Association Of Nucleotide Polymorphisms Research Articles

Nucleotide polymorphisms of the maize ZmFWL7 gene and their association with ear-related traits.

Plant fw2.2-like (FWL) genes, encoding proteins harboring a placenta-specific eight domain, have been suggested to control fruit and grain size through regulating cell division, differentiation, and expansion. Here, we re-sequenced the nucleotide sequences of the maize ZmFWL7 gene, a member of the FWL family, in 256 elite maize inbred lines, and the associations of nucleotide polymorphisms in this locus with 11 ear-related traits were further detected. A total of 175 variants, including 159 SNPs and 16 InDels, were identified in the ZmFWL7 locus. Although the promoter and downstream regions showed higher nucleotide polymorphism, the coding region also possessed 61 SNPs and 6 InDels. Eleven polymorphic sites in the ZmFWL7 locus were found to be significantly associated with eight ear-related traits. Among them, two nonsynonymous SNPs (SNP2370 and SNP2898) showed significant association with hundred kernel weight (HKW), and contributed to 7.11% and 8.62% of the phenotypic variations, respectively. In addition, the SNP2898 was associated with kernel width (KW), and contributed to 7.57% of the phenotypic variations. Notably, the elite allele T of SNP2370 was absent in teosintes and landraces, while its frequency in inbred lines was increased to 12.89%. By contrast, the frequency of the elite allele A of SNP2898 was 3.12% in teosintes, and it was raised to 12.68% and 19.92% in landraces and inbred lines, respectively. Neutral tests show that this locus wasn’t artificially chosen during the process of domestication and genetic improvement. Our results revealed that the elite allelic variants in ZmFWL7 might possess potential for the genetic improvement of maize ear-related traits.

Phenotypic variation and genome-wide association studies of main culm panicle node number, maximum node production rate, and degree-days to heading in rice

BackgroundGrain yield is a complex trait that results from interaction between underlying phenotypic traits and climatic, edaphic, and biotic variables. In rice, main culm panicle node number (MCPNN; the node number on which the panicle is borne) and maximum node production rate (MNPR; the number of leaves that emerge per degree-day > 10°C) are primary phenotypic plant traits that have significant positive direct effects on yield-related traits. Degree-days to heading (DDTH), which has a significant positive effect on grain yield, is influenced by the interaction between MCPNN and MNPR. The objective of this research is to assess the phenotypic variation of MCPNN, MNPR, and DDTH in a panel of diverse rice accessions, determine regions in the rice genome associated with these traits using genome-wide association studies (GWAS), and identify putative candidate genes that control these traits.ResultsConsiderable variation was observed for the three traits in a 220-genotype diverse rice population. MCPNN ranged from 8.1 to 20.9 nodes in 2018 and from 9.9 to 21.0 nodes in 2019. MNPR ranged from 0.0097 to 0.0214 nodes/degree day > 10°C in 2018 and from 0.0108 to 0.0193 nodes/degree-day > 10°C in 2019. DDTH ranged from 713 to 2,345 degree-days > 10°C in 2018 and from 778 to 2,404 degree-days > 10°C in 2019.Thirteen significant (P < 2.91 x 10-7) trait-single nucleotide polymorphism (SNP) associations were identified using the multilocus mixed linear model for GWAS. Significant associations between MCPNN and three SNPs in chromosome 2 (S02_12032235, S02_11971745, and S02_12030176) were detected with both the 2018 and best linear unbiased prediction (BLUP) datasets. Nine SNPs in chromosome 6 (S06_1970442, S06_2310856, S06_2550351, S06_1968653, S06_2296852, S06_1968680, S06_1968681, S06_1970597, and S06_1970602) were significantly associated with MNPR in the 2019 dataset. One SNP in chromosome 11 (S11_29358169) was significantly associated with the DDTH in the BLUP dataset.ConclusionsThis study identifies SNP markers that are putatively associated with MCPNN, MNPR, and DDTH. Some of these SNPs were located within or near gene models, which identify possible candidate genes involved in these traits. Validation of the putative candidate genes through expression and gene editing analyses are necessary to confirm their roles in regulating MCPNN, MNPR, and DDTH. Identifying the underlying genetic basis for primary phenotypic traits MCPNN and MNPR could lead to the development of fast and efficient approaches for their estimation, such as marker-assisted selection and gene editing, which is essential in increasing breeding efficiency and enhancing grain yield in rice. On the other hand, DDTH is a resultant variable that is highly affected by nitrogen and water management, plant density, and several other factors.

Exploring Association Between Serotonin and Neurogenesis Related Genes in Obsessive-Compulsive Disorder in Chinese Han People: Promising Association Between DMRT2, miR-30a-5p, and Early-Onset Patients.

Obsessive-compulsive disorder (OCD) is a deliberating disorder with complex genetic and environmental etiologies. Hypotheses about OCD mainly include dysregulated neurotransmitters, especially serotonin, and disturbed neurodevelopment. Single nucleotide polymorphism (SNP) association studies regarding OCD are often met with inconsistent results. However, stratification by age of onset may sometimes help to limit the heterogenicity of OCD patients. Therefore, we conducted a stratified SNP association study enrolling 636 patients and 612 healthy controls. Patients were stratified by age of onset as early-onset (EO-OCD) and late-onset (LO-OCD). Blood extracted from the patients was used to genotype 18 loci, including serotonin system genes, Slitrk1, Slitrk5, and DMRT2 and related miRNA genes. Logistic regression was used to compare allele and genotype frequencies of variants. A general linear model was used to evaluate the association between variants and trait anxiety. In our study, rs3824419 in DMRT2 was associated with EO-OCD, G allele was the risk allele. Rs2222722 in miR-30a-5p was associated with EO-OCD, with the C allele being the risk allele. Rs1000952 in HTR3D was found associated with trait anxiety in OCD patients. The significance disappeared after FDR correction. Our results supported neurodevelopment-related genes, DMRT2 and miR-30a-5p, to be related to EO-OCD. However, we cannot prove serotonin genes to be directly associated with EO-OCD. While an association between HTR3D and trait anxiety was discovered, comparisons based on biological or clinical traits may be helpful in future studies. As our detective powers were limited, more large-scale studies will be needed to confirm our conclusion.

Зв’язок однонуклеотидних поліморфізмів гена VDR з рівнем остеоасоційованих гормонів при постменопаузальному остеопорозі

У плазмі крові 74 жінок у постменопаузальному періоді з остеопорозом (ОП) та без нього визначали рівні остеоасоційованих гормонів, макроелементів, інтерлейкінів, циклічних нуклеотидів та активність лужної фосфатази (ЛФ). Мінеральну щільність кістки (МЩК) і метакарпальний індекс оцінювали за даними остеоденситометрії. За допомогою полімеразної ланцюгової реакції виявляли алельні поліморфізми T61968С та G3731A гена рецептора вітаміну D (VDR). Мажорний гомозиготний генотип (СС) поліморфізму T61968С траплявся в групі без ОП в 3,4 раза частіше (p(F) = 0,03), знижуючи ризик розвитку захворювання в 5,5 раза (OR = 0,18; CI = 0,04–0,88). Мінорний гомозиготний генотип (ТТ) спостерігався в 3,4 раза частіше (p(F) = 0,04) за наявності ОП, збільшуючи ризик розвитку захворювання в 5,4 раза (OR = 5,42; CI = 0,98–29,92). Обидва варіанти вірогідно впливали на рівні в крові тестостерону (ТС) (F = 3,54; p = 0,48 та F = 5,27; p = 0,015) й інтерлейкіну-1β (F = 3,64; p = 0,04 та F = 2,37; p = 0,12), величину МЩК (F = 7,20; p = 0,0047 та F = 6,65; p = 0,0064). Мажорний гомозиготний генотип (АА) поліморфізму G3731A траплявся у жінок без ОП в 2,9 раза частіше (p(F) = 0,02), знижуючи ризик розвитку ОП в 5,3 раза (OR = 0,19; CI = 0,04–0,86); мінорний гомозиготний поліморфізм (GG) — у 5,4 раза частіше (p(F) = 0,04) за наявності ОП, збільшуючи ризик захворювання у 8 разів (OR = 8,00; CI = 0,88–72,70). Наявність генотипу (GG) асоційована зі збільшенням вмісту в крові паратгормону (F = 6,18; p = 0,0095), фосфору (F = 6,62; p = 0,0065), магнію (F = 5,44; p = 0,013), активності ЛФ (F = 13,85; p = 0,00014) і величини МЩК (F = 6,65; p = 0,0064) та зі зниженням вмісту в крові прогестерону (F = 10,99; p = 0,0006), ТС (F = 5,27; p = 0,015) і кальцію (F = 8,55; p = 0,0022).

Novel genetic variants associated with brain functional networks in 18,445 adults from the UK Biobank

Here, we investigated the genetics of weighted functional brain network graph theory measures from 18,445 participants of the UK Biobank (44–80 years). The eighteen measures studied showed low heritability (mean h2SNP = 0.12) and were highly genetically correlated. One genome-wide significant locus was associated with strength of somatomotor and limbic networks. These intergenic variants were located near the PAX8 gene on chromosome 2. Gene-based analyses identified five significantly associated genes for five of the network measures, which have been implicated in sleep duration, neuronal differentiation/development, cancer, and susceptibility to neurodegenerative diseases. Further analysis found that somatomotor network strength was phenotypically associated with sleep duration and insomnia. Single nucleotide polymorphism (SNP) and gene level associations with functional network measures were identified, which may help uncover novel biological pathways relevant to human brain functional network integrity and related disorders that affect it.

Estrogen enhances the expression of a growth-associated long noncoding RNA in chicken liver via ERα

ABSTRACT 1. The long noncoding RNA lncGLM is significantly differentially expressed in the livers of peak-laying hens compared with that in the livers of pre-laying hens, but its potential biological role and expression regulation are unclear. 2. To explore the potential biological function of lncGLM, single nucleotide polymorphism (SNP) detection and association analysis were carried out in the Gushi×Anka F2 resource population. 3. The tissues and spatiotemporal expression characteristics of lncGLM were analysed by real-time quantitative PCR. The effects of 17β-oestradiol on the expression of lncGLM expression were analysed through in vitro and in vivo experiments. 4. The results showed that a g.19069338 T > C SNP was present in lncGLM. Association analysis revealed that lncGLM was significantly associated with body slanting length at 12 weeks, body weight at 12 weeks, shank length at four weeks, chest depth at eight weeks, pelvic width at 12 weeks, eviscerated weight, head weight, pancreas weight, pectoralis weight, leg muscle weight, muscular stomach weight rate, pancreas weight rate, carcase weight, aspartate aminotransferase, creatinine and pectoral muscle water loss rate. 5. The expression of lncGLM in the liver was higher than that in other sampled tissues. In addition, the expression of lncGLM in the liver was significantly higher in the peak-laying period than at the pre-laying period. Both in vitro and in vivo experiments showed that lncGLM expression was regulated by 17β-oestradiol via oestrogen receptor alpha (ER-α). These results demonstrated that the chicken lncGLM gene is highly expressed in liver tissue and regulated by oestrogen through ER-α.

Design and methods of the prevalence and pharmacogenomics of tenofovir nephrotoxicity in HIV-positive adults in south-western Nigeria study

BackgroundIndividuals of African descent are at higher risk of developing kidney disease than their European counterparts, and HIV infection is associated with increased risk of nephropathy. Despite a safe renal profile in the clinical trials, long-term use of tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy although the underlying mechanisms remain undetermined. We aim to establish the prevalence of and risk factors for TDF-induced kidney tubular dysfunction (KTD) among HIV-I and II individuals treated with TDF in south-west Nigeria. Association between TDF-induced KTD and genetic polymorphisms in renal drug transporter genes and the APOL1 (Apolipoprotein L1) gene will be examined.MethodsThis study has two phases. An initial cross-sectional study will screen 3000 individuals attending the HIV clinics in south-west Nigeria for KTD to determine the prevalence and risk factors. This will be followed by a case-control study of 400 KTD cases and 400 matched controls to evaluate single nucleotide polymorphism (SNP) associations. Data on socio-demographics, risk factors for kidney dysfunction and HIV history will be collected by questionnaire. Blood and urine samples for measurements of severity of HIV disease (CD4 count, viral load) and renal function (creatinine, eGFR, phosphate, uric acid, glucose) will also be collected. Utility of urinary retinol binding protein (RBP) and N-acetyl-beta-D-glucosaminidase (NAG) levels as surrogate markers of KTD will be evaluated. Genomic DNA will be extracted from whole blood and SNP analyses performed using the rhAMP SNP genotyping assays. Statistical analysis including univariate and multivariate logistic regression analyses will be performed to identify factors associated with KTD.DiscussionIn spite of TDF being the most commonly used antiretroviral agent and a key component of many HIV treatment regimens, it has potential detrimental effects on the kidneys. This study will establish the burden and risk factors for TDF-induced KTD in Nigerians, and explore associations between KTD and polymorphisms in renal transporter genes as well as APOL1 risk variants. This study may potentially engender an approach for prevention as well as stemming the burden of CKD in sub-Saharan Africa where GDP per capita is low and budgetary allocation for health is inadequate.

X chromosome variants are associated with male fertility traits in two bovine populations

BackgroundTwenty-five phenotypes were measured as indicators of bull fertility (1099 Brahman and 1719 Tropical Composite bulls). Measurements included sperm morphology, scrotal circumference, and sperm chromatin phenotypes such as DNA fragmentation and protamine deficiency. We estimated the heritability of these phenotypes and carried out genome-wide association studies (GWAS) within breed, using the bovine high-density chip, to detect quantitative trait loci (QTL).ResultsOur analyses suggested that both sperm DNA fragmentation and sperm protamine deficiency are heritable (h2 from 0.10 to 0.22). To confirm these first estimates of heritability, further studies on sperm chromatin traits, with larger datasets are necessary. Our GWAS identified 12 QTL for bull fertility traits, based on at least five polymorphisms (P < 10−8) for each QTL. Five QTL were identified in Brahman and another seven in Tropical Composite bulls. Most of the significant polymorphisms detected in both breeds and nine of the 12 QTL were on chromosome X. The QTL were breed-specific, but for some traits, a closer inspection of the GWAS results revealed suggestive single nucleotide polymorphism (SNP) associations (P < 10−7) in both breeds. For example, the QTL for inhibin level in Braham could be relevant to Tropical Composites too (many polymorphisms reached P < 10−7 in the same region). The QTL for sperm midpiece morphological abnormalities on chromosome X (QTL peak at 4.92 Mb, P < 10−17) is an example of a breed-specific QTL, supported by 143 significant SNPs (P < 10−8) in Brahman, but absent in Tropical Composites. Our GWAS results add evidence to the mammalian specialization of the X chromosome, which during evolution has accumulated genes linked to spermatogenesis. Some of the polymorphisms on chromosome X were associated to more than one genetically correlated trait (correlations ranged from 0.33 to 0.51). Correlations and shared polymorphism associations support the hypothesis that these phenotypes share the same underlying cause, i.e. defective spermatogenesis.ConclusionsGenetic improvement for bull fertility is possible through genomic selection, which is likely more accurate if the QTL on chromosome X are considered in the predictions. Polymorphisms associated with male fertility accumulate on this chromosome in cattle, as in humans and mice, suggesting its specialization.

Integration of genetic and clinical information to improve imputation of data missing from electronic health records.

Clinical data of patients' measurements and treatment history stored in electronic health record (EHR) systems are starting to be mined for better treatment options and disease associations. A primary challenge associated with utilizing EHR data is the considerable amount of missing data. Failure to address this issue can introduce significant bias in EHR-based research. Currently, imputation methods rely on correlations among the structured phenotype variables in the EHR. However, genetic studies have shown that many EHR-based phenotypes have a heritable component, suggesting that measured genetic variants might be useful for imputing missing data. In this article, we developed a computational model that incorporates patients' genetic information to perform EHR data imputation. We used the individual single nucleotide polymorphism's association with phenotype variables in the EHR as input to construct a genetic risk score that quantifies the genetic contribution to the phenotype. Multiple approaches to constructing the genetic risk score were evaluated for optimal performance. The genetic score, along with phenotype correlation, is then used as a predictor to impute the missing values. To demonstrate the method performance, we applied our model to impute missing cardiovascular related measurements including low-density lipoprotein, heart failure, and aortic aneurysm disease in the electronic Medical Records and Genomics data. The integration method improved imputation's area-under-the-curve for binary phenotypes and decreased root-mean-square error for continuous phenotypes. Compared with standard imputation approaches, incorporating genetic information offers a novel approach that can utilize more of the EHR data for better performance in missing data imputation.

Association of XPD Asp312Asn single nucleotide polymorphisms with oxaliplatin based chemotherapy

Objective This study was to determine the role of the Xeroderma pigmentosum group D (XPD) Asp312Asn polymorphism in predicting response to Oxaliplatin based chemotherapies and survival in patients with metastatic colorectal cancer. Methods This study enrolled a total of 106 patients treated with FOLFOX4 (n=72) or XELOX (n=34) regimen. The genotype of XPD Asp312Asn was analyzed by TaqMan probe based real-Time polymerase chain reaction (PCR). Logistic regression was used to predict the response to the treatments. Cox proportion hazards models and Kaplan-Meier method were applied to predict the survival. Results The effective rate of chemotherapy in 106 patients with colorectal cancer was 57.6%(61/106). There was no significant difference in the distribution of G/G, G/A and A/A genotypes between the two groups (P>0.05). Multivariate survival analysis showed that the survival time of patients with A/A genotype, carcinoembryonic antigen (CEA) (>5 ng/ml) and age (>65 years) was relatively short, with statistical significance (P<0.05). Conclusions XPD Asp312Asn single nucleic acid polymorphism can be used as a predictor of survival in patients with metastatic colorectal cancer, but it is not associated with oxaliplatin sensitivity and needs further study. Key words: Colorectal neoplasms/DT; Antineoplastic combined chemotherapy protocols; Organoplatinum compounds/AD; Xeroderma pigmentosum group D protein/GE; Polymorphism, single nucleotide

Association of ORMDL3 and HLA-DQ single nucleotide polymorphisms in children with asthma associated Mycoplasma pneumoniae infection

Objective Childhood asthma is closely related to MP infection.This study was to investigate the distribution of ORMDL3 and HLA-DQ gene SNP in children with MP-associated asthma and gene-gene interactions. Methods One hundred and ninety-four patients with MP infection were enrolled.Extraction of whole blood genomic DNA was carried out.The genotype was collected by Fluidigm Juno 96.96 Genotyping integrated fluid pathway system.The patients were divided into MP-asthma group and MP-non-asthma group.Gene-gene interaction was analyzed by generalized multifactor dimensionality reduction. Results MP-asthma group included 63 cases(32.5%), MP-non asthma group included 131 cases(67.5%). ORMDL3 gene rs4794820 had three genotypes of AG, GG, AA, MP-asthma group GG genotype and G allele frequency was higher than that in MP-non-asthma group.The frequency of AA genotype was the lowest among the two groups, but in the MP-non-asthma group were higher than that in the MP-asthma group.The rs7216389 had three genotypes of TT、TC、CC, the frequency of TT genotype and T allele in MP-asthma group was significantly higher than that in MP-non-asthma group.The frequency of CC genotype was the lowest among the two groups, but CC genotype in MP-non-asthma group was significantly higher than that in MP-asthma group.The rs794820 GG genotype and rs7216389 TT genotype were found to be risk factors.ORMDL3、HLA-DQA1 and HLA-DQA2 have gene-gene interaction. Conclusion MP infection is an important external cause of asthma in children.The genotype of rs7794820 GG genotype and rs7216389 TT genotype are an important internal cause of asthma after childhood MP infection.ORMDL3 rs4794820, rs7216389 and HLA-DQA1 rs9272346, HLA-DQA2 rs7773955 have gene-gene interaction, synergistically enhance the risk of asthma associated with asthma in children with MP. Key words: Asthma; Mycoplasma pneumoniae; Children; Single nucleotide polymorphism; Gene-gene interactions

Association of FOXO1 gene single nucleotide polymorphisms with type 2 diabetic nephropathy

Objective To investigate the association between single nucleotide polymorphisms (SNPs) of FOXO1 gene and type 2 diabetic nephropathy(T2DN). Methods A total of 654 Chinese Han patients with type 2 diabetes mellitus (T2DM; 394 without and 260 with T2DN) were enrolled. Six FOXO1 gene tags SNPs were selected using the Hapmap database. The genotypes of six SNPs in FOXO1 were determined by PCR-RFLP, and the clinical characteristics of the subjects were also evaluated. The interaction of SNPs with these clinical factors was analyzed by multiple factor reduction(MDR) method. Results After adjusting for age, gender, DM course, body mass index(BMI), HbA1C, total cholesterol(TC), triglycerides(TG), high-density lipoprotein-cholesterol(HDL-C), low-density lipoprotein-cholesterol(LDL-C), hypertension history, DM family history, smoking, and drinking, FOXO1 rs17446614 variant genotype was significantly associated with an increased risk of T2DN, while rs17446593 variant genotype was associated with a decreased T2DN risk. In the stratified analysis of risk factors, the correlation between rs17446614 and T2DN was unrelated with patient′s gender, hypertension history, and blood TC level. Simultaneously, rs17446614 variant genotype significantly increased the risk of T2DN in people older than 60 years, BMI less than 24 kg/m2, LDL-C less than or equal to 3.5 mmol/L , or DM family history. rs2721068 variant genotype significantly decreased the risk of T2DN in people less than 60 years old or without DM family history. rs2951787 variant genotype significantly increased the risk of T2DN in people with DM duration longer than 10 years or with DM family history. A variant genotype rs17592236 significantly increased the risk of T2DN in male or TC higher than 5 mmol/L. A variant genotype rs17446593 significantly decreased the risk of T2DN in male or those DM duration longer than 10 years, or BMI≥24 kg/m2. The interactions among rs17446614, DM duration, TC, and hypertension history were also observed. Conclusion The genetic variants rs17446614, rs2721068, rs2951787, rs17592236, and rs17446593 in FoxO1 may contribute to the risk of T2DN in T2DM patients. (Chin J Endocrinol Metab, 2018, 34: 362-370) Key words: FOXO1 gene; Polymorphism, single nucleotide; Diabetic nephropathy

Polymorphism of CONNEXIN37 gene is a risk factor for ischemic stroke in Han Chinese population

BackgroundStroke has a high fatality and disability rate, and is one of the main burdens to human health. It is thus very important to identify biomarkers for the development of effective approaches for the prevention and treatment of stroke. Connexin37 is an anti-inflammatory cytokine and is involved in chronic inflammation and atherosclerosis. Recent studies have found that CONNEXIN37 gene variations are associated with atherosclerosis diseases, such as coronary heart disease and stroke, but its association with stroke in distinct human populations remains to be determined. We report here the analysis of the association of the single nucleotide polymorphisms (SNPs) of CONNEXIN37 with ischemic stroke in Han Chinese population.MethodsTwo SNPs of CONNEXIN37 gene were analyzed in 385 ischemic stroke patients and 362 hypertension control patients using ligase detection reaction (LDR) method.ResultsLogistic regression analysis demonstrated that, AG and GG genotypes of SNP rs1764390 and CC genotype of rs1764391 of CONNEXIN37 were associated with an increased risk of ischemic stroke, and that G allele of rs1764390 is a risk factor for ischemic stroke. Further, we found that SNP rs1764390 and SNP rs1764391 in CONNEXIN37 were associated with ischemic stroke under additive/dominant model, and recessive/dominant model, respectively.ConclusionOur results indicate that CONNEXIN37 gene polymorphism is an ischemic stroke risk factor in Northern Han Chinese.

Abstract P130: Infant Growth as an Effect Modifier of Genetic-lipid Associations: Evidence From a Chilean Infancy Cohort

Background: The postnatal period can function as a window of time for metabolic programming. As evidence from human observational studies is scarce, we examined the role of postnatal weight, length (linear growth), and weight-for-length (WFL) growth trajectories as effect modifiers of established single nucleotide polymorphism (SNP) associations on lipid levels in a cohort of adolescents from the Santiago Longitudinal Study (SLS) (n=484). Methods: Growth trajectories were characterized via two different approaches: nonlinear mixed effects model (SITAR) and a latent growth mixture model (LGMM). We assessed gene-environment interaction in an additive model within: 1) SITAR including product terms that accurately reflects the trichotomous genetic term, and 2) LGMM using stratified SNP-lipid associations by latent growth patterns. Bonferroni-corrected significant findings are reported. Results: SITAR models did not reveal any evidence of gene-environment interaction. In contrast, given three LGMM patterns of growth, gene-environment interactions emerge for both weight and WFL trajectories. One group of infants had lower velocity but higher acceleration; another group had medium velocity and lower acceleration; a third group had high velocity and lower acceleration. The association between the rs7412 (APOE) variant and HDL (mg/dL) was negative for the low velocity/high acceleration weight trajectory group (mean= -10.2; 95% CI = -16.0, -4.5; n~23) compared to the high velocity/low acceleration group (mean = 11.3; 95% CI = 2.6, 20; n~152). Similarly, the association (95% CI) between the rs78536982 (BAI3, LMBRD1) variant and triglycerides (log(mg/dL) was lower for the low velocity/high acceleration WFL group (-0.61; 0.84, -0.37; n~24) when compared to both the medium velocity/low acceleration (-0.09; -0.23, 0.05; n~271) and high velocity/low acceleration (0.001; -0.11, 0.11; n~189). In sex-stratified analyses, the high velocity/low acceleration group for males (n=254) had a negative association (95% CI) between the rs11076175 (CETP) variant and LDL (mg/dL) (-10.6; -16.7, -4.5; n~140) versus a positive association for the low velocity/high acceleration (12.6; 2.93, 22.2; n~114). Summary: These results demonstrate potential heterogeneity in the genetic association between lipid loci and adolescent lipid levels across different patterns of growth from 0 to 5 months. Future work to examine the role of infant growth as a causal factor in direct and indirect effects is of interest.

ARHGEF10 gene polymorphism is closely associated with the risk of ischemic stroke in Northern Han Chinese population

Stroke is a common disease with high mortality and morbidity. It is of high importance to identify biomarkers of stroke. Rho guanine nucleotide-exchange factor(GEF) 10 (ARHGEF10) gene polymorphism has been found to be associated with various human diseases, but its correlation with stroke remains unknown. This study aims to evaluate the potential association of the single nucleotide polymorphisms (SNPs) of ARHGEF10 with ischemic stroke (IS) in northern Han Chinese population. Three SNPs of ARHGEF10 gene were analyzed in 385 IS patients and 362 hypertension control patients using the ligase detection reaction (LDR) method. Logistic regression analysis demonstrated that GG genotypes of SNP rs2280887 were associated with an increased risk of IS in dominant, recessive, and additive models. Moreover, SNP rs9657362 and SNP rs4480162 were significantly associated with IS in dominant and additive models. These results indicate that ARHGEF10 gene polymorphisms may affect IS risk in northern Han Chinese.

Meta-analysis on the association of VEGFR1 genetic variants with sunitinib outcome in metastatic renal cell carcinoma patients.

VEGFR1 rs9582036 and rs9554320 were previously reported the association with sunitinib progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Hereafter, the association of both single nucleotide polymorphisms (SNPs) with PFS/OS was confirmed in two independent mRCC cohorts. The aim of the current study was to validate the associations of both SNPs with sunitinib outcome in three independent well-characterized cohorts (SUTOX, CCF and SOGUG) including 286 sunitinib-treated mRCC patients, as well as to perform a meta-analysis of current and published data combined. We found that rs9582036 and rs9554320 showed a significant association with sunitinib PFS in the CCF cohort (HR: 0.254, 95%CI: 0.092-0.703; P=0.008 and HR: 0.430, 95%CI: 0.200-0.927; P=0.031, respectively). Patients with the variant genotype of rs9582036 and rs9554320 had a shorter median PFS. No significant association of both SNPs with sunitinib PFS or OS was detected in either the SUTOX or SOGUG cohort. After the combination of all available data into a meta-analysis, the association of both SNPs with sunitinib PFS or OS did not achieve the threshold for statistical significance. Our findings suggest that, although VEGFR1 rs9582036 and rs9554320 are involved in sunitinib therapy outcome, its clinical use as biomarkers for prediction of sunitinib outcome in mRCC patients is limited, due to inconsistent findings when analyzing all existing studies together.

Association of interleukin-17 single nucleotide polymorphisms with susceptibility to osteoarthritis

Objective To test single nucleotide polymorphisms (SNP) of IL-17A G-197A and IL-17F T7488C in the Chinese Han nationality population and analyze the association of the SNP with susceptibility to osteoarthritis. Methods Two hundred patients with primary knee OA underwent total knee arthroplasty and 200 healthy individuals were recruited into this study from January 2008 to December 2015. We obtained DNA from 2 ml of whole blood for 200 OA patients (OA group) and 200 healthy (healthy control group) to employed a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay to identify the genotypes IL-17A G-197A (rs2275913) and IL-17F T7488C (rs2275913). The distribution of IL-17A G-197A (rs2275913) and IL-17F T7488C (rs2275913) genotypes and allele frequencies were detected between the two groups. Chi-square test was used to compare genotype and allele frequency of IL-17A G-197A and IL-17F T7488C between the two groups. If the difference between the two groups was statistically significant, then odds ratio (OR) and 95% confidence interval (95%CI) would be calculated. Results The frequency of AA, AG and GG genotype of IL-17A G-197A(rs2275913) was 4.0%, 54.0% and 42.0% in OA group, which differed from control group (18.0%, 53.5% and 28.5%). The frequency of A and G allele were 31.0% and 69.0% in OA group, which differed from control group (44.8% and 55.3%). The risk of OA in carriers with an G allele (G/A or G/G genotypes) was statistically higher compared to that of carriers with the A/A genotype (AG: OR=0.862, 95%CI=0.729-1.019; GG: OR= 1.259, 95% CI=0.967-1.639; A:OR=0.693, 95% CI=0.577-0.831; G:OR=1.249, 95% CI=1.119-1.394). The distributions of TT, TC and CC genotypes for the IL-17F T7488C polymorphism (rs763780) in OA patients and controls shown 76.5%, 18.0%, 5.5% and 81.5%, 15.5%, 3.0%,respectively. The frequency of T and C allele were 85.5%, 14.5% and 89.3%, 10.8% in 2 group. There were no significant differences in the alleles frequency and genotypes distribution for IL-17F T7488C between OA patients and volunteers. Conclusion Polymorphism of IL-17A G-197A may be closely associated with susceptibility to the development of OA in the Chinese Han nationality population. Genotype G/A and G/G of rs2275913 is a high factor for OA while AA is a low risk factor. However, there is no relationship between rs763780 and OA susceptibility. IL-17F T7488C gene does not increase the risk of suffering from OA. Key words: Osteoarthritis, knee; Interleukins; Genetic testing; Disease susceptibility

Association of CD154 gene single nucleotide polymorphisms with its soluble levels and ischemic stroke

Association of CD154 gene single nucleotide polymorphisms with its soluble levels and ischemic stroke

Association of rs27044, rs30187 and rs26653 single nucleotide polymorphisms in the endoplasmic reticulum aminopeptidase 1 gene with psoriasis vulgaris in a Chinese Han population

Objective To investigate the association between endoplasmic reticulum aminopeptidase 1 (ERAP1) gene polymorphisms and psoriasis vulgaris (PsV) in a Chinese Han population. Methods Five milliliters of venous blood samples were collected from 289 patients with PsV and 292 human controls of Han nationality after informed consent. Three single nucleotide polymorphisms (SNPs) in the encoding area of the ERAP1 gene, including rs27044, rs30187 and rs26653, were genotyped by ligase detection reaction (LDR). With the PLINK 1.07 package, statistical analysis was carried out by using the chi-square test for comparisons of allele and genotype frequencies between the patient group and control group. The allelic odds ratio (OR) and its 95% confidence interval (CI) were calculated. In addition, haplotype analysis was conducted with the Haploview software. Results The frequencies of rs30187_C and rs26653_G alleles were significantly lower in the patient group (0.460 2 and 0.430 8 respectively), especially in patients with early-onset PsV (0.448 5 and 0.422 7 respectively), than in the control group (0.534 2 and 0.501 7 respectively, all P< 0.05). The SNPs rs27044, rs30187 and rs26653 showed strong linkage disequilibrium with each other (r2 ≥ 0.717, D' ≥ 0.962). Genotype analysis showed that the frequency of the rs30187 CC genotype was significantly lower in the patient group, especially in patients with early-onset PsV, than in the control group (P< 0.05 and 0.016 7 respectively) under a recessive mode of inheritance. Haplotype analysis revealed that the frequency of the haplotype H4: CTC was significantly increased in the patient group (0.050), especially in patients with early-onset PsV (0.052), compared with the control group (0.022, P< 0.05 and 0.016 7 respectively). Conclusions ERAP1 gene polymorphisms are associated with PsV, especially with early-onset PsV in Chinese Han population. The risk haplotype H4: CTC may be a susceptible factor for PsV. Key words: Psoriasis; Polymorphism, single nucleotide; Genome-wide association study; Haplotypes; Gene frequency; Genotype; Genes, ERAP1

Abstract P1-13-03: Genome wide association study (GWAS) of genetic variants associated with docetaxel toxicity in the ROSE/TRIO-012 trial

Abstract Background: Genetic predisposition to docetaxel (Doc) toxicity contributes to unacceptable toxicity and reduced dose intensity, and may influence disease outcomes. We previously reported variants associated with Doc toxicity in candidate gene single nucleotide polymorphism (SNP) associations in a breast cancer treatment setting (Damaraju et al. Eur J Cancer (suppl); Vol 8 (7), page 175, 2010) and the identified variants were confirmed in an independent validation study (Damaraju et al, J Clin Oncol Vol 33, Issue 15 suppl, 2015: 540). Others have reported candidate SNP (Breast Cancer Res Treat, 2011 SWOG 0221 study) and GWAS (Clin Cancer Res 2012 CALGB 40101 study) identified variants associated with paclitaxel mediated peripheral neuropathy. However, the overlap on the variants identified thus far between Doc and paclitaxel are limited, prompting a genome wide search to find variants contributing to Doc specific toxicity. Methods: TRIO-012 is a double blinded, multinational trial that randomized 1,144 patients with advanced breast cancer to receive first-line Doc in combination with ramucirumab (RAM) or placebo (Mackey et al. J Clin Oncol Jan 10, 2015:141-148). Study subjects (n=719) in the Doc+RAM or Doc+placebo arm with available germline DNA are being genotyped; all subjects provided ethics-committee approved prospective consent for this genetic study. Genotyping are being performed with Affymetrix SNP 6.0 arrays. Genotype data will be filtered for deviations from Hardy Weinberg Equilibrium and minor allele frequency of &amp;gt;0.05. Doc-induced adverse events (AEs) are based on CTCAE (Common Terminology Criteria for Adverse Events v4.1) toxicity grades. Toxicities &amp;gt;2 scored for fatigue (n=96), myalgia (n=22), peripheral neuropathy (n=17) will be analysed as individual phenotypes in comparison with the no toxicity group (toxicity grades 0-1) and in a combined analysis of all Doc induced toxicities (0-1, n=599 vs. &amp;gt;2, n=120). Dominant genotypic model is assumed; Chi-square test, FDR and/or 10000 permutations were employed using SVS v8.3 and p&amp;lt;0.05 considered statistically significant. We will identify population stratification using EIGENSTRAT method and will correct the association statistics using the Eigenvectors along with age and BMI as covariates. Fine mapping of the identified loci will be attempted using imputation tools. We will interrogate the data for cumulative dose to toxicity and correlate SNPs identified with survival outcomes. Results and conclusions: We expect to reconfirm the associations of loci reported in candidate SNP and previous GWAS studies; XKR4 (rs4737264) for peripheral neuropathy, CYP3A5*3 (rs776746) with fatigue, and FACND2 (rs7637888) with myalgia in addition to the potential novel variants distinct from paclitaxel AE GWAS studies. Fine mapping around these loci may help identify potential causal variants. Both candidate SNP and GWAS identified variants may aid in developing risk stratification models. The GWAS identified loci and the flanking genes will be interrogated using the ingenuity pathway analysis for insights in to the biological roles in the drug metabolism. We expect to complete the analysis by mid-November 2015. Citation Format: Damaraju S, Gorbunova V, Gelmon K, García-Saenz J, Morales-Murillo S, AbiGerges D, Canon J-L, Kiselev I, Cohen GL, Jerusalem G, Thireau F, Fresco R, Houé V, Press MF, Kumaran M, Mackey JR. Genome wide association study (GWAS) of genetic variants associated with docetaxel toxicity in the ROSE/TRIO-012 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-03.