Susceptibility Single Nucleotide Polymorphisms Research Articles

CHOROIDAL VASCULARITY IN CHRONIC CENTRAL SEROUS CHORIORETINOPATHY AND ITS ASSOCIATION WITH RISK SINGLE-NUCLEOTIDE POLYMORPHISMS.

To analyze the choroidal parameters of patients with chronic central serous chorioretinopathy (cCSC) and the association with central serous chorioretinopathy susceptibility genes. The choroidal vascular index (CVI) was obtained by binarizing spectral domain optical coherence tomography enhanced depth images of patients with cCSC and healthy age-matched controls. Patients with cCSC were genotyped for three central serous chorioretinopathy susceptibility single-nucleotide polymorphisms: rs4844392 ( mir-29b-2/CD46 ), rs1329428 ( CFH ), and rs2379120 (upstream GATA5 ). One hundred three eyes with cCSC and 53 control eyes were included. There was a significant increase in the subfoveal choroidal area in both the affected (2.4 ± 0.6 mm 2 ) and fellow (2.2 ± 0.6 mm 2 ) eyes of patients with cCSC compared with controls (1.8 ± 0.5 mm 2 , P < 0.0001 and P < 0.0001). The CVI was reduced in patients with cCSC 63.5% ± 3.1% compared with controls 65.4% ± 2.3% ( P < 0.001) and also in the affected compared with the fellow eyes 64.6% ± 2.9% ( P < 0.01). There was a significant association between CVI in the cCSC group and presence of the risk single-nucleotide polymorphisms rs2379120 at GATA5 ( P < 0.01). The relative reduction of CVI in patients with cCSC may suggest a persistence of vessel hyperpermeability over dilation in chronic disease. GATA5 is associated with CVI in patients with cCSC and therefore may have a role in choroidal vascularity.

Correlation of TBX21 gene polymorphisms with ankylosing spondylitis in a Chinese population.

Genome-wide association studies analysis has revealed associations between ankylosing spondylitis (AS) and loci on the TBX21 gene across various populations. This study aimed to investigate if there is a connection between a higher risk of AS in a Chinese population and two polymorphism loci on the TBX21 gene. To achieve this, we performed a case-control investigation involving 363 patients with AS and 907 healthy individuals. Genotyping was carried out using the iPLEX Gold genotyping assay. The analysis of genotypes and haplotypes was performed using SPSS 23.0 and SHEsis software. The results revealed no statistically significant correlation between the two specified single-nucleotide polymorphisms of TBX21 (rs11657479 C/T and rs4794067 C/T) and susceptibility to AS. However, upon conducting stratification analysis, our findings demonstrated a significant association between rs11657479 and susceptibility to human leucocyte antigen (HLA)-B27+ AS in allelic (C vs. T: odds ratio [OR]=1.52, 95%CI=1.09-2.11, corrected p [pc]=.028), heterozygous (CT vs. TT: OR=1.63, 95%CI=1.13-2.34, pc=.016) and dominant (CT+CC vs. TT: OR=1.60, 95%CI=1.12-2.28, pc=.018) models. Furthermore, the haplotype rs4794067/C-rs11657479/C of TBX21 was found to increase the risk of HLA-B27+ AS cases. In conclusion, our findings indicate a correlation between TBX21 gene polymorphism and HLA-B27+ AS patients within the Chinese population.

Genetic susceptibility to prostate cancer in Taiwan: A genome-wide association study.

We conducted the first genome-wide association study (GWAS) of prostate cancer (PCa) in Taiwan with 1844 cases and 80,709 controls. Thirteen independent single-nucleotide polymorphisms (SNPs) reached genome-wide significance (p < 5 × 10-8 ). Among these, three were distinct from previously identified loci: rs76072851 in CORO2B gene (15q23), odds ratio (OR) = 1.54, 95% confidence interval (CI), 1.36-1.76, p = 5.30 × 10-11 ; rs7837051, near two long noncoding RNA (lncRNA) genes, PRNCR1 and PCAT2 (8q24.21), OR = 1.41 (95% CI, 1.31-1.51), p = 8.77 × 10-21 ; and rs56339048, near an lncRNA gene, CASC8 (8q24.21), OR = 1.25 (95% CI, 1.16-1.35), p = 2.14 × 10-8 . We refined the lead SNPs for two previously identified SNPs in Taiwanese: rs13255059 (near CASC8), p = 9.02 × 10-43 , and rs1456315 (inside PRNCR1), p = 4.33 × 10-42 . We confirmed 35 out of 49 GWAS-identified East Asian PCa susceptibility SNPs. In addition, we identified twoSNPs more specific to Taiwanese than East Asians: rs34295433 in LAMC1 (1q25.3) and rs6853490 in PDLIM5 (4q22.3). A weighted genetic risk score (GRS) was developed using the 40 validated SNPs and the area under the receiver-operating characteristiccurvefor the GRS to predict PCa was 0.67 (95% CI, 0.63-0.71). These identified SNPs provide valuable insights into the molecular mechanisms of prostate carcinogenesis in Taiwan and underscore the significant role of genetic susceptibility in regional differences in PCa incidence.

Host-Pathogen Interactions in K. pneumoniae Urinary Tract Infections: Investigating Genetic Risk Factors in the Taiwanese Population.

Klebsiella pneumoniae (K. pneumoniae) urinary tract infections pose a significant challenge in Taiwan. The significance of this issue arises because of the growing concerns about the antibiotic resistance of K. pneumoniae. Therefore, this study aimed to uncover potential genomic risk factors in Taiwanese patients with K. pneumoniae urinary tract infections through genome-wide association studies (GWAS). Genotyping data are obtained from participants with a history of urinary tract infections enrolled at the Tri-Service General Hospital as part of the Taiwan Precision Medicine Initiative (TPMI). A case-control study employing GWAS is designed to detect potential susceptibility single-nucleotide polymorphisms (SNPs) in patients with K. pneumoniae-related urinary tract infections. The associated genes are determined using a genome browser, and their expression profiles are validated via the GTEx database. The GO, Reactome, DisGeNET, and MalaCards databases are also consulted to determine further connections between biological functions, molecular pathways, and associated diseases between these genes. The results identified 11 genetic variants with higher odds ratios compared to controls. These variants are implicated in processes such as adhesion, protein depolymerization, Ca2+-activated potassium channels, SUMOylation, and protein ubiquitination, which could potentially influence the host immune response. This study implies that certain risk variants may be linked to K. pneumoniae infections by affecting diverse molecular functions that can potentially impact host immunity. Additional research and follow-up studies are necessary to elucidate the influence of these risk variants on infectious diseases and develop targeted interventions for mitigating the spread of K. pneumoniae urinary tract infections.

A genome-wide association study of contralateral breast cancer in the Women’s Environmental Cancer and Radiation Epidemiology Study

BackgroundContralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy.FindingsWe performed a genome-wide association analysis in the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10–6). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14–1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (Pheterogeneity = 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.ConclusionsThe present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.

Genome-wide functional integration identified MAZ-controlled RPS14 dysregulation in hepatocellular carcinoma.

Chronic infection with Hepatitis B virus (HBV) significantly increases the risk of hepatocellular carcinoma (HCC), particularly in Eastern Asia. However, only a subset of individuals with chronic HBV infection develop HCC, suggesting the role for genetic factors in HCC etiology. Despite genome-wide association studies (GWASs) identifying multiple single nucleotide polymorphisms (SNPs) associated with HBV-related HCC susceptibility, the underlying mechanisms and causal genetic polymorphisms remain largely unclear. To address this, we developed The Updated Integrative Functional Genomics Approach (TUIFGA), an methodology that combines data from transcription factor (TF) cistromics, ATAC-seq, DNAase-seq, and the 1000 Genomes Project to identify cancer susceptibility SNPs within TF-binding sites across human genome. Using TUIFGA, we discovered SNP rs13170300 which located in the TF MAZ binding motif of RPS14. The RPS14 rs13170300 was significantly associated with HCC risk in two case-control sets, with the T allele as the protective allele (Shandong discovery set: TT OR = 0.60, 95% CI = 0.49-0.74, P = 1.0 × 10-6; CT OR = 0.69, 95% CI = 0.55-0.86, P = 0.001; Jiangsu validation set: TT OR = 0.70, 95% CI = 0.56-0.87, P = 0.001; CT OR = 0.65, 95% CI = 0.53-0.82, P = 1.6 × 10-4). SNP rs13170300 affected MAZ binding in the RPS14 promoter, resulting in allele-specific changes in gene expression. RPS14 functions as a novel oncogene in HCC, specifically via activating the AKT signaling. Our findings present important insights into the functional genetics underlying HBV-related HCC development and may contribute to personalized approaches for cancer prevention and novel therapeutics.

The osteoporosis susceptibility SNP rs188303909 at 2q14.2 regulates EN1 expression by modulating DNA methylation and E2F6 binding.

EN1 encodes a homeodomain-containing transcription factor and is a determinant of bone density and fracture. Previous powerful genome-wide association studies (GWASs) have identified multiple single-nucleotide polymorphisms (SNPs) near EN1 at 2q14.2 locus for osteoporosis, but the causal SNPs and functional mechanisms underlying these associations are poorly understood. The target genes regulated by the transcription factor EN1 are also unclear. In this study, we identified rs188303909, a functional CpG-SNP, as a causal SNP for osteoporosis at 2q14.2 through the integration of functional and epigenomic analyses. Functional experiments demonstrated that unmethylated rs188303909 acted as a strong allele-specific distal enhancer to regulate EN1 expression by modifying the binding of transcription factor E2F6, but rs188303909 methylation attenuated the active effect of E2F6 on EN1 expression. Importantly, transcription factor EN1 could differentially bind osteoporosis GWAS lead SNPs rs4869739-T and rs4355801-G to upregulate CCDC170 and COLEC10 expression, thus promoting bone formation. Our study provided a mechanistic insight into expression regulation of the osteoporosis susceptibility gene EN1, which could be a potential therapeutic target for osteoporosis precision medicine. KEY MESSAGES: CpG-SNP rs188303909 is a causal SNP at the osteoporosis susceptibility locus 2q14.2. Rs188303909 distally regulatesEN1expression by modulating DNA methylation and E2F6 binding. EN1 upregulatesCCDC170 and COLEC10expression through osteoporosis GWAS lead SNPs rs4869739 and rs4355801.

Relationship Between Retinal Layer Thickness and Genetic Susceptibility to Age-Related Macular Degeneration in Asian Populations

For OCT retinal thickness measurements to be used as a prodromal age-related macular degeneration (AMD) risk marker, the 3-dimensional (3D) topographic variation of the relationship between genetic susceptibility to AMD and retinal thickness needs to be assessed. We aimed to evaluate individual retinal layer thickness changes and topography at the macula that are associated with AMD genetic susceptibility. Genetic association study. A total of 1579 healthy participants (782 Chinese, 353 Malays, and 444 Indians) from the multiethnic Singapore Epidemiology of Eye Diseases study were included. Spectral-domain OCT and automatic segmentation of individual retinal layers were performed to produce 10 retinal layer thickness measurements at each ETDRS subfield, producing 3D topographic information. Age-related macular degeneration genetic susceptibility was represented via single nucleotide polymorphisms (SNPs) and aggregated via whole genome (overall) and pathway-specific age-related macular degeneration polygenic risk score (PRSAMD). Associations of individual SNPs, overall PRSAMD, and pathway-specific PRSAMD with retinal thickness were analyzed by individual retinal layer and ETDRS subfield. CFH rs10922109, ARMS2-HTRA1 rs3750846, and LIPC rs2043085 were the top AMD susceptibility SNPs associated with retinal thickness of individual layers (P<1.67×10-3), all at the central subfield. The overall PRSAMD was most associated with thinner L9 (outer segment photoreceptor/retinal pigment epithelium complex) thickness at the central subfield (β=-0.63 μm; P=5.45×10-9). Pathway-specific PRSAMD for the complement cascade (β=-0.53 μm; P=9.42×10-7) and lipoprotein metabolism (β=-0.05 μm; P=0.0061) were associated with thinner photoreceptor layers (L9 and L7 [photoreceptor inner/outer segments], respectively) at the central subfield. The mean PRSAMD score was larger among Indians compared with that of the Chinese and had the thinnest thickness at the L9 central subfield (β=-1.00 μm; P=2.91×10-7; R2=5.5%). Associations at other retinal layers and ETDRS regions were more heterogeneous. Overall genetic susceptibility to AMD and the aggregate effects of the complement cascade and lipoprotein metabolism pathway are associated most significantly with L7 and L9 photoreceptor thinning at the central macula in healthy individuals. Photoreceptor thinning has potential to be a prodromal AMD risk marker, and topographic variation should be considered. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Impact of interaction between interleukin-6 gene polymorphism and Helicobacter pylori infection on susceptibility to gastric cancer.

This study aimed to evaluate the association between four single nucleotide polymorphisms (SNPs) of the interleukin-6 (IL-6) gene and gastric cancer (GC), and impact of interaction between IL-6 SNPs and Helicobacter pylori (H. pylori ) infection on susceptibility to GC. Logistic regression was used to test the relationships between four SNPs of IL-6 gene and GC susceptibility. A generalized multifactor dimensionality reduction (GMDR) model was employed to assess the interaction effect between IL-6 gene and H. pylori infection on GC risk. Logistic regression analysis indicated that the rs1800795-C allele was associated with increased GC risk, adjusted ORs (95% CI) were 1.80 (1.21-2.41) (CC vs. GG) and 1.68 (1.09-2.30) (C vs. G), respectively. The rs10499563-C allele was associated with decreased risk of GC, and adjusted ORs (95% CI) were 0.62 (0.31-0.93) (TC vs. TT), 0.52 (0.18-0.89) (CC vs. TT) and 0.60 (0.29-0.92) (C vs. T), respectively. GMDR methods found a two-dimensional model combination (including rs1800795 and H. pylori infection) was statistically significant. The selected model had testing balanced accuracy of 59.85% and the best cross-validation consistencies of 10/10 ( P = 0.0107). Compared with H. pylori -negative subjects with rs1800795- GG genotype, H. pylori -positive participants with GC or CC genotype had the highest risk of GC, the OR (95% CI) was 3.34 (1.78-4.97). The rs1800795-C allele was associated with increased GC risk and the rs10499563-C allele was associated with decreased GC risk. The interaction between rs1800795 and H. pylori infection was also correlated with increased risk of GC.

Mitochondrial displacement loop region single nucleotide polymorphisms and mitochondrial DNA copy number associated with risk of ankylosing spondylitis.

The pathogenesis of ankylosing spondylitis (AS) seems to be associated with genetics, the environment, heredity, and oxidative stress. Single nucleotide polymorphisms (SNPs) in the displacement loop (D-loop) region of mitochondrial DNA (mtDNA) and mtDNA copy number were investigated for their correlation with AS patients. This study included 83 AS patients and 100 healthy controls from the Second Hospital of Hebei Medical University. DNAs were extracted from blood samples for polymerase chain reaction analysis and quantitative real-time polymerase chain reaction analysis. Plasma reactive oxygen species (ROS) levels were measured by fluorescent probe technology. The distribution frequencies of the minor alleles of nucleotides 16304C (p = .037), 16311C (p = .027), and 152C (p = .034) were remarkably higher in AS patients than in healthy controls, which indicated that the16304C, 16311C, and 152C alleles were correlated with an increased risk of AS. Simultaneously, mtDNA copy number was statistically higher in patients with AS compared with controls (1.450 ± 0.876 versus 0.835 ± 0.626, p < .001). We also observed an increased ROS generation in AS patients compared with controls (27 066.169 ± 18 364.819 versus 14 758.330 ± 5854.946, p < .001) subsequently. In addition, the AS susceptible SNP 16311C is associated with high ROS levels (35 065.177 ± 26 999.934 vs. 25 005.818 ± 14 999.495, p = .043). Our study demonstrated that SNPs in the mtDNA D-loop could be AS risk biomarkers with the potential to promote oxidative stress levels; mtDNA copy number-induced mitochondrial dysfunction may also be involved in AS pathogenesis.

In silico prediction of deleterious non-synonymous SNPs in STAT3.

STAT3, a pleiotropic transcription factor, plays a critical role in the pathogenesis of autoimmunity, cancer, and many aspects of the immune system, as well as having a link with inflammatory bowel disease. Changes caused by non-synonymous single nucleotide polymorphisms (nsSNPs) have the potential to damage the protein's structure and function. We identified disease susceptible single nucleotide polymorphisms (SNPs) in STAT3 and predicted structural changes associated with mutants that disrupt normal protein-protein interactions using different computational algorithms. Several in silico tools, such as SIFT, PolyPhen v2, PROVEAN, PhD-SNP, and SNPs&GO, were used to determine nsSNPs of the STAT3. Further, the potentially deleterious SNPs were evaluated using I-Mutant, ConSurf, and other computational tools like DynaMut for structural prediction. 417 nsSNPs of STAT3 were identified, 6 of which are considered deleterious by in silico SNP prediction algorithms. Amino acid changes in V507F, R335W, E415K, K591M, F561Y, and Q32K were identified as the most deleterious nsSNPs based on the conservation profile, structural conformation, relative solvent accessibility, secondary structure prediction, and protein-protein interaction tools. The in silico prediction analysis could be beneficial as a diagnostic tool for both genetic counseling and mutation confirmation. The 6 deleterious nsSNPs of STAT3 may serve as potential targets for different proteomic studies, large population-based studies, diagnoses, and therapeutic interventions.

IL-10 Polymorphism and Breast Cancer Risk in Georgian Women: A Case-Control Study.

Background Interleukin-10 (IL-10) is a cytokine with a vast variety of functions, but its role in cancer development and progression is not yet clear. It is involved in two of the hallmarks of cancer: vascularization and immune modulation. IL-10 inhibits angiogenesis and hence is antitumorigenic. But it also can suppress the immune system and be tumorigenic. Objective Evaluating the role of IL-10 (-1082 A/G) gene promoter single-nucleotide polymorphism (SNP) in breast cancer susceptibility and progression in Georgian women. Methods A case-control study was performed on a total of 128 women, with 64 of them being histologically confirmed to have breast cancer and 64 healthy controls. SNP genotyping was performed with TaqMan assay with real-time polymerase chain reaction. And pathology report, containing proliferative activity and breast cancer hormonal status, was obtained after surgery of the case individuals. Statistical analysis was done to investigate the significance of data obtained from genotyping and histology reports. Results Statistical analysis revealed that the difference in frequency of genotypes was not statistically significant between cases and controls (chi-square = 0.5812, p = 0.7478). The comparison of proliferative activity of cases with AA genotypes and AG/GG genotypes showed no statistical difference ( t = 0.2575, p = 0.7980). Although when put into a plot (box and whiskers), patients with AG/GG genotype have outliers with very high proliferative activity. Conclusion This study shows that -1082 A/G SNP in the promoter region of the IL-10 gene is not associated with breast cancer risk in Georgian women.

1385-P: Maternal Gestational Weight Gain and Children’s Genetic Susceptibility on Childhood Adiposity—A Longitudinal Cohort Study

Few studies have assessed the association of early-life environmental and genetic factors with the risk of childhood adiposity. The aim of the present study was to investigate the interaction between maternal gestational weight gain (GWG) and children’s genetic susceptibility on childhood adiposity. The present study included 1038 mother-child pairs. Body mass index (BMI) for age Z-score (BMI-Z) and childhood overweight were evaluated according to the World Health Organization (WHO) growth reference. Genetic risk score (GRS) was established by aggregating alleles of 10 BMI susceptibility single-nucleotide polymorphisms identified from a recent study. Children born to mothers with excessive GWG had higher BMI-Z (P&amp;lt;0.001), percentage of body fat (P&amp;lt;0.001), and prevalence of overweight (28.4% vs 15.9%, P&amp;lt;0.001) than those born to mothers with adequate GWG. Children’s BMI GRS was significantly and positively associated with BMI-Z, percentage of body fat and overweight risk (all P&amp;lt;0.05). Stratified analyses showed the positive association of children’s BMI GRS with adiposity risk was especially concentrated among mothers with pre-pregnancy normal weight but excessive GWG. The present study identified an interactive effect between maternal GWG and children’s genetic susceptibility on childhood adiposity risk. The findings provided new insight into the etiology of childhood obesity and highlighted the importance of GWG management. Disclosure H.Liu: None. W.Li: None. L.Wang: None. S.Zhang: None. W.Li: None. X.Yang: None. J.Leng: None. G.Hu: None. S.Wang: None. Funding European Foundation for the Study of Diabetes/Chinese Diabetes Society/Lilly Programme for Collaborative Research between China and Europe; National Institute of Diabetes and Digestive and Kidney Diseases (R01DK100790, R01DK132011); National Institute of General Medical Sciences (U54GM104940)

Development and testing of a polygenic risk score for breast cancer aggressiveness

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS’s association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06–1.21, p = 4.0 × 10–4). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRSER-/ER+). Furthermore, its effect was minimally attenuated when adjusted for PRSER-/ER+, suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention.

A functional SNP in miR-146a and genetic susceptibility to drug-resistant epilepsy

ABSTRACT Objectives The study aimed to assess the relationship between the functional single nucleotide polymorphism (SNP) (rs57095329) of miR-146a, the progression of drug-resistant epilepsy (DRE), and the severity of the disease (seizure frequency) in a group of Egyptian children epilepsy patients. Subjects and Methods 110 Egyptian children were recruited and divided into two groups, the epilepsy patients (n = 60) and the healthy control children (n = 50). The patient’s group was equally subdivided into two subgroups: drug-resistant and drug-responsive epilepsy patients. Genomic DNA samples from all participants were screened for the incidence of the rs57095329 SNP of the miR-146a gene by the Real-Time PCR. Results There was no statistical significance between epilepsy patients compared to controls regarding the rs57095329 SNP genotypes and alleles. Contrarily, there was significant difference between the drug-resistant epilepsy and the drug-responsive cases (P < 0.05). The genotypes AG (P < 0.007, OR: 0.118, 95% CI (0.022–0.636)) and GG (P = 0.016, OR: 0.123, 95% CI (0.023–0.769)) were higher among the drug-resistant, while AA was higher among the drug-responsive patients. The alleles A and G were higher among all cases, with a statistically significant difference (P = 0.028, OR: 0.441, 95% CI (0.211–0.919)). A significant difference was reported in the dominant model (AA versus AG+GG) (P = 0.005, OR: 0.12395% CI (0.025–0.621)). Conclusion Therefore, miR-146a might be a potential therapeutic target for epilepsy treatment. The study was limited by the low number of young epileptic patients, the refusal of some parents to participate, and the incomplete medical history of some cases in the study, which forced their exclusion. More studies might be necessary to investigate other effective drugs to overcome the resistance issues induced by miR-146a rs57095329 polymorphisms.

BHMT polymorphism and susceptibility to PTE in Chinese patients.

Pulmonary thromboembolism (PTE) is as a common form of venous thrombosis and a potentially fatal cardiovascular disorder, which has become a severe clinical problem with high incidence and mortality. The PTE has a strong genetic basis, which contributes up to half of the variance in PTE incidence and susceptibility single-nucleotide polymorphisms (SNPs) is associated with PTE. Betaine homocysteine methyltransferase (BHMT) is an essential enzyme that catalyzes the remethylating reaction from homocysteine to methionine and participates in conserving methionine and detoxifying homocysteine. In this work, we aimed to explore BHMT polymorphism and susceptibility to PTE in Chinese patients. Variant loci of the BHMT gene were screened in serum samples of PTE patients, followed by verification using Sanger sequencing. These polymorphic loci were validated in 16 PTE patients and 16 matched normal patients. The frequency differences between the allele and genotypes were compared using the Hardy-Weinberg equilibrium test and Chi-square test. A SNP was identified in PTE patients and a heterozygous transition of G>A (Arg239Gln) in rs3733890 was found. The variance difference at rs3733890 between normal patients (2/16, 0.125) and PTE patients (9/16, 0.5625) was significant (p<0.01). Therefore, we concluded that the BHMT polymorphism, rs3733890 may be a susceptibility SNP for PTE.

Impact of the RNA allosteric effect triggered by single nucleotide polymorphisms on the splicing process.

The susceptibility single nucleotide polymorphisms (SNPs) obtained by genome-wide association studies leave some thorny questions, such as prioritization, false positives and unknown pathogenesis. Previous studies suggested that genetic variation may perturb the RNA secondary structure, influence protein recruitment and binding and ultimately affect splicing processes. Therefore, exploring the perturbation of SNPs to structure-function correlations may provide an effective bridge toward understanding the genetic contribution to diseases. Here, aiming to decipher the regulatory mechanism of myopia susceptibility variants, we systematically evaluated the roles of SNP-induced structural changes during splicing. In addition, 7.53% of myopia-related SNPs exhibited significant global structural changes, 19.53% presented noteworthy local structural disturbance and there were wide-ranging structural perturbations in the splice-related motifs. We established a comprehensive evaluation system for structural disturbance in the splicing-related motifs and gave the priority ranking for the SNPs at RNA structural level. These high-priority SNPs were revealed to widely disturb the molecular interaction properties between splicing-related proteins and pre-mRNAs by HDOCK. Moreover, mini-gene assays confirmed that structural perturbation could influence splicing efficiency through structural remodelling. This study deepens our understanding of the potential molecular regulatory mechanisms of susceptible SNPs in myopia and contributes to personalized diagnosis, personalized medicine, disease-risk prediction and functional verification study by guiding the prioritization of the susceptibility SNPs.

Abstract 5222: Genetic variants associated with progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL)

Abstract Low count (LC) MBL is characterized by a circulating population of clonal B-cells and is a precursor state to CLL. Most individuals with LC MBL do not progress to CLL and never come to clinical attention. An active area of research is to identify factors that distinguish those individuals with MBL who progress from those who do not. Currently, 41 single nucleotide polymorphisms (SNPs) are known to be associated with CLL risk, and a portion of these SNPs have also been found to be associated with MBL risk. We hypothesize that these CLL-susceptibility SNPs associated with both MBL and CLL risk are SNPs associated with developing a B-cell clone; whereas the remaining SNPs found not to be associated with MBL risk are associated with progression of the B-cell clone (i.e., progression from MBL to CLL). To test this hypothesis, we evaluated the association of these 41 SNPs with risk of progression to CLL using a case-control study of 1,911 CLL cases and 1,579 individuals with MBL from Mayo Clinic. Individuals with MBL were identified through screening using 8-color flow cytometry assay. Individuals with LC MBL (defined by having a clonal B-cell population with the percent clonal B-cells out of total B-cell count &amp;lt;85%) who had an immunophenotype consistent with CLL were included as controls. CLL cases were obtained through the Mayo Clinic hematology practice. DNA was genotyped from whole blood. We analyzed the 41 CLL susceptibility SNPs with risk of progression to CLL using logistic regression and estimated odds ratio (OR) and 95% confidence interval (CI), adjusting for sex and age. We evaluated the CLL polygenic risk score (CLL-PRS), comprised of a weighted average of the 41 SNPs, with risk of CLL. Out of the 41 established CLL susceptibility SNPs, 15 were associated with CLL progression from MBL to CLL (all P&amp;lt;0.05). Nine of these 15 significant SNPs were not previously found to be associated with risk of MBL. The most significant SNPs were rs9880772 (OR=1.23, CI: 1.11-1.36, P=6.1 × 10−5), rs888096 (OR=1.25, CI: 1.12-1.38, P=3.0 × 10−5), and rs305065 (OR=1.28, CI: 1.14-1.43, P=1.5 × 10−5). One SNP (rs77551289) had a suggestive association (OR=1.21, P=0.069). The remaining 25 SNPs had no evidence of association with progression (ORs ranging between 0.9-1.1 and all P&amp;gt;0.1). The CLL-PRS was also associated with CLL risk (continuous OR = 1.25, CI: 1.15 - 1.35, P = 6.7 × 10−8). In our study accounting for the presence of B-cell clonal population, we identified 15 out of 41 CLL-susceptibility SNPs to be significantly associated with progression from LC MBL to CLL. The remaining 25 non-significant CLL-SNPs were not associated with progression and may instead be associated with development or initiation of the B-cell clone. These findings suggest that the established CLL susceptibility SNPs may play differing role (i.e., development or progression of the clone) in the etiology of CLL. Citation Format: Raphael Mwangi, Geffen Kleinstern, Sara J. Achenbach, Dennis Robinson, Aaron D. Norman, Kari G. Rabe, Janet E. Olson, Neil E. Kay, Rosalie G. Waller, Nicholas J. Boddicker, James R. Cerhan, Esteban Braggio, Sameer A. Parikh, Curtis A. Hanson, Celine M. Vachon, Tait Shanafelt, Susan L. Slager. Genetic variants associated with progression from monoclonal B-cell lymphocytosis (MBL) to chronic lymphocytic leukemia (CLL). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5222.

Genome-wide association study of tuberculosis in the western Chinese Han and Tibetan population.

Tuberculosis (TB) remains a serious global public health threat. Accumulated evidence has demonstrated that human susceptibility to TB has a strong genetic basis. And different susceptibility single nucleotide polymorphisms (SNP) have been reported in different studies. To gain greater insight into the host susceptibility to TB, we perform a two-stage genome-wide association study to identify the susceptible loci of TB. In the discovery stage, 3116 (1532TB patients and 1584 healthy controls) and 439 (211TB patients and 228 healthy controls) individuals were genome-wide genotyped from a western Chinese Han and Tibetan population, respectively. Based on the additive genetic model, we discovered 14 and three independent loci that had potential associations with TB susceptibility in the Chinese Han and Tibetan populations, respectively (p<1×10-5). Furthermore, we conducted an imputation-based meta-analysis on another two East Asia cohorts to replicate our findings. We identified one independent locus harbored by the human leukocyte antigen (HLA) class II genes that was genome-wide significantly associated with TB (lead SNP rs111875628 with a p-value of 2.20×10-9). Our findings suggest a novel mechanism of the interaction with the HLA class II genes and reinforce the importance of the HLA class II alleles in response to TB.

Pulmonary Vein Myocardial Sleeve Length and its Association With Sex and 4q25/PITX2 Genotype

BackgroundExperimental evidence suggests genetic variation in 4q25/PITX2 modulates pulmonary vein (PV) myocardial sleeve length. Although PV sleeves are the main target of atrial fibrillation (AF) ablation, little is known about the association between different PV sleeve characteristics with ablation outcomes. ObjectivesThis study sought to evaluate the association between clinical and genetic (4q25) risk factors with PV sleeve length in humans, and to evaluate the association between PV sleeve length and recurrence after AF ablation. MethodsIn a prospective, observational study of patients undergoing de novo AF ablation, PV sleeve length was measured using electroanatomic voltage mapping before ablation. The sentinel 4q25 AF susceptibility single nucleotide polymorphism, rs2200733, was genotyped. The primary analysis tested the association between clinical and genetic (4q25) risk factors with PV sleeve length using a multivariable linear regression model. Covariates included age, sex, body mass index, height, and persistent AF. The association between PV sleeve length and atrial arrhythmia recurrence (>30 seconds) was tested using a multivariable Cox proportional hazards model. ResultsBetween 2014 and 2019, 197 participants were enrolled (median age 63 years [IQR: 55 to 70 years], 133 male [67.5%]). In multivariable modeling, men were found to have PV sleeves 2.94 mm longer than women (95% CI: 0.99-4.90 mm; P < 0.001). Sixty participants (30.5%) had one 4q25 risk allele and 6 (3.1%) had 2 alleles. There was no association between 4q25 genotype and PV sleeve length. Forty-six participants (23.4%) experienced arrhythmia recurrence within 3 to 12 months, but there was no association between recurrence and PV sleeve length. ConclusionsCommon genetic variation at 4q25 was not associated with PV sleeve length and PV sleeve length was not associated with ablation outcomes. Men did have longer PV sleeves than women, but more research is needed to define the potential clinical significance of this observation.