Annals of Human Genetics最新文献

Acute myelitis (AM) is a rare neuro-immune spinal cord disease. This study sought to explore the transcription level of glucocorticoid (GC) receptors α and β (GR-α/GR-β) in peripheral blood mononuclear cells (PBMCs) and their correlation with GC efficacy and sensitivity in AM patients. AM patients were grouped into the GC-sensitive group (N = 80) and GC-refractory group (N = 67). The GR-α and GR-β mRNA levels in PBMCs were detected. The differentiating value of GR-α, GR-β, and GR-α + GR-β on GC sensitivity and resistance in AM patients was assessed. The independent correlation between GR-α and GR-β mRNA levels and GC sensitivity in AM patients,t and the correlation between GR-α and GR-β mRNA levels and spinal function after GC treatment were analyzed. GR-α mRNA level in PBMCs of GC-refractory patients was lower than that of GC-sensitive patients, while GR-β mRNA level was higher than that of GC-sensitive patients. GR-α + GR-β mRNA had a high diagnostic value for GC sensitivity and resistance in AM patients (area under the ROC curve = 0.881, sensitivity = 79.1%, specificity = 85.0%). GR-α and GR-β mRNA levels were independently correlated with GC sensitivity. GR-α and GR-β mRNA levels were correlated with the spinal function of AM patients after GC treatment. Overall, GR-α and GR-β mRNA levels in PBMCs of AM patients can assist in the identification of GC sensitivity and are correlated with GC efficacy.

One of the critical issues in genetic association studies is to evaluate the risk of a disease associated with gene–gene or gene–environment interactions. The commonly employed procedures are derived by assigning a particular set of scores to genotypes. However, the underlying genetic models of inheritance are rarely known in practice. Misspecifying a genetic model may result in power loss. By using some potential genetic variables to separate the genotype coding and genetic model parameter, we construct a model-embedded score test (MEST). Our test is free of assumption of gene–environment independence and allows for covariates in the model. An effective sequential optimization algorithm is developed. Extensive simulations show the proposed MEST is robust and powerful in most of scenarios. Finally, we apply the proposed method to rheumatoid arthritis data from the Genetic Analysis Workshop 16 to further investigate the potential interaction effects.

Despite the robustness of DRD4 polymorphism associations with brain-based behavioral characteristics in candidate gene research, investigations have minimally explored associations between these polymorphisms and emotional responses. In particular, the prevalent single nucleotide polymorphism (SNP) -521C/T (rs1800955) in the promoter region of DRD4 remains unexplored relative to emotions. Here, two independent samples were evaluated using different emotion elicitation tasks involving social stimuli: Study 1 (N = 120) evoked positive and negative emotional responses to validated film clips; Study 2 (N = 122) utilized Cyberball to simulate social rejection and acceptance. Across studies, C/C individuals self-reported higher mean positive affect scores using Likert scales versus T carrier individuals, selectively when presented with neutral or negative (but not positive) social stimuli. The consistent findings across these two studies supports a functional consequence of this DRD4 SNP on emotion processing during changing social contexts. Continued investigation will help clarify if a C/C genotype enhances positive emotions under negative circumstances, or if the presence of the T allele reduces positive emotions, and how rs1800955 behavioral associations might generalize across different demographics. Future studies could also reveal if this SNP interacts with other changing environmental conditions to affect emotional responses, such as social limitations during the COVID-19 pandemic.

Primary microcephaly and Seckel syndrome are rare genetically and clinically heterogenous brain development disorders. Several exonic/splicing mutations are reported for these disorders to date, but ∼40% of all cases remain unexplained. We aimed to uncover the genetic correlate(s) in a family of multiple siblings with microcephaly. A novel homozygous intronic variant (NC_000013.10:g.25459823T>C) in CENPJ (13q12) segregating with all four affected male siblings was identified by exome sequencing and validated by targeted linkage approach (logarithm of the odds score 1.8 at θ 0.0). RT-PCR of CENPJ in affected siblings using their EBV derived cell lines showed aberrant transcripts suggestive of exon skipping confirmed by Sanger sequencing. Significantly reduced wild type transcript/protein in the affected siblings having the splice variant indicates a leaky gene expression of pathological relevance. Based on known CENPJ function, assessing for mitotic alterations revealed defect in centrosome duplication causing mono/multicentrosome(s) at prophase, delayed metaphase, and unequal chromosomal segregation in patient cells. Clinical features witnessed in this study expand the spectrum of CENPJ-associated primary microcephaly and Seckel syndrome. Furthermore, besides the importance of regulatory variants in classical monogenic disorders these findings provide new insights into splice site biology with possible implications for ASO-based therapies.

Background

The circadian locomotor output cycles kaput (CLOCK) gene and the alcohol dehydrogenase 4 (ADH4) gene are promising candidates for susceptibility to cluster headaches (CH). Associations of the three single nucleotide polymorphisms (SNPs)—CLOCK SNP rs1801260 and ADH4 SNPs rs1800759, and rs1126671—with CH were studied previously, but the results were inconsistent.

Methods

Associations between the three SNPs (rs1801260, rs1126671, and rs1800759) and CH risk were separately assessed by pooled odds ratios (ORs) along with 95% confidence intervals (95% CIs) based on five different genetic models. Methodological quality was assessed using the Newcastle–Ottawa Quality Assessment Scale (NOS). All statistical analyses were carried out with RevMan 5.3 software.

Results

Eight studies involving 1437 CH patients and 2541 healthy controls were selected for quantitative synthesis, from five studies on CLOCK rs1801260, five on ADH4 rs1800759, and three on ADH4 rs1126671. Our pooled data did not support associations between the three SNPs (rs1801260 in the CLOCK gene, rs1800759 and rs1126671 in the ADH4 gene) and susceptibility to CH (rs1801260: OR 1.10, 95% CI: 0.95–1.28; p = 0.19; rs1800759: OR 1.06, 95% CI: 0.93–1.22; p = 0.37; and rs1126671: OR 1.09, 95% CI: 0.92–1.28; p = 0.32).

Conclusion

We found no significant associations between the three SNPs (rs1801260 in the CLOCK gene and rs1800759 and rs1126671 in the ADH4 gene) and the susceptibility to CH across both Caucasian and Asian ethnicities in our meta-analysis.

Purpose

The polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene C677T has been linked to H-type hypertension. But the conclusion remained controversial. To elucidate this issue, we performed a comprehensive meta-analysis to analyze the MTHFR C677T polymorphism and H-type hypertension.

Materials and methods

The English and Chinese databases were systematically searched to identify relevant studies until November 2020. RevMan 5.3 and Stata 12.0 software were used for meta-analysis. The odds ratio (ORs) and 95% confidence intervals (95% CIs) were used to assess the relationship between the MTHFR C677T polymorphism and H-type hypertension.

Results

A total of 14 studies involving 1769 cases and 1443 controls were included. The meta-analysis results showed the association between MTHFR C677T polymorphism and H-type hypertension with the homozygous codominant model (OR = 3.30, 95% CI = 1.94–5.60), heterozygous codominant model (OR = 2.34, 95% CI = 1.53–3.58), dominant model (OR = 1.79, 95% CI = 1.33–2.41), recessive model (OR = 2.70, 95% CI = 1.73–4.21),and the allelic model (OR = 1.82, 95% CI = 1.41–2.35). All p-values were less than 0.05. Therefore, MTHFR C677T polymorphism has a positive correlation with the risk of H-type hypertension. Among them, TT mutation has the greatest impact on the activity of this enzyme, which causes Hcy to rise and leads to H-type hypertension.

Conclusion

In summary, our results provide sufficient data to support the hypothesis that the MTHFR C677T polymorphism is related to H-type hypertension susceptibility.

Metabolic syndrome (MetS) is diagnosed by the presence of high scores on three or more metabolic traits, including systolic and diastolic blood pressure (SBP, DBP), glucose and insulin levels, cholesterol and triglyceride (TG) levels, and central obesity. A diagnosis of MetS is associated with increased risk of cardiovascular disease and type 2 diabetes. The components of MetS have long been demonstrated to have substantial genetic components, but their genetic overlap is less well understood. The present paper takes a multi-prong approach to examining the extent of this genetic overlap. This includes the quantitative genetic and additive Bayesian network modeling of the large TwinsUK project and examination of the results of genome-wide association study (GWAS) of UK Biobank data through use of LD score regression and examination of the number of genes and pathways identified in the GWASes which overlap across MetS traits. Results demonstrate a modest genetic overlap, and the genetic correlations obtained from TwinsUK and UK Biobank are nearly identical. However, these correlations imply more genetic dissimilarity than similarity. Furthermore, examination of the extent of overlap in significant GWAS hits, both at the gene and pathway level, again demonstrates only modest but significant genetic overlap. This lends support to the idea that in clinical treatment of MetS, treating each of the components individually may be an important way to address MetS.

Aim

Nonalcoholic fatty liver disease (NAFLD) is a complex metabolic condition in which both lifestyle and genetic factors have a pathogenic role. The LEP gene encodes leptin, which regulates appetite, body weight, and several metabolic functions. Proopiomelanocortin (POMC), regulates food intake and energy balance. The aim of the study was to determine partial or complete deletions of genes associated with obesity in patients diagnosed with NAFLD.

Material and methods

Blood samples and DNA from 43 individuals diagnosed with NAFLD by ultrasonographic technique (Fibroscan) were obtained. The partial or complete deletions of genes were determined by MLPA (Multiplex Ligation-dependent Probe Amplification) using the SALSA probemix P220-B2 Obesity only on 43 individuals. Fifty blood samples from healthy individuals were included.

Results

Eleven out of 43 individuals analyzed by MLPA presented some deletion of the genes analyzed: six were female and five were male. The partial or complete deletion of the LEPR and POMC genes was observed in eight patients (18.6%), SIM1 in six patients (13.9%), GRIK2 and SH2B1 in two patients (4.7%), SEZGL2 in four patients (9.3%), and MCR4 in one patient (2.3%).

Conclusion

Partial deletion was observed in LEPR, POMC, SIM1, GRIK2, SH2B1, SEZGL2, and MCR4 genes in 26% of the cases, and we suggest that these alterations probably has a potential relationship for the development of NAFLD.