The rs1076560 polymorphism of DRD2 (encoding dopamine receptor D2) is associated with alternative splicing and cognitive functioning; however, a mechanistic relationship to schizophrenia has not been ...shown. Here, we demonstrate that rs1076560(T) imparts a small but reliable risk for schizophrenia in a sample of 616 affected families and five independent replication samples totaling 4017 affected and 4704 unaffected individuals (odds ratio=1.1; P=0.004). rs1076560(T) was associated with impaired verbal fluency and comprehension in schizophrenia but improved performance among healthy comparison subjects. rs1076560(T) also associated with lower D2 short isoform expression in postmortem brain. rs1076560(T) disrupted a binding site for the splicing factor ZRANB2, diminished binding affinity between DRD2 pre-mRNA and ZRANB2 and abolished the ability of ZRANB2 to modulate short:long isoform-expression ratios of DRD2 minigenes in cell culture. Collectively, this work implicates rs1076560(T) as one possible risk factor for schizophrenia in the Han Chinese population, and suggests molecular mechanisms by which it may exert such influence.
A positive linkage of schizophrenia with chromosome 1q loci has been reported in Caucasian patients. This study was designed to evaluate the linkage of schizophrenia with markers of the 1q22-44 ...region in 52 Taiwanese families with at least two affected siblings. In the region 1q22-31 (17.8 cM), marker D1S1679 had a maximal proportion (0.57, P=0.03) of shared identity by descent (IBD) under a narrow phenotype (DSM-IV schizophrenia only). In the region 1q42-44 (26.8 cM), the marker D1S251, located near the breakpoint of a balanced translocation t (1;11) (q42.1;q14.3) segregated with schizophrenia, and also near the neurodevelopment-related 'Disrupted in Schizophrenia 1' gene, had a maximum NPL score of 1.73 (P=0.03) under the narrow phenotype model and 2.18 (P=0.01) under the broad phenotype model comprised of schizophrenia, schizoaffective disorder, and other nonaffective psychotic disorders as defined by DSM-IV criteria. The marker D1S2836 also had a maximal proportion (0.57, P=0.05) of shared IBD under the broad model. These findings may provide guidance for positional cloning studies on candidate genes in the 1q22-31 and 1q41-44 regions.
The marker D1S251 of chromosome 1q42.1 showed significant association with schizophrenia in a Taiwanese sample. We used single nucleotide polymorphism (SNP) fine mapping to search for the ...vulnerability genes of schizophrenia.
We selected 120 SNPs covering 1 Mb around D1S251 from the public database. These selected SNPs were initially validated if allele frequency was >10%. Forty-seven validated SNPs were genotyped in 102 families with at least 2 siblings affected with schizophrenia.
Two SNP blocks showed significant association with schizophrenia. Block 1 (five-SNP), located between intron 2 and intron 13 of the glyceronephosphate O-acyltransferase (
GNPAT) gene, showed the most significant associations using single-locus TDT (
z = −2.07,
p = .038,
df = 1) and haplotype association analyses (
z = −1.99,
p = .046,
df = 1). Block 2 (two-SNP), located between intron 4 and intron 5 of the disrupted-in-schizophrenia 1 (
DISC1) gene, also showed the most significant results in both the single-locus (
z
=
−3.22,
p = .0013,
df = 1) and haplotype association analyses (
z = 3.35,
p = .0008,
df = 1). The association of the DISC1 gene with schizophrenia was mainly in the patient group with sustained attention deficits as assessed by the Continuous Performance Test.
Chromosome 1q42.1 harbors
GNPAT and
DISC1 as candidate genes for schizophrenia, and
DISC1 is associated with sustained attention deficits.
Graves' disease (GD) is a common organ-specific autoimmune disorder inherited as a complex trait. Although there has not been consensus regarding the genuine susceptibility alleles, many ...population-based genetic studies showed association of the cytotoxic T-lymphocyte antigen-4 (CTLA4) gene with GD. In contrast, evidence utilizing family-based studies came only from the Caucasian population. Here we performed a family-based association study in the Han population in Taiwan. We enrolled 374 affected individuals and 347 unaffected family members in 151 GD pedigrees. Four single-nucleotide polymorphisms (SNP) and a short tandem repeat polymorphism (STRP) at CTLA4 were genotyped. Association of GD with a novel risk SNP at the 5' upstream region, CTLA4_-1722_T/C (rs733618), was demonstrated (P=0.0096). We also replicated the association signal of a coding SNP, CTLA4_+49_G/A (rs231775, P=0.0219). A common haplotype composed of CTLA4_-1722_T/C and CTLA4_(AT)n (an STRP marker: UniSTS:48500) showed protective effect (P=0.0004). Our results of family-based association study, taken together with those from the Caucasian population, provide evidence that CTLA4 confers susceptibility to GD across different ethnic backgrounds.
Evidence for association with schizophrenia has been reported for NOTCH4, although results have been inconsistent. Previous studies have focused on polymorphisms in the 5′ promoter region and first ...exon of NOTCH4. Our aim was to test the association of the entire genomic region of NOTCH4 in 218 families with at least two siblings affected by schizophrenia in Taiwan. We genotyped seven single nucleotide polymorphisms (SNPs) of this gene, with average intermarker distances of 5.3 kb. Intermarker linkage disequilibrium (LD) was calculated using gold software, and single‐locus and haplotype association analyses were performed using transmit software. We found that the T allele of SNP rs2071285 (P= 0.035) and the G allele of SNP rs204993 (P= 0.0097) were significantly preferentially transmitted to the affected individuals in the single‐locus association analysis. The two SNPs were in high LD (D′ > 0.8). Trend for overtransmission was shown for the T‐G haplotype of the two SNPs to affected individuals (P= 0.053), with the A‐A haplotype significantly undertransmitted (P= 0.034). The associated region distributed across the distal portion of the NOTCH4 gene and overlapped with the genomic region of the G‐protein signaling modulator 3 and pre‐B‐cell leukemia transcription factor 2. In summary, we found modest association evidence between schizophrenia and the distal genomic region of NOTCH4 in this Taiwanese family sample. Further replication for association with the distal genomic region of NOTCH4 is warranted.
Bovine Tuberculosis in Michigan Wildlife and Livestock SCHMITT, STEPHEN M.; O'BRIEN, DANIEL J.; BRUNING-FANN, COLLEEN S. ...
Annals of the New York Academy of Sciences,
October 2002, Letnik:
969, Številka:
1
Journal Article
Recenzirano
Odprti dostop
: Since 1994, the state of Michigan has recognized a problem with bovine tuberculosis (TB), caused by Mycobacterium bovis, in wild white‐tailed deer from a 12‐county area in northeastern Lower ...Michigan. A total of 65,000 free‐ranging deer have been tested, and 340 have been found to be positive for M. bovis. The disease has been found in other wildlife species, and, in 1998, in domestic cattle, where to date 13 beef cattle and 2 dairy cattle herds have been diagnosed with bovine TB. Unfortunately, the situation is unique in that there have never been reports of self‐sustaining bovine TB in a wild, free‐ranging cervid population in North America. Scientists, biologists, epidemiologists, and veterinarians who have studied this situation have concluded that the most logical theory is that high deer densities and the focal concentration caused by baiting (the practice of hunting deer over feed) and feeding are the factors most likely responsible for the establishment of self‐sustaining TB in free‐ranging Michigan deer. Baiting and feeding have been banned since 1998 in counties where the disease has been found. In addition, the deer herd has been reduced by 50% in the endemic area with the use of unlimited antlerless permits. The measures of apparent TB prevalence have been decreased by half since 1997, providing hopeful preliminary evidence that eradication strategies are succeeding.
OBJECTIVES: Use of PCV13 is recommended to the elderly and the adults with immunocompromising conditions. Additionally, use of PCV13 to immunocompromised adults who also receiving a single dose of ...23-Valent Pneumococcal Polysaccharide Vaccine (PPV23) before is also recommended (PPV23-PCV13 sequence vaccination). This study is aimed to predict the potential cost-effectiveness of PPV23-PCV13 sequence vaccination to the elderly and immunocompromised adults in Taiwan. METHODS: Cost-effectiveness analysis from societal perspective was performed using a micro-simulation model. Cost-effectiveness of PPV23-PCV13 sequence vaccination versus PPV23 alone vaccination to a population of 50,000 was predicted on the time horizon of 70 years. Parameters in the model included demographic, epidemiological data, direct medical costs, indirect costs and vaccine efficacy data were derived from published literatures and Taiwan's National Health Insurance Database. All Results of cost-effectiveness analysis were presented by the incremental cost-effectiveness ratio (ICER) to illustrate the incremental cost (in New Taiwan Dollars, NTD) for one additional life-year (LY) gained. Sensitivity analysis was performed to evaluate the robustness of the results of micro-simulation model. RESULTS: Compared with PPV23 alone vaccination, PPV23-PCV13 sequence vaccination definitely increased vaccination cost but it would reduce total costs including vaccination costs, direct medical costs and indirect costs. Overall, PPV23-PCV13 sequence vaccination was more cost-saving than PPV23 alone vaccination. And, PPV23-PCV13 sequence vaccination would save an additional 0.0065 discounted LYs. The ICER for PPV23-PCV13 sequence vaccination for the elderly and immunocompromised adults was estimated about -284,000 NTDs per LY. CONCLUSIONS: PPV23-PCV13 sequence vaccination could achieve potential health economic and clinical benefits. For the elderly and immunocompromised adults in Taiwan, PPV23-PCV13 sequence vaccination was considered as the dominant vaccination strategy compared with PPV23 alone vaccination.
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