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PurposeA two-allele haplotype of TC (OCTN1 rs1050152 and OCTN2 -207G→C) is associated with Crohn's disease (CD). The association has been replicated in different populations, but also failed in some studies. The present study is to replicate the association of OCTN1 rs1050152 and examine another variant rs272879 with familial and sporadic inflammatory bowel disease (IBD) in a cohort from central Pennsylvania, USA.MethodsThe study samples (n = 465) included 212 inflammatory bowel disease patients (CD = 115, UC = 97), including 103 familial (CD = 55, UC = 46) and 111 sporadic (CD = 60, UC = 51) IBD, 139 non-IBD family members from a familial IBD registry, and 114 unrelated healthy controls. A total of 12 OCTN1 variants within exonic sequences were examined. Two nonsynonymous SNPs, rs1050152 (L503F) and rs272879 (L395V) were genotyped by a PCR-based RFLP/cRFLP method and statistically analyzed. These samples with an additional 141 unrelated healthy samples were also genotyped for rs1050152 using the SNPlex? Genotyping System.ResultsThe OCTN1 rs1050152 is associated with CD (OR = 1.745, 95% CI = 1.019–2.990, χ2 = 4.129, p = 0.042) and with IBD (OR = 1.68, 95% CI = 1.052–2.676, χ2 = 4.732, p = 0.030); while the variant rs272879 is not associated with IBD, CD or ulcerative colitis (UC). The distribution of the rs1050152 variant showed a high level of the T allele in male UC (OR = 2.585, 95% CI = 1.139–5.869, p = 0.023) and IBD (OR = 2.039, 95% CI = 1.024–4.059, p = 0.042) patients, and in female CD patients (OR = 2.329, 95% CI = 1.038–5.226, ρ value = 0.039).ConclusionThe present results replicated the association of the OCTN1 rs1050152 (L503F) variant with CD and IBD overall. A weak gender-specific effect of rs1050152 (L503F) on male UC and female CD was observed.  相似文献   
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A recent study in Caucasians found an association between the single nucleotide polymorphism (SNP) of SCN1A, IVS5N +5 G>A (rs3812718), and febrile seizures (FS). We examined whether this and other tagging SNPs of SCN1A were associated with an increased risk of FS in Han Chinese. A total of 728 Han Chinese patients with focal epilepsy were recruited: 97 had a history of FS (58% male, mean age 35 ± 12 years) and 631 did not (50% male, mean age 40 ± 15 years). Genotyping was performed for IVS5N +5 G>A and seven other tagging SNPs selected from the HapMap database. Genotyping was also performed in 848 ethnically matched population controls (50% male, mean age 37 ± 17 years). There was no statistically significant difference in either allele or genotype frequency of any of the SNPs studied between epilepsy patients with and without FS, and between epilepsy patients with FS and controls. The results do not suggest that SCN1A SNPs are susceptibility factors for FS in Han Chinese.  相似文献   
97.

BACKGROUND AND PURPOSE

Cannabinoid receptor activation induces prostate carcinoma cell (PCC) apoptosis, but cannabinoids other than Δ9-tetrahydrocannabinol (THC), which lack potency at cannabinoid receptors, have not been investigated. Some of these compounds antagonize transient receptor potential melastatin type-8 (TRPM8) channels, the expression of which is necessary for androgen receptor (AR)-dependent PCC survival.

EXPERIMENTAL APPROACH

We tested pure cannabinoids and extracts from Cannabis strains enriched in particular cannabinoids (BDS), on AR-positive (LNCaP and 22RV1) and -negative (DU-145 and PC-3) cells, by evaluating cell viability (MTT test), cell cycle arrest and apoptosis induction, by FACS scans, caspase 3/7 assays, DNA fragmentation and TUNEL, and size of xenograft tumours induced by LNCaP and DU-145 cells.

KEY RESULTS

Cannabidiol (CBD) significantly inhibited cell viability. Other compounds became effective in cells deprived of serum for 24 h. Several BDS were more potent than the pure compounds in the presence of serum. CBD-BDS (i.p.) potentiated the effects of bicalutamide and docetaxel against LNCaP and DU-145 xenograft tumours and, given alone, reduced LNCaP xenograft size. CBD (1–10 µM) induced apoptosis and induced markers of intrinsic apoptotic pathways (PUMA and CHOP expression and intracellular Ca2+). In LNCaP cells, the pro-apoptotic effect of CBD was only partly due to TRPM8 antagonism and was accompanied by down-regulation of AR, p53 activation and elevation of reactive oxygen species. LNCaP cells differentiated to androgen-insensitive neuroendocrine-like cells were more sensitive to CBD-induced apoptosis.

CONCLUSIONS AND IMPLICATIONS

These data support the clinical testing of CBD against prostate carcinoma.

LINKED ARTICLE

This article is commented on by Pacher et al., pp. 76–78 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2012.02121.x  相似文献   
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For major genes known to influence the risk of cancer, an important task is to determine the risks conferred by individual variants, so that one can appropriately counsel carriers of these mutations. This is a challenging task, since new mutations are continually being identified, and there is typically relatively little empirical evidence available about each individual mutation. Hierarchical modeling offers a natural strategy to leverage the collective evidence from these rare variants with sparse data. This can be accomplished when there are available higher-level covariates that characterize the variants in terms of attributes that could distinguish their association with disease. In this article, we explore the use of hierarchical modeling for this purpose using data from a large population-based study of the risks of melanoma conferred by variants in the CDKN2A gene. We employ both a pseudo-likelihood approach and a Bayesian approach using Gibbs sampling. The results indicate that relative risk estimates tend to be primarily influenced by the individual case-control frequencies when several cases and/or controls are observed with the variant under study, but that relative risk estimates for variants with very sparse data are more influenced by the higher-level covariate values, as one would expect. The analysis offers encouragement that we can draw strength from the aggregating power of hierarchical models to provide guidance to medical geneticists when they offer counseling to patients with rare or even hitherto unobserved variants. However, further research is needed to validate the application of asymptotic methods to such sparse data.  相似文献   
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