The effect of vitamin D status on the occurrence of Kawasaki Disease: a meta-analysis.

AIM: The relationship between vitamin D status and Kawasaki Disease (KD), as well as coronary artery lesion (CAL), has yet to be established. METHODS: A meta-analysis was conducted to assess the correlation between vitamin D status and KD, as well as the impact of vitamin D status on the progression of KD into CAL. RESULTS: The meta-analysis revealed a consistent and significant association between serum 25(OH)D level and the occurrence KD (studies N = 22; z = -3.51, P < 0.001). Patients with KD had markedly lower levels of vitamin D than healthy controls (SMD: -1.30 ng/mL, 95%CI: -2.05 to -0.55 ng/mL). CONCLUSION: The study provided evidence supporting a significant association between lower serum vitamin D levels and the occurrence of KD, particularly within the Chinese population. However, the findings did not suggest a direct impact of vitamin D on the development of CAL in KD patients.

Types of milk consumed and risk of essential hypertension: A 2-sample Mendelian randomization analysis.

Observational associations between milk consumption and essential hypertension have been reported. However, their causal inferences have not been proven, and the effects of different types of milk consumption on hypertension risk remain poorly characterized. The Mendelian randomization (MR) analysis was performed using public summary-level statistics from genome-wide association studies to determine whether the different types of milk consumption affect essential hypertension differently. Six different milk consumption types were defined as exposure conditions, whereas essential hypertension identified by the ninth and tenth revisions of the International Classification of Diseases was considered the outcome of interest. Genetic variants, which were genome-wide associated with the types of milk consumed, were used as an instrumental variable for MR analysis. In primary MR analysis, the inverse-variance weighted method was adopted followed by several sensitivity analyses. Our findings suggested that of the 6 common types of milk consumed, semi-skimmed and soya milk products were protective against essential hypertension, whereas skim milk had the opposite effect. Consistent results were also observed in sensitivity analyses that followed. The present study provided genetic evidence that a causal link between milk consumption and the risk of essential hypertension and a new reference for the diet antihypertensive treatment plan for patients with hypertension.

Neoadjuvant checkpoint blockade in combination with Chemotherapy in patients with tripe-negative breast cancer: exploratory analysis of real-world, multicenter data.

PURPOSE: Despite the poor prognosis of triple-negative breast cancer (TNBC), it has been demonstrated that neoadjuvant immunotherapy in combination with chemotherapy can improve the pathologic complete response (pCR) rate and/or long-term outcome of TNBC. However, there have been no real-world studies reporting on the effectiveness of neoadjuvant checkpoint inhibitors in early TNBC. METHODS: Between November 2019 and December 2021, 63 early TNBC patients treated with anti-PD-1 antibodies (pembrolizumab or camrelizumab) or anti-PD-L1 antibody (atezolizumab) in combination with chemotherapy at seven institutions were included. PCR1 defined as ypT0/Tis and ypN0 was the primary endpoint. Secondary endpoints included pCR2 defined as ypT0/Tis, overall response rate (ORR), disease-free survival (DFS), drug-related adverse events (AEs) and biomarkers. RESULTS: Among the patients in the current study, 34.9% of patients were able to achieve pCR1, and 47.6% of patients had achieved pCR2. The ORR was 82.5%. 33 patients with non-pCR2 tumors were found to have a median DFS of 20.7 months (95% CI 16.3 months-not reached). The DFS of patients with pCR2 and non-pCR2 after neoadjuvant therapy was significantly different (HR = 0.28, 95% CI 0.10-0.79; P = 0.038). The most common AEs were nausea (63.4%), fatigue (42.7%), leucopenia (30.0%) and elevated transaminase (11.7%). CONCLUSION: It is possible to achieve a meaningful pCR rate and DFS by combining neoadjuvant checkpoint blockade with chemotherapy in patients with high-risk TNBC. Compared to clinical trials, however, there was a slightly lower pCR rate in this multicentered real-world study.

Kidney ion handling genes and their interaction in blood pressure control.

Hypertension affects 30% of adults and is the leading risk factor for cardiovascular disease. Kidney sodium reabsorption plays a vital role in the initial stage and development of essential hypertension. It has been extensively reported that the variants of kidney ion handling genes are associated to blood pressure, and clinical features of hypertension. However, the underlying mechanisms by which these variants alter protein function are rarely summarized. In addition, the variation of one single gene is often limited to induce a significant effect on blood pressure. In the past few decades, the influence by genes × genes (G × G) and/or genotype × environment (G × E) interactions on a given trait, for example, blood pressure, have been widely considered, especially in studies on polygenic genetic traits. In the present review, we discuss the progress in genetics studies on kidney ion handling genes, encoding Na+ channels (Na+-Cl- cotransporter [NCC], Na-K-2Cl cotransporter [NKCC2], epithelial Na+ channels [ENaCs]), K+ channel (renal outer medullary potassium channel [ROMK]), and Cl- channels (Pendrin, chloride voltage-gated channel Kb [CLC-Kb]), respectively, and their upstream kinases, WNKs and SGK1. We seek to clarify how these genes are involved in kidney sodium absorption and influence blood pressure, especially emphasizing the underlying mechanisms by which genetic variants alter protein functions and interaction in blood pressure regulation. The present review aims to enhance our understanding of the important role of kidney ion handling genes/channels in blood pressure control.

Correlation between novel compound heterozygous ADAMTSL4 variants and primary phenotypes of ectopia lentis et pupillae.

PURPOSE: To investigate molecular pathogenesis of congenital ectopia lentis accompanied by various ophthalmic manifestations in a pedigree. METHODS: Three female siblings, their spouse and offspring underwent ophthalmic and general medical examinations. Genetic variants were screened with the whole exome sequencing and analyzed in either a dominant or recessive inheritance manner. Gene mutations were ascertained with the Sanger sequencing after the polymerase chain reaction. RESULTS: All three female siblings were diagnosed as the Ectopia lentis et pupillae (ELeP) through combination of clinical examination and genetic analysis. No characteristic pathological changes of skeletal, metabolic and cardiac abnormalities were observed. Thirteen genetic variants were selected out through analyzing in the dominant or recessive inheritance manner, but they were not associated with EL. Among them, ALOX15B variant may explain the skin disease in this pedigree. After inspection the known genes related to EL, novel compound heterozygous mutations (p.Ser264LeufsX37/p.Gly757ValfsX62) in ADAMTSL4 were discreetly identified in this ELeP pedigree. CONCLUSIONS: Novel compound heterozygous ADAMTSL4 variants are responsible for ELeP in the current pedigree. Correlation between ADAMTSL4 variants and ELeP was firstly established based on our 12 years follow-up studies and previous reports of ELeP and of ADAMTSL4-related eye disorders. The primary phenotypes caused by ADAMTSL4 variants include EL, EP, poor pupillary dilation, and axial elongation. Highly varying phenotypes including glaucoma, high myopia retinapathy, and poor vision and so on may be the secondary impairments. All these secondary impairments may be improved if proper clinical interventions are implemented in time.

Association between the ABCA1 (R219K) polymorphism and lipid profiles: a meta-analysis.

Conflicting evidence was found about the relationship between lipid profiles and R219K polymorphism in adenosine triphosphate-binding cassette exporter A1 (ABCA1) gene. In this study, four meta-analyses were conducted to assess the effect of R219K on lipid levels, including high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, total cholesterol, and triglycerides (TG). A total of 125 samples of 87 studies (about 60,262 subjects) were included. The effect of each study was expressed using the standard mean difference (SMD) and 95% confidence interval (95% CI) and pooled by meta-analysis in the random-effects model. Subgroup and meta-regression analyses were conducted to explore potential heterogeneity sources. The overall pooled effect showed the following results. (1) The R219K was significantly associated with HDLC level (SMD = - 0.25 mmol/L, 95%CI - 0.32 to - 0.18, z = - 6.96, P < 0.01, recessive genetic model). People with different genotypes had significantly different HDLC levels under the recessive, codominant and dominant genetic models (all Ps < 0.01). (2) A weak and indeterminate relationship between R219K and TG level was observed (SMD = 0.18 mmol/L, 95%CI 0.06-0.30, z = 3.01, P < 0.01, recessive genetic model). These findings suggested that R219K was associated with HDLC and TG levels, which might implicate a promising clinical application for lipid-related disorders, though the influences of race, health status, BMI, and other heterogeneity sources should be considered when interpreting current findings. The protocol was registered at PROSPERO (registration number: CRD42021231178).

Intranasal oxytocin administration but not peripheral oxytocin regulates behaviors of attachment insecurity: A meta-analysis.

In light of the roles of oxytocin (OT) in social bonding and interpersonal relationship, studies have examined the roles of OT in human attachment, but by and large previous findings are inconsistent. Here, we conducted - meta-analyses to estimate the associations between peripheral OT level (e.g., blood and salivary OT) and attachment (i.e., attachment dimensions and behaviors of attachment insecurity) and examine the effects of intranasal OT administration on behaviors of attachment insecurity. The analyses indicated that: (1) Peripheral OT level was not significantly associated with attachment dimensions (e.g., attachment anxiety and attachment avoidance) and behaviors of attachment insecurity; (2) intranasal OT administration significantly reduced behaviors of attachment insecurity of neutral contexts, particularly behaviors of attachment avoidance. The findings suggest that intranasal OT administration is an available approach for reducing behaviors of attachment insecurity of interpersonal situations with ambiguous social cues, which implicates suggestions for therapeutic treatments of attachment-related dysfunctions.

Genetic Variants of the MTMR9 Gene Are Associated with Nonspecific Intellectual Disability: A Family-Based Association Study.

Background: Mutations within the myotubularin-related protein 9 gene (MTMR9) have been identified in several families with nonsyndromic intellectual disability (NSID), a generalized neurodevelopmental disorder; however, the relationship between MTMR9 and NSID needs to be verified using a larger sample size. Aim: To explore whether genetic variants in the MTMR9 gene are linked to susceptibility of NSID among the Chinese population. Materials and Methods: Seven single nucleotide polymorphisms (SNPs) of the MTMR9 gene (rs4559208, rs3824211, rs2164272, rs2164273, rs1897951, rs6991606, and rs7815802) were analyzed using family-based association testing among 258 Han Chinese NSID families. Results: Three SNPs of MTMR9 were significantly associated with NSID (z = 2.152, p = 0.031 for rs4559208; z = 2.403, p = 0.016 for rs2164273; and z = 2.758, p = 0.006 for rs7815802). Three alleles of these SNPs were more likely to be transferred from the carrier parents to the affected offspring. Haplotypes constructed using these SNPs also showed a similar transmitting trend (z = 2.505, p = 0.012, χ2(3) = 8.835, and global p = 0.032). Carriers with the G-G-C haplotype showed a higher risk of NSID (odds ratio = 1.46, 95% confidence interval [1.01-2.09], p = 0.04) than others. In silico functional predictions supported an etiological role for these three SNPs in NSID biology. Conclusions: This study provides additional insights into the association of NSID with specific alleles, and haplotypes within the MTMR9 gene. Genotypic analyses of the MTMR9 gene should be considered for patients presenting with NSID of unknown etiology.

Revisiting the relationships of 2D:4D with androgen receptor (AR) gene and current testosterone levels: Replication study and meta-analyses.

The relationships of digit ratio (2D:4D) with the length of AR (CAG)n, and testosterone levels from saliva and blood have been extensively debated over the years. This research including three studies further clarifies such controversies. To do so, we re-examined the relationships between the length of AR (CAG)n, 2D:4D, and current testosterone levels, through replication study and meta-analysis for each study. The results indicate: (a) the length of AR (CAG)n is not significantly associated with 2D:4D; (b) current testosterone levels are not significantly associated with the ratio; and (c) the length is not significantly associated with testosterone levels. Thus, AR (CAG)n and current testosterone levels are not significantly related to 2D:4D at individual level.

Prediction of Alzheimer's disease with serum lipid levels in Asian individuals: a meta-analysis.

Background: The serum lipid profile has become a routine clinical test and used as an important predictor for Alzheimer's disease (AD), although its predictive value remains undetermined. Objective: To evaluate the role of serum lipid levels in predicting the risk of AD. Methods: Meta-analyses were conducted using Comprehensive Meta-analyses (CMA) software to investigate the association between four conventional serum lipid profile parameters and the risk of AD, focused on samples from Asian. Results: In total, 3423 AD patients and 6127 healthy participants were involved. The results demonstrated that AD patients showed higher LDL-C and TC levels (SMD = 0.27, 95% CI: 0.04-0.51, p = 0.02 for LDL-C; SMD = 0.25, 95% CI: 0.05-0.46, p = 0.02 for TC) compared with those of healthy controls. People with higher LDL-C and/or TC levels had an increased risk of AD (OR = 1.64, 95% CI: 1.07-2.51 for LDL-C and OR = 1.58, 95% CI: 1.10-2.92 for TC). Conclusions: This study provided evidence that serum LDL-C and TC levels were associated with the risk of AD in Asian individuals. The routine lipid profile may be useful for AD diagnosis, monitoring and treatment.

Mutations of ARX and non-syndromic intellectual disability in Chinese population.

Mutations of Aristaless-related homeobox (ARX) gene were looked as the third cause of non-syndromic intellectual disability (NSID), while the boundary between true disease-causing mutations and non-disease-causing variants within this gene remains elusive. To investigate the relationship between ARX mutations and NSID, a panel comprising six reported causal mutations of the ARX was detected in 369 sporadic NSID patients and 550 random participants in Chinese. Two mutations, c.428_451 dup and p.G286S, may be disease-causing mutations for NSID, while p.Q163R and p.P353L showed a great predictive value in female NSID diagnosis with significant associations (X2 = 19.60, p = 9.54e-6 for p.Q163R; X2 = 25.70, p = 4.00e-07 for p.P353L), carriers of these mutations had an increased risk of NSID of more than fourfold. Detection of this panel also predicted significant associations between genetic variants of the ARX gene and NSID (p = 3.73e-4). The present study emphasized the higher genetic burden of the ARX gene on NSID in the Chinese population, molecular analysis of this gene should be considered for patients presenting NSID of unknown etiology.

Genetic variants of SLC12A3 modulate serum lipid profiles in a group of Mongolian pedigree population.

BACKGROUND: The serum lipid profile, including LDL-C level, is associated with hypertension which is the major cause of cerebrovascular disease (CVD) amounting 30% of global death rate. Previous work also demonstrated important roles of genetic variants of SLC12A3 gene on human CVD, hypertension and other diseases in Mongolian population. However, the relationship between SLC12A3 gene polymorphisms on individuals' lipid profile is still unknown. METHODS: A panel of 15 SNPs of SLC12A3 gene was genotyped within a 424 Mongolians pedigree cohort. The associations between SLC12A3 polymorphisms and four lipid profiles were analyzed by family-based association test (FBAT) and confirmed with haplotype analysis. RESULTS: From both single site and haplotype analyses, the results demonstrated a close relationship between SLC12A3 polymorphisms and LDL-C level. Two SNPs, rs5803 and rs711746 showed significant associations with individuals' serum LDL-C level (z = - 2.08, P -e = 0.038; z = 2.09, P -e = 0.023, respectively), and distribution of haplotypes constructed by two SNPs also associated with participants' serum LDL-C level, significantly (Global Chi2 = 9.06 df = 3, P = 0.028). CONCLUSION: Our results demonstrated the importance of SLC12A3 polymorphisms in individuals' difference about their serum lipid profiles, thereby providing evidence that the genetic variants may contribute to CVD development via modulating person's LDL-C level and blood pressure, in certain contexts.

MiR-767 promoted cell proliferation in human melanoma by suppressing CYLD expression.

MicroRNAs (miRNAs) have emerged as critical regulators for cancer development and progression of human melanoma. However, the potential molecular mechanism of miR-767 in human melanoma has not been intensively investigated. In this present study, we confirmed that miR-767 was frequently up-regulated in human melanoma tissues and cell lines. Ectopic expression of miR-767 promoted cell proliferation in human melanoma cell lines A375 and WM35, whereas miR-767-in reversed the function. Bioinformatics analysis revealed that cylindromatosis (CYLD) was hypothesized to be a possible target gene of miR-767, and this was confirmed by luciferase activity assay. Knockdown of CYLD counteracted the proliferation arrest by miR-767-in in melanoma cells A375 and WM35. In conclusion, our study indicated that miR-767 acted as a role of tumor promoter by targeting CYLD in human melanoma, and might serve as a prognostic or therapeutic target for human melanoma.

Independent self-construal mediates the association between CYP19A1 gene variant and subjective well-being.

Testosterone and estrogen are involved in self-related behavioral dispositions and experiences of subjective well-being. In this study, we investigated to what extent the aromatase (CYP19A1) gene, which encodes an enzyme in converting testosterone into estrogen, contributes to subjective well-being and in another self-related disposition: independent and interdependent self-construal. In study 1, a meta-analysis showed that the GG genotype of CYP19A1 (a G/A substitution at Val80, rs700518) was associated with higher testosterone and lower estradiol. In study 2, an empirical study of individuals with the GG (n=115), AG (n=286) and AA (n=193) genotypes indicated that individuals with the GG genotype exhibited higher independent self-construal and higher subjective well-being. The association between the GG genotype of CYP19A1 Val80 and subjective well-being was mediated by the independent self-construal. Our findings reinforce the idea that personality traits such as independent self-construal explain the link between genetic variant and subjective well-being.

Revisiting the impact of OXTR rs53576 on empathy: A population-based study and a meta-analysis.

Oxytocin in the brain is related to empathy, which refers to the ability to understand and share others' internal states or responses. Previous studies have investigated the impact of OXTR rs53576, the most intensively examined polymorphism in the oxytocin receptor (OXTR) gene, on individual differences in empathy. However, these studies produced inconsistent results. In the current study, we reexamined the association of OXTR rs53576 with empathy in a relatively large population (N=1830) and also evaluated the association by a comprehensive meta-analysis (N=6631, 13 independent samples). The replication study indicated that OXTR rs53576 was indeed associated with individual differences in empathy. Individuals with a greater number of G alleles showed better empathic ability, particularly in fantasizing other's feelings and actions. The meta-analysis not only confirmed this association, but also indicated that the impact of this polymorphism was significant in both Europeans and Asians. These findings provide convincing evidence for the impact of OXTR rs53576 on empathy, highlighting the importance of OXTR gene in individuals' social cognition.

SLC12A3 variants modulate LDL cholesterol levels in the Mongolian population.

BACKGROUND: Abnormalities in lipid metabolism are crucial factors in the pathogenesis of cardiovascular disease (CVD). Variants of many genes have been verified to confer risk for lipid metabolism abnormalities. However, the relationship between genetic variants of the NCC-encoding SLC12A3 gene and lipid metabolism in the Mongolian population remains unclear. In the present study, we aimed to elucidate the effects of SLC12A3 variants on Mongolian lipid metabolism, including total cholesterol (TCHO), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c). METHODS: A randomly selected population of Mongolians (n = 331) from China underwent clinical testing. An ANOVA test, Kruskal-Wallis H test (K-W test) and haplotype analysis were used to evaluate the association between the levels of lipids (TCHO, TG, LDL-c, and HDL-c) and polymorphisms in SLC12A3 loci. RESULTS: We identified three single nucleotide polymorphisms (SNPs) rs5803, rs2010501 and rs711746 in the SLC12A3 gene that were significantly associated with an individual's serum LDL-c level. Haplotypes combining these SNPs also showed the same trend (all p values < 0.01). Furthermore, the influence of SLC12A3 genetic polymorphisms on differences in individual serum LDL-c levels remained significant, even after we controlled gender, and demographic and other non-genetic factors. CONCLUSION: These results suggest that variants of the SLC12A3 gene confer susceptibility to the abnormal serum LDL-c level in the Mongolian population.

Genetic Polymorphism of GABRR2 Modulates Individuals' General Cognitive Ability in Healthy Chinese Han People.

Previous studies have indicated that the cognitive impairment or deficit is associated with GABAergic signaling in central nervous system. Inspired by the finding that receptor GABRR2 modulates concentration of GABA and phasic inhibitory GABAergic transmission in brain. This study investigated to what extent a genetic variant (c.1423C>T, rs282129) of GABRR2 gene modulates individuals' general cognitive ability in 987 Chinese Han people. Results showed a significant influence of GABRR2 gene polymorphism on individuals' Raven's Standard Progressive Matrices (RSPM) performance (F = 3.58, P = .028 by ANOVA and χ 2 = 9.35, P = .009 by K-W test, respectively), even if non-genetic factors were partialed out (gender, major, types of birthplace, and socioeconomic index) (B = -.67, SE = .26, t = 2.63, P = .009). The finding provided a strong evidence, to our knowledge, for the view that genetic variant of GABRR2 gene may contribute to the difference of individuals' general cognitive ability, independently.

The c.553G>T Genetic Variant of the APOA5 Gene and Altered Triglyceride Levels in the Asian Population: A Meta-Analysis of Case-Control Studies.

AIM: To explore the association of the APOA5 gene c.553G>T polymorphism with hypertriglyceridemia (HTG) susceptibility and altered triglyceride levels. METHODS: We searched the PubMed, Google Scholar, and CNKI databases for published studies relating to analyses of these associations. Case-control and comparative studies of the association between the APOA5 c.553G>T variant and altered triglyceride levels were included. In total, the meta-analysis involved 10 studies on HTG, which provided 2219 cases and 3401 controls. To measure the correlation between the c.553G>T polymorphism and HTG susceptibility, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. The overall OR was calculated using a random-effects model. RESULTS: Compared with APOA5 c.553 GG carriers, c.553T carriers displayed an increased risk of HTG in the Asian population, with an overall random effects OR of 3.55 (95% CI: 2.46-5.13) in the dominant model. There was significant heterogeneity among the studies (Pheterogeneity: Chi2 = 45.80, I2 = 75.98%), which may be largely explained by certain patient types. Both the sensitivity analysis and publication bias suggested that the overall result was acceptable. Subgroup analysis showed a large difference in serum triglyceride levels based on the c.553 G > T polymorphism in healthy individuals and HTG patients. APOA5 c.553T carriers exhibit higher triglyceride levels than GG carriers. CONCLUSION: Our results suggest that APOA5 c. 553T is an independent risk factor for HTG and increased triglyceride levels in the Asian population. APOA5 c. 553T could be employed as a genetic risk marker for HTG and increased triglyceride levels.

Polymorphic variation in CHAT gene modulates general cognitive ability: An association study with random student cohort.

The choline O-acetyltransferase (CHAT) gene has been associated with various human disorders that involve cognitive impairment or deficiency. However, the influence of disease-associated variants of CHAT on normal individuals remains dubious. Here we demonstrated the impact of CHAT sequence variants (G-120A) on general human cognitive ability in a cohort of 750 Chinese undergraduate students. A multiple choice questionnaire was used to obtain basic demographic information, such as parents' occupations and education levels. We also administered and scored the Raven's Standard Progressive Matrices (RSPM). A one-way analysis of variance (ANOVA) and Kruskal-Wallis test (K-W) revealed a significant association between sequence polymorphisms of G-120A and individuals' Raven score (p=0.031 for ANOVA and p=0.026 for K-W tests). Moreover, further hierarchical analysis showed a similar trend in the association between G-120A variants and Raven scores only in the female subjects (p=0.008 for ANOVA and p=0.024 for K-W tests) but not in the male subjects. The results of a multiple linear regression confirmed that after we controlled gender, age, birthplace and other non-genetic factors, CHAT G-120A polymorphisms still significantly influenced individual Raven scores (B=-0.70, SE=0.28, t=-2.50, p=0.013). Our results demonstrated that sequence variants of CHAT were associated with human cognitive ability in not only patients with psychiatric disorders but also normal healthy individuals. However, some issues remained indeterminable, such as gender differences and the extent of the influence on individuals' general cognitive abilities; thus, the further research using an independent random sample was required.