Meta-analysis Followed by Replication Identifies Loci in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as Associated with Systemic Lupus Erythematosus in Asians

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic involvement and ethnic differences. Susceptibility genes identified so far only explain a small portion of the genetic heritability of SLE, suggesting that many more loci are yet to be uncovered for this disease. In this study, we performed a meta-analysis of genome-wide association studies on SLE in Chinese Han populations and followed up the findings by replication in four additional Asian cohorts with a total of 5,365 cases and 10,054 corresponding controls. We identified genetic variants in or near CDKN1B, TET3, CD80, DRAM1, and ARID5B as associated with the disease. These findings point to potential roles of cell-cycle regulation, autophagy, and DNA demethylation in SLE pathogenesis. For the region involving TET3 and that involving CDKN1B, multiple independent SNPs were identified, highlighting a phenomenon that might partially explain the missing heritability of complex diseases

Phenomic analysis of chronic granulomatous disease reveals more severe integumentary infections in X-Linked compared with autosomal recessive chronic granulomatous disease

BACKGROUND : Chronic granulomatous disease (CGD) is an inborn error of immunity (IEI), characterised by recurrent bacterial and fungal infections. It is inherited either in an Xlinked (XL) or autosomal recessive (AR) mode. Phenome refers to the entire set of phenotypes expressed, and its study allows us to generate new knowledge of the disease. The objective of the study is to reveal the phenomic differences between XL and AR-CGD by using Human Phenotype Ontology (HPO) terms. METHODS : We collected data on 117 patients with genetically diagnosed CGD from Asia and Africa referred to the Asian Primary Immunodeficiency Network (APID network). Only 90 patients with sufficient clinical information were included for phenomic analysis. We used HPO terms to describe all phenotypes manifested in the patients. RESULTS : XL-CGD patients had a lower age of onset, referral, clinical diagnosis, and genetic diagnosis compared with AR-CGD patients. The integument and central nervous system were more frequently affected in XL-CGD patients. Regarding HPO terms, perianal abscess, cutaneous abscess, and elevated hepatic transaminase were correlated with XL-CGD. A higher percentage of XL-CGD patients presented with BCGitis/BCGosis as their first manifestation. Among our CGD patients, lung was the most frequently infected organ, with gastrointestinal system and skin ranking second and third, respectively. Aspergillus species, Mycobacterium bovis, and Mycobacteirum tuberculosis were the most frequent pathogens to be found. CONCLUSION : Phenomic analysis confirmed that XL-CGD patients have more recurrent and aggressive infections compared with AR-CGD patients. Various phenotypic differences listed out can be used as clinical handles to distinguish XL or AR-CGD based on clinical features.The Society for Relief of Disabled Children and Jeffrey Modell Foundation.https://www.frontiersin.org/journals/immunologydm2022Paediatrics and Child Healt

Protein genes in repetitive sequence—antifreeze glycoproteins in Atlantic cod genome

Highly repetitive sequences are the bane of genome sequence assembly, and the short read lengths produced by current next generation sequencing technologies further exacerbates this obstacle. An adopted practice is to exclude repetitive sequences in genome data assembly, as the majority of repeats lack protein-coding genes. However, this could result in the exclusion of important genotypes in newly sequenced non-model species. The absence of the antifreeze glycoproteins (AFGP) gene family in the recently sequenced Atlantic cod genome serves as an example. The Atlantic cod (Gadus morhua) genome was assembled entirely from Roche 454 short reads, demonstrating the feasibility of this approach. However, a well-known major adaptive trait, the AFGP, essential for survival in frigid Arctic marine habitats was absent in the annotated genome. To assess whether this resulted from population difference, we performed Southern blot analysis of genomic DNA from multiple individuals from the North East Arctic cod population that the sequenced cod belonged, and verified that the AFGP genotype is indeed present. We searched the raw assemblies of the Atlantic cod using our G. morhua AFGP gene, and located partial AFGP coding sequences in two sequence scaffolds. We found these two scaffolds constitute a partial genomic AFGP locus through comparative sequence analyses with our newly assembled genomic AFGP locus of the related polar cod, Boreogadus saida. By examining the sequence assembly and annotation methodologies used for the Atlantic cod genome, we deduced the primary cause of the absence of the AFGP gene family from the annotated genome was the removal of all repetitive Roche 454 short reads before sequence assembly, which would exclude most of the highly repetitive AFGP coding sequences. Secondarily, the model teleost genomes used in projection annotation of the Atlantic cod genome have no antifreeze trait, perpetuating the unawareness that the AFGP gene family is missing. We recovered some of the missing AFGP coding sequences and reconstructed a partial AFGP locus in the Atlantic cod genome, bringing to light that not all repetitive sequences lack protein coding information. Also, reliance on genomes of model organisms as reference for annotating protein-coding gene content of a newly sequenced non-model species could lead to omission of novel genetic traits

Salivary glands: Echo-planar versus PROPELLER diffusion-weighted MR imaging for assessment of ADCs

Purpose: To compare the image distortion and the quantification variation in parotid gland apparent diffusion coefficients (ADCs) on periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) versus echoplanar diffusion-weighted (DW) magnetic resonance (MR) images and to investigate the relationship between parotid gland ADC and parotid gland fat content. Materials and Methods: This prospective study was approved by a local institutional review board. Written informed consent was obtained from all 33 enrolled healthy volunteers (15 men, 18 women; mean age, 36.4 years ± 11.8 [standard deviation]). All participants underwent 1.5-T non - fat-saturated and fat-saturated PROPELLER DW MR imaging as well as 1.5-T nonaccelerated and twofold-accelerated echo-planar DW MR imaging. Image distortion on the DW images was qualitatively scored, and parotid ADC was quantitatively analyzed. The correlation between parotid ADC and parotid fat content was evaluated by using linear regression analysis. Wilcoxon signed rank and t tests were used for statistical analysis, with Bonferroni correction applied for multiple comparisons. Results: Echo-planar DW images showed distortion, which was completely eliminated on the PROPELLER DW images. The mean parotid ADCs measured with non - fat-saturated PROPELLER (0.670 x 10-3 mm2/sec ± 0.149), nonaccelerated echo-planar (0.892 x 10-3 mm2/sec ± 0.128), twofold-accelerated echo-planar (1.088 x 10-3 mm2/sec x 0.124), and fat-saturated PROPELLER (1.307 x 10-3 mm2/sec ± 0.217) DW imaging differed significantly from one another (P < .001 for all comparisons). Parotid ADC had a significant negative correlation with parotid fat content (x) measured at non - fat-saturated PROPELLER DW imaging: ADC = -0.0087x + 1.1173 (r = 0.80, P < .001). Conclusion: PROPELLER DW imaging pulse sequences can yield distortion-free images for parotid ADC measurements and enable quantitative evaluation of the relationship between parotid ADC and parotid fat content. © RSNA, 2009.Link_to_subscribed_fulltex

Effects of gender, age, and body mass index on fat contents and apparent diffusion coefficients in healthy parotid glands: An MRI evaluation

Objectives: To establish standard apparent diffusion coefficient (ADC) and the fat content as a function of age, gender and body mass index (BMI) in healthy parotid glands, and to address the influences of fat suppression on ADC measurements. Methods: A total of 100 healthy adults (gender and age evenly distributed) were prospectively recruited, with parotid fat content measured from gradient-echo images with fat-water separated using iterative decomposition with echo asymmetry and least squares (IDEAL). The ADCs were estimated using both fat-saturated and non-fat-saturated diffusion-weighted imaging via a periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) technique. Results: Parotid fat content was larger in men than in women by about 10 percentage points (P<0.005), and positively associated with BMI and age for both genders (mostly with P<0.001). ADCs estimated with non-fat-saturated PROPELLER were significantly lower in men than in women (P<0.005), but showed no gender difference if measured using fat-saturated PROPELLER (P=0.840). The negative association between parotid ADC and age/BMI/fat (P<0.001) showed greater regression slopes in non-fat-saturated PROPELLER than in fat-saturated data. Conclusions: Parotid fat content in healthy adults correlates positively with both age and BMI; the correlation with age is gender-dependent. Parotid ADC measurements are strongly influenced by fat saturation. Key Points: • Parotid fat content in healthy adults correlates positively with age and BMI. • The rate of aging-related increase in fat contents is gender-dependent. • Parotid ADC measurements are strongly influenced by fat saturation. © 2014 European Society of Radiology.Link_to_subscribed_fulltex

Parotid fat contents in healthy subjects evaluated with iterative decomposition with echo asymmetry and least squares fat-water separation

Purpose: To evaluate the effectiveness of three fat measurement methods for parotid glands in healthy subjects, with or without metallic dental implants. Materials and Methods: The institutional review board approved this study, with informed consent obtained from 114 volunteers undergoing magnetic resonance (MR) imaging at 1.5 T. Fat-saturated (FS) and non-fat-saturated (NFS) fast spin-echo T1-weighted imaging (T1 method), FS and NFS T2-weighted periodically rotated overlapping parallel lines with enhanced reconstruction fast spin-echo imaging (T2 method), and gradient-echo imaging with fat-water separation using iterative decomposition with echo asymmetry and least squares (IDEAL) method were used to derive parotid fat contents. Two raters examined the homogeneity of fat saturation to determine whether parotid fat quantification was successful, with the success rate in the 114 subjects recorded for each protocol. In subjects whose fat quantification was successful with all three imaging methods, linear regression was used to analyze the correlation between any pair of the three parotid fat content measurement methods. Results: Success rates in parotid fat measurements by using T1, T2, and IDEAL methods were 87.7% (100 of 114), 87.7% (100 of 114), and 100% (114 of 114), respectively. The means of measured parotid fat contents revealed significant differences (P < .001) between any pair of the three measurement methods. The parotid fat contents measured with the three methods were significantly correlated with each other between any pair of combinations. Conclusion: The IDEAL method provided a high success rate for parotid fat measurements, even in subjects with metallic dental implants. © RSNA, 2013.Link_to_subscribed_fulltex