A Systematic Review and Meta-Analysis of Pharmacogenetic Studies in Patients with Chronic Kidney Disease

Chronic kidney disease (CKD) is an important global public health problem due to its high prevalence and morbidity. Although the treatment of nephrology patients has changed considerably, ineffectiveness and side effects of medications represent a major issue. In an effort to elucidate the contribution of genetic variants located in several genes in the response to treatment of patients with CKD, we performed a systematic review and meta-analysis of all available pharmacogenetics studies. The association between genotype distribution and response to medication was examined using the dominant, recessive, and additive inheritance models. Subgroup analysis based on ethnicity was also performed. In total, 29 studies were included in the meta-analysis, which examined the association of 11 genes (16 polymorphisms) with the response to treatment regarding CKD. Among the 29 studies, 18 studies included patients with renal transplantation, 8 involved patients with nephrotic syndrome, and 3 studies included patients with lupus nephritis. The present meta-analysis provides strong evidence for the contribution of variants harbored in the ABCB1, IL-10, ITPA, MIF, and TNF genes that creates some genetic predisposition that reduces effectiveness or is associated with adverse events of medications used in CKD.

Cannabinoid CB2 Receptor Functional Variation (Q63R) is Associated with COVID-19 Severity: from Human Study to Molecular Docking

Background: Evidence supports the role of host genetic diversity for the clinical course variation of coronavirus disease 2019 (COVID-19). Variation in the cannabinoid CB2 receptor gene (CNR2) could affect the endocannabinoids regulatory actions on the immune system, resulting in an increased risk of various inflammatory diseases. The present study investigated the relationship between the CNR2 rs35761398 (Q63R) functional variation and COVID-19 severity. Results: A total of 200 Iranian COVID-19 patients (100 expired and 100 discharged) were enrolled in the study and genotyped through TaqMan assay. The co-dominant, dominant, recessive, over-dominant, and additive inheritance models were analyzed using SNPStats software. In silico molecular docking was also performed to simulate the effects of Q63R variation on CB2 binding with a ligand and with G-protein. A significant difference in the Q63R allele and genotype distributions was found between COVID-19 expired and discharged patients in co-dominant (OR: 3.33, 95% CI: 1.25-8.88, p = 0.043), recessive (OR: 2.92, 95% CI: 1.16-7.33, p = 0.017), and additive inheritance (OR: 1.62, 95% CI: 1.06-2.48, p = 0.025) models. The molecular docking results showed that the predicted structure of mutant CB2 (63R type) could not bind to G-protein in the correct position.Conclusions: The data implied the involvement of the CNR2 gene in the severity of COVID-19 in Iranian patients. Identification of genes related to susceptibility and severity of COVID-19 may lead to specific targets for repurposing or drug development.

EVALUATION OF PURE AND CROSSBRED PARENT STOCK PULLETS

The relationships between egg weight, body weight and sexual maturity and their inheritance were studied in the F1 of two grandparent strains of laying birds. Each strain had two lines. Data used for analyses comprised body weight at first egg, 30 weeks and 40 weeks of age (BFE, B30 and B40); weight of first egg (WFE), weight of egg at 30 weeks and 40 weeks (W30, W40) and age of birds at first egg (AFE). Phenotypic correlations between AFE and BFE, AFE and WFE and between WFE and BFE were 0.45 and 0.40; 0.96 and 0.11, 0.65 and 0.85 for male and female lines respectively. While AFE generally showed additive inheritance which was sire influenced, BFE and WFE were line dependent. The crossbred groups however, appeared to be at advantage over the purebreds in respect of these three traits.

Association Analysis between SNPs in LATS1 and LATS2 and Non-Cardia Gastric Cancer

Background: Many studies have found that large tumor suppressor kinase 1 (LATS1) and LATS2 play important roles in many diseases, but studies have been rare on the relationship between these genes and non-cardia gastric cancer (GC). We performed a case-control association study to investigate the associations between single nucleotide polymorphisms (SNPs) in LATS1 and LATS2 genes and Helicobacter pylori (H. pylori) infection as well as the risk of non-cardia GC. Methods: First, H. pylori infection was determined by the serological test using enzyme-linked immunoassay. Then genotyping of SNPs was performed for 808 samples by the Taqman method. Finally, unconditional logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for age and gender, for the association of each SNP with the infection of H. pylori, the risk of non-cardia gastric cancer, as well as the expression of LATS1 and LATS2 proteins in non-cardia GC tissues, using the codominant, dominant, recessive, overdominant, and additive inheritance models, respectively. Results: The statistical results showed that LATS2 rs9552315 was associated with H. pylori infection, and the CC+CT genotype could reduce the risk of H. pylori infection (odds ratio [OR]: 0.549, 95% confidence interval [CI]: 0.339–0.881, P<0.05) compared with the TT genotype in a dominant model. LATS1 rs9393175 was associated with the risk of non-cardia GC, and the AG genotype reduced the risk of non-cardia GC (OR: 0.702, 95% CI: 0.516–0.952, P<0.05) compared with the GG+AA genotype in an overdominant model. LATS2 rs9509492 was associated with the risk of GC in an additive model. No associations were found between five SNPs and expression of LATS1 and LATS2 proteins in non-cardia GC tissue. Conclusions: LATS2 rs9552315 CT genotype may be a protective factor against infection of H. pylori. LATS1 rs9393175 AG genotype and LATS2 rs9509492 GG genotype may be protective factors for non-cardia GC.

The Ser290Asn and Thr715Pro Polymorphisms of the SELP Gene Are Associated with A Lower Risk of Developing Acute Coronary Syndrome and Low Soluble P-Selectin Levels in A Mexican Population

Recent studies have shown that P-selectin promotes the early formation of atherosclerotic plaque. The aim of the present study was to evaluate whether the SELP gene single nucleotide polymorphisms (SNPs) are associated with presence of acute coronary syndrome (ACS) and with plasma P-selectin levels in a case-control association study. The sample size was estimated for a statistical power of 80%. We genotyped three SELP (SELP Ser290Asn, SELP Leu599Val, and SELP Thr715Pro) SNPs using 5’ exonuclease TaqMan assays in 625 patients with ACS and 700 healthy controls. The associations were evaluated with logistic regressions under the co-dominant, dominant, recessive, over-dominant and additive inheritance models. The genotype contribution to the plasma P-selectin levels was evaluated by a Student’s t-test. Under different models, the SELP Ser290Asn (OR = 0.59, pCCo-Dominant = 0.047; OR = 0.59, pCDominant = 0.014; OR = 0.58, pCOver-Dominant = 0.061, and OR = 0.62, pCAdditive = 0.015) and SELP Thr715Pro (OR = 0.61, pCDominant = 0.028; OR = 0.63, pCOver-Dominant = 0.044, and OR = 0.62, pCAdditive = 0.023) SNPs were associated with a lower risk of ACS. In addition, these SNPs were associated with low plasma P-selectin levels. In summary, this study established that the SELP Ser290Asn and SELP Thr715Pro SNPs are associated with a lower risk of developing ACS and with decreased P-selectin levels in plasma in a Mexican population.

Variation and inheritance of small RNAs in maize inbreds and F1 hybrids

Small RNAs (sRNAs) regulate gene expression, play important roles in epigenetic pathways, and have been hypothesised to contribute to hybrid vigor in plants. Prior investigations have provided valuable insights into associations between sRNAs and heterosis, often using a single hybrid genotype or tissue. However, our understanding of the role of sRNAs and their potential value to plant breeding are limited by an incomplete picture of sRNA variation between diverse genotypes and development stages. Here, we provide a deep exploration of sRNA variation and inheritance among a panel of 108 maize samples spanning five tissues from eight inbred parents and 12 hybrid genotypes, covering a spectrum of heterotic groups, genetic variation, and levels of heterosis for various traits. We document substantial developmental and genotypic influences on sRNA expression, with varying patterns for 21-nt, 22-nt and 24-nt sRNAs. We provide a detailed view of the distribution of sRNAs in the maize genome, revealing a complex make-up that also shows developmental plasticity, particularly for 22-nt sRNAs. sRNAs exhibited substantially more variation between inbreds as compared to observed variation for gene expression. In hybrids, we identify locus-specific examples of non-additive inheritance, mostly characterised as partial or complete dominance, but rarely outside the parental range. However, the global abundance of 21-nt, 22-nt and 24-nt sRNAs varies very little between inbreds and hybrids, suggesting that hybridization affects sRNA expression principally at specific loci rather than on a global scale. This study provides a valuable resource for understanding the potential role of sRNAs in hybrid vigor.One-sentence summaryCharacterizing the roles of development and genotype in driving expression variation of different small RNA populations in maize inbreds and their F1 hybrids.

Non-linear phenotypic variation uncovers the emergence of heterosis inArabidopsis thaliana

Heterosis describes the phenotypic superiority of hybrids over their parents in traits related to fitness. Understanding and predicting non-additive inheritance such as heterosis is crucial for evolutionary biology, as well as for plant and animal breeding. However, the physiological bases of heterosis remain debated. Moreover, empirical data in various species have shown that diverse genetic and molecular mechanisms are likely to explain heterosis, making it difficult to predict its emergence and amplitude from parental genotypes alone. In this study, we evaluated a model of physiological dominance proposed by Sewall Wright to explain the non-additive inheritance of metabolic fluxes at the cellular level. We used 450 hybrids derived from crosses among natural inbred accessions ofArabidopsis thalianato test Wright’s model for two fitness-related traits at the whole-plant level: growth rate and fruit number. We found that allometric relationships between traits constrain phenotypic variation in hybrids and inbreds to a similar extent. These allometric relationships behave predictably, in a non-linear manner, explaining up to 75% of heterosis amplitude, while genetic distance among parents at best explains 7%. Thus, our findings are consistent with Wright’s model of physiological dominance on plant performance, and suggest that the emergence of heterosis is an intrinsic property of non-linear relationships between traits. Furthermore, our study highlights the potential of a geometric approach of phenotypic relationships for predicting heterosis of two major components of crop productivity and yield.

GxEMM: Extending linear mixed models to general gene-environment interactions

Gene-environment interaction (GxE) is a well-known source of non-additive inheritance. GxE can be important in applications ranging from basic functional genomics to precision medical treatment. Further, GxE effects elude inherently-linear LMMs and may explain missing heritability. We propose a simple, unifying mixed model for polygenic interactions (GxEMM) to capture the aggregate effect of small GxE effects spread across the genome. GxEMM extends existing LMMs for GxE in two important ways. First, it extends to arbitrary environmental variables, not just categorical groups. Second, GxEMM can estimate and test for environment-specific heritability. In simulations where the assumptions of existing methods do not hold, we show that GxEMM improves estimates of ordinary and GxE heritability and increases power to test for polygenic GxE. We then use GxEMM to prove that the heritability of major depression (MD) is reduced by stress, which we previously conjectured but could not prove with prior methods, and that a tail of polygenic GxE effects remains unexplained by MD GWAS.