Potential association of VAMP5 polymorphisms with total colonic aganglionosis in Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital bowel disease caused by the absence of nerve cells in portions of the intestine. Our recent genome-wide association study has identified a variant (rs1254900) of vesicle-associated membrane protein 5 (VAMP5) as a potential risk locus for total colonic aganglionosis (TCA) in HSCR. In addition, VAMP5 is a member of the VAMP/synaptobrevin protein complex, which participates in nerve signal transduction by regulating the vesicular fusion of the neurotransmitter in synaptic transmission. METHODS: A total of 11 single nucleotide polymorphisms (SNPs), including those in the functionally important coding region, were selected on the basis of linkage disequilibrium and genotyped in 187 HSCR patients and 283 unaffected controls by using a TaqMan assay. Logistic analysis was conducted to investigate the possible association between VAMP5 SNPs and the risk of HSCR. KEY RESULTS: Genetic variants of VAMP5 showed increased association signals in the TCA subgroup of HSCR patients (minimum p = 9.69 × 10(-5) , OR = 3.93 at rs10206961) compared to other subgroups, even after Bonferroni correction (pcorr = 0.002). In haplotype analysis, three haplotypes (BL1_ht1, BL2_ht1, and BL2_ht2) were associated with the risk of TCA (minimum pcorr = 0.005). In additional combined analysis after imputation based on our previous GWAS, five SNPs still retained significant associations with the TCA subtype (minimum pcorr = 0.006 at rs10206961). CONCLUSIONS & INFERENCES: Considering that differential genetic effects on the development of the enteric nervous system, our results suggest that VAMP5 may be associated with the TCA of HSCR. However, further replications and functional evaluations are required.

Genetic variants of IL-11 associated with risk of Hirschsprung disease.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital and heterogeneous disorder characterized by the absence of enteric ganglia during enteric nervous system (ENS) development. Our recent genome-wide association study has identified a variant (rs6509940) of interleukin-11 (IL-11) as a potential susceptible locus for HSCR. As interleukins play important roles in the ENS, we further studied associations with HSCR of nine common single nucleotide polymorphisms (SNPs) on IL-11. METHODS: Biopsy specimens or surgical materials from all patients that were tested for histological examination based on the absence of the enteric ganglia were collected. A total of nine SNPs on IL-11 were genotyped in 187 HSCR patients and 283 unaffected controls using TaqMan genotyping assay. KEY RESULTS: Combined analysis revealed that several SNPs (minimum p = 1.57 × 10(-7) ) showed statistically significant associations with HSCR, even after Bonferroni correction (pcorr  = 1.73 × 10(-6) for the SNP). Moreover, the most common haplotype was strongly associated with HSCR (pcorr  = 2.20 × 10(-6) ). In further analysis among three HSCR subtypes (short segment, S-HSCR; long segment, L-HSCR; total colonic aganglionosis, TCA) based on the extent of aganglionic segment, the result showed a different association pattern depending on the subtypes (minimum pcorr  = 6.12 × 10(-5) for rs6509940 in S-HSCR; but no significant SNP in L-HSCR and TCA). CONCLUSIONS & INFERENCES: Although further replication in a larger cohort and functional evaluations are needed, our findings suggest that genetic variations of IL-11 may be associated with the risk of HSCR and/or the mechanisms related to ENS development.

Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway.

Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B(4) receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappaB stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis.

Depression and the vision-related quality of life in patients with retinitis pigmentosa.

AIMS: To assess the relationship between depression and the vision-related quality of life in patients with retinitis pigmentosa (RP). METHODS: The study included 144 patients diagnosed as having RP. The mean age of the patients was 38.5 (SD 13.3) years, and 42% of the subjects were women. They answered the National Eye Institute Visual Function Questionnaire (NEI-VFQ) to assess the vision-related quality of life and the Beck Depression Inventory (BDI) to assess depressive symptoms. Patients were classified into groups with and without depression according to the BDI score. The NEI-VFQ composite and subscale scores were compared between groups. The correlations between the BDI and the NEI-VFQ, weighted visual acuity (WVA) and functional vision score (FVS) were investigated. RESULTS: The depressed group had significantly less subjective visual function compared with the non-depressed group. A negative correlation was observed between the BDI and the NEI-VFQ scores, while no correlation was found between the BDI score and WVA or FVS. CONCLUSION: The RP patients with depression had poorer vision-related functions compared with those patients without depression, which cannot be explained by the visual acuity. Interventions to diagnose and treat depression are necessary to enhance the overall quality of life in RP patients.

Clinical characteristics of cyclodeviation.

PURPOSE: To retrospectively evaluate the incidence of cyclodeviation among patients with diplopia and analyse the causative diseases and clinical manifestations of cyclodeviation. METHODS: The medical records of 266 consecutive patients of 15 years of age or older presenting with diplopia, who had undergone the Lancaster red-green test (LRGT) from January 2001 to December 2002, were retrospectively reviewed. The presence of cyclodeviation on LRGT, predisposing conditions, causative diseases, and clinical manifestations of cyclotropia were analysed. Cyclodeviation on the LRGT were compared with those from the Maddox double-rod test (MDRT) and fundus photography. RESULTS: A total of 63 (24%) out of 266 patients exhibited cyclodeviation on LRGT. Eight out of 63 patients with cyclodeviation on the LRGT complained of torsional diplopia. Superior oblique palsy (SOP) was the most common causative disease (42 patients), followed by skew deviation (six) and thyroid orbitopathy (three). Excyclodeviation was found in 57 patients and incyclodeviation in four patients on the LRGT. The spontaneous recovery rate was 83% in patients of vascular origin and 17% of traumatic origin. Cyclodeviation with the MDRT and fundus photography showed good correlation with those obtained from the LRGT. There was no association of the amount of cyclotropia with the presence of torsional diplopia as well as with its recovery. CONCLUSION: In spite of the rare complaint of torsional diplopia, 24% of the patients with diplopia showed cyclodeviation on the LRGT. SOP was the most common causative disease. Most of the patients with cyclodeviation of a vascular origin showed spontaneous improvement.