Association Of Genotype Research Articles

Association of killer immunoglobulin-like receptor genotypes and haplotypes with acute lymphoblastic leukemia risk.

Killer immunoglobulin-like receptors (KIRs) are key molecules used by natural killer (NK) cells to interact with target cells. These receptors exhibit extensive genotypic polymorphism which has been associated with varying outcomes in immune responses against diseases. This study aimed to investigate the relationships between KIR genotypes and haplotypes with acute lymphoblastic leukemia (ALL) in Saudi patients. A total of 259 Saudi subjects including 145 cases of acute lymphoblastic leukemia (ALL) and 114 healthy controls living in Riyadh were genotyped for 16 KIR genes and the two HLA-C1 and -C2 allotypes using PCR-SSP genotyping method. A significant high frequency of the two inhibitory KIR genes; 2DL1 (OR = 2.4; p < 0.0001) and 3DL1(OR = 10.87; p = 0.0068) in ALL compared to healthy group was observed. In contrast, the activating 2DS4 gene was significantly higher in healthy controls (OR = 0.15, p < 0.0001) compared to ALL patients. Haplotype analysis shows that BX haplogroup was strongly associated with the occurrence of ALL (OR = 4.39; p < 0.0001). Further combinatory analysis of KIR genes with their HLA-C1 and -C2 ligands demonstrated strong statistically protective effect of the 2DS1-C2 combination from ALL (OR = 0.06; p = 0.0003). This study presents strong evidence supporting the connection between certain KIR genotypes, haplotypes, and KIR-HLA combinations with acute ALL in the Saudi population. The heightened occurrence of inhibitory KIR genes (2DL1 and 3DL1) and the BX haplotype in ALL patients indicates a possible involvement of these genetic variability with the dysfunctional of NK cells in the context of ALL disease.

Genetics of sorghum: grain quality, molecular aspects, and drought responses.

Sorghum kernel composition is a crucial characteristic that determines its functional qualities. The total protein content of sorghum grain increases under drought stress, but starch, protein digestibility, and micronutrient contents decrease. Sorghum (Sorghum bicolor L.) is a staple source of starch, protein, and micronutrients in Ethiopia, where it is a key ingredient in local foods like injera and traditional beverages such as tela and areke. It has adapted remarkably to the diverse climatic conditions and soils of both highland and lowland regions. However, grain quality is influenced by climate change, drought stress, and genotype-environment interactions. Under drought conditions, sorghum shows reduced starch content, protein digestibility, and micronutrient levels, as well as increased kernel hardness and total protein content. The genetic and geographic diversity of sorghum makes it an adaptable crop, essential for breeding and diversity studies. Genome-wide association studies (GWAS) have emerged as essential tools for identifying candidate genes linked to key traits, thereby advancing genetic improvement initiatives, particularly for Ethiopian sorghum landraces. Advances in genotyping techniques, particularly genotyping-by-sequencing (GBS) and association mapping, have facilitated the identification of quantitative trait loci (QTL) associated with grain quality, enhancing breeding efficiency and the development of resilient, high-quality sorghum varieties. This review explored the genetic and phenotypic diversity of sorghum, focusing on grain quality traits, molecular mechanisms, and responses to drought stress.

Clinical Diagnosis and Differential Diagnosis Between CSF1R- and AARS2-Related Leukoencephalopathy.

CSF1R-related leukoencephalopathy (CSF1R-L) and AARS2-related leukoencephalopathy (AARS2-L) were two disease entities sharing similar phenotype and even pathological changes. Although clinically, radiologically, and pathologically similar, they were caused by mutation of two different genes. As the rarity of the two diseases, the differential diagnosis of them was difficult. 23 CSF1R-L and 6 AARS2-L patients were enrolled from the Leukoencephalopathy Clinic, Peking Union Medical College Hospital in China. Detailed clinical information, neuroimaging manifestations, and genetic data were collected and analyzed. Demographically, female patients were more in AARS2-L than CSF1R-L. Clinically, cognitive impairment and emotion/personality change were common in both groups. Bulbar palsy, extrapyramidal symptoms, and hemiplegia/pyramidal impairment were more common in CSF1R-L, while ataxia was significantly more common in AARS2-L. Abnormal menstruation including infertility was significantly more in AARS2-L. Radiologically, similar features were found, including lateral ventricle-centered white matter lesions, involving corpus callosum, avoiding U fibers. The lesions showed persistent hyperintensity on DWI image and were not contrasted after gadolinium enhancement. In CSF1R-L, the lesions could be widespread confluent or patchy and spotted, extending to centrum semiovale and subcortical white matter occasionally, which was significantly different from AARS2-L. Besides, brain stem lesion caused by pyramidal degeneration, spotted or linear calcification and obviously brain atrophy were common in CSF1R-L. In AARS2-L, periventricular white matter rarefaction was significantly common. No genotype and phenotype association was found in these two diseases. Although similar, there were several clinical and radiological features helping differentiating the two distinct diseases.

P0897 Association of HLA Genotypes with Anti-Drug Antibody Development in Taiwanese Inflammatory Bowel Disease Patients Undergoing Biologic Therapies

Abstract Background Anti-drug antibodies (ADAs) are a primary factor in the loss of response to infliximab and other adverse drug reactions. The genetic variant HLA-DQA1*05 has been associated with infliximab antibody development in Crohn’s disease (CD) among European populations. This study aims to assess the relationship between HLA genotypes and ADA formation in non-European inflammatory bowel disease (IBD) patients receiving anti-tumor necrosis factor (TNF), anti-integrin, or anti-IL-12/23 therapies. Methods This prospective cohort study enrolled patients with IBD receiving anti-TNF, anti-integrin, or anti-IL-12/23 therapy between January 2022 and March 2024. NGS-based HLA genotyping was performed for all participants. The occurrence of ADAs was assessed, and the frequencies of specific HLA alleles were compared between patients who developed ADAs and those who did not. Additionally, HLA allele frequencies in ADA-positive patients were analyzed against the general population in Taiwan. Results A total of 95 patients with IBD were included in the study, along with HLA genotype data from 1,097 control individuals obtained from the Taiwan Biobank. Among the IBD patients, 58 received anti-TNF therapy, 27 underwent anti-integrin therapy, and 10 were treated with anti-IL-12/23 therapy. According to the reimbursement criteria in Taiwan, all patients have to be treated with conventional therapy and when with inadequate response or with adverse effects, then biologics would be reimbursed. Therefore, all the 95 patients were under the biologics and immunosuppressive agents (either thiopurine or methotrexate) combination therapy. No ADA development was observed in patients treated with anti-integrin or anti-IL-12/23 therapies. However, among the 58 patients treated with anti-TNF therapy (38 with infliximab and 20 with adalimumab), 21 developed ADAs (18 infliximab-related and 3 adalimumab-related). A comparison of patients with and without ADAs revealed a significant association between the HLA-C*03:04:01 allele and ADA development (33.3% vs. 10.8%, p=0.035), whereas the HLA-DQA1*05 allele showed no association (52.3% vs. 51.4%, p=0.940). The frequency of the HLA-C*03:04:01 allele was comparable between IBD patients and the broader Taiwanese population (16.8% vs. 11.2%, p=0.0915). Conclusion This study demonstrated that the different HLA locus associated with ADA development among different ethnics. While HLA-DQA1*05 was found in European cohort, our data showed that HLA-C*03:04:01 was significantly associated with an increased risk of anti-TNF antibodies formation in Taiwanese IBD patients.

Identifying New Susceptibility Genes of Non-Syndromic Orofacial Cleft Based on Syndromes Accompanied With Craniosynostosis.

Orofacial cleft (OC) can be classified into syndromic orofacial cleft (SOC) and non-syndromic orofacial cleft (NSOC), depending on whether there are other congenital deformities. Craniosynostosis, the premature closure of cranial sutures, is a common phenotype of SOC resulting in abnormal ossification of skull and brain development disorders. Its correlation with OC offers a promising approach to identify susceptibility genes for NSOC by examining causative genes of SOCs with craniosynostosis. This study included 2556 patients with NSOC and 2255 normal controls from western Han Chinese with their genomic DNA samples. We selected 31 causative genes of 34 syndromes with both craniosynostosis and OC as candidate genes and performed quality control. Allelic and genotypic association analyses and haplotype analysis were performed to identify statistically significant single nucleotide polymorphisms (SNPs). In allelic association analysis performed with 1265 qualified SNPs in 20 genes, only rs2239936, located in MYH3 gene, was statistically associated with non-syndromic cleft lip only (NSCLO) (P = 1.70×10-07, OR = 1.33, 95%CI: 1.17-1.52) and non-syndromic cleft palate only (NSCPO) (P = 6.43×10-05, OR = 1.33, 95%CI: 1.16-1.52). The higher frequency of allele G in NSCPO suggesting that minor allele G at rs2239936 will result in an elevated risk of NSCPO. However, rs2239936 only exhibited a statistical association with NSCPO in genotypic association analysis (P = 8.06×10-06) and haplotype analysis (P = 1.43×10-05). This study identified that allele G at rs2239936 in MYH3 gene was significantly associated with NSCPO as a risk factor and MYH3 was a new susceptibility gene for NSCPO in western Han Chinese population.

Impact of IL-32 Gene Polymorphisms on Tuberculosis Susceptibility in a Chinese Han population.

Interleukin (IL)-32, encoded by the IL-32 gene, is a crucial constituent of the autophagy pathway and is involved in the regulation of Mycobacterium tuberculosis (M.tb) infection, a major global health challenge. This study aimed to examine the potential association between IL-32 polymorphisms and susceptibility to Tuberculosis(TB), highlighting the significance of genetic factors in TB risk. Sequence analysis of IL-32 was conducted in 570 individuals diagnosed with pulmonary tuberculosis (PTB), 363 individuals diagnosed with extrapulmonary tuberculosis (EPTB), and 604 healthy controls from the Chinese Han population, representing a broad spectrum of TB manifestations. Five single nucleotide polymorphisms(SNPs) were selected for analysis based on their potential impact on IL-32 function and TB susceptibility. The study revealed that the polymorphism rs12934561 C allele exhibits a positive correlation with elevated susceptibility to PTB (P=0.003, OR (95%CI) = 1.28 (1.09-1.51)), highlighting its potential role as a biomarker for PTB risk. A noteworthy relationship was observed between the rs12934561 TT genotype and the decreased likelihood of PTB, further underscoring the complexity of IL-32's role in PTB susceptibility. Moreover, it was found that protective haplotypes for PTB are TCAAC (P=0.001, OR (95%CI) = 0.75 (0.62-0.90)) and TCGTT (P=0.002, OR (95%CI) = 0.47 (0.29-0.77)) may be present in IL-32; Conversely, the potential risk haplotypes for PTB are CCGAA (P=0.007, OR (95%CI) = 1.29 (1.07-1.55)) and TCATT (P=0.033, OR (95%CI) = 1.30 (1.02-1.66)), indicating genetic variations that increase PTB susceptibility. In contrast, neither allelic nor genotypic associations were statistically significant among EPTB cases, highlighting the distinct genetic influences on the different forms of TB. In this study, we discovered that polymorphisms in IL-32 are significantly associated with increased susceptibility to pulmonary TB. This finding underscores the crucial role of genetic variation in the development of TB and provides a potential avenue for targeted interventions.

Genotype-environment interaction in the formation of lipid profile of adolescents

Many genetic variants associated with metabolic disorders have incomplete penetrance in human. Their phenotypic manifestation depends on the life style factors. In this work, we compared the associations of genotypes at 11 polymorphic sites with body mass index (BMI) and lipid metabolism parameters (levels of total cholesterol (TC), triglycerides, high- and low-density lipoprotein cholesterol (HDL-C and LDL-C)) in three groups of adolescents from Novosibirsk, examined in 1999, 2009 and 2019. In each group, from 187 to 665 persons were genotyped at each site. One-way analysis of variance (independent covariates: gender and age) was used for evaluation. For rs1800497 in the ANKK1 gene, rs53576 in the OXTR gene, rs1360780 in the FKBP5 gene, and rs4680 in the COMT gene, as well as for tandem repeats in the promoter of the MAOA gene, promoter and intron 2 of the SLC6A4 gene (separately and as part of a haplotype), and 3′-untranslated region of the SLC6A3 no associations of genotypes with BMI and lipid metabolism parameters were found in any of the groups. For APOE genotype, an association was obtained with TC levels: p = 0.042 and 0.034, respectively, in the 1999 and 2009 collection groups, as well as with LDL-C: p = 0.001 and 0.002, respectively, in the 2009 and 2019 groups. Moreover, the maximum levels of TC and LDL-C were found among carriers of most common genotype ε3ε3 in 1999 group, and among carriers of atherogenic allele ε4 in other two groups. Thus, it was shown that in adolescents there was an opposite correlation of carriage of the ε4ε4 genotype for the APOE gene with the levels of total cholesterol and LDL cholesterol in the case of normal and reduced calorie intake. For rs6265 in the BDNF gene, the level of statistical significance of the association of the common C allele with TC and LDL-C levels was directly correlated with dietary caloric intake (p = 0.617 and 0.573; p = 0.049 and 0.090; p = 0.010 and 0.024, respectively, in the groups of 1999, 2009 and 2019).

Association of NOS2A Gene Polymorphisms with Susceptibility to Tuberculosis in Manipuri Population of Northeast India.

Single nucleotide polymorphisms (SNPs) have been reported to influence the activity of specific genes involved with the innate immune response to Mycobacterium; hence, they are crucial in tuberculosis (TB) susceptibility studies. The study aimed to investigate the polymorphism in the NOS2A (Nitric oxide synthase 2A)geneand its association with susceptibility to TB in the Manipuri population of northeast India. This case-control study includes 495 subjects- 220TB patients and 275 control individuals. TaqMan allelic discrimination assay was used to study the gene polymorphism, and Griess's test was employed to determine the serum nitric oxide (NO) levels. Serum NO levels were analysed to correlate with the functional changes associated with the polymorphisms. Two SNPs of the gene,NOS2A(rs8078340 and rs2274894), were studied. For the SNP-rs8078340, a significant difference in the genotypic and allelic frequencies was observed between the cases and control groups (p = 0.001; AA genotype OR = 30.288, 95% CI: 1.703-538.44 and A allele OR = 2.937, 95%CI: 1.762-4.896). However, for the SNP-rs2274894, only the T allele (with OR = 1.464; 95%CI: 1.080-1.983, p = 0.014) was associated with susceptibility to TB. Serum levels of NO were significantly different between the cases and control groups (p < 0.05). Significant associations of both homozygous AA genotype and allele A of the NOS2A (rs8078340) and minor allele T of NOS2A (rs2274894) were observed with susceptibility to TB. Patients with the AA genotype of NOS2A show a higher NO level, suggesting its role in greater expression of the NOS2A gene.

Evaluating the association of APOE genotype and cognitive resilience in SuperAgers.

"SuperAgers" are oldest-old adults (ages 80+) whose memory performance resembles that of adults in their 50s to mid-60s. Factors underlying their exemplary memory are underexplored in large, racially diverse cohorts. To determine the frequency of APOE genotypes in non-Hispanic Black and non-Hispanic White SuperAgers compared to middle-aged (ages 50-64), old (ages 65-79), and oldest-old (ages 80+) controls and Alzheimer's disease (AD) dementia cases. This multicohort study selected data from eight longitudinal cohort studies of normal aging and AD. Variable recruitment criteria and follow-up intervals, including both population-based and clinical-based samples. Inclusion in our analyses required APOE genotype, that participants be age 50+, and are identified as either non-Hispanic Black or non-Hispanic White. In total, 18,080 participants were included in the present study with a total of 78,549 datapoints. Harmonized, longitudinal memory, executive function, and language scores were obtained from the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium (ADSP-PHC). SuperAgers, controls, and AD dementia cases were identified by cognitive scores using a residual approach and clinical diagnoses across multiple timepoints when available. SuperAgers were compared to AD dementia cases and cognitively normal controls using age-defined bins (middle-aged, old, oldest-old). Across racialized groups, SuperAgers had significantly higher proportions of APOE -ε2 alleles and lower proportions of APOE -ε4 alleles compared to cases. Similar differences were observed between SuperAgers and middle-aged and old controls. Non-Hispanic White SuperAgers had significantly lower proportions of APOE- ε4 alleles and significantly higher proportions of APOE -ε2 alleles compared to all cases and controls, including oldest-old controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE- ε4 alleles compared to cases and younger controls, and significantly higher proportions of APOE- ε2 alleles compared only to cases. In the largest study to date, we demonstrated strong evidence that the frequency of APOE -ε4 and -ε2 alleles differ between non-Hispanic White SuperAgers and AD dementia cases and cognitively normal controls. Differences in the role of APOE in SuperAging by race underlines distinctions in mechanisms conferring resilience across race groups given likely differences in genetic ancestry. Question: Does the frequency of APOE -ε4 and APOE -ε2 alleles explain the exceptional memory of non-Hispanic Black and non-Hispanic White SuperAgers? Findings: In this multicohort, multiracial study, SuperAgers had significantly higher proportions of APOE -ε2 alleles and lower proportions of APOE -ε4 alleles compared to Alzheimer's disease dementia cases. Non-Hispanic White SuperAgers had significantly lower proportions of APOE- ε4 alleles and significantly higher proportions of APOE -ε2 alleles compared to all cases and controls, including oldest-old (ages 80+) controls. In contrast, non-Hispanic Black SuperAgers had significantly lower proportions of APOE- ε4 alleles compared to cases and younger controls, and only significantly higher proportions of APOE- ε2 alleles compared to cases. Meaning: This is the largest study to date to identify differences in APOE- ε4 allele frequency based on SuperAger status, and the first study of SuperAgers to find a relationship between APOE- ε2 allele frequency and SuperAger status. As has been found in studies of middle-aged (ages 50-64) and old (ages 65-79) adults, genetic resiliency in oldest-old (80+) age likely differs by genetic ancestry.

Association between METTL14 gene polymorphisms and risk of ovarian endometriosis.

Endometriosis, a prevalent chronic gynecological condition, is frequently associated with infertility and pelvic pain. Despite numerous studies indicating a correlation between epigenetic regulation and endometriosis, its precise genetic etiology remains elusive. Methyltransferase-like 14 (METTL14), a crucial component of the N6-methyladenosine (m6A) RNA methyltransferase complex and an RNA binding scaffold, is known to play a pivotal role in various human diseases. The possibility that single nucleotide polymorphisms (SNPs) in the METTL14 gene contribute to susceptibility of endometriosis has not been thoroughly investigated. We assessed the genotype frequencies of five potential functional METTL14 SNPs (rs298982G>A, rs62328061A>G, rs9884978G>A, rs4834698C>T, and rs1064034A>T) in a Chinese population consisting of 458 patients with ovarian endometriosis and 462 healthy controls. We employed unconditional logistic regression and stratified analyses to evaluate their genotypic associations with the risk of ovarian endometriosis. Among the five SNPs examined, we found that the rs298982 A allele was significantly associated with increased risk, whereas the rs62328061G allele was linked to a decreased risk of ovarian endometriosis. Individuals harboring two unfavorable genotypes demonstrated a significantly elevated risk of ovarian endometriosis (adjusted odds ratio (AOR) = 1.57, 95% confidence interval (CI) = 1.16-2.13, P = 0.004) compared with those with no risk genotypes. Stratified analysis revealed the risk effect of rs298982 GA/AA genotypes in the gravidity≤1, parity≤1, rASRM stage I, and rASRM stage II + III + IVsubgroups. Haplotype analysis showed that individuals with the GATAA haplotype were at higher risk of ovarian endometriosis (AOR = 5.54, 95% CI = 1.63-18.87, P = 0.006), whereas the AGTTG haplotype exhibited protective effects (AOR = 0.55, 95% CI = 0.31-0.97, P = 0.039) compared with wild-type GACAG haplotype carriers. Additionally, Bayesian false discovery probability and false positive report probability analysis confirmed the robustness of the significant findings. Expression quantitative trait loci analysis revealed a significant association between the rs9884978 GA/AA genotypes and elevated METTL14 mRNA levels in fibroblasts and adrenal gland. Conversely, the rs298982GA/GG genotypes were significantly associated with reduced METTL14 mRNA levels in the nucleus accumbens and frontal cortex. Our results demonstrate that METTL14 polymorphisms are associated with susceptibility to ovarian endometriosis among Chinese women.

Exploring associations between the FTO rs9939609 genotype and plasma concentrations of appetite-related hormones in adults with obesity.

Associations between variants in the FTO locus and plasma concentrations of appetite related hormones are inconsistent, and might not work in a dose dependent fashion in people with obesity. Moreover, it is relevant to report meal related plasma concentrations of these hormones in persons with obesity given the growing interest in their pharmacological potential in obesity therapy. We find it clinically relevant to examine associations between the SNP rs9939609 genotypes and homeostatic appetite regulation in individuals with BMI ≥35 kg/m2. This study explored associations of the rs9939609 genotypes to plasma concentrations of acylated ghrelin, active glucagon-like peptide 1 (GLP-1), and total peptide YY (PYY), and moderating effects of fat mass (FM), in 96 adults (69% female) with BMI ≥35 kg/m2, using a cross sectional observation study designed to have 1/3 of participants each with genotypes TT, AT and AA, respectively. Participants were median (25th, 75th percentile) 42.5 (32, 50) years of age, weighed 120.9 (109.6, 142.4) kg, and had a BMI of 42.8 (39.5, 46.4) kg/m2. Acylated ghrelin, active GLP-1, and total PYY were measured in the fasted state and half-hourly for 2.5h after a standardized meal. We evaluated associations between genotype and appetite hormones in regression analysis controlling for FM and sex. Genotype did not associate with fasting or postprandial (area under curve, AUC) GLP-1 or PYY. Genotype did not associate with fasting acylated ghrelin, but in females with genotype AA, increased FM was associated with higher fasting and postprandial (AUC) acylated ghrelin concentrations relative to genotypes TT (fasting p = 0.025; AUC p = 0.004) and AT (fasting p = 0.002; AUC p < 0.001). This novel finding warrants further investigation.

Investigation of Genetic Polymorphisms Related GSTM1, GSTT1, GSTP1 Genes and their Association with Radiotherapy Toxicity among Head and Neck Cancer Patients.

In this study we explored the association of polymorphisms of glutathione s transferase gene including GSTM1, GSTT1 and GSTP1 with adverse acute normal tissue reactions resulted from radiotherapy in HNC patients. We assessed the association of GSTM1 and GSTT1 null genotypes and Ile105Val of exon-5 and Ala114Val of exon-6 of GSTP1 gene polymorphisms with the risk of acute skin toxicity reactions after therapeutic radiotherapy in HNC patients. Four hundred HNC patients administered with Intensity modulated radiation therapy were enrolled in this study for the evaluation of radiotherapy associated toxicity reactions. The genotyping of GSTM1 and GSTT1 were performed by polymerase chain reaction (PCR). The GSTP1 Ile/Val of exon-5 and Ala/Val of exon-6 polymorphism was determined by PCR followed by restriction fragment length polymorphism (PCR-RFLP). The univariate logistic regression analysis showed that GSTM1 and GSTT1 null genotypes were not associated with either skin reaction or oral mucositis in response to radiotherapy induced after effects. When we studied, A313G polymorphism at exon 5 and C341T polymorphism at exon 6 of GSTP1 gene, majority of genotypes were wild type A/A genotype for exon 5 showed non-significant association with Skin reactions whereas, C/T genotype of exon-6 showed significant negative association with skin reactions. The findings obtained from this study concluded that the null genotypes of GSTM1 and GSTT1 gene polymorphisms showed no association with radiotherapy induced acute toxicities such as dermatitis and oral mucositis. The results indicated negative association of heterozygous C/T genotype of exon-6 of GSTP1 with acute skin reactions.

Haptoglobin 2-2 genotype is associated with increased risk of cardiovascular disease in patients with rheumatoid arthritis: a matched case-control study.

Traditional risk factors do not fully explain the increased risk of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). The Haptoglobin (Hp) 2-2 genotype confers a lower anti-oxidant and higher inflammatory effect on the vasculature compared to the non-Hp 2-2 genotype. This study investigates the association of the Hp genotype with CVD in patients with RA. Data from 69 RA patients with CVD and 207 sex- and ethnicity-matched RA patients without CVD, collected from 1 January 2000 to 31 December 2020, were retrieved from the Tan Tock Seng Hospital RA Registry. CVD was examined against demographics, clinical and laboratory variables in univariate models. Associations between the Hp genotypes and CVD were analyzed using conditional logistic regression. We studied 276 patients (65.2% female, 82.6% Chinese, median age 60.9 years). Most participants were in low disease activity or remission (79.3%). The Hp 2-2 genotype was present in 49.6% (137/276). In the group with CVD, the prevalence of the Hp 2-2 genotype was 50.9% (29/57) in the Chinese, 100% (5/5) in the Indians, and 28.6% (2/7) in the Malays. In the non-CVD group, the respective prevalence was 46.8% (80/171), 66.7% (10/15), and 52.4% (11/21). In univariate analysis, the matched odds ratio (OR) of the Hp 2-2 genotype for CVD in RA was 1.34 [95% confidence interval (CI): 1.22-1.47; p < 0.001]. The Hp 2-2 genotype was significantly associated with CVD (adjusted matched OR: 1.13; 95% CI: 1.01-1.27; p = 0.033) in the multivariate logistic regression model after adjusting the confounding factors, including age, smoking, diabetes, hypertension, hyperlipidemia, anti-CCP autoantibodies, and disease activity. The Hp 2-2 genotype is associated with an increased risk of CVD in patients with RA in this multi-ethnic cohort.

Association of ADH1B and ALDH2 genotypes with the risk of lung adenocarcinoma.

The incidence of lung adenocarcinoma (LAD) is increasing worldwide. Single-nucleotide polymorphisms in aldehyde dehydrogenase 2 family member gene (ALDH2) rs671 and alcohol dehydrogenase 1B (ADH1B) rs1229984 are common and functionally important genetic variants to metabolize endogenous and exogenous aldehyde chemicals, related to cancer. This is a case-control study. A total of 150 newly diagnosed LAD patients were from Kaohsiung Medical University Hospital, Taiwan, between 2019 and 2022. Two control groups, TWB-1 (n = 600) and TWB-2 (n = 29 683), were selected from Taiwan Biobank (TWB), and the case patients were frequency-matched with TWB-1 based on age category (30-60 or >60 years old), sex, and education levels. Logistic regression models were employed to analyze the association between two genetic variants and LAD risk. A significant association was noted between ALDH2 and LAD risk. Those with ALDH2 rs671 *2/*2 in TWB-1 and TWB-2 controls had a 2.68-fold (95% CI = 1.43-4.99) and a 1.83-fold (95% CI = 1.07-3.11) increased risk of LAD, respectively, compared with those with ALDH2 rs671 *1/*1 or *1/*2, after adjusting for covariates. This association was particularly pronounced in females. No overall significant association between ADH1B rs1229984 and LAD risk was observed. The findings indicate a strong and robust risk association between ALDH2 rs671*2/*2 and LAD in the Taiwan population, particularly in Taiwanese female adults.

A phenome-wide association study of tandem repeat variation in 168,554 individuals from the UK Biobank

Most genetic association studies focus on binary variants. To identify the effects of multi-allelic variation of tandem repeats (TRs) on human traits, we perform direct TR genotyping and phenome-wide association studies in 168,554 individuals from the UK Biobank, identifying 47 TRs showing fine-mapped associations with 73 traits. We replicate 23 of 31 (74%) of these associations in the All of Us cohort. While this set includes several known repeat expansion disorders, novel associations we found are attributable to common polymorphic variation in TR length rather than rare expansions and include e.g. a coding polyhistidine motif in HRCT1 influencing risk of hypertension and a poly(CGC) in the 5’UTR of GNB2 influencing heart rate. Fine-mapped TRs are strongly enriched for associations with local gene expression and DNA methylation. Our study highlights the contribution of multi-allelic TRs to the “missing heritability” of the human genome.

CHRNA5-A3-B4, CYP2A6, and DBH genetic associations with smoking cessation throughout adulthood within two longitudinal studies of women.

Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. Within seven genes (CHRNA3, CHRNA5, CHRNB2, CHRNB4, DRD2, DBH and CYP2A6) influencing biological mechanisms relevant to smoking, this study aimed to identify single nucleotide polymorphisms (SNPs) associated with smoking cessation throughout up to 38-years of follow-up. Participants were from two all-female cohort studies, Nurses' Health Study (NHS) (n = 10,017) and NHS-2 (n = 2,793). For 132 SNPs providing coverage of these genes, genotype associations with the probability of quitting smoking over time were evaluated using generalized estimating equations models. For SNPs reaching nominal statistical significance (p < 0.05) within NHS, NHS-2 was used as the replication cohort to control for multiple testing (false discovery rate (FDR) < 0.05). SNP genotype by smoking intensity (lifetime light versus non-light smoking) interactions were also evaluated. Five SNPs identified in NHS were replicated in NHS-2 with FDR < 0.05. Women with the minor alleles of CHRNA5 SNPs rs637137 [OR = 1.21] and rs503464 [OR = 1.24] had increased odds of cessation. Women with the minor alleles of CYP2A6 SNPs rs56113850 [OR = 0.81] and rs56267346 [OR = 0.82] and DBH SNP rs6479643 [OR = 0.78] had lower odds of cessation throughout adulthood. An interaction with smoking intensity was indicated for three SNPs, CHRNB4 rs4887074, CHRNA3 SNP rs77438700, and CHRNA5 SNP rs76474922. Genetic associations with smoking cessation over decades of follow-up were observed and may guide targeted approaches for smokers most at risk for long-term relapse. This study identified single nucleotide polymorphisms (SNPs) within CHRNA5-A3-B4, CYP2A6, and DBH that were associated with smoking cessation in women over decades of follow-up. This study is the first to examine these genetic associations over years of follow-up. Some associations were novel while others replicated previous findings from short-term studies for the first time. Potential differences in some associations between light and non-light smokers were also observed. Genetic factors associated with long-term smoking behavior may help inform interventions modeled on long-term chronic disease management approaches; specifically, targeted maintenance interventions to sustain abstinence could be implemented among high-risk smokers.

Prognostic Significance and Associations of Neural Network-Derived Electrocardiographic Features.

Subtle, prognostically important ECG features may not be apparent to physicians. In the course of supervised machine learning, thousands of ECG features are identified. These are not limited to conventional ECG parameters and morphology. We aimed to investigate whether neural network-derived ECG features could be used to predict future cardiovascular disease and mortality and have phenotypic and genotypic associations. We extracted 5120 neural network-derived ECG features from an artificial intelligence-enabled ECG model trained for 6 simple diagnoses and applied unsupervised machine learning to identify 3 phenogroups. Using the identified phenogroups, we externally validated our findings in 5 diverse cohorts from the United States, Brazil, and the United Kingdom. Data were collected between 2000 and 2023. In total, 1 808 584 patients were included in this study. In the derivation cohort, the 3 phenogroups had significantly different mortality profiles. After adjusting for known covariates, phenogroup B had a 20% increase in long-term mortality compared with phenogroup A (hazard ratio, 1.20 [95% CI, 1.17-1.23]; P<0.0001; phenogroup A mortality, 2.2%; phenogroup B mortality, 6.1%). In univariate analyses, we found phenogroup B had a significantly greater risk of mortality in all cohorts (log-rank P<0.01 in all 5 cohorts). Phenome-wide association study showed phenogroup B had a higher rate of future atrial fibrillation (odds ratio, 2.89; P<0.00001), ventricular tachycardia (odds ratio, 2.00; P<0.00001), ischemic heart disease (odds ratio, 1.44; P<0.00001), and cardiomyopathy (odds ratio, 2.04; P<0.00001). A single-trait genome-wide association study yielded 4 loci. SCN10A, SCN5A, and CAV1 have roles in cardiac conduction and arrhythmia. ARHGAP24 does not have a clear cardiac role and may be a novel target. Neural network-derived ECG features can be used to predict all-cause mortality and future cardiovascular diseases. We have identified biologically plausible and novel phenotypic and genotypic associations that describe mechanisms for the increased risk identified.

A non-synonymous variant of C21R in the ABCG2 gene is significantly associated with brown eggshell color of Lueyang black-boned chicken.

Eggshell colors have a significant effect on sale of eggs. The aim of this study is to identify sequence variants associated with color variation of chicken brown eggs in the ABCG2, a protoporphyrin transport-related gene. Three successive eggs were collected from each of 381 Lueyang black-boned hens at the 31 weeks old. Eggshell color was quantified via the L*a*b color space. g.18378442T>C (a non-synonymous mutation C21R), g.18383682A>G and g.18391548A>T were genotyped via the MassARRAY platform. The associations of genotypes with color indexes were tested by one-way ANOVA. The conservation of the C21R locus was analyzed by multiple alignment of 52 avian genomes from the UCSC database. We predicted 3D structures of ABCG2 with C21 and R21 by homology modelling using the MODELLER program to analyze effect of C21R on protein structures. Results showed that g.18378442T>C was significantly associated with L and b values. The L value (75.3±4.0) of CC was significantly lower than ones of CT (76.6±4.3) and TT (78.0±4.4) genotypes. The b value (16.2±3.5) of CC was significantly higher than ones of CT (15.7±3.6) and TT (15.7±3.6). g.18383682A>G was only associated with the L value (P<0.05). There was no any association between g.18391548A>T and three color indexes (P>0.05)。The C21 was completely conserved among 45 bird species. In contrast, the R21 was only present in two species of Psittaciformes. Structure comparisons showed that C21R potentially cause 468 structure alternations, of which 49.6% belong to hydrogen bond alternations, 38.8% for solvent accessible, 8.1% for positive φ angle and 3.5% for changes of secondary structures. In conclusion, this study identifies C21R as a molecular marker that is associated with color variation of chicken brown eggs and has a potential effect on protein structures. The CC genotype of C21R is associated with dark brown color and the TT for light brown.

Genetic variants of the XRCC3 DNA repair gene: risk implications in breast cancer among Iraqi patients.

Breast cancer is the predominant form of malignancy among women. Polymorphisms in DNA repair genes, such as X-ray repair cross complementing 3 (XRCC3), can influence an individual's capability to repair damaged DNA. This can result in genetic instability and potentially contribute to the development of cancer. This study investigates the correlation between the XRCC3 Thr241Met genetic variants and the risk of breast cancer. This study is considered the first study in Iraq that sheds light on studying the effect of the XRCC3 Thr241Met genotype variants and their relationship with increased risk of breast cancer. The blood of 75 Iraqi women who had been diagnosed with breast cancer was used in this study to extract DNA, in addition to using 50 blood samples from women who appeared to be healthy and without a family history of any other cancer, as a control group. Genotyping of the XRCC3 Thr241Met gene was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The single nucleotide polymorphism (SNP) genotypes were determined in all participants. The findings of this study demonstrated that the Met/Met allele occurred more frequently in patients than controls (OR = 3.3, 95% CI: 1.8-6.04; p = 0.0001), particularly in patients with positive lymph node metastases, grade II and III, and stages III/IV. These findings established the association of the Thr241Met genotype with breast cancer among Iraqi women; specifically, the homozygous (Met/Met) genotype appeared to be correlated with risk of breast cancer and cancer prognosis. This genotype was notably more prevalent among women diagnosed with high-grade tumours, as well as advanced stage and metastatic breast cancer.

Association of COMT rs4680 Genotype With Chronic Neuropathic Pain Experience in Patients With Sickle Cell Disease.

The pain experience of patients with sickle cell disease (SCD) frequently consists of episodes of acute exacerbation. However, recent studies suggest that many patients who suffer from SCD have symptoms of chronic neuropathic pain. Additional research is needed to determine what role genotype plays in the patient's pain phenotype experience in SCD. The purpose of our project was to determine whether a catechol-O-methyltransferase (COMT) single nucleotide polymorphism (SNP), rs4680, was associated with the experience of chronic neuropathic pain in patients with SCD. Cross sectional study. In our study, 184 patients (98% African American, mean age 36.5 ± 11.6 years, 63% female) completed the Self-Reported Leeds Assessment of Neuropathic Symptoms and Signs (S-LANNS) and the Neuropathic Pain Symptom Inventory (NPSI) and provided blood samples for genotyping of the rs4680 SNP. We conducted a cross-sectional association study using a likelihood ratio test that compared a model with and without genotype as a predictor. We also used linear regression model to determine whether the Met allele was associated with pain in an additive model. 50% of the study participants had a Val/Val genotype, 41% had a Val/Met, and 9% had a MET/MET. Between the three rs4680 genotypes, the differences in the mean S-LANNS or NPSI scores were not statistically significant. The Met allele was also not significantly associated with neuropathic pain (S-LANNS p = .23; NPSI p = .73) in an additive SNP model. Further studies with larger samples are needed to determine if the Met/Met genotype predisposes patients with SCD to neuropathic pain and if other polymorphisms in the COMT gene play a role in this process.