Candidate Single Nucleotide Polymorphisms Research Articles

A Cohort Study to Evaluate Genetic Predictors for Aromatase Inhibitor Musculoskeletal Symptoms (AIMSS): Results from ECOG-ACRIN E1Z11.

Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS) are common and frequently lead to AI discontinuation. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate associations between 10 SNPs and AI discontinuation due to AIMSS. Postmenopausal women with stage I-III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcomes (PRO) to assess AIMSS (Stanford Health Assessment Questionnaire; HAQ) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS, and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial strata provided 80% power to detect an effect size of 1.5-4. SNPs were in ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Of 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. While more Black and Asian women developed AIMSS compared to White women (49% vs 39%, p=0.017; 50% vs 39%, p=0.004, respectively), AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population, or in distinct cohorts. The odds ratio for rs2296972 (HTR2A) approached significance for developing AIMSS. We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, PRO predictors of AIMSS, and differences by race.

Genetic diversity, disease resistance, and environmental adaptation of Arachis duranensis L.: New insights from landscape genomics.

The genetic diversity that exists in natural populations of Arachis duranensis, the wild diploid donor of the A subgenome of cultivated tetraploid peanut, has the potential to improve crop adaptability, resilience to major pests and diseases, and drought tolerance. Despite its potential value for peanut improvement, limited research has been focused on the association between allelic variation, environmental factors, and response to early (ELS) and late leaf spot (LLS) diseases. The present study implemented a landscape genomics approach to gain a better understanding of the genetic variability of A. duranensis represented in the ex-situ peanut germplasm collection maintained at the U.S. Department of Agriculture, which spans the entire geographic range of the species in its center of origin in South America. A set of 2810 single nucleotide polymorphism (SNP) markers allowed a high-resolution genome-wide characterization of natural populations. The analysis of population structure showed a complex pattern of genetic diversity with five putative groups. The incorporation of bioclimatic variables for genotype-environment associations, using the latent factor mixed model (LFMM2) method, provided insights into the genomic signatures of environmental adaptation, and led to the identification of SNP loci whose allele frequencies were correlated with elevation, temperature, and precipitation-related variables (q < 0.05). The LFMM2 analysis for ELS and LLS detected candidate SNPs and genomic regions on chromosomes A02, A03, A04, A06, and A08. These findings highlight the importance of the application of landscape genomics in ex situ collections of peanut and other crop wild relatives to effectively identify favorable alleles and germplasm for incorporation into breeding programs. We report new sources of A. duranensis germplasm harboring adaptive allelic variation, which have the potential to be utilized in introgression breeding for a single or multiple environmental factors, as well as for resistance to leaf spot diseases.

Genome-wide association study identified five quantitative trait loci and two candidate genes for digestive traits in Suhuai pigs.

This work aimed to identify markers and candidate genes underlying porcine digestive traits. In total, 331 pigs were genotyped by 80 K Chip data or 50 K Chip data. For apparent neutral detergent fiber digestibility, a total of 19 and 21 candidate single nucleotide polymorphisms (SNP) were respectively identified using a genome-wide efficient mixed-model association algorithm and linkage-disequilibrium adjusted kinship. Among them, three quantitative trait locus (QTL) regions were identified. For apparent acid detergent fiber digestibility, a total of 16 and 17 SNPs were identified by these two methods, respectively. Of these, three QTL regions were also identified. Moreover, two candidate genes (MST1 and LATS1), which are functionally related to intestinal homeostasis and health, were detected near these significant SNPs. Taken together, our results could provide a basis for deeper research on digestive traits in pigs.

Association of Gene Polymorphisms with Normal Tension Glaucoma: A Systematic Review and Meta-Analysis.

Normal tension glaucoma (NTG) is becoming a more and more serious problem, especially in Asia. But the pathological mechanisms are still not illustrated clearly. We carried out this research to uncover the gene polymorphisms with NTG. We searched in Web of Science, Embase, Pubmed and Cochrane databases for qualified case-control studies investigating the association between single nucleotide polymorphisms (SNPs) and NTG risk. Odds ratios (ORs) and 95% confidence intervals (CIs) for each SNP were estimated by fixed- or random-effect models. Sensitivity analysis was also performed to strengthen the reliability of the results. Fifty-six studies involving 33 candidate SNPs in 14 genetic loci were verified to be eligible for our meta-analysis. Significant associations were found between 16 SNPs (rs166850 of OPA1; rs10451941 of OPA1; rs735860 of ELOVL5; rs678350 of HK2; c.603T>A/Met98Lys of OPTN; c.412G>A/Thr34Thr of OPTN; rs10759930 of TLR4; rs1927914 of TLR4; rs1927911 of TLR4; c.*70C>G of EDNRA; rs1042522/-Arg72Pro of P53; rs10483727 of SIX1-SIX6; rs33912345 of SIX1-SIX6; rs2033008 of NCK2; rs3213787 of SRBD1 and c.231G>A of EDNRA) with increased or decreased risk of NTG. In this study, we confirmed 16 genetic polymorphisms in 10 genes (OPA1, ELOVL5, HK2, OPTN, TLR4, EDNRA, P53, NCK2, SRBD1 and SIX1-SIX6) were associated with NTG.

Association study of FLT4 and HYDIN single nucleotide polymorphisms with atrial septal defect susceptibility in the Han Chinese population of Southwest China

BackgroundAtrial septal defect (ASD) is a common form of congenital heart disease. Although several genes related to ASD have been found, the genetic factors of ASD remain unclear. This study aimed to evaluate the correlation between 10 candidate single nucleotide polymorphisms (SNPs) and sporadic atrial septal defects.MethodsBased on the results of 34 individual whole exome sequences, 10 candidate SNPs were selected. In total, 489 ASD samples and 420 normal samples were collected. The 10 SNPs in the case group and the control group were identified through Snapshot genotyping technology. The χ2-test and unconditional regression model were used to evaluate the relationship between ASD and each candidate SNP. Haploview software was used to perform linkage disequilibrium and haplotype analysis.ResultsThe χ2 results showed that the FLT4 rs383985 (P = 0.003, OR = 1.115–1.773), HYDIN rs7198975 (P = 0.04621, OR = 1.003–1.461), and HYDIN rs1774266 (P = 0.04621, OR = 1.003–1.461) alleles were significantly different between the control group and the case group (P < 0.05). Only the association with the FLT4 polymorphism was statistically significant after adjustment for multiple comparisons.ConclusionThese findings suggest that a possible molecular pathogenesis associated with sporadic ASD is worth exploring in future studies.

Identification of potential candidate genes associated with milk protein differences in Holstein cows: A meta-Analysis integrating GWAS and RNA-Seq transcriptome

Despite the identification of candidate genes influencing milk protein, the connections between genes and regulatory pathways remains elusive. This study aimed integrate findings from genome wide association studies (GWAS) and RNA sequencing (RNA-Seq) through meta-analysis to pinpoint single nucleotide polymorphisms (SNPs) and genes responsible for high and low protein yield in cows. Previous GWAS and RNA-Seq analyses had identified 663 SNPs and 1,106 genes (P&lt;0.05). 20 SNPs from GWAS, 10 genes from RNA-Seq, and 49 SNP/gene associations from both datasets, were identified using meta-analysis. Meta-analysis validated several SNPs previously identified through GWAS, such as rs135549651 (P=2.6×〖10〗^(-256)), rs109146371 (P=3.1×〖10〗^(-208)), rs109350371 (P=4.0×〖10〗^(-207)), and rs109774038 (P=8.6×〖10〗^(-587)). Genes identified in RNA-Seq experiments, including NR4A1 (P=3.2×〖10〗^(-7)), ATF3 (P=9.6×〖10〗^(-7)), CDH16 (P=9.9×〖10〗^(-7)), VEGFA (P=1.0×〖10〗^(-6)), and SAA3 (P=7.3×〖10〗^(-11)), were confirmed. The combined GWAS and RNA-Seq datasets highlighted CCND2 (P=8.9×〖10〗^(-111)), MAPK15 (P=1.3×〖10〗^(-151)), and CPSF1 (P=1.2×〖10〗^(-306)) as the most significant genes. Additionally, significant GO terms including ionizing radiation (P=1.5×〖10〗^(-4)), nuclear pore cytoplasmic filaments (P=9.4×〖10〗^(-5)), and phenylalanine 4-monooxygenase activity (P=1.4×〖10〗^(-5)) were identified. In conclusion, the integration of GWAS and RNA-Seq, coupled with GO enrichment, allowed identification of candidate SNPs and genes with higher accuracy. These findings improve our knowledge about genomic architecture of milk protein, and enhance evaluation of Holstein cows.

Integration of apaQTL and eQTL analysis reveals novel SNPs associated with occupational pulmonary fibrosis risk.

To explore the association between apaQTL/eQTL-SNPs and the susceptibility to silicosis. A silicosis-related GWAS was initially conducted to screen for single nucleotide polymorphisms (SNPs) associated with the risk of silicosis. Candidate SNPs with apaQTL and eQTL functions were then obtained from the 3'aQTL-atlas and GTEx databases. Subsequently, additional case-control studies were performed to validate the relationship between the candidate apaQTL/eQTL-SNPs and the risk of silicosis. Finally, experiments were conducted to illustrate APA events occurring at different alleles of the identified apaQTL/eQTL-SNPs. The combined results of the GWAS and iMLDR validations indicate that the variant T allele of the rs2974341 located on SMIM19 (additive model: OR = 0.66, the 95% CI = 0.53-0.84, P = 0.001) and the variant T allele of the rs2390488 located on TMTC4 (additive model: OR = 0.72, 95% CI = 0.57-0.90, P = 0.005) were significantly associated with decreased risk of developing silicosis susceptibility. Furthermore, 3'RACE experiments verified the presence of two poly (A) sites (proximal and distal) in SMIM19, rs2974341 may remotely regulate the binding between miRNA-3646 and SMIM19 with its high LD locus rs2974353 to affect the expression level of SMIM19. The rs2974341 variant T allele may contribute to the generation of the shorter 3'UTR transcript of SMIM19 and affect the binding of miRNA-3646 to the target gene SMIM19. The apaQTL/eQTL-SNPs may provide new perspectives for evaluating the regulatory function of SNPs in the development of silicosis.

Associations of PNPLA3 and LEP genetic polymorphisms with metabolic-associated fatty liver disease in Thai people living with human immunodeficiency virus.

The prevalence of metabolic-associated fatty liver disease (MAFLD) is a growing public health issue in people living with human immunodeficiency virus (PLWH). However, the pathophysiology of MAFLD is still unknown, and the role of genetic variables is only now becoming evident. To evaluate the associations of gene-polymorphism-related MAFLD in PLWH. The study employed transient elastography with a controlled attenuation parameter ≥ 248 dB/m to identify MAFLD in patients from a Super Tertiary Hospital in central Thailand. Candidate single-nucleotide polymorphisms (SNPs) were genotyped using TaqMan® MGB probe 5' nuclease assays for seven MAFLD-related genes. Statistical analyses included SNP frequency analysis, Fisher's Exact and Chi-square tests, odds ratio calculations, and multivariable logistic regression. The G-allele carriers of PNPLA3 (rs738409) exhibited a two-fold rise in MAFLD, increasing by 2.5 times in MAFLD with human immunodeficiency virus infection. The clinical features and genetic patterns imply that LEP rs7799039 A-allele carriers had a nine times (P = 0.001) more significant chance of developing aberrant triglyceride among PLWH. The current study shows an association between PNPLA3 rs738409 and LEP rs7799039 with MAFLD in PLWH.

Rs822336 binding to C/EBPβ and NFIC modulates induction of PD-L1 expression and predicts anti-PD-1/PD-L1 therapy in advanced NSCLC

Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small cell lung cancer (NSCLC). Testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aim to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of the identified SNP candidate. rs822336 efficiently predicted response to anti-PD-1/PD-L1 immunotherapy in advanced non-oncogene addicted NSCLC patients as compared to rs2282055 and rs4143815. rs822336 mapped to the promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines as well as their susceptibility to HLA class I antigen matched PBMCs incubated with anti-PD-1 monoclonal antibody nivolumab. The induction of PD-L1 expression by rs822336 was mediated by a competitive allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially regulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. Analysis by binding microarray further validated the competitive allele-specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. These findings have high clinical relevance since identify rs822336 and induction of PD-L1 expression as novel biomarkers for predicting anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients.

Abstract 6130: Association of vitamin D-related genetic variants and prostate cancer risk in Black men

Abstract Background: What we know of the relationship between vitamin D status and prostate cancer has largely been characterized among men of European ancestry, hereafter referred to as “White”. Research among White men indicate positive associations between circulating vitamin D status, as measured by concentrations of 25-hydroxyvitamin D (25(OH)D), with prostate cancer risk, and that genetic scores based on genome-wide associated single nucleotide polymorphisms (SNPs) reflecting high vs. low 25(OHD) is positively associated with aggressive disease. Limited research exists elucidating this relationship among men of African ancestry, hereafter referred to as “Black”. This is despite the fact that Black populations experience chronically lower circulating 25(OH)D, and ancestry-specific differences in genetic variants in some vitamin D-related genes. Given the paucity of research in this area, we examined the role of genetic variants in six commonly studied genes in the vitamin D pathway involved in synthesis (CYP27A1 and CYP27B1), transport (GC), activity (VDR and RXR), and metabolism (CYP24A1) in relation to prostate cancer among Black men. Methods: We assessed a total of 78 candidate SNPs in six vitamin D pathway genes that were either previously associated with circulating 25(OHD) and/or associated with prostate cancer risk in studies of White men. We compared vitamin D gene SNP associations with prostate cancer in Black and White men using summary statistics from a large GWAS of over 10,000 prostate cancer cases and 10,000 controls among Black men and over 85,000 cases and 91,000 controls among White men. A statistical significance threshold of 0.00064 (0.05/78 candidate SNPs) was used to adjust for multiple comparisons. Results: None of the examined SNPs were significantly associated with prostate cancer risk among Black men after adjustment for multiple comparisons. However, four SNPs were nominally significant in Black men, including two in RXR [rs41400444 OR=1.09, 95% CI: 1.01-1.17, P = 0.024 and rs10881574 OR = 0.93, 0.867-0.999, P = 0.04556] and two in VDR [rs2853563 OR = 1.07, 1.012-1.13, P = 0.0173 and rs1156882 OR = 1.06, 1.00-1.12, P = 0.0495]. The latter SNP rs1156882 was also positively associated with prostate cancer risk in White men (OR = 1.035, 1.02-1.06, P = 0.00024), along with VDR SNP rs4516035 (OR = 1.027, 1.012-1.042, P = 0.00055), both after correction for multiple comparisons. Conclusions: We observed non-significant, though suggestive, associations between genetic variants in vitamin D pathway genes previously associated with prostate cancer or vitamin D levels in White populations and prostate cancer risk in Black men. Future research exploring the potential role of vitamin D pathway genes and prostate cancer in Black men – a population at high risk both for low circulating vitamin D and prostate cancer - will need to identify vitamin D-related genetic variants specific to carcinogenesis in Black men. Citation Format: Tracy M. Layne, Joseph H. Rothstein, Xiaoyu Song, Weiva Sieh, Robert J. Klein. Association of vitamin D-related genetic variants and prostate cancer risk in Black men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6130.

Abstract 6103: The association of genetic polymorphisms in DNA repair genes XRCC1 and 3 with cervical cancer risk among Bangladeshi females

Abstract Introduction and Objective: Worldwide, cervical cancer ranks the second most common cancer in women. Sequence variations in DNA repair genes X-ray repair cross complementing (XRCC) 1 and 3 genes can lead to can result cellular function aberration leading to cancers. Single nucleotide polymorphisms (SNPs) in XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) genes have been shown to cause individual variation in their DNA repair capacity. The aim of this study was to investigate the association of XRCC1 Arg399Gln and XRCC3 Thr241Met SNPs with susceptibility to cervical cancer among Bangladeshi populations. Methods: In the current case-control study 124 cervical cancer patients and 148 age matched healthy controls were recruited. Genomic DNAs were isolated from peripheral blood collected from the participants and genotyped for candidate SNPs using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: For XRCC1, heterozygous Arg/Gln and combined heterozygous plus variant homozygous Gln/Gln genotypes showed 1.78-fold (95% CI 1.0037 to 2.8771, p=0.0484) and 1.8627-fold (95% CI 1.1470 to 3.0250, p = 0.0119) increased risk of cervical cancer, respectively, when compared with normal homozygous Arg/Arg genotype. The variant Gln allele was positively associated with cervical cancer by 1.68-fold increase (95% CI 1.1732 to 2.3980, p = 0.0046). Similarly, for XRCC3, Thr/Met heterozygous and combined Thr/Met + Met/Met genotypes were found to be associated with 1.6993-fold (95% CI 1.0398 to 3.0166, p=0.0354) and 1.8312-fold (95% CI 1.0890 to 3.0791, p = 0.0225) higher risk, respectively, when compared with normal homozygous Thr/Thr genotypes. The variant Met allele showed significant association with 1.71-fold increased risk. Conclusion: XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) SNPs may be positively associated with increased cervical cancer risk in Bangladeshi females. Citation Format: Md Mustafizur Rahman, Laboni Das, Sadia Rahman, Amir Hossain, Razia Sultana. The association of genetic polymorphisms in DNA repair genes XRCC1 and 3 with cervical cancer risk among Bangladeshi females [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6103.

Abstract 2531: rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms

Abstract Efficient predictive biomarkers are needed for immune checkpoint inhibitor (ICI)-based immunotherapy in non-small-cell lung cancer (NSCLC). So far, testing the predictive value of single nucleotide polymorphisms (SNPs) in programmed cell death 1 (PD-1) or its ligand 1 (PD-L1) has shown contrasting results. Here, we aimed to validate the predictive value of PD-L1 SNPs in advanced NSCLC patients treated with ICIs as well as to define the molecular mechanisms underlying the role of identified SNP candidate. rs822336 SNP efficiently predicted response to anti-PD-1/PD-L1-based immunotherapy in advanced NSCLC patients as compared to rs2282055 and rs4143815 SNPs. rs822336 SNP mapped on promoter/enhancer region of PD-L1, differentially affecting the induction of PD-L1 expression in human NSCLC cell lines. The induction of PD-L1 expression by rs822336 SNP was predicted by allele-specificity binding of two identified transcription factors: C/EBPβ and NFIC. As a result, silencing of C/EBPβ and NFIC differentially modulated the induction of PD-L1 expression in human NSCLC cell lines carrying different rs822336 genotypes. In addition, binding microarray validated the allele- specificity binding of C/EBPβ and NFIC to PD-L1 promoter/enhancer region based on rs822336 genotype in human NSCLC cell lines. Lastly, the induction of PD-L1 expression by rs822336 genotype differentially affected the susceptibility to anti-PD-1 monoclonal antibody nivolumab of human NSCLC cell lines co-cultured with HLA class I antigen matched PBMC. These results have clinical relevance since identified rs822336 SNP and the induction of PD-L1 expression as novel biomarkers for predicting ICI-based immunotherapy in NSCLC patients. Citation Format: Giovanna Polcaro, Luigi Liguori, Valentina Manzo, Annalisa Chianese, Giuliana Donadio, Alessandro Caputo, Giosuè Scognamiglio, Federica Dell'Annunziata, Maddalena Langella, Graziamaria Corbi, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Margot De Marco, Jessica Dal Col, Valentina Pagliara, Pio Zeppa, Amelia Filippelli, Gianluigi Franci, Fabrizio Dal Piaz, Valeria Conti, Stefano Pepe, Francesco Sabbatino. rs822336 as a predictive biomarker for anti-PD-1/PD-L1 immunotherapy in advanced NSCLC: Unraveling molecular mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2531.

Identification of SNPs and candidate genes associate with growth performance in all-female mandarin fish (Siniperca chuatsi) by a genome-wide association study

The all-female mandarin fish (Dinggui I, Siniperca Chuatsi) was recently approved by Ministry of Agriculture and Rural Affairs of the People's Republic of China as a new strain of mandarin fish (GS-04-001-2021). Select breeding of fast-growing lines is an important goal of the mandarin fish industry. However, single nucleotide polymorphisms (SNPs) associated with growth of Dinggui I mandarin fish remains unclear. Therefore, a genome-wide association study (GWAS) was performed on 5 growth traits (body weight, body length, whole length, body height and body thickness) of 192 mandarin fish. A total of 49,940 SNPs were identified by ddRAD-seq. Among them, a total of 6 significant SNPs were detected on multiple chromosomes. The proportion of phenotypic variance explained for these SNPs ranged from 9.66% to 19.47% for growth traits. Specifically, 4 SNPs were associated with all traits. Several candidate genes (AKT2, CCNT2, EPB41L2 and CAMKMT) were identified based on these SNPs. The loci were verified in 100 individuals, indicating the reliability of candidate SNPs. Our results contribute to understanding of growth traits and the development of molecular marker-assisted selection in all-female mandarin fish.

Whole-genome resequencing identifies candidate genes and SNPs in genomic regions associated with shell color selection in the Pacific oyster, Crassostrea gigas

The various shell colors of bivalves not only result in a better visual perception but also show great commercial value as a highly potential breeding trait. Four shell color strains of Pacific oyster (Crassostrea gigas) characterized by black (SB), white (SW), gold (SG), and orange (SO) were bred purposefully for more than ten generations. In this study, whole-genome resequencing was performed on 20 oysters from each of the four strains, and a total of 14.67 million single nucleotide polymorphisms (SNPs) were obtained after stringent filtering, with an average sequencing depth of >10×. The population structure analysis provided support for the subdivision of all samples into four major genetic clusters corresponding to shell color phenotypes, indicating a high level of genomic differentiation driven by artificial selection. Then, a composite measure of fixation index (FST) and cross-population composite likelihood ratio (XP-CLR) allowed us to identify 336 to 414 candidate divergent regions (CDRs) in pairwise comparisons of different shell colors, with a total of 480 to 614 corresponding genes distributed. Of particular interest were tyrosinase (TYR) and perilipin2 (PLIN2) occurring with extremely high frequency, which participates in shell color determination by regulating melanin production and carotenoid metabolism, respectively. In addition, two genes, namely porphobilinogen deaminase (PBGD) and hephaestin (HEPH), may have a potential function in the accumulation of specific porphyrin in orange shells, while the kynurenine 3-monooxygenase (KMO) gene, known to be involved in ommochrome biosynthesis, may contribute to the darker coloration in black shells. Further, a total of 304 SNPs were extracted from the exons of candidate genes mentioned above, of which 25 loci had highly significant differences among populations (p-value ≤0.01). After Sanger sequencing in another population, 14 SNPs were successfully validated as specific loci closely linked to different shell colors of black, white, gold, and orange, respectively. All in all, the results of this study shed light on the molecular basis of pigmentation and facilitate the selective breeding of C. gigas with desired phenotypic color.

New candidate SNPs for genetic association with Alzheimer's disease: a linkage disequilibrium analysis for the FCGRIIB and PILRA genes.

Two new SNPs have been recently associated to Alzheimer's disease in African American populations: FCGRIIB rs1050501 C/T, and PILRA rs1859788 A/G. The risk of Alzheimer's disease in FCGRIIB C and PILRA A allele carriers is three times higher than in non-carriers. However, the association between these and other single nucleotide polymorphisms (SNPs) has not been assessed. Linkage disequilibrium analysis, with r= 0.8 as a threshold value, was used to impute new candidate SNPs, on genomic data from both genes in 26 populations worldwide (n= 2504) from the 1000Genomes database. Four SNPs (rs13376485, rs3767640, rs3767639 and rs3767641) were linked to rs1050501 and one (rs2405442) to rs1859788 in the whole sample. Five novel SNPs could be associated with Alzheimer's disease susceptibility and play a causal role, even if none of them are exon variants since their potential roles in the regulation of gene expression.

Identifying Relationships between Glutathione S-Transferase-2 Single Nucleotide Polymorphisms and Hypoxia Tolerance and Growth Traits in Macrobrachium nipponense.

Investigating hypoxia tolerance and growth trait single nucleotide polymorphisms (SNPs) in Macrobrachium nipponense is conducive to cultivating prawns with hypoxia tolerance and good growth characteristics. The glutathione S-transferase-2 gene (GST-2) has been shown to regulate hypoxia responses in M. nipponense. In this study, we identified a single GST-2 SNP in M. nipponense, and analyzed its regulatory relationship with hypoxia tolerance and growth. The GST-2 sequence was amplified with a polymerase chain reaction from 197 "Taihu Lake No. 3", "Taihu Lake No. 2", and Pearl River population samples to identify SNP loci. The full-length Mn-GST2 sequence was 2317 bp, including three exons and two introns. In total, 38 candidate SNP loci were identified from GST-2 using Mega11.0 comparisons, with most loci moderately polymorphic in terms of genetic diversity. Locus genotypes were also analyzed, and basic genetic parameters for loci were calculated using Popgene32 and PIC_CALC. The expected heterozygosity of the 38 SNP loci ranged from 0.2334 to 0.4997, with an average of 0.4107, while observed heterozygosity ranged from 0.1929 to 0.4721, with an average of 0.3401. The polymorphic information content ranged from 0.21 to 0.37. From SPSS analyses, the G+256A locus was significantly correlated with hypoxia tolerance across all three M. nipponense populations, while the SNP loci A+261C, C+898T, A+1370C, and G+1373T were significantly associated with growth traits. Further analyses revealed that the T+2017C locus was significantly correlated with hypoxia tolerance in "Taihu Lake No. 2" populations, G+256A, A+808T, C+1032T, and A+1530G loci were significantly correlated with hypoxia tolerance in "Taihu Lake No. 3" populations, while no SNP loci were correlated with hypoxia tolerance in Pearl River populations. A+1370C and G+1373T loci, which were associated with growth traits, exhibited a high degree of linkage disequilibrium (r2 = 0.89 and r2 > 0.8), suggesting potential genetic linkage. Our data suggest associations between hypoxia tolerance and growth trait SNP loci in M. nipponense, and provide valuable evidence for the genetic improvement of growth and hypoxia tolerance in this prawn species.

Associations of IL6R and IL10 Gene Polymorphisms with Susceptibility to Ankylosing Spondylitis with or without Acute Anterior Uveitis

ABSTRACT Background This research aims to explore the associations between ten candidate single nucleotide polymorphisms (SNPs) on Interleukin-6 receptor (IL6R) and Interleukin-10 (IL10) genes and ankylosing spondylitis (AS) patients with or without acute anterior uveitis (AAU). Methods This study involved a case-control approach that examined 354 cases with AS and AAU, 377 AS cases without AAU, and 918 healthy controls. Genotyping of ten SNPs of IL10 and IL6R genes was performed using iPLEX Gold genotyping method. The allele and genotype frequencies of cases and healthy individuals were contrasted using the chi-square test. The IL10 mRNA level in various IL10 genotypes was tested using real-time PCR. Results Two loci associated with AS with AAU were identified: IL10//rs3790622 (OR = 0.664; 95%CI = 0.503–0.878; Pc = 0.038); IL10//rs3021094 (OR = 1.365; 95%CI = 1.110–1.679; Pc = 0.032). The other eight loci located on IL10 and IL6R did not show significant associations with the diseases. Additionally, as shown by functional experiments, there was no correlation between the mRNA expression of IL10 and various genotypes. Conclusion Our study suggests that the IL10 gene contributes to the susceptibility of the Chinese population to AS with AAU.

Genome-wide search for associations method for identification of molecular markers and candidate genes of breed affiliation of sheep of the North Caucasian meat and wool breed

To determine the loci associated with pedigree traits, a genome-wide search was conducted for associations of 275 heads of Russian sheep breeds genotyped using 600 thousand single nucleotide polymorphisms (SNPs). The studies were conducted according to the “case-control” type, where the “case” group is represented by animals of the North Caucasian meat and wool breed, the “control” included animals of other breeds (Karachay, Romanovskaya, Dzhalginsky merino and Russian meat merino). In this study, over 100 SNPs were identified with highly reliable differences in the frequency of occurrence in sheep of the North Caucasian meat and wool breed. For the subsequent analysis, 18 single nucleotides with the highest confidence indices localized on chromosomes were selected 1, 10, 11, 15, 17. As a result of a genome-wide study, significant SNP markers characteristic of the sheep breed under study, located directly in the genes or close to them, were determined. The conducted studies provide a set of new SNP markers and candidate genes associated with the breed characteristics of North Caucasian meat-wool sheep.

Interaction of genetic variation at ADH1B and MLXIPL with alcohol consumption for elevated serum urate level and gout among people of European ethnicity

BackgroundAlcohol consumption is a risk factor for hyperuricaemia and gout. Multiple single-nucleotide polymorphisms (SNPs) have been identified as associated with both alcohol consumption and serum urate or gout in separate genome-wide association studies (GWAS). This study aimed to identify and characterise interactions between these shared signals of genetic association and alcohol consumption for serum urate level, hyperuricaemia, and gout.MethodsThis research was conducted using the UK Biobank resource. The association of alcohol consumption with serum urate and gout was tested among 458,405 European participants. Candidate SNPs were identified by comparing serum urate, gout, and alcohol consumption GWAS for shared signals of association. Multivariable-adjusted linear and logistic regression analyses were conducted with the inclusion of interaction terms to identify SNP-alcohol consumption interactions for association with serum urate level, hyperuricaemia, and gout. The nature of these interactions was characterised using genotype-stratified association analyses.ResultsAlcohol consumption was associated with elevated serum urate and gout. For serum urate level, non-additive interactions were identified between alcohol consumption and rs1229984 at the ADH1B locus (P = 3.0 × 10−44) and rs6460047 at the MLXIPL locus (P = 1.4 × 10−4). ADH1B also demonstrated interaction with alcohol consumption for hyperuricaemia (P = 7.9 × 10−13) and gout (P = 8.2 × 10−9). Beer intake had the most significant interaction with ADH1B for association with serum urate and gout among men, while wine intake had the most significant interaction among women. In the genotype-stratified association analyses, ADH1B and MLXIPL were associated with serum urate level and ADH1B was associated with hyperuricaemia and gout among consumers of alcohol but not non-consumers.ConclusionsIn this large study of European participants, novel interactions with alcohol consumption were identified at ADH1B and MLXIPL for association with serum urate level and at ADH1B for association with hyperuricaemia and gout. The association of ADH1B with serum urate and gout may occur through the modulation of alcohol metabolism rate among consumers of alcohol.

Interactions of genetic variations in FAS, GJB2 and PTPRN2 are associated with noise-induced hearing loss: a case-control study in China

BackgroundThis study aimed to screen and validate noise-induced hearing loss (NIHL) associated single nucleotide polymorphisms (SNPs), construct genetic risk prediction models, and evaluate higher-order gene-gene, gene-environment interactions for NIHL in Chinese population.MethodsFirst, 83 cases and 83 controls were recruited and 60 candidate SNPs were genotyped. Then SNPs with promising results were validated in another case-control study (153 cases and 252 controls). NIHL-associated SNPs were identified by logistic regression analysis, and a genetic risk model was constructed based on the genetic risk score (GRS), and classification and regression tree (CART) analysis was used to evaluate interactions among gene-gene and gene-environment.ResultsSix SNPs in five genes were significantly associated with NIHL risk (p < 0.05). A positive dose-response relationship was found between GRS values and NIHL risk. CART analysis indicated that strongest interaction was among subjects with age ≥ 45 years and cumulative noise exposure ≥ 95 [dB(A)·years], without personal protective equipment, and carried GJB2 rs3751385 (AA/AB) and FAS rs1468063 (AA/AB) (OR = 10.038, 95% CI = 2.770, 47.792), compared with the referent group. CDH23, FAS, GJB2, PTPRN2 and SIK3 may be NIHL susceptibility genes.ConclusionGRS values may be utilized in the evaluation of the cumulative effect of genetic risk for NIHL based on NIHL-associated SNPs. Gene-gene, gene-environment interaction patterns play an important role in the incidence of NIHL.