Genetic variation at a splicing branch point in intron 7 of STK11: a rare variant decreasing its expression in a Chinese family with Peutz-Jeghers syndrome.

BACKGROUND: Peutz-Jeghers syndrome (PJS), a rare dominantly inherited disease, is primarily characterized by hamartomatous polyps and melanotic macules as well as by an increased risk of cancer. The current study aimed to identify the pathogenic gene and pathogenic mechanism of a proband with PJS, thereby offering precise prevention and treatment strategies for PJS. METHODS: A detailed clinical examination was performed of the proband diagnosed with PJS and her family members. In addition, peripheral venous blood was collected from the family members to extract genomic DNA. The pathogenic genes of the proband were identified using whole-exome sequencing, and the candidate pathogenic variants were verified via Sanger sequencing. Meanwhile, co-segregation tests were performed among six family members. Finally, reverse transcription-polymerase chain reaction (RT-PCR) was performed to assess transcript variants in the peripheral blood cells of patients and non-related healthy controls. RESULTS: Genetic testing revealed a rare splicing variant c.921-1G > C in STK11 in the proband and in her sister and nephew, and the variant co-segregated among the affected family members and nonrelated healthy controls. The proband phenotypically presented with a rare gastric-type adenocarcinoma of the cervix. RT-PCR revealed that the STK11 c.921-1G > C variant could produce two transcripts. Of note, 40 base pairs were deleted in the aberrant transcript between exons 3 and 4, resulting in a frameshift variant and premature termination of the amino acid in exon 6 and ultimately leading to the loss of its functional domain in the STK11 protein. Finally, RT-PCR showed that compared with healthy controls, STK11 mRNA expression level was < 50% in patients. CONCLUSION: The present study results indicated that the rare splicing variant c.921-1G > C in intron 7 of STK11 may be a pathogenic variant in patients with PJS. However, this variant (in intron 7) may not produce abnormal transcripts (deletion of 40 base pairs between exons 3 and 4), and PJS may be attributed to the decrease in STK11 expression. Therefore, this study emphasized the importance of genetic counseling, pre-symptomatic monitoring, and early complication management in PJS.

Association of a novel frameshift variant and a known deleterious variant in MMR genes with Lynch syndrome in Chinese families.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. This condition is characterized by germline variants in DNA mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2. In this study, we analyzed the molecular defects and clinical manifestations of two families affected with CRC and proposed appropriate individual preventive strategies for all carriers of the variant. METHODS: We recruited two families diagnosed with CRC and combined their family history and immunohistochemical results to analyze the variants of probands and those of other family members by using whole exome sequencing. Subsequently, gene variants in each family were screened by comparing them with the variants available in the public database. Sanger sequencing was performed to verify the variant sites. An online platform ( https://www.uniprot.org ) was used to analyze the functional domains of mutant proteins. RESULTS: A novel frameshift variant (NM_001281492, c.1129_1130del, p.R377fs) in MSH6 and a known deleterious variant (NM_000249.4:c.1731G > A, p.S577S) in MLH1 were identified in the two families with CRC. Using bioinformatics tools, we noted that the frameshift variant reduced the number of amino acids in the MSH6 protein from 1230 to 383, thereby leading to no MSH6 protein expression. The silent variant caused splicing defects and was strongly associated with LS. 5-Fluorouracil-based adjuvant chemotherapy is not recommended for patients with LS. CONCLUSIONS: The novel frameshift variant (MSH6, c.1129_1130del, p.R377fs) is likely pathogenic to LS, and the variant (MLH1, c.1731G > A, p.S577S) has been further confirmed to be pathogenic to LS. Our findings underscore the significance of genetic testing for LS and recommend that genetic consultation and regular follow-ups be conducted to guide individualized treatment for cancer-afflicted families, especially those with a deficiency in MMR expression.

Dynamical vaccination behavior with risk perception and vaccination rewards.

Vaccination is the most effective way to control the epidemic spreading. However, the probability of people getting vaccinated changes with the epidemic situation due to personal psychology. Facing various risks, some people are reluctant to vaccinate and even prefer herd immunity. To encourage people to get vaccinated, many countries set up reward mechanisms. In this paper, we propose a disease transmission model combining vaccination behaviors based on the SIR (Susceptible-Infected-Recovered) model and introduce three vaccination mechanisms. We analyze the impact of the infection rate and the recovery rate on the total cost and the epidemic prevalence. Numerical simulations fit with our intuitive feelings. Then, we study the impact of vaccination rewards on the total social cost. We find that when vaccination rewards offset vaccination costs, both the total cost and the epidemic prevalence reach the lowest levels. Finally, this paper suggests that encouraging people to get vaccinated at the beginning of an epidemic has the best effect.

Engineering functional skin constructs: A quantitative comparison of three-dimensional bioprinting with traditional methods.

Tissue engineering has been successful in reproducing human skin equivalents while incorporating new approaches such as three-dimensional (3D) bioprinting. The latter method offers a plethora of advantages including increased production scale, ability to incorporate multiple cell types and printing on demand. However, the quality of printed skin equivalents compared to those developed manually has never been assessed. To leverage the benefits of this method, it is imperative that 3D-printed skin should be structurally and functionally similar to real human skin. Here, we developed four bilayered human skin epidermal-dermal equivalents: non-printed dermis and epidermis (NN), printed dermis and epidermis (PP), printed epidermis and non-printed dermis (PN), and non-printed epidermis and printed dermis (NP). The effects of printing induced shear stress [0.025 kPa (epidermis); 0.049 kPa (dermis)] were characterized both at the cellular and at the tissue level. At cellular level, no statistically significant differences in keratinocyte colony-forming efficiency (CFE) (p = 0.1641) were observed. In the case of fibroblasts, no significant differences in the cell alignment index (p < 0.1717) and their ability to contract collagen gel (p = 0.851) were detected. At the tissue levels, all the four skin equivalents were characterized using histological and immunohistochemical analysis with no significant differences found in either epidermal basal cell count, thickness of viable epidermis, and relative intensity of filaggrin and claudin-1. Our results demonstrated that 3D printing can achieve the same high-quality skin constructs as have been developed traditionally, thus opening new avenues for numerous high-throughput industrial and clinical applications.

Correlation between the thyroid hormone levels and nonalcoholic fatty liver disease in type 2 diabetic patients with normal thyroid function.

BACKGROUND: The objective of this study is to retrospectively analyze the correlation between the thyroid hormones and nonalcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients with normal thyroid function. METHODS: Totally 586 T2DM patients with normal thyroid function participated in this research and were divided into T2DM without NAFLD (240 cases) group and T2DM with NAFLD (346 cases) group. The NAFLD fibrosis score (NFS) > 0.676 was defined as progressive liver fibrosis and used to categorize the patients into T2DM without progressive liver fibrosis group (493 cases) and T2DM with progressive liver fibrosis group (93 cases). RESULTS: The results indicated that the levels of free triiodothyronine (FT3), total triiodomethylamine (TT3) and FT3/free thyroxine ratio (FT3/FT4) were significantly higher while the FT4 level was lower in T2DM with NAFLD group than that in T2DM without NAFLD group (p < 0.05). The levels of FT3, FT4, TT3 and TT4 in patients with progressive liver fibrosis were significantly lower in patients with progressive liver fibrosis than that in patients without progressive liver fibrosis (p < 0.05). Logistic regression analysis showed a positive connection between FT3/FT4 ratio and NAFLD (p = 0.038), a negative relationship between FT4 level and NAFLD (p = 0.026), between the levels of FT4, TT3 and total thyroxine (TT4) and the risk of progressive hepatic fibrosis (p = 0.022, p = 0.007, p = 0.046). CONCLUSION: There is a certain correlation between thyroid hormone levels and NAFLD in T2DM patients, suggesting that the assessment of thyroid hormone levels in T2DM patients with normal thyroid function could be helpful in the prevention and treatment of NAFLD.

Light triggered release of a triple action porphyrin-cisplatin conjugate evokes stronger immunogenic cell death for chemotherapy, photodynamic therapy and cancer immunotherapy.

Photodynamic therapy (PDT) has emerged as an attractive therapeutic approach which can elicit immunogenic cell death (ICD). However, current ICD inducers are still very limited as the representative ICD induces of photosensitizers can only evoke insufficient ICD to achieve unsatisfactory cancer immunotherapy. Herein, we demonstrated the use of a triple action cationic porphyrin-cisplatin conjugate (Pt-1) for drug delivery by a reactive oxygen species (ROS) sensitive polymer as nanoparticles (NP@Pt-1) for combined chemotherapy, PDT and immunotherapy. This unique triple action Pt-1 contains both chemotherapeutic Pt drugs and Porphyrin as a photosensitizer to generate ROS for PDT. Moreover, the ROS generated by Pt-1 can on the one hand degrade polymer carriers to release Pt-1 for chemotherapy and PDT. On the other hand, the ROS generated by Pt-1 subsequently triggered the ICD cascade for immunotherapy. Taken together, we demonstrated that NP@Pt-1 were the most effective and worked in a triple way. This study could provide us with new insight into the development of nanomedicine for chemotherapy, PDT as well as cancer immunotherapy.

Synthesis of an Effective Flame-Retardant Hydrogel for Skin Protection Using Xanthan Gum and Resorcinol Bis(diphenyl phosphate)-Coated Starch.

We report on the production of a flame-resistant xanthan gum (XG)-based hydrogel formulation, which could be directly applied onto the skin for protection against burning projectiles. The hydrogel cream represents an efficient use of XG and starch, both of which are biodegradable, reusable natural materials and are also GRAS-certified. The flame-retardant agent resorcinol bis(diphenyl phosphate) (RDP) was shown to be nontoxic to cells in vitro when adsorbed directly onto the starch delivery vehicle. Three hydrogel formulations were studied, the pure XG hydrogel, commercial FireIce hydrogel, and RDP-XG/RDP-starch hydrogel. After application of a direct flame for 150 s, the RDP-XG/RDP-starch hydrogel produced a thick char layer, which was easily removed, showing undamaged chicken skin and tissue underneath. In contrast, complete burning of skin and tissue was observed on untreated control samples and those covered with FireIce and pure XG hydrogels. The thermal protective performance test was also performed, where the heat transfer was measured as a function of time for all three hydrogels. The RDP-XG/RDP-starch hydrogel was able to prolong the protection time before obtaining a second-degree burn for 103 s, which is double that for FireIce and triple that for the pure XG hydrogel. The model proposed involves endothermic reactions, producing char and burning "cold", as opposed to simply relying on the adsorbed water in the hydrogel for burn protection.

Correlational study on the levels of 25-hydroxyvitamin D and non-alcoholic fatty liver disease in type 2 diabetic patients.

BACKGROUND: It is widely acknowledged that nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus(T2DM) are all chronic metabolic diseases. The objective of this study is to retrospectively probe the association between the 25-hydroxyvitamin D (25-(OH)D) and NAFLD in type 2 diabetic patients. METHODS: Three hundred thirty-nine T2DM patients participated in this research and from November 2018 to September 2019 and were divided into simple T2DM group (108 cases) and T2DM with NAFLD group (231 cases) in conformity with abdominal ultrasound diagnosis. The NAFLD fibrosis score (NFS) ≥0.676 was defined as progressive liver fibrosis.231 T2DM with NAFLD patients were categorized into two subgroups: progressive liver fibrosis subgroup (48 cases) and without progressive liver fibrosis subgroup (183 cases). RESULTS: The prevalence of NAFLD by Abdominal ultrasonography was 68%.The results indicated that the levels of 25-(OH) D were significantly lower in T2DM with NAFLD group than that in simple T2DM group(P < 0.01). The levels of 25-(OH) D were significantly lower in progressive liver fibrosis subgroup than that in patients without progressive liver fibrosis and simple T2DM,and 25-(OH) D levels were lower in without progressive liver fibrosis subgroup than that in simple T2DM group(p < 0.01 or p < 0.05). Multivariate logistic regression analysis showed that levels of 25-(OH) D were negative correlation with risk of NAFLD and progressive liver fibrosis(p = 0.011、p = 0.044,respectively). CONCLUSIONS: we could come to a conclusion that low levels of 25-(OH) D was a risk factor for NAFLD and progressive liver fibrosis in T2DM patients.

Synchronizability of double-layer dumbbell networks.

Synchronization of multiplex networks has been a topical issue in network science. Dumbbell networks are very typical structures in complex networks which are distinguished from both regular star networks and general community structures, whereas the synchronous dynamics of a double-layer dumbbell network relies on the interlink patterns between layers. In this paper, two kinds of double-layer dumbbell networks are defined according to different interlayer coupling patterns: one with the single-link coupling pattern between layers and the other with the two-link coupling pattern between layers. Furthermore, the largest and smallest nonzero eigenvalues of the Laplacian matrix are calculated analytically and numerically for the single-link coupling pattern and also obtained numerically for the two-link coupling pattern so as to characterize the synchronizability of double-layer dumbbell networks. It is shown that interlayer coupling patterns have a significant impact on the synchronizability of multiplex systems. Finally, a numerical example is provided to verify the effectiveness of theoretical analysis. Our findings can facilitate company managers to select optimal interlayer coupling patterns and to assign proper parameters in terms of improving the efficiency and reducing losses of the whole team.

COVID-19 infection may cause ketosis and ketoacidosis.

The present study included 658 hospitalized patients with confirmed COVID-19. Forty-two (6.4%) out of 658 patients presented with ketosis on admission with no obvious fever or diarrhoea. They had a median (interquartile range [IQR]) age of 47.0 (38.0-70.3) years, and 16 (38.1%) were men. Patients with ketosis were younger (median age 47.0 vs. 58.0 years; P = 0.003) and had a greater prevalence of fatigue (31.0% vs. 10.6%; P < 0.001), diabetes (35.7% vs. 18.5%; P = 0.007) and digestive disorders (31.0% vs. 12.0%; P < 0.001). They had a longer median (IQR) length of hospital stay (19.0 [12.8-33.3] vs. 16.0 [10.0-24.0] days; P < 0.001) and a higher mortality rate (21.4% vs. 8.9%; P = 0.017). Three (20.0%) out of the 15 patients with diabetic ketosis developed acidosis, five patients (26.7%) with diabetic ketosis died, and one of these (25.0%) presented with acidosis. Two (7.4%) and four (14.3%) of the 27 non-diabetic ketotic patients developed severe acidosis and died, respectively, and one (25.0%) of these presented with acidosis. This suggests that COVID-19 infection caused ketosis or ketoacidosis, and induced diabetic ketoacidosis for those with diabetes. Ketosis increased the length of hospital stay and mortality. Meanwhile, diabetes increased the length of hospital stay for patients with ketosis but had no effect on their mortality.

GBA3 promotes fatty acid oxidation and alleviates non-alcoholic fatty liver by increasing CPT2 transcription.

BACKGROUND: Excessive lipids accumulation and hepatocytes death are prominent characteristics of non-alcoholic fatty liver disease (NAFLD). Nonetheless, the precise pathophysiological mechanisms are not fully elucidated. METHODS: HepG2 cells stimulated with palmitic acids and rats fed with high-fat diet were used as models for NAFLD. The impact of Glucosylceramidase Beta 3 (GBA3) on fatty acid oxidation (FAO) was assessed using Seahorse metabolic analyzer. Lipid content was measured both in vitro and in vivo. To evaluate NAFLD progression, histological analysis was performed along with measurements of inflammatory factors and liver enzyme levels. Western blot and immunohistochemistry were employed to examine the activity levels of necroptosis. Flow cytometry and reactive oxygen species (ROS) staining were utilized to assess levels of oxidative stress. RESULTS: GBA3 promoted FAO and enhanced the mitochondrial membrane potential without affecting glycolysis. These reduced the lipid accumulation. Rats supplemented with GBA3 exhibited lower levels of inflammatory factors and liver enzymes, resulting in a slower progression of NAFLD. GBA3 overexpression reduced ROS and the ratio of cell apoptosis. Phosphorylation level was reduced in the essential mediator, MLKL, implicated in necroptosis. Mechanistically, as a transcriptional coactivator, GBA3 promoted the expression of Carnitine Palmitoyltransferase 2 (CPT2), which resulted in enhanced FAO. CONCLUSIONS: Increased FAO resulting from GBA3 reduced oxidative stress and the production of ROS, thereby inhibiting necroptosis and delaying the progression of NAFLD. Our research offers novel insights into the potential therapeutic applications of GBA3 and FAO in the management and treatment of NAFLD.

A missense GDF5 variant causes brachydactyly type A1 and multiple-synostoses syndrome 2.

Objective: This study aimed to identify the molecular defects and clinical manifestations in a Chinese family with brachydactyly (BD) type A1 (BDA1) and multiple-synostoses syndrome 2 (SYNS2). Methods: A Chinese family with BDA1 and SYNS2 was enrolled in this study. Whole-exome sequencing was used to analyze the gene variants in the proband. The sequences of the candidate pathogenic variant in GDF5 was validated via Sanger sequencing. I-TASSER and PyMOL were used to analyze the functional domains of the corresponding mutant proteins. Results: The family was found to have an autosomal-dominantly inherited combination of BDA1 and SYNS2 caused by the S475N variant in the GDF5 gene. The variant was located within the functional region, and the mutated residue was found to be highly conserved among species. Via bioinformatic analyses, we predicted this variant to be deleterious, which perturb the protein function. The substitution of the negatively charged amino acid S475 with the neutral N475 was predicted to disrupt the formation of salt bridges with Y487 and impair the structure, stability, and function of the protein, consequently, the abnormalities in cartilage and bone development ensue. Conclusions: A single genetic variant (S475N) which disrupt the formation of salt bridges with Y487, in the interface of the antagonist- and receptor-binding sites of GDF5 concurrently causes two pathological mechanisms. This is the first report of this variant, identified in a Chinese family with BDA1 and SYNS2.

Identification and Validation of Hub Immune-Related Genes in Non-Alcoholic Fatty Liver Disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is the most common progressive liver disease worldwide. It can cause liver cancer and possibly death. Abnormal immune infiltration is involved in the progression of NAFLD. The aim of this study was to identify and validate the hub immune-related genes in NAFLD. Methods: Microarray data were downloaded from Gene Expression Omnibus, and immune-related differentially expressed genes (IRDEGs) were obtained. A protein-protein interaction network was used to further screen. The diagnostic value of the IRDEGs was evaluated by receiver operating characteristic curves. Differences in immune infiltration levels were analyzed using single-sample gene set enrichment analysis. Hub IRDEGs were identified by correlation analysis with immune infiltration levels. Finally, molecular experiments were used to confirm the expression of the hub IRDEGs and explore their roles in NAFLD. Results: We obtained 18 IRDEGs. Five hub genes were further identified by protein-protein interaction network, receiver operating characteristic curves and correlation analysis: AQP9, BACH2, CD4, IL17RE and S100A9. Based on functional enrichment analysis, the hub genes were enriched primarily in many immune-related pathways. In NAFLD, AQP9, CD4, and IL17RE expression was significantly reduced, whereas BACH2 and S100A9 expression was elevated. PCR, oil red O staining and triglyceride detection revealed that the knock-down of BACH2 and S100A9 reduced lipid accumulation in NAFLD cells. Conclusion: This study provided insight into the profile of immune infiltration underlying NAFLD and identified AQP9, BACH2, CD4, IL17RE and S100A9 as ancillary diagnostic indicators of NAFLD. And BACH2 and S100A9 might be therapeutic targets for NAFLD.

Identification of a novel CNV at the APC gene in a Chinese family with familial adenomatous polyposis.

Introduction: Familial adenomatous polyposis (FAP) is the second most commonly inherited colorectal cancer (CRC) predisposition caused by germline mutations within the adenomatous polyposis coli (APC) gene. The molecular defects and clinical manifestations of two FAP families were analyzed, and individual prevention strategies suitable for mutation carriers in different families were proposed. Methods and results: The pathogenic gene mutations were identified among the two families using whole-exome sequencing and verified with Sanger sequencing or quantitative polymerase chain reaction (qPCR). One novel (GRCh37:Chr5: 112145676-112174368, del, 28,692 bp) and a known (c.C847T:p.R283X) mutation in the APC gene were pathogenic mutations for FAP, according to the sequencing data and tumorigenesis pattern among the family members. The two mutations led to a premature translational stop signal, synthesizing an absent or disrupted protein product. Conclusion: Our findings expand the known germline mutation spectrum of the APC gene among the Chinese population. This reaffirms the importance of genetic testing in FAP. Genetic consultation and regular follow-ups are necessary for the individualized treatment of cancer-afflicted families with APC expression deficiency. Additional work is required to develop safe and effective chemotherapy and immunotherapy for FAP based on the mutation type.

Enhancement of acellular biomineralization, dental pulp stem cell migration, and differentiation by hybrid fibrin gelatin scaffolds.

OBJECTIVE: The current in vitro study aims to evaluate cross-linked hydrogels with and without the addition of fibrin that could potentially be used in endodontic regeneration as a scaffold material. METHODS: Synthesis of gelatin/fibrin scaffold, and performing nanoscale characterization using cryo-electron microscopy, dynamic rheology, and XRF for structure property relations; plating dental pulp stem cells and determining mineralization, migration, and differentiation using rt-PCR, XRF, and Raman spectroscopy. RESULTS: Cryo electron imaging shows gelatin and fibrin, when gelled separately to form classical rectangular cross-linked networks, where the modulus scales inversely with the cube root of the mesh size. When gelled together, a network with a fundamentally different structure is formed, which has higher ductility and when placed as a scaffold in osteogenic media, produces twice the mineral content. Immunofluorescence, RT-PCR and Rahman Spectroscopy indicate that the hybrid gel enhances cell migration, induces odontogenic differentiation of dental pulp stem cells, and promotes formation of dentin. SIGNIFICANCE: The mechanical properties of the hybrid gel scaffold enhance in-migration of stem cells and subsequent differentiation, which are critical for regenerative procedures. Under acellular conditions, placement of the hybrid gel enhances biomineralization, which would strengthen the root if used as a scaffold for endodontic regeneration. Our in vitro findings are consistent with previous in vivo studies which show improved mineralization when bleeding is induced into the canal, given that fibrin is a primary component in blood clotting. Therefore, insertion of the hybrid gelatin-fibrin scaffold could enable more reproducible and consistent outcomes if used for regenerative endodontic treatment (RET).

Identification of an LDLR variant in a Chinese familial hypercholesterolemia and its relation to ROS/NLRP3-Mediated pyroptosis in hepatic cells.

BACKGROUND: Familial hypercholesterolemia (FH) is a common autosomal dominant hereditary disease. Its early diagnosis and intervention significantly improve the patient's quality of life. However, there are few types of research on the FH pathogenic genes in China. METHODS: In this study, we recruited a family diagnosed with FH and used whole exome sequencing (WES) to analyze the proband variants. Intracellular cholesterol level, reactive oxygen species (ROS) level, and the expression of pyroptosis-related genes were detected after overexpression of wild-type or variant LDLR in L02 cells. RESULTS: A heterozygous missense variant predicted to be deleterious to LDLR (c.1879G > A, p.Ala627Thr) was identified in the proband. Mechanistically, intracellular cholesterol level, ROS level, and the expression of pyroptosis-related genes, nucleotide-binding oligomerization domain-like receptor family protein 3 (NLRP3) inflammasome and components (caspase 1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and NLRP3), gasdermin D (GSDMD), interleukin (IL) -18, IL-1ß was elevated in the variant LDLR group, which was attenuated by inhibition of ROS. CONCLUSIONS: FH is associated with a variant (c.1879G>A, p.Ala627Thr) in the LDLR gene. Regarding the mechanism, the ROS/NLRP3-mediated pyroptosis in hepatic cells may contribute to the pathogenesis of the LDLR variant.

Corrigendum: A heterozygous mutation in NOTCH3 in a Chinese family with CADASIL.

[This corrects the article DOI: 10.3389/fgene.2022.943117.].

Association Between Systemic Lupus Erythematosus and Primary Hypothyroidism: Evidence from Complementary Genetic Methods.

INTRODUCTION: Systemic lupus erythematosus (SLE) and hypothyroidism often coexist in observational studies; however, the causal relationship between them remains controversial. METHODS: Complementary genetic approaches, including genetic correlation, Mendelian randomization (MR), and colocalization analysis, were conducted to assess the potential causal association between SLE and primary hypothyroidism using summary statistics from large-scale genome-wide association studies. The association between SLE and thyroid-stimulating hormone (TSH) was further analyzed to help interpret the findings. In addition, findings were verified using a validation data set, as well as through different MR methods with different model assumptions. RESULTS: The linkage disequilibrium score regression revealed a shared genetic structure between SLE and primary hypothyroidism, with the significant genetic correlation estimated to be 0.2488 (P = 6.00 × 10-4). MR analysis with the inverse variance weighted method demonstrated a bidirectional causal relationship between SLE and primary hypothyroidism. The odds ratio (OR) of SLE on primary hypothyroidism was 1.037 (95% CI, 1.013-1.061; P = 2.00 × 10-3) and that of primary hypothyroidism on SLE was 1.359 (95% CI, 1.217-1.520; P < 0.001). The OR of SLE on TSH was 1.007 (95% CI, 1.001-1.013; P = 0.032). However, TSH was not causally associated with SLE (P = 0.152). Similar results were found using different MR methods. In addition, colocalization analysis suggested that shared causal variants existed between SLE and primary hypothyroidism. The results of the validation analysis indicated a bidirectional causal relationship between SLE and primary hypothyroidism, as well as shared loci. CONCLUSION: In summary, a bidirectional causal relationship between SLE and primary hypothyroidism was observed with complementary genetic approaches.

Association Between Educational Attainment and Thyroid Function: Results From Mendelian Randomization and the NHANES Study.

CONTEXT: Many observational studies have reported on the association between educational attainment (EA) and thyroid function, but the causal relationship remains unclear. OBJECTIVE: We aimed to obtain causal effects of EA on thyroid function and to quantify the mediating effects of modifiable risk factors. METHODS: Two-sample mendelian randomization (MR) was performed by using summary statistics from large genome-wide association studies (GWAS) to assess the effect of EA on thyroid function, including hypothyroidism, hyperthyroidism, thyrotropin (TSH), and free thyroxine (FT4). A multivariable analysis was conducted to assess the mediating role of smoking and help to explain the association between EA and thyroid function. Similar analysis was further performed using data from the National Health and Nutrition Examination Survey (NHANES) 1999 to 2002. RESULTS: In MR analysis, EA was causally associated with TSH (ß = .046; 95% CI, 0.015-0.077; P = 4.00 × 10-3), rather than hypothyroidism, hyperthyroidism, and FT4. Importantly, smoking could serve as a mediator in the association between EA and TSH, in which the mediating proportion was estimated to be 10.38%. After adjusting for smoking in the multivariable MR analysis, the ß value of EA on TSH was attenuated to 0.030 (95% CI, 0.016-0.045; P = 9.32 × 10-3). Multivariable logistic regression model in NHANES suggested a dose-response relationship between TSH (quartile [Q]4 vs Q1: odds ratio = 1.33; 95% CI, 1.05-1.68; P for trend = .023) and EA. Smoking, systolic blood pressure, and body mass index partially mediated the association between EA and TSH, with the proportion of the mediation effects being 43.82%, 12.28%, and 6.81%, respectively. CONCLUSION: There is a potentially causal association between EA and TSH, which could be mediated by several risk factors, such as smoking.