups was compared with that in the control group, matched by age and sex. We also evaluated the risk factors for long- and short-term outcomes. Results: A total of 8,426 patients were included in our study: 118 very elderly, 4,583 elderly, and 3,725 non-elderly. The overall survival and cancer-specific survival rates were significantly lower in the very elderly group than in the elderly and the non-elderly groups. Congestive heart failure was negatively associated with cancer-specific survival. A significantly decreased risk for mortality was observed in all groups (p<0.001). The very elderly group had significantly higher readmission and mortality rates within 3 months of endoscopic resection than the non-elderly and elderly groups. Furthermore, the cerebrovascular disease was associated with mortality within 3 months after endoscopic resection. Conclusions: Endoscopic resection for EGC can be helpful for very elderly patients, and it may play a role in achieving overall survival comparable to that of the control group.

Comparison of the outcomes of navigation-assisted revision of unicompartmental knee arthroplasty to total knee arthroplasty versus navigation-assisted primary TKA.

PURPOSE: Revision of unicompartmental knee arthroplasty (UKA) to total knee arthroplasty (TKA) is technically demanding but can be performed with computer navigation system guidance. The purpose of this study was (1) to compare the outcomes of revision of UKA to TKA to those of primary TKA and (2) to describe a surgical technique for the revision of UKA to TKA using a navigation system. METHODS: From May 2011 to April 2014, a total of 298 knees underwent primary navigation-assisted TKA (group 1), and navigation-assisted UKA revision to TKA was performed in 15 patients (group 2). One to three propensity score matching was performed to compare the two groups after a minimum of three years of follow-up. Radiographic and clinical outcomes in addition to radiolucent lines were evaluated during follow-up. RESULTS: In group 1, there was one case that required metal block augmentation with the long stem under the tibial plate due to severe bone loss, while in other cases, short stems were used, and cement and autogenous bone grafts were used to fill bone defects due to minimal bone loss. Pre- and post-operative outcomes were significantly improved in both groups (p < 0.001). There were no statistical differences between groups in pre- and post-operative outcomes except post-operative Knee Society Function Score (KSFS) (p = 0.008). There were no radiolucent lines in the tibia or femur in either group during follow-up. CONCLUSIONS: With the use of an appropriate surgical technique, navigation-assisted revision of UKA to TKA can yield clinical and radiologic outcomes comparable to those of primary navigation-assisted TKA. LEVEL OF EVIDENCE: Level IV.

Reliability and Validity of the Femorotibial Mechanical Axis Angle in Primary Total Knee Arthroplasty: Navigation versus Weight Bearing or Supine Whole Leg Radiographs.

PURPOSE: To evaluate the reliability and validity of the femorotibial mechanical axis angle from radiographs in the weight bearing (WB) and supine positions compared with navigation-measured values. MATERIALS AND METHODS: Sixty-eight cases of navigation-assisted total knee arthroplasty (TKA) were included. The pre- and postoperative whole leg radiographs (WLRs) in WB and supine positions were compared with the initial and final navigation values. RESULTS: The mean mechanical axis angle from the preoperative WBWLR and navigation were not statistically different (p=0.079) and were correlated strongly with each other (intraclass correlation [ICC], 0.818). However, on postoperative measurements, although the WBWLR and navigation values were not different (p=0.098), they were not correlated with each other (ICC, 0.093). The standard error of measurement was 1.8°±3.6° for the preoperative WBWLR and 2.5°±4.8° for the postoperative WBWLR. The validity that was determined by the Bland-Altman plot was not acceptable for both pre- and postoperative measurements. CONCLUSIONS: The preoperative WBWLR could provide accurate but not precise measurement value of the femorotibial mechanical axis angle for navigation-assisted TKA, and postoperative measurements in navigation were not comparable with radiographic measurements. The lack of agreement was found between the radiographic and navigation measurements of the coronal alignment regardless of pre- or postoperative evaluation although the accuracy was found acceptable. LEVEL OF EVIDENCE: Level 4.

No influence of femoral component rotation by the lateral femoral posterior condylar cartilage remnant technique on clinical outcomes in navigation-assisted TKA.

PURPOSE: To investigate whether cartilage thickness in the lateral femoral posterior condyle affects the femoral rotation angles on navigation and clinical outcomes of navigation-assisted total knee arthroplasty (TKA). METHODS: This is a prospective randomized study of navigation-assisted TKA. Fifty cases underwent TKA without removal of the lateral posterior femoral cartilage (Group 1), and 56 cases underwent TKA with removal of the lateral posterior femoral cartilage (Group 2). The femoral rotation was evaluated using CT and compared with navigation values. The angle between the clinical transepicondylar axis and posterior condylar axis measured on CT was defined as the femoral rotation angle on CT. Elevation of the joint line and patellar measurements were also evaluated. RESULTS: The clinical outcomes were not statistically different in the two groups. The radiographic measurements were not statistically different except femoral rotation angle on navigation. The mean femoral rotation angle of navigation was 4.0° ± 2.2° without cartilage removal and 5.1° ± 2.5° with cartilage removal. The reliability and validity were high between the femoral rotation angle on navigation in the cartilage removal group and that on CT, but there were no differences in clinical outcomes between the two groups. CONCLUSION: There was little effect of navigation-assisted TKA on radiographic and clinical outcomes, although femoral rotational differences were caused by the lateral femoral posterior condylar cartilage. Although the rotational differences due to cartilage would be within the clinical safety margin, surgeons should consider that difference during TKA. LEVEL OF EVIDENCE: Lower quality randomized trial (no masking), Level II.

Time-dependent clinical results of rotating-platform total knee arthroplasty according to mechanical axis deviation.

PURPOSE: We hypothesized that the low contact stress (LCS) posterior stabilization system in knees with ≤3° deviation of coronal alignment would provide more favorable clinical outcomes and survival rate over the course of time. MATERIALS AND METHODS: A retrospective study was performed on 253 consecutive cases of primary total knee arthroplasty (TKA). Patients were classified according to the degree of deviation of coronal alignment on the initial postoperative radiograph as Group 1 (≤3° deviation) and Group 2 (>3° deviation). The clinical assessments were performed using the Knee Society score and Hospital for Special Surgery systems and Western Ontario and McMaster Universities index. RESULTS: The survival rate was 97.4% in Group 1 and 96.8% in Group 2. No statistically significant intergroup difference was observed in the clinical scores before surgery and since 1 year after surgery (p>0.05). However, a significant intergroup difference was noted between 6 months to 1 year after surgery (p<0.001). Less than 2 mm radiolucent lines were found more frequently in Group 2. Time-dependent improvement was noted within one year after TKA in both groups. CONCLUSIONS: Most of the expected improvements were achieved at 6 months after surgery in Group 1 and at 1 year after surgery in Group 2. The present study suggests that the LCS system yields time-dependent improvement regardless of coronal alignment deviation.