Association Of Gene Variation Research Articles

Association of SLC30A8, CDKAL1, TCF7L2 and HHEX Gene Polymorphisms with Type 2 Diabetes in the Population of North East India

India currently has the second largest number of individuals suffering from diabetes across the world. Hence, it is pertinent to explore the genetic variations in Indian populations to comprehend the extent of genetic heterogeneity. We studied the association of gene variations of four candidate genes [SLC30A8 (rs11558471), CDKAL1 (rs94655871), TCF7L2 (rs12255372) and HHEX (rs1111875)] with Type 2 Diabetes (T2D) in the North East Indian population on whom there is very little data available. DNA was extracted from 155 diabetic patients and 100 non-diabetic controls. Genotyping was performed by Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP). Logistic regression analysis was performed to detect the association between genetic variants and type 2 diabetes. The CT genotype of rs9465871 (CDKAL1 gene) showed significant protection against diabetes [OR = 0.39 (0.17–0.91), p = 0.029] as compared to the CC genotype even after adjusting for age, sex and BMI. When analysed under a recessive model, the GG genotype of rs1111875 (HHEX gene) also showed significant protection against diabetes [OR = 0.38 (0.18–0.82), p = 0.014] as compared to the AA+AG genotypes. Both these findings did not remain significant after Bonferroni threshold of p = 0.0041 was applied. There is considerable variation in the pattern of association of these genes with T2D amongst the North East Indian population, when compared to the other ethnically and geographically diverse Indian populations.

Association of Gene Variations in Ionotropic Glutamate Receptor and Attention-Deficit/Hyperactivity Disorder in the Chinese Population: A Two-Stage Case–Control Study

Objective: The aim of this study was to comprehensively explore the relationship between genetic variations within GRIN2A, GRIN2B, GRIK1, GRIK4, GRID2, and ADHD. Method: Genotyping was performed with the Sequenom MassARRAY system in a two-stage case–control study. ADHD symptoms were assessed using the Swanson, Nolan, and Pelham version IV scale and the Integrated Visual and Auditory Continuous Performance Test. In silico analysis was performed with website resources. Results: GRID2 rs1385405 showed a significant association with ADHD risk in the codominant model (OR = 2.208, 95% CI = [1.387, 3.515]) in the first stage and in the codominant model (OR = 1.874, 95% CI = [1.225, 2.869]) and recessive model (OR = 1.906, 95% CI = [1.265, 2.873]) in the second stage and related to inattention and hyperactivity symptom. In addition, rs1385405 disturbed the activity of exonic splicing enhancer and mediated GRID2 gene expression in the frontal cortex. Conclusion: our data provided evidence for the participation of GRID2 variants in conferring the risk of ADHD.

Association of genetic variations in genes implicated in the axis with outcome in patients (pts) with metastatic colorectal cancer (mCRC) treated with cetuximab plus chemotherapy.

3585 Background: Accumulating evidence suggests that right- and left-sided CRCs have different prognoses and different sensitivities to EGFR inhibitors in several phase3 trials. These differences might be related to different embryological origins, which are reflected in different molecular profiles of tumors. LEFTY, Nodal and ACVR2B, which are TGF-betasuperfamily, are key regulators of left-right axis during embryogenesis; these expressions control sidedness. Our aim was to evaluate whether SNPs in these genes are associated with clinical outcomes in mCRC pts enrolled in the FIRE3 trial. Methods: Genomic DNA was obtained from mCRC pts receiving cetuximab plus FOLFIRI as first-line treatment and analyzed by using PCR-based direct sequencing. Four functional SNPs in 4 genes ( LEFTY1, LEFTY2, Nodal, and ACVR2B) were tested in 305 pts in FIRE3 trial cetuximab cohort (NCT00433927). Main characteristics were the following: male/female = 207/98; median age = 64; RAS-wildtype/mutant = 195/95; median PFS = 9.6 months; median OS = 26.5 months, median follow-up time = 41.8 months. Results: In patients with left sided tumor ( N= 237), LEFTY2 rs3007716 G/G variants ( N= 14) showed shorter PFS than any A variants ( N= 222) in univariate (8.0 months (M) vs. 10.3 M, HR = 2.24, 95%CI = 1.27-3.94, P < 0.01) and multivariate analyses (HR = 2.12, 95%CI = 1.20-3.75, P < 0.01). Nodal rs1904589 T/T ( N= 36) showed longer OS than any C variants ( N= 196) in univariate analysis (50.1 m vs. 29.8 M, HR = 0.61, 95% = 0.37-1.01, P = 0.048) and multivariate analyses (HR = 0.59, 95%CI = 0.35-0.99, P = 0.046). In patients with right sided tumors ( N= 58), ACVR2B rs2268753 C/C ( N= 12) showed shorter PFS than any T variants ( N= 43) in univariate analysis (3.7 m vs. 7.7 M, HR = 1.93, 95% = 0.99-3.77, P = 0.038) and multivariate analysis (HR = 2.24, 95%CI = 1.12-4.51, P = 0.023). Conclusions: Our study showed for the first time that genetic variations in sidedness related genes are associated with PFS and OS in patients receiving cetuximab based chemotherapy, which may dependent on location.

Genetic variations in immunomodulatory pathways to predict survival in patients with locoregional gastric cancer.

Immunomodulator-targeting therapies are under development in gastric cancer (GC). However, the role of genes modulating anti-tumor immunity in GC remains poorly understood. We investigated the association of variations in genes involved in immunomodulatory pathways with overall survival (OS) in locoregional GC patients. Extracted genomic DNA was analyzed for 35 functional single-nucleotide polymorphisms in genes, PDCD1, CD274, CTLA4, FOXP3, LAG3, ADORA2A, NT5E and IDO1, in 162 Japanese patients as discovery set and 277 US patients as validation set. The C allele of PDCD1 rs10204525 had univariate and multivariable associations with shorter OS in Japanese cohort (P=0.015, P=0.043, respectively). In US cohort the C allele predicted worse OS (P=0.007). Univariate and multivariable analyses revealed IDO1 rs9657182 associated with OS in the Japanese cohort; moreover, the association was confirmed in the US cohort. Genetic predisposition of the host in the immunomodulators may serve as a prognostic biomarker in patients with locoregional GC.

The Regulated Secretory Pathway and Human Disease: Insights from Gene Variants and Single Nucleotide Polymorphisms

The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

Variation in IL10 and Other Genes Involved in the Immune Response and in Oxidation and Prostate Cancer Recurrence

To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer. We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI). The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence. Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors. This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.

Anti-microbial peptide (AMP): nucleotide variation, gene expression, and host resistance in the white pine blister rust (WPBR) pathosystem

Pinus monticola antimicrobial peptide (PmAMP1) inhibits growth of Cronartium ribicola and other fungal pathogens. C. ribicola causes white pine blister rust and has resulted in a dramatic reduction of native white pines across North America. Quantitative disease resistance (QDR) is a highly desirable trait screened in breeding programs for durable resistance against C. ribicola. Along with phenotyping on a collection of germplasms, we analyzed PmAMP1 transcript and protein expression and re-sequenced the full-length gene including its promoter region. A mixed linear model was used to identify the association of single nucleotide polymorphisms (SNPs) with accumulated protein and stem QDR levels. Among 16 PmAMP1 SNPs identified in the present study, we found an association of protein levels with 6 SNPs (P<0.05), including 2 in the 5'-untranslated region (UTR), 3 in the open reading frame (ORF) region with 2 nonsynonymous SNPs, and 1 SNP in the 3'-UTR. Another set of six SNPs was associated with stem QDR levels (P<0.05), with one localized in the promoter region and the other five in the ORF region with four nonsynonymous changes, suggesting that multiple isoforms may have antifungal activity to differing degrees. Of three common PmAMP1 haplotypes, the trees with haplotype 2 showed high QDR levels with moderate protein abundance while those trees with haplotype 3 exhibited low QDR levels in the susceptible range and the lowest level of protein accumulation. Thus, an association of gene variations with protein abundance and resistance-related traits may facilitate elucidation of physiological contribution of PmAMP1 to host resistance.

Use of variation in sex steroid methyl transferases to predict efficacy of androgen-deprivation therapy (ADT) in advanced prostate cancer.

14 Background: We evaluated the association of germline variation in genes regulating hormonal pathways with duration of treatment response in prostate cancer patients receiving ADT, focusing on genes in the androgen biosynthesis (the C4 Δ; C5 Δ; C21 CYP pathways and the alternate “backdoor pathway”) and metabolism pathways. Methods: We successfully genotyped 747 single nucleotide polymorphisms (SNPs) from 84 genes in a cohort of 304 patients with advanced prostate cancer who progressed on ADT. Tagging SNPs with a minor allele frequency (MAF) of &gt;5% and r2 ≥0.8 were selected from HapMap, NIEHS and Seattle SNP databases. The primary endpoint was time to ADT failure, and we conducted a gene-level test (principal components), along with individual SNP level tests adjusted for patient age and Gleason score. To account for multiple testing, we calculated the false discovery rate (FDR), and FDRs of 0.10 were considered noteworthy. Results: The median age of the cohort at ADT failure was 72 years (range 65-78 years), and the overall median time to ADT failure was 3.21 years (IQ [25-75]: 1.54-6.20 years). At the gene level, TRMT11 (tRNA methyltransferase 11 homologue) showed the strongest association with time to ADT failure (p&lt;0.0008; adjusted p-value for FDR-0.068). Two of four TRMT11 tag SNPs were associated with time to ADT failure. The first was the intronic SNP rs1268121 (A&gt;G) with a MAF of 15%, for which there was a positive association of median time to ADT failure with the number of variant alleles (p=0.023): 3.1 years for 0, 4.1 years for 1, and 5.9 years for 2 variant alleles. The second was the SNP rs6900796 (A&gt;G) in the 3' untranscribed region with a MAF of 49%, for which the median time to ADT failure was 2.6 years for 0, 2.5 years for 1, and 3.8 years for 2 variant alleles (p=0.023). Four additional genes showed an association with ADT response at the p&lt;0.10 level, including LOC390956, PRMT3, SLC7A6OS, and WBSCR22, although all FDRs were &gt;0.95. Conclusions: Variation in TRMT11 was associated with time to ADT failure. Confirmation of these findings in an independent cohort is needed. No significant financial relationships to disclose.