Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, ...Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) ($P<10^{-7}$). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value=4.7× 10-24 and in 19 (20%) of 93 of healthy subjects 393.51 (23.23-6665.26); corrected P value=8.1× 10-18. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.
We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese ...population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 (SP8) and ST8 α-N-acetyl- neuraminide α-2,8-sialyltransferase (ST8SIA2) are associated with Bipolar I, with P-values of 4.87 × 10(-7) (rs2709736) and 6.05 × 10(-6) (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene (KCTD12) (rs2073831, P=9.74 × 10(-6)) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P=5.15 × 10(-5)), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study (P=6.55 × 10(-5) and P=1.48 × 10(-5), respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.
The gene encoding type II collagen,
COL2A1,
was found to be mutated in affected members of three families with an inherited form of avascular osteonecrosis of the femoral head. This finding will spur ...studies of this gene in persons with the idiopathic form of the disease.
The gene encoding type II collagen,
COL2A1,
was found to be mutated in affected members of three families with an inherited form of avascular osteonecrosis of the femoral head.
It has been estimated that 300,000 to 600,000 people in the United States have avascular necrosis of the femoral head (ANFH).
1
Approximately 15,000 new cases of this common and disabling disorder, also called ischemic necrosis of the femoral head or osteonecrosis of the femoral head, are reported annually.
2
The age at the onset of this disease is earlier than that for osteoarthritis; the diagnosis is typically made when patients are between the ages of 30 and 60 years. The clinical manifestations, such as pain on exertion, a limping gait, and a discrepancy in leg length, cause considerable disability. Moreover, nearly . . .
Copy number variation (CNV) is a form of DNA sequence variation in the human genome. CNVs can affect expression of nearby and distant genes, and some of them might cause certain phenotypic ...differences. CNVs vary slightly in location and frequency among different populations. Because currently-available CNV information from Asian population was limited to fewer small-scale studies with only dozens of subjects, a high-resolution CNV survey was conducted using a large number of Han Chinese in this study. The Illumina HumanMap550K single-nucleotide polymorphism array was used to identify CNVs from 813 unrelated Han Chinese residing in Taiwan. A total of 365 CNV regions were identified in this population, and the average size of the CNV regions was 235 kb (covering a total of 2.86% of the human genome), and 67 (18.4%) were newly-discovered CNV regions. Two hundred and seventy-nine CNV regions (76%) were verified from 304 randomly-selected samples by Affymetrix 500K GeneChip and qPCR experiments. These regions contain 1029 genes, some of which are associated with diseases. Consistent with previous studies, most CNVs were rare structural variations in the human genome, and only 64 regions (17.5%) had a CNV allele frequency greater than 1%. Our discovery of 67 new CNV regions indicates that previous CNV coverage of the human genome is incomplete and there is diversity among different ethnic populations. The comprehensive knowledge of CNVs in the human genome is very important and useful in further genetic studies.
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.
Calcineurin is a calcium/calmodulin-dependent protein phosphatase composed of two subunits, a regulatory subunit of calcineurin B (CNB) and a catalytic subunit of calcineurin A (CNA). PPP3CC is the ...gamma isoform of CNA located at the chromosome 8p21.3 region. To evaluate the association between PPP3CC and schizophrenia in the Taiwanese population, 10 single nucleotide polymorphism (SNP) markers across the gene were genotyped by the method of MALDI-TOF in 218 schizophrenia families with at least two affected siblings. One SNP (rs2272080) located around the exon 1 untranslated region was nominally associated with schizophrenia (P=0.024) and significantly associated with the expression of PPP3CC in lymphoblast cell line; the TT and TG genotype had significantly higher relative expression levels than the GG genotype (P=0.0012 and 0.015, respectively). In further endophenotype stratification, the single locus of rs2272080 and the haplotypes of both two-SNP haplotype (rs7833266-rs2272080) and seven-SNP haplotype (rs2461491-rs2469758-rs2461489-rs2469770-rs2449340-rs1482337-rs2252471) showed significant associations with the subgroup of schizophrenia with deficits of the sustained attention as tested by the continuous performance test (CPT, P<0.05) and the executive functioning as tested by the Wisconsin Card Sorting Test (WCST, P<0.05). The results suggest that PPP3CC gene may be a true susceptibility gene for schizophrenia.
Heme oxygenase-1 (HO-1) is a rate-limiting enzyme in heme degradation, producing carbon monoxide (CO), which carries potent antiproliferative and anti-inflammatory effects in the vascular walls. ...Transcription of the HO-1 gene is regulated by the length polymorphism of dinucleotide guanosine thymine repeat (GT)n in the promoter region, which was measured in this study to determine its association with arteriovenous fistula (AVF) failure in Chinese hemodialysis (HD) patients in Taiwan. L allele means (GT)n≥30 and S allele means (GT)n<30. Therefore, there are two L alleles for L/L genotype, one L and one S allele for L/S genotype, and two S alleles for S/S genotype. Among the 603 HD patients who were enrolled in this study, 178 patients had history of AVF failure, while 425 patients did not. Significant associations were found between AVF failure and the following factors (hazard ratio): longer HD duration (1.004 month), lower pump flow (0.993 ml/min), higher dynamic venous pressure (1.010 mmHg), location of AVF on the right side (1.587 vs left side) and upper arm (2.242 vs forearm), and L/L and L/S genotypes of HO-1 (2.040 vs S/S genotype). The proportion of AVF failure increased from 20.3% in S/S genotype and 31.0% in L/S genotype to 35.4% in L/L genotype (P=0.011). Relative incidences were 1/87.6 (1 episode per 87.6 patient-months), 1/129, and 1/224.9 for HD patients with L/L, L/S, and S/S genotypes, respectively (P<0.002). The unassisted patency of AVF at 5 years decreased significantly from 83.8% (124/148) to 75.1% (223/297) and 69% (109/158) in S/S, L/S, and L/L genotypes, respectively (P<0.0001). In comparison with HD patients with S/S genotype, those with L/L genotype had a higher prevalence of coronary artery disease (29.1 vs 14.2%; P=0.005). A longer length polymorphism with (GT)n ≥30 in the HO-1 gene was associated with a higher frequency of access failure and a poorer patency of AVF in HD patients. The longer GT repeat in the HO-1 promoter might inhibit gene transcription, and consequently offset the CO-mediated protective effect against vascular injury.
Background. A high initial or peak severe acute respiratory syndrome (SARS)—associated coronavirus (SARS-CoV) load in nasopharyngeal specimens was shown to be associated with a high mortality rate. ...Because all infected individuals were devoid of preeexisting protective immunity against SARS-CoV, the biological basis for the variable virus burdens in different patients remains elusive. Methods. The nationwide SARS database in Taiwan was analyzed, and genotyping of 281 single-nucleotide polymorphisms (SNPs) of 65 genes was performed for 94 patients with SARS, to identify SNPs for which distribution between patients with or without detectable nasopharyngeal shedding of SARS-CoV was biased. Results. Titers of SARS-CoV shed in nasopharyngeal specimens varied widely, ranging from nondetectable to 108 SARS-CoV RNA copies/mL, and they were correlated positively with a high mortality rate (P < .0001, by trend test) and with early death (i.e., death occurring within 2 weeks of the onset of illness) (P = .0015, by trend test). Virus shedding was found to be higher among male patients (P = .0014, by multivariate logistic regression) and among older patients (P = .015, by multivariate logistic regression). Detectable nasopharyngeal shedding of SARS-CoV was associated with polymorphic alleles of interleukins 18 (P = .014) and 1A (P = .031) and a member of NFκB complex (reticuloendotheliosis viral oncogene homolog B RelB) (P = .034), all of which are proinflammatory in nature, as well as the procoagulation molecule fibrinogen-like protein 2 (P = .008). Conclusion. The SARS-CoV load is a determinant of clinical outcomes of SARS, and it is associated with polymorphisms of genes involved in innate immunity, which might be regulated in an age- and sex-dependent manner. The findings of the present study provided leads to genes involved in the host response to SARS-CoV infection; if substantiated with functional studies, these findings may be applicable to other newly emerged respiratory viruses (e.g., the influenza pandemic strain).
: Background: Nonselective opioid antagonists reduce alcohol consumption under various experimental situations, and several association studies have examined possible roles of opioid receptor mu ...(OPRM), delta (OPRD), and kappa (OPRK) genes in the development of alcohol dependence.
Methods: We examined 20 single nucleotide polymorphisms (SNPs) across the OPRM, OPRD, and OPRK genes in 158 alcohol‐dependent subjects and 149 controls. Differences in allele frequency and genotype distribution between case subjects and controls, as well as the deviation from Hardy‐Weinberg equilibrium, were examined using Fisher's exact tests.
Results: No significant difference in either allele or genotype frequency was found between case subjects and controls for each of the SNPs.
Conclusions: Our findings do not support a possible role of the opioid receptor genes for the proclivity to alcohol dependence in the Taiwanese Han.
Background: A large number of potential obesity loci have been reported. At least 18 genes have been replicated in a minimum of 5 studies on obesity-related phenotypes. Fourteen additional genes have ...been associated with obesity in Asians. Objectives: Our objectives were to examine how many common variants of these candidate genes are associated with severe obesity in Han Chinese and how they are combined to exert their effects. Design: In total, 304 severely obese patients body mass index (BMI; in kg/m super(2)) .39 and 304 control subjects (BMI , 24) participated in a 2-staged association study. Subsequently, 220 additional severely obese patients (BM . 35) and 338 controls (BMI , 24) were recruited to replicate the results. All of the controls were age-, sex-, education- and residence-matched. Finally, a pooled analysis was carried out based on all 514 cases and 606 controls with complete information. Results: The first-stage association analysis in 94 cases and 94 controls found 18 potentially associated single nucleotide polymorphisms (SNPs) (P = 0.01-0.1). The significance of 3 novel common SNPs, 1 on ESR1 and 2 on PPARg, were confirmed in the second stage and replicated further with odds ratios ranging from 1.89 to 2.24. The combined effect of these 3 genes was stronger (odds ratio: 5.27; 95% CI: 2.25, 12.32) than that from any individual gene. Conclusions: Severe obesity in Han Chinese was associated with 3 novel common SNPs for ESR1 and PPAR7. These 2 genes collectively result in a >5-fold risk of severe obesity. This information may contribute to the assessment of risk of severe obesity.
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