Allele Odds Ratio Research Articles

High Frequency of Ancestral Haplotype A of Fatty Acid Desaturase Genes in the Yakut Population.

Aims: The purpose of this study was to study the correlation of the body weight of Yakuts with the variability of polymorphisms rs174537, rs174546 and rs3834458 of the FADS1 - FADS2 region to identify the connection of certain genotypes with obesity. Materials and Methods: For genotyping, classical methods of PCR-RFLP analysis were used. A sample of 446 DNA samples from Yakut volunteers without chronic diseases (143 women and 303 men) was studied. Results: The predominance of the ancestral alleles of SNPs rs174537, rs174546 and rs3834458 was established in all of our studied groups. Analysis of the odds ratio of allele and genotype frequencies in patients with normal BMI, high BMI and obesity did not show statistically significant values. We did not find an association between rs174537, rs174546 and rs3834458 with obesity, but we did not take into account the diet of the subjects, which may have had a stronger effect on BMI. Analysis of pairwise linkage disequilibrium and assessment of haplotypes for 3 SNPs in the FADS1 and FADS2 genes showed strong linkage of all three SNPs to each other (r2 = 0.93-0.96). Conclusions: According to the result of genotyping of SNP rs174537, the frequency of haplotype A in the Yakut population was 0.76 and, in comparison with other world data, is quite high. Which in turn is associated with lower conversion of short-chain polyunsaturated fatty acid to long-chain polyunsaturated fatty acid. Accordingly, a shift in nutrition towards more plant foods can negatively impact the health of the Yakuts. At the moment, the exact dosage of polyunsaturated fatty acids (PUFAs) for humans has not yet been established, but judging by the fact that all recommendations are mainly made on the basis of European populations, in connection with the results of the study, the Yakuts have a particularly high need for PUFAs.

Genetic determinants of renal scarring in children with febrile UTI

BackgroundFebrile urinary tract infections (UTIs) are among the most severe bacterial infections in infants, in which a subset of patients develops complications. Identifying infants at risk of recurrent infections or kidney damage based on clinical signs is challenging. Previous observations suggest that genetic factors influence UTI outcomes and could serve as predictors of disease severity. In this study, we conducted a nationwide survey of infant genotypes to develop a strategy for infection management based on individual genetic risk. Our aims were to identify genetic susceptibility variants for renal scarring (RS) and genetic host factors predisposing to dilating vesicoureteral reflux (VUR) and recurrent UTIs.MethodsTo assess genetic susceptibility, we collected and analyzed DNA from blood using exome genotyping. Disease-associated genetic variants were identified through bioinformatics analysis, including allelic frequency tests and odds ratio calculations. Kidney involvement was defined using dimercaptosuccinic acid (DMSA) scintigraphy.ResultsIn this investigation, a cohort comprising 1087 infants presenting with their first episode of febrile UTI was included. Among this cohort, a subset of 137 infants who underwent DMSA scanning was subjected to gene association analysis. Remarkable genetic distinctions were observed between patients with RS and those exhibiting resolved kidney involvement. Notably, the genetic signature indicative of renal scarring prominently featured mitochondrial genes.ConclusionsIn this nationwide study of genetic susceptibility to RS after febrile UTIs in infancy, we identified a profile dominated by mitochondrial polymorphisms. This profile can serve as a predictor of future complications, including RS and recurrent UTIs.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

XRCC1 and hOGG1 polymorphisms and endometrial carcinoma: A meta-analysis.

Endometrial carcinoma's (EC) etiology is complex and involves DNA repair gene polymorphisms like XRCC1-Arg399Gln and hOGG1-Ser326Cys, but their association with the disease is unclear. Following PRISMA, we conducted a systematic review and meta-analysis, collecting data from four databases. The studies needed to be population-based case-control studies examining the association between the named polymorphisms and EC. Quality was assessed with the Newcastle-Ottawa Scale. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated, and subgroup analyses were conducted based on ethnicity. Seven studies were included. Both polymorphisms were found to significantly increase EC risk, particularly in Caucasians. XRCC1-Arg399Gln showed a dominant model OR of 1.14 (95% CI: 1.01-1.29) and a homozygous model OR of 1.59 (95% CI: 1.12-2.25). The heterozygote model OR for hOGG1-Ser326Cys was 1.29 (95% CI: 1.02-1.63), and the allele OR was 1.31 (95% CI: 1.07-1.60). XRCC1-Arg399Gln and hOGG1-Ser326Cys may increase EC risk, primarily in Caucasian women, emphasizing the role of DNA repair in disease susceptibility. More extensive studies are needed to validate these findings in diverse ethnicities and investigate other DNA repair gene polymorphisms.

Identification of Pancreatic Cancer Germline Risk Variants With Effects That Are Modified by Smoking.

Pancreatic cancer (PC) is a deadly disease most often diagnosed in late stages. Identification of high-risk subjects could both contribute to preventative measures and help diagnose the disease at earlier timepoints. However, known risk factors, assessed independently, are currently insufficient for accurately stratifying patients. We use large-scale data from the UK Biobank (UKB) to identify genetic variant-smoking interaction effects and show their importance in risk assessment. We draw data from 15,086,830 genetic variants and 315,512 individuals in the UKB. There are 765 cases of PC. Crucially, robust resampling corrections are used to overcome well-known challenges in hypothesis testing for interactions. Replication analysis is conducted in two independent cohorts totaling 793 cases and 570 controls. Integration of functional annotation data and construction of polygenic risk scores (PRS) demonstrate the additional insight provided by interaction effects. We identify the genome-wide significant variant rs77196339 on chromosome 2 (per minor allele odds ratio in never-smokers, 2.31 [95% CI, 1.69 to 3.15]; per minor allele odds ratio in ever-smokers, 0.53 [95% CI, 0.30 to 0.91]; P = 3.54 × 10-8) as well as eight other loci with suggestive evidence of interaction effects (P < 5 × 10-6). The rs77196339 region association is validated (P < .05) in the replication sample. PRS incorporating interaction effects show improved discriminatory ability over PRS of main effects alone. This study of genome-wide germline variants identified smoking to modify the effect of rs77196339 on PC risk. Interactions between known risk factors can provide critical information for identifying high-risk subjects, given the relative inadequacy of models considering only main effects, as demonstrated in PRS. Further studies are necessary to advance toward comprehensive risk prediction approaches for PC.

Genetic Susceptibility to Astrovirus Diarrhea in Bangladeshi Infants.

Astroviral infections commonly cause acute nonbacterial gastroenteritis in children globally. However, these infections often go undiagnosed outside of research settings. There is no treatment available for astrovirus, and Astroviridae strain diversity presents a challenge to potential vaccine development. To address our hypothesis that host genetic risk factors are associated with astrovirus disease susceptibility, we performed a genome-wide association study of astrovirus infection in the first year of life from children enrolled in 2 Bangladeshi birth cohorts. We identified a novel region on chromosome 1 near the loricrin gene (LOR) associated with astrovirus diarrheal infection (rs75437404; meta-analysis P = 8.82 × 10-9; A allele odds ratio, 2.71) and on chromosome 10 near the prolactin releasing hormone receptor gene (PRLHR) (rs75935441; meta-analysis P = 1.33 × 10-8; C allele odds ratio, 4.17). The prolactin-releasing peptide has been shown to influence feeding patterns and energy balance in mice. In addition, several single-nucleotide polymorphisms in the chromosome 1 locus have previously been associated with expression of innate immune system genes PGLYRP4, S100A9, and S100A12. This study identified 2 significant host genetic regions that may influence astrovirus diarrhea susceptibility and should be considered in further studies.

Association of vitamin D receptor gene polymorphisms with type 2 diabetes mellitus in Taif population: a case-control study.

Several reasons may underlie the dramatic increase in type2 diabetes mellitus. One of these reasons is the genetic basis and variations. Vitamin D receptor polymorphisms are associated with different diseases such as rheumatoid arthritis and diabetes. The aim of this study is to investigate the possible association of two identified mutations ApaI (rs7975232) and TaqI (rs731236). Eighty-nine healthy individuals and Fifty-six Type 2 Diabetic (T2D) patients were investigated using RFLP technique for genotyping and haplotyping as well. The distribution of Apal genotypes was not statistically significant among the control (P=0.65) as well as for diabetic patients (P=0.58). For Taql allele frequencies of T allele was 0.61 where of G allele was 0.39. The frequency distribution of Taql genotypes was not statistically significant among the control (P=0.26) as well as diabetic patients (P=0.17). Relative risk of the allele T of Apa1 gene is 1.28 and the odds ratio of the same allele is 1.53, while both estimates were < 1.0 of the allele G. Similarly, with the Taq1 gene the relative risk and the odds ratio values for the allele T are 1.09 and 1.27 respectively and both estimates of the allele C were 0.86 for the relative risk and 0.79 for the odds ratio. The pairwise linkage disequilibrium between the two SNPs Taq1/apa1 was statistically significant in control group (D = 0.218, D' = 0.925 and P value < 0.001) and similar data in diabetic groups (D = 0.2, D' = 0.875 and P value < 0.001). These data suggest that the T allele of both genes Apa1 and Taq1 is associated with the increased risk of type 2 diabetes. We think that we need a larger number of volunteers to reach a more accurate conclusion.

Transferrin receptor 1 rs3817672 variant genotyping in Egyptian children diagnosed with iron-deficiency anemia: a case–control study

Background Cell surface transferrin receptor 1 (TFR1) is a gatekeeper controling cellular iron uptake. The association of iron-deficiency anemia (IDA) in humans with TFR1 variants was not extensively studied. Among these variants is TFR1 rs3817672, an exonic missense variation that may affect the TFR1 protein structure. This is the first study in Egypt and the second worldwide that genotype TFR1 rs3817672 variant in IDA pediatric patients. Aim The aim of the current study was to investigate the association between TFR1 rs3817672 variant with susceptibility risk for IDA. Patients and methods The study was conducted on 50 IDA Egyptian pediatric patients and 50 healthy controls. Complete blood count, iron profile, and TFR1 rs3817672 variant genotyping were performed for all participants. Results TT genotype was associated with a high risk of IDA among cases compared to controls in the recessive model (odds ratio 24, 95% confidence interval 5.253–109.650, P≤0.001) with the predominance of T allele (odds ratio 7.3187, 95% confidence interval 3.919–13.669, P≤0.001). TT genotype was associated with a significant decrease in serum iron (P=0.001 and 0.003) and transferrin saturation (P=0.003 and 0.005) compared to CT genotype and CC+CT genotypes in the recessive model, respectively. In IDA patients, serum iron had a significant positive correlation with transferrin saturation (r=0.984, P≤0.001) and a significant negative correlation with total iron-binding capacity (r=−0.555, P≤0.001). Conclusion TT genotype was the predominant genotype among Egyptian pediatric IDA patients. TFR1 rs3817672 genotyping might be used as a potential screening test for IDA risk susceptibility in pediatrics.

Impacts of Matrix Metalloproteinase-9 Promoter Genotypes on Asthma Risk.

The overexpression of matrix metalloproteinase-9 (MMP9) has been observed in asthmatic patients, yet the role of MMP9 genotype in determining asthma susceptibility remains unresolved. This study aimed to elucidate the contribution of MMP9 promoter rs3918242 genotype to asthma risk in Taiwan. A cohort comprising 453 non-asthmatic healthy controls and 198 asthmatic cases was assembled, and the MMP9 rs3918242 genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism methodology. Our findings indicated that people carrying the variant CT or TT genotype of MMP9 rs3918242 did not demonstrate an elevated risk of asthma compared to wild-type CC carriers (odds ratio=1.28 and 1.72, 95% confidence interval=0.87-1.87 and 0.72-4.13; p=0.2417 and 0.3201, respectively). Furthermore, individuals carrying the T allele at MMP9 rs3918242 did not exhibit a higher risk of asthma than those carrying the C allele (odds ratio=1.31, 95% confidence interval=0.96-1.79, p=0.0869). Interestingly, a positive association was observed between MMP9 rs3918242 CT or TT genotypes and the severity of asthma symptoms among asthmatic patients (p=0.0035). Although the T allele at MMP9 rs3918242 was not associated with asthma risk, it may serve as a predictor for asthma symptom severity. These findings warrant validation in larger and more diverse populations to further elucidate the significance of MMP9 in asthma etiology.

The Contribution of DNA Ligase 4 Polymorphisms to Colorectal Cancer.

While numerous biomarkers associated with genetic susceptibility to colorectal cancer (CRC) have been identified and validated through epidemiological studies, the specific influence of DNA ligase 4 (Lig4) genotypes remains unexplored. This study aimed to elucidate the hitherto unexamined relationship between Lig4 genotypes and CRC risk. The genotypes of Lig4 rs1805388 were determined applying the polymerase chain reaction-restriction fragment length polymorphism methodology. The potential association between these genotypes and CRC risk was assessed in a Taiwanese population comprising 362 CRC cases and an equal number of age- and sex-matched controls. In the genotypic analysis, the distribution of CC, CT, and TT genotypes for Lig4 rs1805388 among CRC cases was 54.7%, 38.1%, and 7.2%, respectively. This distribution was not significantly different from the controls, which exhibited genotypic frequencies of 57.2%, 36.7%, and 6.1%, respectively (p for trend=0.7314). Analysis of allelic distribution indicated that individuals carrying the T allele of Lig4 rs1805388 displayed a slightly elevated CRC risk compared to those carrying the C allele (odds ratio=1.10, 95% confidence interval=0.87-1.39, p=0.4685). The variant genotypes of Lig4 rs1805388 may not serve as predictive markers for CRC risk in the Taiwanese population.

Relationship between interleukin 17 polymorphism in rs 2275913 and rs 763780 and interleukin 6 in rs 1800795 gene region with sensitivity to antiretroviral drugs in patients with human immunodeficiency virus

Drug complication is still considered as one of the most important causes of death and drug in-compliance around the world. In this cross sectional study, 372 people living with HIV (PLHIV) above 16 years were enrolled. The drug complication was extracted based on the information of the patient's file. The molecular test was performed by the Restriction Fragment length polymorphism-Polymerase Chain Reaction method. Allelic frequency, haplotype analyses, linkage disequilibrium and odds ratio (OR) were calculated. The linear regression model was used to analyze the association of IL’SNPs with drug complication after adjustment for age and sex. Drug complications were observed in 150(40.3%) participants. The most common drug complications were hematological 94(62.7%) ones. The SNPs- rs 2275913 and rs763780- of IL-17were in complete linkage (D́ = 1 and r = 1). A-A haplotype of IL-17 in SNPs- rs 2275913 and rs763780 can increase the risk of drug complication up to 1.628 times more than other haplotypes and G-G and G-A haplotypes have a protective role among them 0.268 and 0.628 times, respectively. Our result for the first time demonstrated the role of IL-17 polymorphism in induced antiretroviral drug complication incidence. Probably A-A haplotype could increase the immune response to anti-retroviral drugs, and G-G and A-G haplotypes can decrease it.

Novel variants in genes related to vesicle-mediated-transport modify Parkinson's disease risk.

VPS35 and VPS13 have been associated with Parkinson's disease (PD), and their shared phenotype in yeast when reduced in function is abnormal vacuolar transport. We aim to test if additional potentially deleterious variants in other genes that share this phenotype can modify the risk for PD. 77 VPS and VPS-related genes were analyzed using whole-genome-sequencing data from 202 PD patients of Ashkenazi Jewish (AJ) ancestry. Filtering was done based on quality and functionality scores. Ten variants in nine genes were further genotyped in 1200 consecutively recruited unrelated AJ-PD patients, and allele frequencies and odds ratio calculated compared to gnomAD-AJ-non-neuro database, in un-stratified (n=1200) and stratified manner (LRRK2-G2019S-PD patients (n=145), GBA-PD patients (n=235), and non-carriers of these mutations (NC, n=787)). Five variants in PIK3C3, VPS11, AP1G2, HGS and VPS13D were significantly associated with PD-risk. PIK3C3-R768W showed a significant association in an un-stratified (all PDs) analysis, as well as in stratified (LRRK2, GBA, and NC) analyses (Odds ratios=2.71, 5.32, 3.26. and 2.19 with p=0.0015, 0.002, 0.0287, and 0.0447, respectively). AP1G2-R563W was significantly associated in LRRK2-carriers (OR=3.69, p=0.006) while VPS13D-D2932N was significantly associated in GBA-carriers (OR=5.45, p=0.0027). VPS11-C846G and HGS-S243Y were significantly associated in NC (OR=2.48 and 2.06, with p=0.022 and 0.0163, respectively). Variants in genes involved in vesicle-mediated protein transport and recycling pathways, including autophagy and mitophagy, may differentially modify PD-risk in LRRK2-carriers, GBA carriers, or NC. Specifically, PIK3C3-R768W is a PD-risk allele, with the highest effect size in LRRK2-G2019S carriers. These results suggest oligogenic effect that may depends on the genetic background of the patient. An unbiased burden of mutations approach in these genes should be evaluated in additional PD and control groups. The mechanisms by which these novel variants interact and increase PD-risk should be researched in depth for better tailoring therapeutic intervention for PD prevention or slowing disease progression.

Risk of chronic pancreatitis in carriers of the c.180C>T (p.Gly60=) CTRC variant: case-control studies and meta-analysis

Chymotrypsin C (CTRC) is a digestive serine protease produced by the pancreas that regulates intrapancreatic trypsin activity and provides a defensive mechanism against chronic pancreatitis (CP). CTRC exerts its protective effect by promoting degradation of trypsinogen, the precursor to trypsin. Loss-of-function missense and microdeletion variants of CTRC are found in around 4% of CP cases and increase disease risk by approximately 3-7-fold. In addition, a commonly occurring synonymous CTRC variant c.180C>T (p.Gly60=) was reported to increase CP risk in various cohorts but a global analysis of its impact has been lacking. Here, we analyzed the frequency and effect size of variant c.180C>T in Hungarian and pan-European cohorts, and performed meta-analysis of the new and published genetic association data. When allele frequency was considered, meta-analysis revealed an overall frequency of 14.2% in patients and 8.7% in controls (allelic odds ratio (OR) 2.18, 95% confidence interval (CI) 1.72–2.75). When genotypes were examined, c.180TT homozygosity was observed in 3.9% of CP patients and in 1.2% of controls, and c.180CT heterozygosity was present in 22.9% of CP patients and in 15.5% of controls. Relative to the c.180CC genotype, the genotypic OR values were 5.29 (95% CI 2.63–10.64), and 1.94 (95% CI 1.57–2.38), respectively, indicating stronger CP risk in homozygous carriers. Finally, we obtained preliminary evidence that the variant is associated with reduced CTRC mRNA levels in the pancreas. Taken together, the results indicate that CTRC variant c.180C>T is a clinically relevant risk factor, and should be considered when genetic etiology of CP is investigated.

Single Nucleotide Polymorphism at rs7903146 of Transcription Factor 7-like 2 gene Among Subjects with Type 2 Diabetes Mellitus in Myanmar.

To investigate the association between the single nucleotide polymorphism (SNP) rs7903146 in the transcription factor 7-like 2 (TCF7L2) gene and type 2 diabetes mellitus (T2DM) and to examine the impact of this variant on pancreatic beta-cell function in the Myanmar population. A case-control study was undertaken in 100 subjects with T2DM and 113 controls. The SNP rs7903146 was genotyped using the allele-specific polymerase chain reaction method. Plasma glucose and serum insulin levels were determined using the enzymatic colorimetric method and ELISA respectively. Beta-cell function was calculated by the HOMA-β formula. The frequencies of carrier genotypes (CT and TT) were higher in subjects with T2DM than in controls. The minor T alleles of rs7903146 were found to statistically increase type 2 diabetes risk than the C allele with an allelic odds ratio of 2.07 (95% CI 1.39-3.09, p=0.0004). The mean HOMA-β level of the group with non-carrier genotype (CC) was significantly higher than that of the groups with carrier genotypes (CT and TT) in subjects with T2DM and controls with a p-value of 0.0003 and less than 0.0001, respectively. The rs7903146 variant of the TCF7L2 gene was found to be associated with T2DM and low β-cell function among Myanmar subjects.

Mediation analysis unveils a carcinogenic effect of ADH1B rs1229984 through mechanisms other than change in drinking intensity: oesophageal cancer case-control study.

Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both. To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio. The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum. These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.

Genome-Wide Association Studies of Diarrhea Frequency and Duration in the First Year of Life in Bangladeshi Infants.

Diarrhea is the second leading cause of death in children under 5 years old worldwide. Known diarrhea risk factors include sanitation, water sources, and pathogens but do not fully explain the heterogeneity in frequency and duration of diarrhea in young children. We evaluated the role of host genetics in diarrhea. Using 3 well-characterized birth cohorts from an impoverished area of Dhaka, Bangladesh, we compared infants with no diarrhea in the first year of life to those with an abundance, measured by either frequency or duration. We performed a genome-wide association analysis for each cohort under an additive model and then meta-analyzed across the studies. For diarrhea frequency, we identified 2 genome-wide significant loci associated with not having any diarrhea, on chromosome 21 within the noncoding RNA AP000959 (C allele odds ratio [OR] = 0.31, P = 4.01 × 10-8), and on chromosome 8 within SAMD12 (T allele OR = 0.35, P = 4.74 × 10-7). For duration of diarrhea, we identified 2 loci associated with no diarrhea, including the same locus on chromosome 21 (C allele OR = 0.31, P = 1.59 × 10-8) and another locus on chromosome 17 near WSCD1 (C allele OR = 0.35, P = 1.09 × 10-7). These loci are in or near genes involved in enteric nervous system development and intestinal inflammation and may be potential targets for diarrhea therapeutics.

Investigation of TNF-&amp;alpha; and DC-SIGN promoter polymorphisms in patients with dengue fever in Lahore city of Pakistan

&lt;p&gt;&lt;strong&gt;Background and Objective:&lt;/strong&gt; Dengue fever (DF) has been a major health concern globally. Pakistan is also combating this infection for the last decade. Cytokine genes play an important role in DF pathogenesis. This study aimed to analyze dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) and tumor necrosis factor &amp;alpha; (TNF-&amp;alpha;) genes promoter polymorphisms in DF patients.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Methods:&lt;/strong&gt; A total of 140 (n = 140) dDF patients were recruited for study at the Department of Human Genetics and Molecular Biology of University of Health Sciences, Lahore, Pakistan over a period of 3 years. Simple DF was noted in 105 patients (75%) while 35 (25%) showed bleeding complications. All patients were found positive for dengue non-structural protein or dengue IgM. All patients were tested for two polymorphisms in TNF-&amp;alpha; (-238G/A, and -308G/A) and one polymorphism in DC-SIGN (-336G/A) using restriction fragment length polymorphism technique. A single nucleotide polymorphism stats program was used for statistical analysis.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Results:&lt;/strong&gt; Susceptibility to develop dengue infection in the presence of -336G allele odds ratio (OR = 27.95, p = &amp;lt;0.0001) and GG genotype (OR = 183.77, p = &amp;lt;0.0001) was found to be significantly associated in this study. Presence of a combination of alleles -336G/-238A/-308A was noted in 59.4% of DF cases and 7.6% healthy controls, a difference with statistical significance (OR = 31.46, p = &amp;lt;0.0001). Moreover, prevalence of DF symptoms showed a trend higher in G-carriers versus non-G-carriers of DC-SIGN -336 polymorphism.&lt;/p&gt;&#x0D; &lt;p&gt;&lt;strong&gt;Conclusion:&lt;/strong&gt; This work suggests a potential association of DC-SIGN -336 polymorphism with susceptibility to develop symptomatic dengue illness. However, no potential association was found between TNF-&amp;alpha; promoter polymorphisms and dengue infection in this study.&lt;/p&gt;

The IRF6 AP-2α binding site polymorphism relate to the severity of non-syndromic orofacial cleft of Indonesian patients.

IRF6 AP-2α binding site polymorphism is known as IRF6 rs642961. It has been associated with a nonsyndromic orofacial cleft (NS OFC). This study aimed to determine the IRF6 rs642961 as a risk factor associated with NS OFC and its phenotypes. The case-control design used for 264 subjects consists of 158 NS CLP subjects (42 CU CLP, 34 CB CLP, 33 CLO, 49 CPOs) and 106 healthy controls. The DNA is extracted from venous blood. The segment of IRF6 rs642961 amplified by polymerase chain reaction (PCR) followed by restriction fragment length of polymorphisms (RFLPs) used the MspI digestion enzyme. The qPCR method to identify the mRNA expression levels of the IRF6 gene rs642961 was analyzed by the Livak method. The study results show that in NS CB CLP phenotype as the most severe phenotype of NS OFC, the Odds Ratio (OR) of A mutant allele was 5.094 (CI=1.456-17.820; P=0.011) and the OR of AA homozygous mutant genotype was 13.481 (CI=2.648-68.635; P=0.001). There are different levels of mRNA expression changes from NS OFC and its phenotypes. It is substantial among the 2-ΔΔCt and the group of AA, GA, and GG genotypes (P<0.05); in the NS CPO phenotype, it shows IRF6 mRNA under-expression in GA, AA genotypes while in other phenotypes it shows IRF6 mRNA overexpression. The IRF6 AP-2α binding site polymorphism is strongly associated with the severity of NS OFC, and this polymorphism has a functional role in affecting IRF6 mRNA expression that is variable in each phenotype.

P607 HLA-DQA1*05 Allele Carriage and Anti-TNF Therapy Persistence in Inflammatory Bowel Disease

Abstract Background Carriage of HLA-DQA1*05 allele is associated with development of antidrug antibodies (ADA) in patients with Crohn’s Disease (CD) receiving anti-TNF therapy. The presence of ADA is not uniformly associated with anti-TNF therapy failure as patients with adequate trough drug concentrations, even where ADA are present, can maintain therapy response. We aimed to determine the impact of carriage of HLA-DQA1*05 allele on outcome of anti-TNF therapy evaluated by drug persistence in routine clinical practice. Methods A multi-centre retrospective study of IBD patients treated with anti-TNF therapy was performed. HLA-DQA1*05 genotypes were generated for each included patient by imputation from whole genome sequence using HIBAG. Only outcome of first anti-TNF therapy received by patients was evaluated in this study. Study primary endpoint was anti-TNF therapy persistence, expressed as time to discontinuation of anti-TNF therapy, segregated by HLA-DQA1*05 allele genotype. Patients discontinuing anti-TNF therapy due to primary or secondary loss of response or due to side-effects were considered therapy failures. Statistical analysis was performed using survival analysis and multivariate cox logistic regression with effect of covariates on outcome expressed as odds ratios (OR). Results 921 IBD patients were identified with 877 included in the study population. Baseline demographics for the entire cohort and segregated by HLA-DQA1*05 allele status are summarised in Figure 1. In the study population, 543 (62%) had no copy, 281 (32%) one copy and 53 (6%) two copies of HLA-DQA1*05 allele. Median time to anti-TNF therapy discontinuation in patients with 2 copies of HLA-DQA1*05 allele was significantly shorter compared to patients with 1 or no copy at 700-days follow-up: 418 versus 513 versus 541 days respectively, p=0.007 (Figure 2) with similar results observed at 2000-days follow-up (p=0.04). In a multivariate regression, factors independently associated with time to anti-TNF therapy discontinuation included: carriage of HLA-DQA1*05 allele OR 1.2, p=0.02; male gender OR 1.6, p=4.2 x 10-5; CD phenotype OR 0.7, p=0.009; and anti-TNF therapy type (infliximab) OR 1.5, p=0.002. Concomitant immunomodulator use was not associated with time to anti-TNF therapy discontinuation in this model, OR 0.97, p=0.84. Conclusion Carriage of two HLA-DQA1*05 alleles is associated with a less favorable outcome of anti-TNF therapy with shorter time to therapy discontinuation. Carriage of one HLA-DQA1*05 allele is not associated with outcome of anti-TNF therapy. Assessing HLA-DQA1*05 genotype has value in routine clinical practice as HLA-DQA1*05 homozygotes are at increased risk of anti-TNF failure which should be a consideration in IBD therapy selection.

Polymorphisms in the gene encoding CYP1A2 influence prostate cancer risk and progression.

The role of the cytochrome P450 1A2 (CYP1A2) rs2472299, rs2470890 and rs11072508 polymorphisms in prostate cancer risk, disease progression and tumour development remains unclear. The potential associations of these three CYP1A2 polymorphisms and haplotypes with prostate cancer susceptibility and its clinicopathological characteristics were therefore investigated. The present case-control study consisted of 522 patients with prostate cancer and 554 healthy controls. High-resolution melting analysis was used to determine the CYP1A2 polymorphisms. No significant association in prostate cancer risk was seen for CYP1A2 rs2472299 and rs11072508. However, a significantly decreased risk of prostate cancer was found for CYP1A2 rs2470890 [odds ratio (OR), 0.67; P=0.02] in the recessive model. After analysis of the associations of clinical status and these three CYP1A2 polymorphisms, the CYP1A2 rs2470890 and rs11072508 polymorphisms showed a positive association with a higher Gleason score (rs2470890 OR, 1.36, P=0.04 in the allelic model; rs11072508 OR, 1.37, P=0.04 in the allelic model and OR, 1.60, P=0.03 in the dominant model). All three polymorphisms showed a significant positive association with pathological T stage in the additive, allelic and dominant genetic models (P<0.05). Haplotype analysis revealed that the most common haplotypes 'GTT' and 'ACC' were significantly associated with pathological T stages 3 and 4 (OR, 0.62; P=0.02 and OR, 1.54; P=0.03, respectively). A significant association was found between the 'GTT' haplotype and the Gleason score (OR, 0.71; P=0.03). In conclusion, these CYP1A2 polymorphisms and haplotypes have the potential to predict prostate cancer disease progression.

Chemotherapy-related hyperbilirubinemia in pediatric acute lymphoblastic leukemia: a genome-wide association study from the AIEOP-BFM ALL study group

BackgroundCharacterization of clinical phenotypes in context with tumor and host genomic information can aid in the development of more effective and less toxic risk-adapted and targeted treatment strategies. To analyze the impact of therapy-related hyperbilirubinemia on treatment outcome and to identify contributing genetic risk factors of this well-recognized adverse effect we evaluated serum bilirubin levels in 1547 pediatric patients with acute lymphoblastic leukemia (ALL) and conducted a genome-wide association study (GWAS).Patients and methodsPatients were treated in multicenter trial AIEOP-BFM ALL 2000 for pediatric ALL. Bilirubin toxicity was graded 0 to 4 according to the Common Toxicity Criteria (CTC) of the National Cancer Institute. In the GWAS discovery cohort, including 650 of the 1547 individuals, genotype frequencies of 745,895 single nucleotide variants were compared between 435 patients with hyperbilirubinemia (CTC grades 1-4) during induction/consolidation treatment and 215 patients without it (grade 0). Replication analyses included 224 patients from the same trial.ResultsCompared to patients with no (grade 0) or moderate hyperbilirubinemia (grades 1-2) during induction/consolidation, patients with grades 3-4 had a poorer 5-year event free survival (76.6 ± 3% versus 87.7 ± 1% for grades 1-2, P = 0.003; 85.2 ± 2% for grade 0, P < 0.001) and a higher cumulative incidence of relapse (15.6 ± 3% versus 9.0 ± 1% for grades 1-2, P = 0.08; 11.1 ± 1% for grade 0, P = 0.007). GWAS identified a strong association of the rs6744284 variant T allele in the UGT1A gene cluster with risk of hyperbilirubinemia (allelic odds ratio (OR) = 2.1, P = 7 × 10− 8). TT-homozygotes had a 6.5-fold increased risk of hyperbilirubinemia (grades 1-4; 95% confidence interval (CI) = 2.9-14.6, P = 7 × 10− 6) and a 16.4-fold higher risk of grade 3-4 hyperbilirubinemia (95% CI 6.1-43.8, P = 2 × 10− 8). Replication analyses confirmed these associations with joint analysis yielding genome-wide significance (allelic OR = 2.1, P = 6 × 10− 11; 95% CI 1.7-2.7). Moreover, rs6744284 genotypes were strongly linked to the Gilbert’s syndrome-associated UGT1A1*28/*37 allele (r2 = 0.70), providing functional support for study findings. Of clinical importance, the rs6744284 TT genotype counterbalanced the adverse prognostic impact of high hyperbilirubinemia on therapy outcome.ConclusionsChemotherapy-related hyperbilirubinemia is a prognostic factor for treatment outcome in pediatric ALL and genetic variation in UGT1A aids in predicting the clinical impact of hyperbilirubinemia.Trial registrationhttp://www.clinicaltrials.gov; #NCT00430118.