Strong Linkage Disequilibrium Research Articles

Influence of MHC on genetic diversity and testicular expression of linked olfactory receptor genes

BackgroundOlfactory receptor (OR) genes are highly polymorphic and form extensive families that recognize a wide range of vertebrate odorants. To explore the genetic diversity of MHC-linked OR genes and their connection to MHC genes, we conducted a combined haplotype analysis of MHC-linked OR and MHC class I genes to determine the influence of MHC on OR diversity, which could be associated with MHC-based mate selection.ResultsWe selected nine MHC-linked OR genes based on their expression levels in pig testes and developed a sequence-based typing method for these genes. We then performed high-resolution typing of these OR genes, along with three major classical MHC class I genes (SLA-1, -2, and − 3), in 48 pigs across six breeds. We observed significantly higher allelic diversity (P < 0.01) in ORs with strong linkage disequilibrium (LD) to SLA compared to those with weak or no LD, and we identified 48 SLA class I-OR haplotypes using the expectation-maximization algorithm. The genetic diversity of SLA-linked ORs was positively correlated with their expression levels in the testis. Specifically, SLA-linked ORs with higher testicular expression (FPKM ≥ 0.1) exhibited an increase in the number of codons under mutually diversifying selection with SLA compared to those with lower expression (FPKM < 0.1).ConclusionsThe presence of evolutionary interactions between MHC and linked OR genes supports the potential involvement of MHC-linked ORs in MHC-based mate selection. The use of combined haplotype information for MHC and linked ORs could provide new insights into the reproductive biology of animals.

STAT4 gene polymorphism may be associated with microscopic polyangiitis susceptibility in a Chinese Guangxi population: A case-control analysis based on propensity score matching.

Microscopic polyangiitis (MPA) is a severe multisystem autoimmune disease featured by small-vessel vasculitis with few or no immune complex, also has a significant genetic predisposition. Growing evidence has confirmed that STAT4 gene is tightly associated with multiple autoimmune diseases, but its contribution to MPA onset is still elusive. The aim was to investigated the association between STAT4 gene polymorphisms (rs7572482, rs7574865 and rs12991409) and MPA susceptibility in a Guangxi population of China. 260 MPA patients and 295 healthy adult volunteers were selected, 1:1 propensity score matching (PSM) was performed to control potential confounding variables, then 199 MPA patients and 199 healthy adult volunteers matched in gender, ethnicity and age were included in this study. High-throughput sequencing and multiplex PCR were applied to detect the target STAT4 SNPs. SHEsis and SNPstats were used to evaluated the allele frequency, genotype frequency, linkage disequilibrium (LD), haplotype, and the association between SNPs and the MPA susceptibility in multiple genetic models. SNP-SNP interactions were explored based on generalized multifactor dimensionality reduction (GMDR) algorithm. Some clinical indicators, such as renal pathology and therapeutic effects, were collected and compared. The allele and genotype frequencies of rs7574865 displayed significant diversities between case group and control group (p < 0.05). Strong LD was found between rs7572482 and rs12991409 (D'=0.9). The haplotype GGT was related to a reduced risk of MPA (OR = 0.661, 95 %CI: 0.469-0.931, p = 0.017), and haplotype GTT might perform an increased risk of MPA (OR = 1.922, 95 %CI: 1.225-3.015, p = 0.004). Rs7574865 polymorphism was associated with an increased risk of MPA in codominant model (OR:2.03; p = 0.0093), dominant model (OR: 1.88p = 0.0023), and overdominant model (OR:1.57; p = 0.027). In Han and male subgroups, rs7574865 polymorphism dramatically increased the MPA risk. GMDR suggested that STAT4 rs7574865 and PTPN22 rs3811021 composed the most risk combinations (p = 0.0010). Moreover, renal pathology, Birmingham vasculitis activity score (BVAS), and alanine aminotransferase (ALT) might be linked with STAT4 gene polymorphisms (p < 0.05). The genetic polymorphism of STAT4 may be associated with MPA susceptibility and renal pathological classification in Chinese Guangxi population; the T allele of rs7574865 may be an important risk factor for MPA.

Genetic Polymorphisms in HMGCS1 Gene and Its Association with Slaughter Characteristics, Meat Quality, and Organ Coefficients in Guizhou White Goats.

This study aimed to identify polymorphisms in the gene encoding the 3-hydroxy-3-methylglutaryl-CoA synthase 1, HMGCS1, and analyze their association with slaughter characteristics, meat quality, and organ coefficients in Guizhou white goats. A total of 153 twelve-month-old Guizhou white goats (78 male and 75 female) were included in the study. Slaughter characteristics, meat quality, and organ coefficients were assessed. Association analyses between genotypes and phenotypic traits were conducted using a generalized linear model. Four polymorphic loci were identified, i.e., g.15523T>C, g.15530G>C, g.18413T>C, g.19711G>A in exons 5, 8, and 9 of the HMGCS1 gene. Across all polymorphic loci, males of the same genotype generally exhibited significantly better slaughter traits compared to females of the same genotype (p < 0.05). At the g.18413T>C locus, differences in shear force were observed between males and females of the same genotype and within the same sex across different genotypes (p < 0.05). Organ coefficients were significantly higher in males of the same genotype compared to females (p < 0.05). The g.15523T>C and g.15530G>C loci were found in strong linkage disequilibrium and significantly associated with intramuscular fat content (p < 0.05). Fat content in diploid Hap2/2 individuals was significantly higher than in Hap1/1 and Hap1/2 (p < 0.05). At the g.19711G>A locus, female goats with the CC genotype showed significantly higher levels of dry matter compared to male goats of the same genotype and female goats of other genotypes within the group. Organ coefficients for the liver and hooves in male goats were significantly higher than in females of the same genotype (p < 0.05). The strongly linked loci g.15523T>C and g.15530G>C were significantly associated with intramuscular fat content and could be used as molecular markers for enhancing this trait in goat breeding programs, fostering the development of goat production.

The VEGFB Gene Variants and the Effectiveness of Platelet-Rich Plasma Treatment of Lateral Elbow Tendinopathy: A Prospective Cohort Study with a Two-Year Follow-Up.

Platelet-rich plasma (PRP) is an autologous preparation used to accelerate regeneration; however, this form of therapy is not always effective. Vascular endothelial growth factor B (VEGFB), which affects vessel survival, pathological angiogenesis, and muscle development may differentiate the risk and treatment of lateral elbow tendinopathy (LET). In this study, we analyzed the influence of VEGFB gene polymorphisms on the effectiveness of LET treatment with PRP. Therapeutic effectiveness was analyzed in 107 patients (132 elbows) using patient-reported outcome measures (PROMs), specifically the visual analog scale (VAS); quick version of disabilities of the arm, shoulder, and hand score (QDASH); and patient-rated tennis elbow evaluation (PRTEE), for two years (weeks 2, 4, 8, 12, 24, 52, and 104). The polymorphisms selected for the study were rs72922019, rs12366035, rs4930152, rs594942, and rs595880, being in strong linkage disequilibrium. Patients with TT (rs72922019), TT (rs12366035), AA (rs4930152), CC (rs594942), and GG (rs595880) genotypes showed better treatment effectiveness. Statistically important differences were shown for rs72922019 VAS (week 2), QDASH (weeks 0-4), and PRTEE (week 2); rs12366035 and rs4930152 VAS (week 2), QDASH (week 2), and PRTEE (weeks 2 and 4); and rs594942 and rs595880 VAS (weeks 2 and 4), QDASH (week 2), and PRTEE (weeks 2, 52, and 104). The studied polymorphisms also showed an association with blood morphological parameters, including mean platelet volume, platelet distribution width, and eosinophil levels, as well as some comorbidities (heart failure). Genotyping due to patient selection for therapy may be considered for any of the rs72922019, rs12366035, or rs4930152 polymorphisms.

The Association of PLA2G7 Gene Polymorphisms with Serum Lp-PLA2 Activity and Lipid Profile in Han Chinese Patients with Coronary Heart Disease.

This study aimed to investigate the distribution patterns of PLA2G7 gene variants in Han Chinese patients with coronary heart disease (CHD), and their relationships with serum lipoprotein-associated phospholipase A2 (Lp-PLA2) levels and lipid profiles. A total of 93han Chinese CHD patients were recruited. Serum Lp-PLA2 levels were determined using enzyme-linked immunosorbent assay (ELISA), while comprehensive analysis of PLA2G7 gene polymorphisms was conducted through whole-exome sequencing. Concurrently, multiple lipid parameters were measured and analyzed. Among these Han Chinese CHD patients, the PLA2G7 gene rs1051931 (c.1136T>C p.Val379Ala) rare variant was highly prevalent (variant rate: 94.62%) among the study population, and showed negative correlation with serum Lp-PLA2 activity. The rs1765208290 (c.233G>A p.Gly78Asp) rare variant showed positive correlation with TG, ApoA, ApoB, HDL, LDL and TCHO levels in the serum. Strong linkage disequilibrium was observed between the rs1805018 (c.593T>C p.Ile198Thr) and rs76863441 (c.835G>T p.Val279Phe), both of which were related to lower Lp-PLA2 activity. In these Han Chinese CHD patients, the rs1051931 (c.1136T>C p.Val379Ala) rare variant in the PLA2G7 gene is closely linked to decreased Lp-PLA2 activity, whereas the rs1765208290 (c.233G>A p.Gly78Asp) rare variant influences lipid homeostasis. The strong LD between rs1805018 (c.593T>C p.Ile198Thr) and rs76863441 (c.835G>T p.Val279Phe) loci may act synergistically to reduce Lp-PLA2 activity.

Three Fields Allelic Haplotype Frequencies of HLA‐DPA1 and ‐DPB1 Typed by Next Generation Sequencing of 563 Families in Chinese Han Population

ABSTRACTThe present study investigated the HLA‐DPA1 and ‐DPB1 allele and haplotype frequencies in the Chinese Han population. A total of 563 families, which have been typed for the purpose of haematopoietic stem cell transplantation, were included, and three‐field allelic resolution typing of HLA‐DPA1 and ‐DPB1 of all individuals were defined by the next‐generation sequencing method. HLA‐DPA1~DPB1 haplotypes were determined by allele segregation within a nuclear family. A total of 9 HLA‐DPA1 and 39 HLA‐DPB1 alleles, and 62 HLA‐DPA1~DPB1 haplotypes were identified. The three most frequent alleles at HLA‐DPA1 locus are HLA‐DPA1*02:02:02 (46.581%), HLA‐DPA1*01:03:01 (36.456%) and HLA‐DPA1*02:01:01 (12.167%); and the three most frequent HLA‐DPB1 alleles are HLA‐DPB1*05:01:01 (34.014%), HLA‐DPB1*02:01:02 (18.428%) and HLA‐DPB1*04:01:01 (10.124%). The three most frequent haplotypes are HLA‐DPA1*02:02:02~DPB1*05:01:01 (32.327%), HLA‐DPA1*01:03:01 ~ DPB1*02:01:02 (14.654%) and HLA‐DPA1*01:03:01~DPB1*04:01:01 (9.458%). The HLA‐DPA1*02:01~DPB1*02:02 and HLA‐DPA1*04:01~DPB1*05:01 haplotypes appear to be unique in Han Chinese. Strong global linkage disequilibrium (LD) between HLA‐DPA1 and ‐DPB1 was confirmed (D′ = 0.848, Wn = 0.684). Moreover, the haplotype frequencies based on the family study were compared with the frequencies estimated by the expectation–maximisation algorithm, and the equivalent results were obtained except for haplotypes with very low frequencies. Our data provide a solid base for HLA‐DP dimer association studies and useful information for transplantation and disease association studies.

Genetic variants in mitochondrial sirtuins associated with brain tumor risk: a case-control study.

Previous studies on brain tumors have been performed on the nuclear genome, but limited studies have been reported on the mitochondrial genome. The mitochondrial sirtuin (SIRT3/SIRT4/SIRT5) has been mutated in different cancers. Limited studies have been performed on brain tumors. Isocitrate dehydrogenase (IDH) is an important marker, and polymorphism in the IDH gene has been reported to differentiate the brain tumor subtypes. The present study was designed to screen mitochondrial sirtuins and IDH polymorphisms in brain tumor patients. One thousand blood samples were collected (500 brain tumor patients and 500 controls). Two SNPs for each gene SIRT3 (rs12226697, rs570591), SIRT4 (rs184496260, 1925909), SIRT5 (rs2841522, rs2841523), and one SNP for IDH (rs11554137) was screened using Tetra-ARMS PCR. Logistic regression showed that the mutant genotype of selected SNPs was associated with increased disease incidence compared to wild type. Haplotype analysis and linkage disequilibrium (LD) showed a strong LD in brain tumor patients. Kaplan-Meier analysis showed that mutant allele frequency was found to be associated with a significant decrease in the survival of brain tumor patients. The present study showed that the mutant allele of selected mitochondrial sirtuins' SNP was associated with increased brain tumor risk.

Genome-Wide Population Structure in a Marine Keystone Species, the European Flat Oyster (Ostrea edulis).

Ostrea edulis, the European flat oyster, was once a widespread economically and ecologically important marine species, but has suffered dramatic declines over the past two centuries. Consequently, there has been a surge in European restoration efforts, many of which focus on restocking as a conservation measure. In this study, we used whole-genome sequencing (WGS) data to investigate the population structure, demographic history, and patterns of local adaptation of O. edulis across its natural distribution with increased sampling densities at Scandinavian localities. Results revealed seven distinct genetic clusters, including previously undescribed complex population structure in Norway, and evidence for introgression between genetic clusters in Scandinavia. We detected large structural variants (SVs) on three pseudo-chromosomes. These megabase long regions were characterised by strong linkage disequilibrium and clear geographical differentiation, suggestive of chromosomal inversions potentially associated with local adaptation. The results indicated that genomic traces of past translocations of non-native O. edulis were still present in some individuals, but overall, we found limited evidence of major impacts of translocations on the scale of contemporary population structure. Our findings highlight the importance of considering population structure and signatures of selection in the design of effective conservation strategies to preserve and restore wild native European flat oyster populations, and we provide direct knowledge safeguarding sustainable mitigation actions in this important species.

Intronic Variants in the MSH2 (rs2303426 and rs10179950) and PMS2 (rs2286681 and rs62456178) Genes Are Not Associated with Colorectal Cancer in Mexican Patients.

In the origin and development of colorectal cancer (CRC), a global public health problem, a dysfunction mismatch repair system appears to be a key factor. The objective was to determine the association of intronic variants in the MSH2 and PMS2 genes with CRC in Mexican patients. Blood samples of 143 CRC patients and 146 reference individuals were genotyped through TaqMan® Genotyping Assays. Genotypic and allelic frequencies were determined by direct counting. To compare genotypic and allelic distributions, the chi-square test was used. For the association analysis, the risks of alleles and genotypes were estimated by odds ratio with 95% confidence intervals. Haplogroups were inferred with a Bayesian algorithm. Linkage disequilibrium was measured using D' and r2 with Arlequin v3.5.2. The in silico analysis was carried out using the SpliceAI, UCSC, JASPAR and TRRUST platforms. All statistical analyses were performed with SPSS v29.0.2.0. In the CRC group, the mean age was 58.2 ± 14.7 years and 60.8% were men. No variant was associated with CRC or implicated in gene post-replicative processing. Linkage disequilibrium was observed for loci rs2303426 and rs10179950 in MSH2 and for loci rs2286681 and rs62456178 in PMS2. The genotypic and allelic frequencies of the four variants are reported for the first time in Mexican patients with CRC. No association was found between gene variants and risk for CRC but there was a strong linkage disequilibrium between the loci of both MSH2 and PMS2 genes. None of the variants showed a possible repercussion on splicing.

ApaI Polymorphism in the Vitamin D Receptor Gene Decreases the Risk of Perianal Fistulas in Crohn’s Disease

Background: Vitamin D, through the activation of its receptor (VDR), plays an immunomodulatory role in the gastrointestinal tract. Single-nucleotide polymorphisms (SNPs) in the VDR gene have been associated with Crohn’s disease (CD) risk, and patients carrying the TaqI polymorphism in this gene run a higher risk of developing a penetrating behavior. Aims: We analyzed the association of BsmI, ApaI, TaqI, and FokI SNPs in the VDR gene with the clinical characteristics of CD. Methods: Four polymorphisms identified in the VDR gene (BsmI, FokI, ApaI, and TaqI) were genotyped in blood samples from CD patients (n = 115) by using PCR-RFLP. The disease’s location and behavior and the presence of perianal fistulas were collected from each patient. Intestinal fibroblasts from ileal resections of CD patients (n = 10) were genotyped, and the expression of fibrotic and inflammatory markers was analyzed by RT-PCR. Results: The data reveal no association between any of the polymorphisms and CD risk. A strong linkage disequilibrium was detected between TaqI and both ApaI and BsmI, which in turn were strongly associated. Homozygosis or heterozygosis for the a allele of the ApaI SNP or b allele of the BsmI SNP was significantly associated with a lower risk of a penetrating behavior, while the aa genotype was associated with a lower risk of perianal fistulas. Fibroblasts carrying the aa genotype expressed lower levels of fibrotic and inflammatory markers. Conclusion: The aa genotype of the ApaI SNP in the VDR gene is associated with a lower risk of perianal fistulas in CD and a reduced expression of fibrotic and inflammatory markers in intestinal fibroblasts.

Identification of candidate causal variants and target genes at 41 breast cancer risk loci through differential allelic expression analysis

Understanding breast cancer genetic risk relies on identifying causal variants and candidate target genes in risk loci identified by genome-wide association studies (GWAS), which remains challenging. Since most loci fall in active gene regulatory regions, we developed a novel approach facilitated by pinpointing the variants with greater regulatory potential in the disease’s tissue of origin. Through genome-wide differential allelic expression (DAE) analysis, using microarray data from 64 normal breast tissue samples, we mapped the variants associated with DAE (daeQTLs). Then, we intersected these with GWAS data to reveal candidate risk regulatory variants and analysed their cis-acting regulatory potential. Finally, we validated our approach by extensive functional analysis of the 5q14.1 breast cancer risk locus. We observed widespread gene expression regulation by cis-acting variants in breast tissue, with 65% of coding and noncoding expressed genes displaying DAE (daeGenes). We identified over 54 K daeQTLs for 6761 (26%) daeGenes, including 385 daeGenes harbouring variants previously associated with BC risk. We found 1431 daeQTLs mapped to 93 different loci in strong linkage disequilibrium with risk-associated variants (risk-daeQTLs), suggesting a link between risk-causing variants and cis-regulation. There were 122 risk-daeQTL with stronger cis-acting potential in active regulatory regions with protein binding evidence. These variants mapped to 41 risk loci, of which 29 had no previous report of target genes and were candidates for regulating the expression levels of 65 genes. As validation, we identified and functionally characterised five candidate causal variants at the 5q14.1 risk locus targeting the ATG10 and ATP6AP1L genes, likely acting via modulation of alternative transcription and transcription factor binding. Our study demonstrates the power of DAE analysis and daeQTL mapping to identify causal regulatory variants and target genes at breast cancer risk loci, including those with complex regulatory landscapes. It additionally provides a genome-wide resource of variants associated with DAE for future functional studies.

Target Gene-Based Association Study of High Mobility Group Box Protein 1 in Intracranial Aneurysms in Koreans.

Objective: We investigated the effect of high mobility group box 1 (HMGB1) on intracranial aneurysms (IAs) by analyzing single-nucleotide polymorphisms (SNPs) based on genome-wide association study (GWAS) data. HMGB1 mRNA and protein expression levels in plasma were also analyzed. Methods: This study was a comprehensive analysis of a GWAS dataset, including 250 patients with IAs and 294 controls. The HMGB1 gene region was targeted within SNP rs3742305 ± 10 kbp. Multivariate logistic regression analysis determined its association with IAs after adjusting for relevant clinical factors. HMGB1 mRNA expression was analyzed in the plasma of 24 patients selected from the GWAS dataset. The HMGB1 protein was analyzed by Western blotting. Results: A total of seven polymorphisms, including rs1360485, rs185382445, rs2039338, rs1045411, rs3742305, rs2249825, and rs189034241, were observed. Two SNPs, including rs1045411 (UTR-3) and rs3742305 (intron), showed strong linkage disequilibrium (r2 = 0.99). However, none of the seven SNPs associated with IAs had an adjusted p-value of < 0.0016 on multiple comparison analysis. HMGB1 mRNA levels (2-ΔCt) did not differ significantly between patients with IAs and the control subjects [1.07 (1.00-1.15) in patients with IAs vs. 1.05 (0.94-1.12) in controls; p = 0.67)]. Also, no significant difference in the degree of plasma HMGB1 protein expression was seen between the two groups (p = 0.82). Conclusions: The number of SNPs associated with HMGB1 and the degree of HMGB1 mRNA and protein expression were not significantly different between patients diagnosed with IAs and the controls.

Candidate SNPs associated with anxiety and depression in children and adolescents in the USH1C gene

Introduction: Anxiety and depression in children and adolescents are growing concerns globally, with significant rates of diagnosis across diverse populations. According to the Centers for Disease Control and Prevention (CDC), approximately 7.1% of children aged 3 to 17 years in the United States have been diagnosed with anxiety, and 3.2% with depression. The aim of this study is to analyze the correlation between SNPs in the USH1C gene and predisposition to anxiety and depression in children and adolescents from specific populations.Methods: Genotypes from the 1000 Genomes Project were used to evaluate SNPs in Southeast Asian and European populations. Linkage disequilibrium (LD) analysis was performed using VcfTools and the biological effects of the SNPs were assessed using the Variant Effect Predictor (VEP).Results: Two SNPs, rs4757538 and rs16934376, were identified, which showed strong LD with SNP rs79878474 in South Asian populations (r² &gt; 0.7), suggesting their possible association with anxiety and depression. Allele frequencies varied significantly between populations. Hardy-Weinberg equilibrium analysis showed significant imbalance at the global level, but not within individual populationsConclusions: The analyzed SNPs might be related to predisposition to anxiety and depression in specific populations. These findings underline the importance of considering genetic diversity in future studies and developing personalized interventions to address these disorders in children and adolescents

The rs3918188 and rs1799983 loci of eNOS gene are associated with susceptibility in patients with systemic lupus erythematosus in Northeast China

To investigate the association between single nucleotide polymorphism (SNP) at the rs3918188, rs1799983 and rs1007311 loci of the endothelial nitric oxide synthase (eNOS) gene and genetic susceptibility to systemic lupus erythematosus (SLE) in northeastern China. The base distribution of eNOS gene rs3918188, rs1799983 and rs1007311 in 1712 human peripheral blood samples from Northeast China was detected by SNaPshot sequencing technology. The correlation between genotype, allele and gene model of these loci of the eNOS gene and the genetic susceptibility to SLE was investigated by logistic regression analysis. The results of the differences in the frequency distribution of their gene models were visualised using R 4.3.2 software. Finally, HaploView 4.2 software was used to analyse the relationship between the haplotypes of the three loci mentioned above and the genetic susceptibility to SLE. A multifactor dimensionality reduction (MDR) analysis was used to determine the best SNP-SNP interaction model. The CC genotype and C allele at the rs3918188 locus may be a risk factor for SLE (CC vs AA: OR = 1.827, P < 0.05; C vs A: OR = 1.558, P < 0.001), and this locus increased the risk of SLE in the dominant model and the recessive model (AC + CC vs AA: OR = 1.542, P < 0.05; CC vs AA + AC: OR = 1.707, P < 0.001), while the risk of SLE was reduced in the overdominant model (AC vs AA + CC: OR = 0.628, P < 0.001). The GT genotype and T allele at locus rs1799983 may be a protective factor for SLE (GT vs GG: OR = 0.328, P < 0.001; T vs G: OR = 0.438, P < 0.001) and this locus reduced the risk of SLE in the overdominant model (GT vs GG + TT: OR = 0.385, P < 0.001). There is a strong linkage disequilibrium between the rs1007311 and rs1799983 loci of the eNOS gene. Among them, the formed haplotype AG increased the risk of SLE compared to GG. AT and GT decreased the risk of SLE compared to GG. In this study, the eNOS gene rs3918188 and rs1799983 loci were found to be associated with susceptibility to SLE. This helps to deeply explore the mechanism of eNOS gene and genetic susceptibility to SLE. It provides a certain research basis for the subsequent exploration of the molecular mechanism of these loci and SLE, as well as the early diagnosis, treatment and prognosis of SLE.

Polygenic polymorphism is associated with NKG2A repertoire and influences lymphocyte phenotype and function

AbstractCD94/NKG2A is a heterodimeric receptor commonly found on natural killer (NK) and T cells, and its interaction with its ligand HLA-E on adjacent cells leads to inhibitory signaling and cell suppression. We have identified several killer cell lectin–like receptor (KLR)C1 (NKG2A) single nucleotide polymorphisms (SNPs) that are associated with NKG2A expression on NK cells, CD8+ T cells, and Vγ9/Vδ2+ T cells. Additionally, due to strong linkage disequilibrium, polymorphisms in KLRC2 (NKG2C) and KLRK1 (NKG2D) are also associated with NKG2A surface density and frequency. NKG2A surface expression correlates with single-cell NK responsiveness, and NKG2A+ NK cell frequency is associated with total NK repertoire response and inhibitability, making the identification of SNPs responsible for expression and frequency important for predicting the innate immune response. Because HLA-E expression is dependent on HLA class I signal peptides, we analyzed the relationship between peptide abundance and HLA-E expression levels. Our findings revealed a strong association between peptide availability and HLA-E expression. We identified the HLA-C killer immunoglobulin–like receptor ligand epitope as a predictive marker for HLA-ABC expression, with the HLA-C1 epitope associated with high HLA-E expression and the HLA-C2 epitope associated with low HLA-E expression. The relationship between HLA-C epitopes and HLA-E expression was independent of HLA-E allotypes and HLA-B leader peptides. Although HLA-E expression showed no significant influence on NKG2A-mediated NK education, it did affect NK cell inhibition. In summary, these findings underscore the importance of NKG2A SNPs and HLA-C epitopes as predictive markers of NK cell phenotype and function and should be evaluated as prognostic markers for diseases that express high levels of HLA-E.

Peripheral pathway gene variants in lifelong premature ejaculation: CYP19A1, CYP1A1, and CYP1A2 enzymes polymorphisms in Chinese Han men

Abstract Background Recent genetic association studies focusing on central pathways have been performed to investigate the correlation between susceptibility alleles and the risk of lifelong premature ejaculation (LPE). However, there remains a dearth of documented genes associated with peripheral pathways. Objective In this study we aimed to investigate the relationship between single nucleotide polymorphisms (SNPs) associated with the peripheral genes CYP19A1, CYP1A1, and CYP1A2 and the risk of LPE. Methods From August 2017 to August 2020, a total of 511 participants (139 LPE patients and 372 controls) were recruited. Trained medical professionals diagnosed LPE according to the standard definition set by the International Society for Sexual Medicine. Nine candidate SNPs were chosen and genotyped using the MassARRAY system. Allele and genotype frequencies of the SNPs among patients and controls were compared using the χ2 test. Logistic regression analysis, adjusted for age, was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) using PLINK version 1.9. Haploview software was employed to analyze linkage disequilibrium and haplotype distribution. The interaction among candidate SNPs concerning LPE risk was evaluated using multifactor dimensionality reduction. The relationship between selected polymorphisms and specific features was assessed using analysis of variance. Outcome Heterozygous SNPs located in the CYP19A1 (rs4646, rs17601876), CYP1A1 (rs1048943), and CYP1A2 (rs762551, rs2470890) genes showed significant correlations with the risk of LPE. Results The findings of this study confirmed that heterozygous SNPs in the CYP19A1 (rs4646 AC vs CC: OR, 1.84; CI, 1.10-3.09; rs17601876 AG vs GG: OR, 1.80; CI, 1.06-3.05) and CYP1A1 genes (rs1048943 CT vs TT: OR, 1.71; CI, 1.02-2.87), respectively, can significantly increase the LPE risk. Participant scores for the Premature Ejaculation Diagnostic Tool (P =.002) and International Index of Erectile Function-5 (P =.020) differed significantly by genotype for the different genotypes of CYP1A1-rs1048943. Haplotype analysis revealed strong linkage disequilibrium under CYP1A2_rs762551-rs2470890 (D' = 1.00). Clinical Implications The findings of this and other investigations of genetic determinants and potential pathogenic mechanisms of LPE may advance diagnostic and therapeutic opportunities in LPE patients. Strengths and Limitations In this study of LPE in men with CYP gene variants we addressed a current research gap. However, data on risk factors such as smoking and drinking were incomplete in both the case and control groups. In future studies we will expand the sample size and enhance data on risk factors for more precise assessments. Conclusion In summary, polymorphisms in the peripheral genes CYP19A1, CYP1A1, and CYP1A2 may play a role in LPE among Chinese men of the Han population.

Association Analysis of METTL23 Gene Polymorphisms with Reproductive Traits in Kele Pigs.

Methyltransferase-like 23 (METTL23) is a kind of RNA methyltransferase that catalyzes the methylation transfer to the N6-adenosine of RNA, serving as one of the key mediators in this process. However, the METTL23 gene has been poorly researched in pigs. In this study, we investigated the genetic effects of METTL23 single-nucleotide polymorphism(SNPs) on reproductive traits in Kele pigs. The DNA was extracted from 228 healthy multiparous Kele sows, and Sanger sequencing revealed three SNPs, g.4804958 G > T (intron 2), g.4805082 C > T (exon 2), and g.4806821 A > G (exon 3). The polymorphism information content (PIC) for each SNP was 0.264, 0.25, and 0.354, indicating moderate polymorphism (0.25 < PIC < 0.5) and providing genetic information. Linkage disequilibrium analysis showed no strong linkage disequilibrium between the three SNPs. The association analysis revealed that in the SNP g.4804958 G > T individuals with the GG genotype had a significantly higher number of piglets born alive, litter birth weight, number of weaned piglets, and weaning litter weight compared to those with the TT genotype (p < 0.05). Individuals with the GG genotype in the SNP g.4806821 A > G group had significantly higher litter birth weight and average birth weight than those with the AA genotype (p < 0.05). The H4H4 diplotype showed significant effects on the number of piglets born alive, litter birth weight, number of weaned piglets, weaning litter weight, and weaning weight (p < 0.05). Together, the METTL23 gene could be used as a candidate gene for the selection of reproductive traits in Kele pigs.

FLT4 gene polymorphisms influence isolated ventricular septal defect predisposition in a Southwest China population

BackgroundVentricular septal defect (VSD) is the most common congenital heart disease. Although a small number of genes associated with VSD have been found, the genetic factors of VSD remain unclear. In this study, we evaluated the association of 10 candidate single nucleotide polymorphisms (SNPs) with isolated VSD in a population from Southwest China.MethodsBased on the results of 34 congenital heart disease whole-exome sequencing and 1000 Genomes databases, 10 candidate SNPs were selected. A total of 618 samples were collected from the population of Southwest China, including 285 VSD samples and 333 normal samples. Ten SNPs in the case group and the control group were identified by SNaPshot genotyping. The chi-square (χ2) test was used to evaluate the relationship between VSD and each candidate SNP. The SNPs that had significant P value in the initial stage were further analysed using linkage disequilibrium, and haplotypes were assessed in 34 congenital heart disease whole-exome sequencing samples using Haploview software. The bins of SNPs that were in very strong linkage disequilibrium were further used to predict haplotypes by Arlequin software. ViennaRNA v2.5.1 predicted the haplotype mRNA secondary structure. We evaluated the correlation between mRNA secondary structure changes and ventricular septal defects.ResultsThe χ2 results showed that the allele frequency of FLT4 rs383985 (P = 0.040) was different between the control group and the case group (P < 0.05). FLT4 rs3736061 (r2 = 1), rs3736062 (r2 = 0.84), rs3736063 (r2 = 0.84) and FLT4 rs383985 were in high linkage disequilibrium (r2 > 0.8). Among them, rs3736061 and rs3736062 SNPs in the FLT4 gene led to synonymous variations of amino acids, but predicting the secondary structure of mRNA might change the secondary structure of mRNA and reduce the free energy.ConclusionsThese findings suggest a possible molecular pathogenesis associated with isolated VSD, which warrants investigation in future studies.

Genomic selection in western redcedar: from proof of concept to operational application.

Forests face many threats. While traditional breeding may be too slow to deliver well-adapted trees, genomic selection (GS) can accelerate the process. We describe a comprehensive study of GS from proof of concept to operational application in western redcedar (WRC, Thuja plicata). Using genomic data, we developed models on a training population (TrP) of trees to predict breeding values (BVs) in a target seedling population (TaP) for growth, heartwood chemistry, and foliar chemistry traits. We used cross-validation to assess prediction accuracy (PACC) in the TrP; we also validated models for early-expressed foliar traits in the TaP. Prediction accuracy was high across generations, environments, and ages. PACC was not reduced to zero among unrelated individuals in TrP and was only slightly reduced in the TaP, confirming strong linkage disequilibrium and the ability of the model to generate accurate predictions across breeding generations. Genomic BV predictions were correlated with those from pedigree but displayed a wider range of within-family variation due to the ability of GS to capture the Mendelian sampling term. Using predicted TaP BVs in multi-trait selection, we functionally implemented and integrated GS into an operational tree-breeding program.

Association of vitamin D status and vitamin D receptor polymorphism in diabetic foot ulcer patients: A prospective observational study in a South-Indian tertiary healthcare facility.

Objective of the study was to find the association of vitamin D receptor (VDR) polymorphisms (Fokl, Taql and Apal) with vitamin D levels in diabetic foot ulcer (DFU) patients in South India. In this case-control study, plasma vitamin D levels and VDR genotype frequencies of 70 cases (DFU patients) were compared with 70 diabetic (diabetes mellitus [DM] [non-DFU]) patients and 70 apparently healthy controls (HC) from South India. Plasma vitamin D levels were measured using the ELISA technique, and genotyping of VDR polymorphisms was carried out using real-time polymerase chain reaction. Logistic regression was used to find the association between DFU versus HC and DFU versus DM traits. Association analysis was performed based on additive, dominant and recessive models with age and gender as covariates. A 45.7% of DFU patients have sufficient vitamin D levels than 48.6% and 40% of DM patients and HC, respectively. Linkage disequilibrium analysis for DFU versus HC and DFU versus DM traits shows that single nucleotide polymorphisms (SNPs) Taq1 (rs731236) and Apal (rs7975232) are in strong linkage disequilibrium in DFU patients. The alleles and genotype frequencies were similar in all three groups. Although the additive model does not show statistical significance, age and sex correlate with the three SNPs (Fokl, Taql and Apal). No association was found between VDR gene polymorphisms and vitamin D levels in DFU patients in Southern India. On the other hand, age and sex correlate with the three SNPs.