rs161802

Sickle cell disease (SCD) is a Mendelian disease characterized by multigenic phenotypes. Previous reports indicated a higher rate of thromboembolic events (TEEs) in SCD patients. A number of candidate polymorphisms in certain genes (e.g., FVL, PRT, and MTHFR) were previously reported as risk factors for TEEs in different clinical conditions. This study aimed to genotype these genes and other loci predicted to underlie TEEs in SCD patients. Methodology: A multi-center genome-wide association study (GWAS) involving Saudi SCD adult patients with a history of TEEs (n = 65) and control patients without TEE history (n = 285) was performed. Genotyping used the 10× Affymetrix Axiom array, which includes 683,030 markers. Fisher’s exact test was used to generate p-values of TEE associations with each single-nucleotide polymorphism (SNP). The haplotype analysis software tool version 1.05, designed by the University of Göttingen, Germany, was used to identify the common inherited haplotypes. Results: No association was identified between the targeted single-nucleotide polymorphism rs1801133 in MTHFR and TEEs in SCD (p = 0.79). The allele frequency of rs6025 in FVL and rs1799963 in PRT in our cohort was extremely low (<0.01); thus, both variants were excluded from the analysis as no meaningful comparison was possible. In contrast, the GWAS analysis showed novel genome-wide associations (p < 5 × 10−8) with seven signals; five of them were located on Chr 11 (rs35390334, rs331532, rs317777, rs147062602, and rs372091), one SNP on Chr 20 (rs139341092), and another on Chr 9 (rs76076035). The other 34 SNPs located on known genes were also detected at a signal threshold of p < 5 × 10−6. Seven of the identified variants are located in olfactory receptor family 51 genes (OR51B5, OR51V1, OR51A1P, and OR51E2), and five variants were related to family 52 genes (OR52A5, OR52K1, OR52K2, and OR52T1P). The previously reported association between rs5006884-A in OR51B5 and fetal hemoglobin (HbF) levels was confirmed in our study, which showed significantly lower levels of HbF (p = 0.002) and less allele frequency (p = 0.003) in the TEE cases than in the controls. The assessment of the haplotype inheritance pattern involved the top ten significant markers with no LD (rs353988334, rs317777, rs14788626882, rs49188823, rs139349992, rs76076035, rs73395847, rs1368823, rs8888834548, and rs1455957). A haplotype analysis revealed significant associations between two haplotypes (a risk, TT-AA-del-AA-ins-CT-TT-CC-CC-AA, and a reverse protective, CC-GG-ins-GG-del-TT-CC-TT-GG-GG) and TEEs in SCD (p = 0.024, OR = 6.16, CI = 1.34–28.24, and p = 0.019, OR = 0.33, CI = 0.13–0.85, respectively). Conclusions: Seven markers showed novel genome-wide associations; two of them were exonic variants (rs317777 in OLFM5P and rs147062602 in OR51B5), and less significant associations (p < 5 × 10−6) were identified for 34 other variants in known genes with TEEs in SCD. Moreover, two 10-SNP common haplotypes were determined with contradictory effects. Further replication of these findings is needed.

2023 · Mohammad A. Alshabeeb, Deemah Alwadaani, Farjah H. Al Qahtani, Salah Abohelaika, Mohsen Alzahrani, Abdullah Al Zayed, Hussain H. Al Saeed, Hala Al Ajmi, Barrak Alsomaie, Mamoon Rashid, Ann K. Daly

The ability to effectively clear infection is fundamental to host survival. Sepsis, defined as dysregulated host response to infection, is a heterogenous clinical syndrome that does not uniformly clear intact bacterial or sterile infection (i.e., lipopolysaccharide). These findings were further associated with increased survival in DJ-1 deficient animals exposed to intact bacteria relative to DJ-1 deficient challenged with lipopolysaccharide. We analyzed bacterial and lipopolysaccharide clearance in bone marrow macrophages (BMM) cultured ex vivo from wild-type and DJ-1 deficient mice. Importantly, we demonstrated that DJ-1 deficiency in BMM promotes Rubicon-dependent increase in L3C-associated phagocytosis, non-canonical autophagy pathway used for xenophagy, during bacterial but not lipopolysaccharide infection. In contrast to DJ-1 deficient BMM challenged with lipopolysaccharide, DJ-1 deficient BMM exposed to intact bacteria showed enhanced Rubicon complexing with Beclin-1 and UVRAG and consistently facilitated the assembly of complete autophagolysosomes that were decorated with LC3 molecules. Our data shows DJ-1 impairs or/and delays bacterial clearance and late autophagolysosome formation by binding to Rubicon resulting in Rubicon degradation, decreased L3C-associated phagocytosis, and decreased bacterial clearance in vitro and in vivo - implicating Rubicon and DJ-1 as critical regulators of bacterial clearance in experimental sepsis.

2022 · Sahil Gupta, Hajera Amatullah, James N. Tsoporis, Kuiru Wei, Ana Paula Teixeira Monteiro, Amin M. Ektesabi, Amir K. Varkouhi, Chirag M. Vaswani, Amanda Formosa, Alexandre Todorovic Fabro, Sri Nagarjun Batchu, Chris D. Fjell, James A. Russell, Keith R. Walley, ANDREW ADVANI, Thomas G. Parker, John C. Marshall, Patrícia R. M. Rocco, Gregory D. Fairn, Tak W. Mak, Claúdia C. dos Santos

Case control studies of nonagenarians and centenarians provide evidence that long‐lived individuals do not differ in the rate of disease associated variants compared to population …

2017 · M Stevenson, H Bae, N Schupf, S Andersen, Q Zhang, T Perls, P Sebastiani

The study of gene regulatory network and protein-protein interaction network is believed to be fundamental to the understanding of molecular processes and functions in systems biology. In this study, the authors are interested in single nucleotide polymorphism (SNP) level and construct SNP-SNP interaction network to understand genetic characters and pathogenetic mechanisms of complex diseases. The authors employ existing methods to mine, model and evaluate a SNP sub-network from SNP-SNP interactions. In the study, the authors employ the two SNP datasets: Parkinson disease and coronary artery disease to demonstrate the procedure of construction and analysis of SNP-SNP interaction networks. Experimental results are reported to demonstrate the procedure of construction and analysis of such SNP-SNP interaction networks can recover some existing biological results and related disease genes.

2013 · Yang Liu, Xutao Li, Zhi-Ping Liu, Luonan Chen, Michael Kwok-Po Ng

An association study of four common polymorphisms in the DJ1 gene and Parkinson disease (PD) was conducted. PD probands were compared with their unaffected siblings matched by gender and closest age at study (416 vs 416) and with unrelated control subjects (691 vs 190). None of the four haplotype tagging single-nucleotide polymorphisms (SNPs) was associated with PD overall, but SNP1 (position 4,345 bp) and SNP3 (position 16,491 bp) were associated with PD in women (p = 0.03 and p = 0.002).

2004 · Demetrius M. Maraganore, Kristen Wilkes, Timothy G. Lesnick, Kari J. Strain, Mariza de Andrade, Walter A. Rocca, James H. Bower, J. Eric Ahlskog, S. Lincoln, Matthew Farrer