Genetic Model Of Inheritance Research Articles

Missense variant rs75603675 within TMPRSS2 gene is associated with the increased risk of severe form of COVID-19

Host genetics among other factors play an important role in COVID-19 disease severity. TMPRSS2, a serine protease, facilitates the priming of the SARS-CoV-2 spike protein, which is essential for the virus to enter the host cell. Several studies had targeted the TMPRSS2 polymorphisms with respect to SARS-CoV-2 infection and COVID-19 disease severity. Initially, the Whole Exome Sequencing (WES) of 7 healthy individuals and 22 COVID-19 patients with different degrees of disease severity was conducted to find the mutational landscape in different genes. A total of 26 single nucleotide polymorphisms (SNPs) were identified of which six were within the exons of TMPRSS2 (four synonymous and two nonsynonymous variants) while the rest of the 20 SNPs were recognized within the flanking intronic regions of TMPRSS2 gene. The nonsynonymous SNPs, rs75603675 and rs12329760, were further evaluated for association with disease severity in a larger sample size of 120 individuals by PCR followed by Sanger sequencing. Neither allelic nor genotypic distributions of rs12329760 were significantly associated with COVID-19 disease severity. However, individuals harboring the A allele of rs75603675 was found to have higher risk of severe COVID-19 compared to the C allele [OR (95%CI): 1.95 (1.11–3.39), p = 0.019]. Also, the genotype A/A [OR (95%CI): 5.13 (1.00–26.38), p = 0.033] of rs75603675 was associated with increased risk of severe COVID-19 under the recessive genetic inheritance model. Although the impact of COVID-19 pandemic has waned due to vaccination and public health measures, continued research on the association of COVID-19 disease severity and infection susceptibility with host genetics is required to shed valuable insights on the future long-term health effects of COVID-19 and impact of new variants on different populations and enable implication of proper informed healthcare strategies during future public health crises.

Genetic analyses of truncated variant rs200185429 in ZNT8 encoding SLC30A8 gene with respect to prediabetes and type 2 diabetes in Bangladeshi population

Zinc transporter ZnT8, encoded by SLC30A8, is expressed highly in pancreatic β-cells that effluxes Zn2+ into insulin granules which is required to secret insulin from the granules. Genome-wide association study identified twelve loss of function mutations in SLC30A8 that play protective role against type 2 diabetes (T2D). This study aimed to find genetic association of a protein truncating variant rs200185429 in Bangladeshi healthy individuals (n = 184), patients with prediabetes (n = 130) and patients with T2D (n = 179). Genetic association study with respect to rs200185429 was performed using TaqMan® probe followed by allelic discrimination plots. Wild type CC genotype was found to be evenly distributed in healthy individuals (96.2 %), patients with prediabetes (95.38 %) and patients with T2D (94.41 %). CT genotype was more prevalent in T2D (5.59 %), less in healthy individuals (3.38 %). However, TT genotype was absent in the study participants. Mutant T allele was neither associated with prediabetes (OR = 1.22, χ2 = 0.12, p = 0.72) nor with T2D (OR = 1.42, χ2 = 0.52, p = 0.47). Similarly, none of the genetic inheritance models showed statistically significant association with T2D. Thus, a large-scale study is warranted to establish our finding regarding the association of rs200185429 with prediabetes and T2D in Bangladeshi population.

LncRNA GAS8-AS1 dinucleotide genetic variantn.713A>G, n.714T>C is associated with early-stage disease, lymph node, and distant metastasis in differentiated thyroid cancer.

Long noncoding RNAs (lncRNAs) play an essential role in the epigenetic regulation of various key genes involved in vital cellular functions. A somatic dinucleotide mutation in the lncRNA GAS8-AS1 was reported in Chinese papillary thyroid cancer. However, GAS8-AS1 dinucleotide alteration and its impact have never been explored in differentiated thyroid cancers and other populations. We extracted genomic DNA from 265 DTCs and 97 normal healthy subjects, PCR amplified and Sanger sequenced to examine the GAS8-AS1 dinucleotide alteration. Calculated genotype/allele frequency to test Hardy-Weinberg Equilibrium (HWE) and performed a genetic model of inheritance to determine its association with DTC risk. Correlated the GAS8-AS1 dinucleotide variant distribution with clinical characteristics to find the association. Predicted GAS8-AS1 RNA secondary structure for wild type and variant using RemuRNA and RNAfold to assess the conformational changes. GAS8-AS1 dinucleotide alteration (n.713A > G, rs55742939; n.714T > C, rs61118444) identified in DTCs is a germline variant not somatic. The GAS8-AS1 genotype and allele frequency significantly deviated for HWE in DTCs (χ2 = 37.954; p = 0.0001) though not associated with its risk. Dinucleotide variant distribution was remarkably associated with early-stage disease (p = 0.002), lymph node (p = 0.01), and distant metastasis (p = 0.01) in DTCs. The GAS8-AS1 bearing dinucleotide variant markedly showed conformational change compared to that of its wild type. These findings indicate that GAS8-AS1 is genetically deregulated and implicated in several stages of DTC tumorigenesis suggesting it could be a promising prognostic biomarker in DTCs.

Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder.

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09-2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype "T-A" containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15-0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Interaction between angiotensin-converting enzyme gene rs4343 polymorphism, environment factors, and angiotensin II level on susceptibility to knee osteoarthritis

ObjectivesOsteoarthritis (OA) is a complex multifactorial disease. The association of knee OA risk with ACE gene rs4343 polymorphism, gene environment synergistic effect, and angiotensin II serum level has not been previously examined. Therefore, we investigate the ACE gene rs4343 polymorphism in knee OA, and its association with severity of knee OA, and angiotensin II serum level. MethodsUsing a case–control design, we recruited 200 subjects (100 cases and 100 controls) and all were subjected to genotyping of rs4343 SNP by real-time polymerase chain reaction and assay of serum angiotensin II level by ELISA. ResultsG containing genotypes (AG and GG) and G allele frequencies of the ACE rs4343 polymorphism were significantly higher in the case group than that in the control group. There was significant association between ACE rs4343 genotypes and risk of knee OA under the following genetic inheritance models: GG vs. AA (P=0.003), AA vs. GG/AG (P=0.014), AG/AA vs. GG (P=0.037), and G vs. A (P<0.001). Stratified analyses showed ACE rs4343 polymorphism was evidently associated with a significantly increased risk of knee OA among those had BMI≥25% (adjusted OR=3.016; 95% CI 1.052–8.648; P=0.040). Additionally, knee OA patients with GG genotype had greater knee specific WOMAC index, Kellgren score, and serum angiotensin II level than those with AA or GA genotypes. ConclusionThe investigated polymorphism in the ACE gene rs4343 may reflect the risk and severity of knee OA in the Egyptian population, particularly with the GG genotype. The interaction between ACE gene rs4343 polymorphism and obesity further increased the risk of knee OA. Moreover, the higher angiotensin II level may be involved in the pathogenesis of knee OA.

The linkage between IL-6 rs1800797 variant and breast cancer susceptibility in Bangladeshi women: A case-control study.

Breast cancer is one of the deadliest diseases affecting women in Bangladesh, and its prevalence is increasing year by year. Although several IL-6single nucleotide polymorphisms have been implicated in BC susceptibility and prognosis in various studies, no research has been done to investigate the relationship between breast cancer and IL-6in Bangladeshi women. This investigation aimed to explore the linkage between the rs1800797 variant of IL-6and the susceptibility to breast carcinoma among women in Bangladesh. The IL-6rs1800797 variant was genotyped in 218 subjects (110 cases and 108 controls) using the tetra-primer ARMS-PCRmethod. The statistical analysis was applied utilizing the SPSS software version 24.0. UALCAN database was used for IL-6 mRNA analysis, and genotype-based gene expression was retrieved from GTEx Portal. This study found a significant link between IL-6rs1800797 variants and increased chance of breast cancer across different genetic inheritance models, including additive model 1 (AGvs. GG: OR = 2.16, p = 0.035); dominant model (AG + AA vs. GG: OR = 2.26, p < 0.05); overdominant model (AGvs. GG + AA: OR = 2.08, p < 0.05); and allelic model (A vs. G: OR = 2.15, p < 0.05). However, an insignificant association of breast cancer was found in both additive model 2 (AAvs. GG: OR = 2.91, p > 0.05) and the recessive model (AAvs. GG + AG: OR = 2.52, p > 0.05). Under the analysis of the probability of false positive reports, no significant values were found in different models when the OR was 1.5, and the prior probability was 0.25. A significant relationship was found between the IL-6rs1800797 genetic variant and the risk of breast cancer. However, the findings of the study should be further investigated with a larger sample size to validate the correlation.

G894T of nos3 gene polymorphism and resistant arterial hypertension in Uzbek population

Abstract Aim To estimate the influence of G894T polymorphism of NOS3 gene on the risk of developing resistant arterial hypertension (AH) in the Uzbek population. Materials and Methods The study included 176 patients with AH I-III degree (ESH / ESC, 2018) of both sexes of Uzbek population. The mean age of the patients was 57.12 ± 11.03 years, the mean duration of AH was 9.58 ± 5.76 years. Resistant hypertension was defined in uncontrolled BP, even though ≥ 3 drugs of different classes were taken. Genotyping of the G894T polymorphism of NOS3 gene was performed using real-time PCR using gene-specific primers of allele-specific probes, followed by fluorescence detection of the corresponding alleles. Relative risk (RR) was calculated using genetic models. Calculations were performed using the online program "Calculator for calculating statistics in case-control studies". The results of all studies were considered statistically significant at p&amp;lt;0.05. Results All patients were divided into two groups: group 1 - patients with resistant hypertension (cases, n=61) and group 2 - patients with controlled hypertension (controls, n=115). Among patients of group 1, the following distribution of the G894T polymorphism of the NOS3 gene was revealed: GG genotype - determined in 45.9% of patients, GT genotype - in 44.3%, TT genotype - 9.8%, χ2=22.770, p=0.000 . The allelic distribution showed the predominance of carriage of the G allele: G allele - 68.0%, T allele - 32.0%, χ2=30.311, p=0.000. Among patients of group 2, the allelic distribution was with a significant prevalence of the G allele: G allele in 80.9%, T allele in 19.1%, respectively, χ2=172.878, p=0.000. The ratio of GG:GT:TT genotypes was as follows: 67.8% : 26.1% : 6.1%, χ2=102.704, p=0.000. An analysis using genetic models of inheritance revealed a protective effect of the G allele G894T of the NOS3 gene polymorphism on the risk of developing resistant hypertension in the Uzbek population: among 115 patients with controlled hypertension of group 2, the G allele was significantly more common than in patients with resistant hypertension of group 1 (80.9%; χ² = 7.29 P=0.007; OR=0.50, 95% CI 0.30-0.83) and only 19.1% of patients had the T allele (χ²=P=0.007; OR=1.99 95% CI 1.20-3.28). The general model of inheritance demonstrated a significant accumulation of the GG genotype among patients of group 2 67.8% (χ² = 8.01; P = 0.02; OR = 0.40, 95% CI 0.21-0.76), while the GT genotype was less common in 26.1% cases and the TT genotype is even rarer in 6.1% of cases. Whereas in 1st group of patients GG and GT genotypes were found in the same ratio: 45.9%: 44.3%, respectively. Conclusion The results obtained indicate a significantly greater accumulation of the G allele G894T of NOS3 gene polymorphism among patients with controlled hypertension. Carrying the G allele and GG genotype G894T of NOS3 gene polymorphism is associated with a low risk of developing resistant hypertension in Uzbek population.

Genetic Inheritance Models of Non-Syndromic Cleft Lip with or without Palate: From Monogenic to Polygenic.

Non-syndromic cleft lip with or without palate (NSCL/P) is a prevalent birth defect that affects 1/500-1/1400 live births globally. The genetic basis of NSCL/P is intricate and involves both genetic and environmental factors. In the past few years, various genetic inheritance models have been proposed to elucidate the underlying mechanisms of NSCL/P. These models range from simple monogenic inheritance to more complex polygenic inheritance. Here, we present a comprehensive overview of the genetic inheritance model of NSCL/P exemplified by representative genes and regions from both monogenic and polygenic perspectives. We also summarize existing association studies and corresponding loci of NSCL/P within the Chinese population and highlight the potential of utilizing polygenic risk scores for risk stratification of NSCL/P. The potential application of polygenic models offers promising avenues for improved risk assessment and personalized approaches in the prevention and management of NSCL/P individuals.

Association between chronic tinnitus and brain-derived neurotrophic factor antisense RNA polymorphisms linked to the Val66Met polymorphism in BDNF

Tinnitus is the sound heard in the ear or head of a person in the absence of external stimuli. Its etiopathogenesis is still not fully understood and the etiological causes responsible for tinnitus are quite variable. Brain-derived neurotrophic factor (BDNF) is one of the key neurotrophic factors in the growth, differentiation, and survival of neurons and in the developing auditory pathway, including the inner ear sensory epithelium. The regulation of BDNF gene is known to be managed by BDNF antisense (BDNF-AS) gene. BDNF-AS is located downstream of the BDNF gene and transcribes a long non-coding RNA. Inhibition of BDNF-AS upregulates BDNF mRNA, which increases protein levels and stimulates neuronal development and differentiation. Thus, BDNF and BDNF-AS both may play roles in the auditory pathway. Polymorphisms in both genes may have impact on hearing performance. A link was suggested between tinnitus and BDNF Val66Met polymorphism. However, there is no study questioning the relationship of tinnitus with BDNF-AS polymorphisms linked with BDNF Val66Met polymorphism. Therefore, this study aimed to scrutinize the role of BDNF-AS polymorphisms showing linkage with the BDNF Val66Met polymorphism in the course of tinnitus pathophysiology. Six BDNF-AS polymorphisms were analyzed on the tinnitus patients (n = 85) and the control subjects (n = 60) by Fluidigm Real-Time PCR using the Fluidigm Biomark microfluidic platform. When BDNF-AS polymorphisms were compared between the groups in terms of genotype and gender distribution, statistically significant differences were detected in rs925946, rs1519480, and rs10767658, polymorphisms (p less than 0.05). When the polymorphisms were compared by the duration of tinnitus, significant differences were found in rs925946, rs1488830, rs1519480, and rs10767658 polymorphisms (p less than 0.05). According to genetic inheritance model analysis, 2.33 and 1.53-fold risks were found for the rs10767658 polymorphism in the recessive and the additive models, respectively. For the rs1519480 polymorphism, a 2.25 fold risk was observed in the additive model. For the rs925946 polymorphism, 2.44 fold protective effect in dominant model, and 0.62 fold risk was found in the additive model. In conclusion, four of the polymorphisms in BDNF-AS gene (rs955946, rs1488830, rs1519480, and rs10767658) are potential gene loci that may play a role in the auditory pathway and affect auditory performance.

Characteristic of the uncontrolled hypertension course in patients of the aral sea region with uncomplicated hypertensive crisis

Abstract Purpose To study the features of the course of uncontrolled arterial hypertension (AH) in the Aral Sea region with the identification of the prevalence of various genotypes of the angiotensinogen (AGT) gene in patients with uncomplicated hypertensive crisis. Methods The genetic part included 94 patients with uncomplicated hypertensive crisis, an average age of 55.3±8.6 years, 54 (58.3%)women and 40 men (41.7%). The control group consisted of 50 healthy women and men, an average age of 52.7±6.4 years in equal proportion. The genetic study was carried out by real-time PCR with the determination of the prevalence of genotypes and alleles of genetic polymorphisms AGT 521 C&amp;gt;T, AGT 704 T&amp;gt;C. Results Patients with uncomplicated hypertensive crisis were characterized by LV hypertrophy, thickening of the intima-media thickness of the common carotid artery, and kidney damage. Henken's test showed that patients with AH require a significantly higher concentration of table salt to determine the threshold of taste sensitivity than in the control group: 0.51±0.17% versus 0.21±0.14% concentration of NaCl. The distribution of 704T&amp;gt;C genotypes of the AGT gene polymorphism was as follows: CC genotype 43.6%, CT genotype 45.8%, TT genotype 10.6% of cases, χ2=32.777, p=0.000; C allele – 66.5%, T allele - 33.5% of cases, χ2=40.894, p=0.000. Among healthy individuals, the distribution by genotypes showed a significant predominance of the CC genotype: CC 76%, CT 24%, TT genotype was not detected in the presented sample, χ2=67.92, p=0.000; C-allele 88%, T-allele 12%, χ2=115.52, p=0.000. The above data of the group of patients and healthy people corresponded to the theoretical Hardy-Weinberg equilibrium. The distribution of 521T&amp;gt;C genotypes of the AGT gene polymorphism among AH patients was as follows: CC genotype – 79.8%, CT genotype – 16%, TT genotype – 4.2% of cases, χ2=139.8, p=0.000; C-allele – 87.8%, T-allele – 12.2%, χ2=214.5, p=0.000. Among healthy individuals, a significant predominance of the CT genotype was shown: CC genotype – 40%, CT genotype – 60% of cases, χ2=42.0, p=0.000; C-allele – 70%, T-allele – 30%, χ2=32.0, p=0.000. The above data of the group of patients and healthy people did not correspond to the theoretical Hardy-Weinberg equilibrium Conclusion Patients with uncomplicated hypertensive crisis, living in the aral sea region, are characterized by severe damage of target organs, a high threshold of taste sensitivity to table salt. Based on genetic models of inheritance, a significant prevalence of the C-allele and CC genotype 704 T&amp;gt;C AGT gene polymorphism in healthy individuals was revealed, which characterizes the C-allele and CC genotype as protective against AH in people of the Aral Sea region. Significantly greater accumulation of the C-allele 521 C&amp;gt;T polymorphism of the AGT gene among AH patients is a factor of predisposition to a complicated course of AH in people of the aral sea region. Funding Acknowledgement Type of funding sources: None.

A strong association between VEGF-A rs28357093 and amyotrophic lateral sclerosis: a brazilian genetic study.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease that affects motor neurons and promotes progressive muscle atrophy. Vascular Endothelial Growth Factor A (VEGF-A) plays multiple roles in the central nervous systems (CNS). The purpose of this study was to evaluate the association between single nucleotide polymorphism (SNP) VEGF-A rs28357093 and ALS. This case-control study was conducted in 101 ALS patients and 119 healthy individuals. Genotyping was performed by Polymerase Chain Reaction - Restriction Fragment Length Polymorphism (PCR-RFLP). The statistical analysis was carried out using the RStudio® and SNPStats© software's. Analysis of genetic inheritance models was performed by logistic regression. Our findings demonstrated a strong association between VEGF- A rs28357093 and ALS in all genetic inheritance models, with a 9-fold increased risk for A/C - C/C genotypes (95%CI = 3.70-21.88; p < 0.001). The mutant allele was more frequent in ALS patients (p < 0.001) and this finding could be associated with ALS risk. This first study from the Brazilian central population was conducted to provide new insight into the pathogenesis of ALS.

Using potential variable to study gene-gene and gene-environment interaction effects with genetic model uncertainty.

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.

Sperm histone H3 lysine 4 tri-methylation serves as a metabolic sensor of paternal obesity and is associated with the inheritance of metabolic dysfunction

ObjectiveParental environmental exposures can strongly influence descendant risks for adult disease. How paternal obesity changes the sperm chromatin leading to the acquisition of metabolic disease in offspring remains controversial and ill-defined. The objective of this study was to assess (1) whether obesity induced by a high-fat diet alters sperm histone methylation; (2) whether paternal obesity can induce metabolic disturbances across generations; (3) whether there could be cumulative damage to the sperm epigenome leading to enhanced metabolic dysfunction in descendants; and (4) whether obesity-sensitive regions associate with embryonic epigenetic and transcriptomic profiles. Using a genetic mouse model of epigenetic inheritance, we investigated the role of histone H3 lysine 4 methylation (H3K4me3) in the paternal transmission of metabolic dysfunction. This transgenic mouse overexpresses the histone demethylase enzyme KDM1A in the developing germline and has an altered sperm epigenome at the level of histone H3K4 methylation. We hypothesized that challenging transgenic sires with a high-fat diet would further erode the sperm epigenome and lead to enhanced metabolic disturbances in the next generations. MethodsTo assess whether paternal obesity can have inter- or transgenerational impacts, and if so to identify potential mechanisms of this non-genetic inheritance, we used wild-type C57BL/6NCrl and transgenic males with a pre-existing altered sperm epigenome. To induce obesity, sires were fed either a control or high-fat diet (10% or 60% kcal fat, respectively) for 10–12 weeks, then bred to wild-type C57BL/6NCrl females fed a regular diet. F1 and F2 descendants were characterized for metabolic phenotypes by examining the effects of paternal obesity by sex, on body weight, fat mass distribution, the liver transcriptome, intraperitoneal glucose, and insulin tolerance tests. To determine whether obesity altered the F0 sperm chromatin, native chromatin immunoprecipitation-sequencing targeting H3K4me3 was performed. To gain insight into mechanisms of paternal transmission, we compared our sperm H3K4me3 profiles with embryonic and placental chromatin states, histone modification, and gene expression profiles. ResultsObesity-induced alterations in H3K4me3 occurred in genes implicated in metabolic, inflammatory, and developmental processes. These processes were associated with offspring metabolic dysfunction and corresponded to genes enriched for H3K4me3 in embryos and overlapped embryonic and placenta gene expression profiles. Transgenerational susceptibility to metabolic disease was only observed when obese F0 had a pre-existing modified sperm epigenome. This coincided with increased H3K4me3 alterations in sperm and more severe phenotypes affecting their offspring. ConclusionsOur data suggest sperm H3K4me3 might serve as a metabolic sensor that connects paternal diet with offspring phenotypes via the placenta. This non-DNA-based knowledge of inheritance has the potential to improve our understanding of how environment shapes heritability and may lead to novel routes for the prevention of disease. This study highlights the need to further study the connection between the sperm epigenome, placental development, and children's health. Summary sentencePaternal obesity impacts sperm H3K4me3 and is associated with placenta, embryonic and metabolic outcomes in descendants.

Effect of MTTP -493G/T, I128T, Q95H and Q244E polymorphisms on hepatic steatosis in patients with chronic hepatitis

BackgroundChronic hepatitis C is characterized by a progressive deterioration of liver function and is involved in metabolic complications, such as hepatic steatosis. ObjectiveThe aim of this study was to investigate the role of host and viral characteristics associated with -493G/T (rs1800591), I128T (rs3816873), Q95H (rs61733139), and Q244E (rs17599091) Single Nucleotide Polymorphisms (SNPs) in the Microsomal Triglyceride Transfer Protein (MTTP) gene on hepatic steatosis in chronic hepatitis C. MethodsSNPs were genotyped by PCR-RFLP and analyzed in combination with host and viral characteristics by multiple logistic regression in different genetic models of inheritance. ResultsThe authors analyzed 236 patients with chronic hepatitis C, and 53% had hepatic steatosis. The mutated allele frequencies were > 5%, and the genotypes were in Hardy-Weinberg equilibrium (p ≥ 0.05). It was observed that patients with HCV genotype 3 infection (OR = 2.74, 95% CI 1.24‒6.06, p = 0.013), female sex (OR = 2.28, 95% CI 1.21‒4.28, p = 0.011) and moderate- and high-intensity liver inflammatory activity (A2-A3) (OR = 3.61, 95% CI 1.86‒7.01, p < 0.001) alone exhibited a higher risk of steatosis. The results of multiple logistic regression analysis for interaction showed that for the -493G/T SNP, when the GT/TT genotype (dominant model) and the GT genotype (codominant model) were each combined with HCV genotype 3 infection, an 11.51-fold (95% CI 2.08‒63.59, p = 0.005) and a 15.69-fold (95% CI 2.46‒99.85, p = 0.004) increased risk of steatosis, respectively, was observed. For the I128T SNP, when both the IT/TT genotype (dominant model) and the IT genotype (codominant model) were combined with HCV genotype 3 infection, an 8.51-fold (95% CI 1.59‒45.54, p = 0.012) and an 8.40 fold (95% CI 1.51‒46.91, p = 0.015) increased risk of steatosis, respectively, was observed. ConclusionThe present study showed that the viral genotype combined with the -493G/T and I128T SNPs in the MTTP gene influences hepatic steatosis.

Quantitative Trait Loci Identification by Estimating the Genetic Model based on the Extremal Samples.

Background In genetic association studies with quantitative trait loci (QTL), the association between a candidate genetic marker and the trait of interest is commonly examined by the omnibus F test or by the t-test corresponding to a given genetic model or mode of inheritance. It is known that the t-test with a correct model specification is more powerful than the F test. However, since the underlying genetic model is rarely known in practice, the use of a model-specific t-test may incur substantial power loss. Robust-efficient tests, such as the Maximin Efficiency Robust Test (MERT) and MAX3 have been proposed in the literature.Methods In this paper, we propose a novel two-step robust-efficient approach, namely, the genetic model selection (GMS) method for quantitative trait analysis. GMS selects a genetic model by testing Hardy-Weinberg disequilibrium (HWD) with extremal samples of the population in the first step and then applies the corresponding genetic model-specific t-test in the second step.Results Simulations show that GMS is not only more efficient than MERT and MAX3, but also has comparable power to the optimal t-test when the genetic model is known.Conclusion Application to the data from Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort demonstrates that the proposed approach can identify meaningful biological SNPs on chromosome 19.

BLK polymorphisms and expression level in neuromyelitis optica spectrum disorder

AimThis study aimed to determine the correlation between B‐lymphoid tyrosine kinase (BLK) polymorphism, mRNA gene expression of BLK, and NMOSD in a Chinese Han population.BackgroundB‐lymphoid tyrosine kinase gene expressed mainly in B cells plays a key role in various autoimmune disorders. However, no studies have investigated the association of BLK polymorphisms with neuromyelitis optica spectrum disorder (NMOSD).MethodsHan Chinese population of 310 subjects were recruited to analyze three single nucleotide polymorphisms (rs13277113, rs4840568, and rs2248932) under allele, genotype, and haplotype frequencies, followed by clinical characteristics stratified analysis. Real‐time PCR was used to analyze mRNA expression levels of BLK in the peripheral blood mononuclear cells of 64 subjects.ResultsPatients with NMOSD showed lower frequencies of the minor allele G of rs2248932 than healthy controls (odds ratio (OR) =0.57, 95% confidence intervals (CI) 0.39–0.83, p = 0.003). The association between minor allele G of rs2248932 and reduced NMOSD susceptibility was found by applying genetic models of inheritance (codominant, dominant, and recessive) and haplotypes analysis. Subsequently, by stratification analysis for AQP4‐positivity, the minor allele G frequencies of rs2248932 in AQP4‐positive subgroup were significantly lower than in the healthy controls (OR =0.46, 95% CI 0.30–0.72, p = 0.001). Notably, the genotype GG of rs2248932 was more frequent in AQP4‐negative subgroup (n = 14) than in AQP4‐positive subgroup (n = 93) (p = 0.003, OR =0.05, 95% CI =0.01–0.57). BLK mRNA expression levels in the NMOSD patients (n = 36) were lower than in healthy controls (n = 28) (p < 0.05). However, the acute non‐treatment (n = 7), who were untreated patients in the acute phase from the NMOSD group, showed BLK mRNA expression levels 1.8‐fold higher than healthy controls (n = 8) (p < 0.05).ConclusionThis study evaluated that the minor allele G of rs2248932 in BLK is associated with reduced susceptibility to NMOSD and protected the risk of AQP4‐positive. BLK mRNA expression in NMOSD was lower as compared to healthy controls while significantly increased in acute‐untreated patients.

Correlation between the Polymorphism of Coagulation-Related Genes and Lower Extremity Deep Venous Thrombosis.

Objective To investigate the correlation between the polymorphism of 4 coagulation-related genes, rs1799963 （coagulation factor V gene Leiden）, rs6025 （prothrombin gene G20210A）, rs1042579 （thrombomodulin protein gene c.1418C>T） and rs1801131 （methylenetetrahydroflate reductase gene） and lower extremity deep venous thrombosis （LEDVT）. Methods The 4 genotypes mentioned above of 150 LEDVT patients and 153 healthy controls were detected by the kompetitive allele specific polymerase chain reaction （KASP）, then related blood biochemical indicators were collected, binary Logistic regression was established to screen the independent risk factors of LEDVT, and the correlation between polymorphism of 4 coagulation-related genes and LEDVT and its indicators under different genetic modes after adjusting confounding factors were analyzed. Results Five variables, D-dimer, fibrinogen degradation product, homocysteine, sex and age might be the risk factors of LEDVT. These variables were put into 4 genetic inheritance models, and adjusted in binary Logistic regression. The results suggested that the mutations of rs1042579 were correlated with LEDVT under dominant inheritance mode. Conclusion The gene polymorphism of rs1799963, rs6025 and rs1801131 has no significant correlation with the formation of LEDVT. The gene polymorphism of rs1042579 plays a role under dominant inheritance mode, and might be an independent risk factor for formation of LEDVT.

No association of GSTP1 rs1695 polymorphism with amyotrophic lateral sclerosis: A case-control study in the Brazilian population.

Amyotrophic Lateral Sclerosis (ALS) is a rare neurodegenerative disease that affects motor neurons and promotes progressive muscle atrophy. It has a multifactorial etiology, where environmental conditions playing a remarkable role through the increase of oxidative stress. Genetic polymorphisms in cell detoxification genes, such as Glutathione S-Transferase Pi 1 (GSTP1) can contribute to excessive oxidative stress, and therefore may be a risk factor to ALS. Thus, this study aimed to investigate the role of the GSTP1 rs1695 polymorphism in ALS susceptibility in different genetic inheritance models and evaluate the association of the genotypes with risk factors, clinical and demographic characteristics of ALS patients from the Brazilian central population. This case-control study was conducted with 101 patients with ALS and 101 healthy controls. GSTP1 rs1695 polymorphism genotyping was performed with Polymerase Chain Reaction–Restriction Fragment Length Polymorphism (PCR-RFLP). The statistical analysis was carried out using the SPSS statistical package and SNPStats software. Analysis of genetic inheritance models was performed by logistic regression, which was used to determine the Odds Ratio. The results of this first study in the Brazilian population demonstrated that there was no risk association between the development of ALS and the GSTP1 rs1695 polymorphism in any genetic inheritance model (codominant, dominant, recessive, overdominant, and logarithmic); and that the polymorphic variants were not associated with the clinical and demographic characteristics of ALS patients. No association of the GSTP1 rs1695 polymorphism and ALS development in the Brazilian central population was found. These findings may be justified by the multifactorial character of the disease.

ADORA2A rs5760423 and CYP1A2 rs762551 Polymorphisms as Risk Factors for Parkinson's Disease.

Background: Parkinson’s disease (PD) is the second commonest neurodegenerative disease. The genetic basis of PD is indisputable. Both ADORA2A rs5760423 and CYP1A2 rs762551 have been linked to PD, to some extent, but the exact role of those polymorphisms in PD remains controversial. Objective: We assessed the role of ADORA2A rs5760423 and CYP1A2 rs762551 on PD risk. Methods: We genotyped 358 patients with PD and 358 healthy controls for ADORA2A rs5760423 and CYP1A2 rs762551. We also merged and meta-analyzed our data with data from previous studies, regarding these two polymorphisms and PD. Results: No significant association with PD was revealed (p > 0.05), for either ADORA2A rs5760423 or CYP1A2 rs762551, in any of the examined genetic model of inheritance. In addition, results from meta-analyses yield negative results. Conclusions: Based on our analyses, it appears rather unlikely that ADORA2A rs5760423 or CYP1A2 rs762551 is among the major risk factors for PD, at least in Greek patients with PD.

Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance.

Advancing the molecular knowledge surrounding fertility and inheritance has become critical given the halving of sperm counts in the last 40 years, and the rise in complex disease which cannot be explained by genetics alone. The connection between both these trends may lie in alterations to the sperm epigenome and occur through environmental exposures. Changes to the sperm epigenome are also associated with health risks across generations such as metabolic disorders and cancer. Thus, it is imperative to identify the epigenetic modifications that escape reprogramming during spermatogenesis and embryogenesis. Here, we aimed to identify the chromatin signature(s) involved in transgenerational phenotypes in our genetic mouse model of epigenetic inheritance that overexpresses the histone demethylase KDM1A in their germ cells. We used sperm-specific chromatin immunoprecipitation followed by in depth sequencing (ChIP-seq), and computational analysis to identify whether differential enrichment of histone H3 lysine 4 trimethylation (H3K4me3), and histone H3 lysine 27 trimethylation (H3K27me3) serve as mechanisms for transgenerational epigenetic inheritance through the paternal germline. Our analysis on the sperm of KDM1A transgenic males revealed specific changes in H3K4me3 enrichment that predominantly occurred independently from bivalent H3K4me3/H3K27me3 regions. Many regions with altered H3K4me3 enrichment in sperm were identified on the paternal allele of the pre-implantation embryo. These findings suggest that sperm H3K4me3 functions in the transmission of non-genetic phenotypes transgenerationally.