METHODS: We performed an allelic association analysis in patients with SLE, followed by a meta-analysis assessing genome-wide association data across 11 independent cohorts (n = 28,872). In silico bioinformatics analysis and experimental validation in SLE-relevant cell lines were applied to determine the functional consequences of rs34330.
RESULTS: We replicated a genetic association between SLE and rs34330 (meta-analysis P = 5.29 × 10-22 , odds ratio 0.84 [95% confidence interval 0.81-0.87]). Follow-up bioinformatics and expression quantitative trait locus analysis suggested that rs34330 is located in active chromatin and potentially regulates several target genes. Using luciferase and chromatin immunoprecipitation-real-time quantitative polymerase chain reaction, we demonstrated substantial allele-specific promoter and enhancer activity, and allele-specific binding of 3 histone marks (H3K27ac, H3K4me3, and H3K4me1), RNA polymerase II (Pol II), CCCTC-binding factor, and a critical immune transcription factor (interferon regulatory factor 1 [IRF-1]). Chromosome conformation capture revealed long-range chromatin interactions between rs34330 and the promoters of neighboring genes APOLD1 and DDX47, and effects on CDKN1B and the other target genes were directly validated by clustered regularly interspaced short palindromic repeat (CRISPR)-based genome editing. Finally, CRISPR/dead CRISPR-associated protein 9-based epigenetic activation/silencing confirmed these results. Gene-edited cell lines also showed higher levels of proliferation and apoptosis.
CONCLUSION: Collectively, these findings suggest a mechanism whereby the rs34330 risk allele (C) influences the presence of histone marks, RNA Pol II, and IRF-1 transcription factor to regulate expression of several target genes linked to proliferation and apoptosis. This process could potentially underlie the association of rs34330 with SLE.
METHODS: Seven single-nucleotide polymorphisms (SNPs) in IKZF1, three SNPs in DDC, two SNPs in CDKN2A, two SNPs in CEBPE, and three SNPs in LMO1 were genotyped in 289 Yemeni children (136 cases and 153 controls), using the nanofluidic Dynamic Array (Fluidigm 192.24 Dynamic Array). Logistic regression analyses were used to estimate ALL risk, and the strength of association was expressed as odds ratios with 95% confidence intervals.
RESULTS: We found that the IKZF1 SNP rs10235796 C allele (p = 0.002), the IKZF1 rs6964969 A>G polymorphism (p = 0.048, GG vs. AA), the CDKN2A rs3731246 G>C polymorphism (p = 0.047, GC+CC vs. GG), and the CDKN2A SNP rs3731246 C allele (p = 0.007) were significantly associated with ALL in Yemenis of Arab-Asian descent. In addition, a borderline association was found between IKZF1 rs4132601 T>G variant and ALL risk. No associations were found between the IKZF1 SNPs (rs11978267; rs7789635), DDC SNPs (rs3779084; rs880028; rs7809758), CDKN2A SNP (rs3731217), the CEBPE SNPs (rs2239633; rs12434881) and LMO1 SNPs (rs442264; rs3794012; rs4237770) with ALL in Yemeni children.
CONCLUSION: The IKZF1 SNPs, rs10235796 and rs6964969, and the CDKN2A SNP rs3731246 (previously unreported) could serve as risk markers for ALL susceptibility in Yemeni children.
METHODS: To this end, we undertook a pilot genome-wide CNV analysis approach in 36 subjects (18 patients with high-grade PCa and 18 controls that were matched by age and ethnicity) in search of more accurate biomarkers that could potentially explain susceptibility toward high-grade PCa. We conducted this study using the array comparative genomic hybridization technique. Array results were validated in 92 independent samples (46 high-grade PCa, 23 benign prostatic hyperplasia, and 23 healthy controls) using polymerase chain reaction-based copy number counting method.
RESULTS: A total of 314 CNV regions were found to be unique to PCa subjects in this cohort (P<0.05). A log2 ratio-based copy number analysis revealed 5 putative rare or novel CNV loci or both associated with susceptibility to PCa. The CNV gain regions were 1q21.3, 15q15, 7p12.1, and a novel CNV in PCa 12q23.1, harboring ARNT, THBS1, SLC5A8, and DDC genes that are crucial in the p53 and cancer pathways. A CNV loss and deletion event was observed at 8p11.21, which contains the SFRP1 gene from the Wnt signaling pathway. Cross-comparison analysis with genes associated to PCa revealed significant CNVs involved in biological processes that elicit cancer pathogenesis via cytokine production and endothelial cell proliferation.
CONCLUSION: In conclusion, we postulated that the CNVs identified in this study could provide an insight into the development of advanced PCa.
METHODS: The genotypes were assessed on 144 histologically confirmed NAFLD patients and 198 controls using a Sequenom MassARRAY platform.
RESULTS: The GCKR rs1260326 and rs780094 allele T were associated with susceptibility to NAFLD (OR 1.49, 95 % CI 1.09-2.05, p = 0.012; and OR 1.51, 95 % CI 1.09-2.09, p = 0.013, respectively), non-alcoholic steatohepatitis (NASH) (OR 1.55, 95 % CI 1.10-2.17, p = 0.013; and OR 1.56, 95 % CI 1.10-2.20, p = 0.012, respectively) and NASH with significant fibrosis (OR 1.50, 95 % CI 1.01-2.21, p = 0.044; and OR 1.52, 95 % CI 1.03-2.26, p = 0.038, respectively). Following stratification by ethnicity, significant association was seen in Indian patients between the two SNPs and susceptibility to NAFLD (OR 2.64, 95 % CI 1.28-5.43, p = 0.009; and OR 4.35, 95 % CI 1.93-9.81, p < 0.0001, respectively). The joint effect of GCKR with adiponutrin rs738409 indicated greatly increased the risk of NAFLD (OR 4.14, 95 % CI 1.41-12.18, p = 0.010). Histological data showed significant association of GCKR rs1260326 with high steatosis grade (OR 1.76, 95 % CI 1.08-2.85, p = 0.04).
CONCLUSION: This study suggests that risk allele T of the GCKR rs780094 and rs1260326 is associated with predisposition to NAFLD and NASH with significant fibrosis. The GCKR and PNPLA3 genes interact to result in increased susceptibility to NAFLD.
METHODS: Consecutive biopsy-proven NAFLD patients (n = 191) and healthy controls (n = 188) were enrolled and genotyped for HLA-DQA1 and HLA-DQB1 alleles using the sequence-specific oligonucleotide-polymerase chain reaction method.
RESULTS: No association was found between the HLA alleles and NAFLD or NASH in a case-control setting. Nevertheless, among NAFLD patients, the frequency of HLA-DQB1*06 allele was significantly the lowest in NASH with significant fibrosis (10.4%) and approximately similar for NASH without significant fibrosis (22.9%) and NAFL (22.5%) (P = 0.004). It is noteworthy that the association remains significant after correction for multiple comparisons (Pc = 0.04). Multivariate analysis revealed that HLA-DQB1*06 allele is also associated with fibrosis score (P = 0.001); the result remains significant after correction for multiple comparisons.
CONCLUSION: These findings suggest that HLA-DQB1*06 is associated with lower fibrosis score in NAFLD patients.
METHODS: The discovery stage of our genome-wide association studies included 4505 cases and 21 968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10(-6) and performed in silico association analyses in an independent sample of ≤1003 cases and 7745 controls.
RESULTS: One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10(-9)). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII-activating protease levels, a product of HABP2.
CONCLUSIONS: HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.