Biomedical subjects
Publications and source records attributed to H-W Deng.
A database application has been developed for phenotype data management employing the Entity-Attribute-Value (EAV) model. By applying the EAV model, this application allows users to manage arbitrary phenotypes and customize data entry forms; therefore, it is suitable for different and multi-center projects.
BACKGROUND: In both familial and sporadic atypical haemolytic-uraemic syndrome (aHUS), mutations have been reported in regulators of the alternative complement pathway including factor H (CFH), membrane cofactor protein (MCP), and the serine protease factor I (IF). A characteristic feature of both MCP and CFH associated HUS is reduced penetrance and variable inheritance; one possible explanation for this is that functional changes in complement proteins act as modifiers. OBJECTIVE: To examine single nucleotide polymorphisms in both CFH and MCP genes in two large cohorts of HUS patients (Newcastle and Paris). RESULTS: In both cohorts there was an association with HUS for both CFH and MCP alleles. CFH and MCP haplotypes were also significantly different in HUS patients compared with controls. CONCLUSIONS: This study suggests that there are naturally occurring susceptibility factors in CFH and MCP for the development of atypical HUS.
Under several assumptions such as infinite population size with unlinked loci at linkage equilibrium (LD) under mutation-selection (M-S) balance, the rate (U), and the average effects (dominance and selection coefficients h and s) of deleterious genomic mutations (DGM) can be estimated by the Deng-Lynch method in some natural populations. However, all natural populations are finite in size and many of them are not large enough to be considered as approximately infinite. In the absence of an analytical estimation approach to characterize DGM in finite populations, we test the robustness and applicability of the Deng-Lynch method in finite populations with computer simulations. The results indicate that the estimation obtained by the Deng-Lynch method in finite populations with LD is generally robust when population size is greater than 400. With constant mutation effects, in outcrossing populations, the estimates U and ĥ are unbiased or only slightly upwardly biased, and ŝ is unbiased for most cases. In highly selfing populations, U and ĥ are upwardly biased, U is no more than 1.5U and ĥ is less than 1.1 h, and ŝ is either unbiased or slightly downwardly biased. With variable mutation effects, U ranges from 0.56 to 0.72U, and s ranges from 1.4 to 1.8s. Generally speaking, with the same finite population size, the estimation in outcrossing populations is better than in highly selfing populations. Given that even the order of the magnitude of the parameters of DMG (U in particular) is controversial, our investigation here may provide a basis for using the Deng-Lynch method to characterize DGM in finite populations of size greater than 400 in the presence of LD.
OBJECTIVE: To perform a meta-analysis of genome-wide linkage scans using body mass index (BMI) to identify genetic loci predisposing to obesity. DATA: A total of 13 published genome scans on obesity have used BMI as their primary end point. Five of these 13 groups agreed to provide detailed results from their scans that were required for a meta-analysis. Collectively, these five studies included a total of 2814 individuals from 505 families. METHODS: The results of the five studies were analysed using the GSMA (genome scans meta-analysis) method. RESULTS: The analysis revealed significant evidence for linkage of the quantitative phenotype BMI to 8p (P<0.0005).
Three loci for benign familial infantile seizures (BFIS, traditionally named benign familial infantile convulsions) have been mapped to the chromosome regions of 19q12-13.1, 2q24, and 16p12-q12. We characterized the clinical features of a newly discovered Chinese family with BFIS and investigated whether it is linked to these loci. A four-generation Chinese family was investigated and nineteen family members were examined. Fourteen microsatellite markers covering the three BFIS loci on the chromosome regions of 19q12-13.1, 2q24, and 16p12-q12 were genotyped. Linkage analysis was performed. The main clinical features of our patients include onset of afebrile seizures between 3 and 10 months, normal psychomotor development, normal interictal electroencephalogram (EEG), and autosomal dominant inheritance. Magnetic resonance imaging (MRI) changes were found in the proband. Two-point LOD scores are < -2.0 at the recombination rate of 0.0 for all the markers on the 2q24 region. Multipoint LOD scores are < -3.0 for the regions of 19q12-13.1 and 16p12-q12. Linkage analysis showed no evidence that the disease gene of this BFIS family is linked to the chromosome regions previously identified as the critical regions of the disease. Another chromosome region harboring the disease gene may exist in the new Chinese family.
BACKGROUND: The vitamin D receptor (VDR) gene is important to human stature, as it mediates metabolic pathways, calcium homeostasis, and phosphate homeostasis, which influence growth. METHODS: We examined the relationship between VDR and adult height in 1873 white subjects from 406 nuclear families. Four SNPs, namely -4817A/G at intron 1, FokI C/T at exon 2 start codon, BsmI A/G at intron 8, and TaqI T/C at exon 9 in VDR were tested for linkage and association with adult height variation by the program QTDT (quantitative transmission disequilibrium test). The bT haplotype of the BsmI and TaqI loci was further tested for its association with height in unrelated samples randomly chosen from the 406 nuclear families by traditional population association methods. RESULTS: All four tested SNPs were linked to adult height. Within family associations with height were detected at BsmI and TaqI loci (p = 0.048 and 0.039, respectively). Analyses based on BsmI/TaqI haplotypes also revealed evidence for linkage (p = 0.05) and association (p = 0.001) with height. The bT haplotype was significantly associated with higher adult height (p = 0.033, within family association test). Such an association might be female specific and influenced by menstrual status. CONCLUSIONS: Our results strongly suggest that VDR may be linked to and associated with adult height variation in white populations.
BACKGROUND: The haplotype based association method offers a powerful approach to complex disease gene mapping. In this method, a few common haplotypes that account for the vast majority of chromosomes in the populations are usually examined for association with disease phenotypes. This brings us to a critical question of whether rare haplotypes play an important role in influencing disease susceptibility and thus should not be ignored in the design and execution of association studies. METHODS: To address this question we surveyed, in a large sample of 1873 white subjects, six candidate genes for osteoporosis (a common late onset bone disorder), which had 29 SNPs, an average marker density of 13 kb, and covered a total of 377 kb of the DNA sequence. RESULTS: Our empirical data demonstrated that two rare haplotypes of the parathyroid hormone (PTH)/PTH related peptide receptor type 1 and vitamin D receptor genes (PTHR1 and VDR) with frequencies of 1.1% and 2.9%, respectively, had significant effects on osteoporosis phenotypes (p = 4.2 x 10(-6) and p = 1.6 x 10(-4), respectively). Large phenotypic differences (4.0 approximately 5.0%) were observed between carriers of these rare haplotypes and non-carriers. Carriers of the two rare haplotypes showed quantitatively continuous variation in the population and were derived from a wide spectrum rather than from one extreme tail of the population phenotype distribution. CONCLUSIONS: These findings indicate that rare haplotypes/variants are important for disease susceptibility and cannot be ignored in genetics studies of complex diseases. The study has profound implications for association studies and applications of the HapMap project.
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Low bone mineral density (BMD) is a major risk factor for osteoporotic fracture. To identify genomic regions harboring quantitative trait loci (QTLs) contributing to BMD variation, we performed a two-stage genome screen. The first stage involved genotyping of a sample of 53 pedigrees with 630 individuals using 400 microsatellite markers spaced at approximately 10-cM intervals throughout the genome. Ten genomic regions with multi- and/or two-point LOD scores greater than 1.5 were observed. In the present second-stage study, 60 microsatellite markers, with a mean spacing of about 5 cM, were genotyped in these regions in an expanded sample of 79 pedigrees that contained 1816 subjects. Each pedigree was ascertained through a proband with extreme BMD at the hip or spine. BMD at the spine (L1-4), hip (the femoral neck, trochanter, and intertrochanteric region), and wrist (the ultradistal region) was measured by dual-energy X-ray absorptiometry (DXA) and was adjusted for age, sex, height, and weight. Two-point and multipoint linkage analyses were performed for each BMD site using statistical genetic methods that are implemented in the computer package SOLAR. Several regions (7q11, 10q26, 12q13, and 12q24) achieved LOD scores in excess of 1 in the second-stage followup study. The current results replicate some of our previous linkage findings and also highlight some of the difficulties facing microsatellite linkage mapping for complex human diseases.
BACKGROUND: Osteoporosis, mainly characterised by low bone mineral density (BMD), is a serious public health problem. The collagen type I alpha 1 (COL1A1) gene is a prominent candidate gene for osteoporosis. Here, we examined whether genetic variants at the COL1A1 gene can influence BMD variation. METHODS: BMD was measured at nine skeletal sites in 313 Caucasian males and 308 Caucasian females. We screened four single nucleotide polymorphisms (SNPs) at the COL1A1 gene: PCOL2 (-1997 G/T) in the promoter, Sp1 (1546 G/T) in the intron 1, Gly19Cys (3911 G/A) in exon 8, and Ala897Thr (13 773 G/A) in exon 45. Univariate and multivariate association approaches were used in the analyses. RESULTS: In multivariate analyses, we found a strong association between the PCOL2 SNP and BMD (p = 0.007 to 0.024) and a suggestive association between the Sp1 SNP and BMD (p = 0.023 to 0.048) in elderly Caucasian females. Interestingly, the interaction of these two SNPs was highly significantly associated with BMD variation (p = 0.001 to 0.003). The haplotype GG at the two SNPs had, on average, 2.7% higher BMD than non-carriers (p = 0.006 to 0.026). CONCLUSIONS: Our data suggested that the common genetic variants at the PCOL2 and Sp1 sites, and importantly, their interactive effects, may contribute to BMD variation in elderly Caucasian females. Further studies are necessary to delineate the mechanisms underlying the effects of these common variants on BMD variation and to test their clinical relevance for general populations. In addition, our study highlighted the importance of multivariate analyses when multiple correlated phenotypes are under study.
BACKGROUND: Osteoporosis is a major public health problem, mainly quantified by low bone mineral density (BMD). The majority of BMD variation is determined by genetic effects. A pilot whole genome linkage scan (WGS) was previously reported in 53 white pedigrees with 630 subjects. Several genomic regions were suggested to be linked to BMD variation. OBJECTIVE: To substantiate these previous findings and detect new genomic regions. METHODS: A WGS was conducted on an extended sample where the size was almost tripled (1816 subjects from 79 pedigrees). All the subjects were genotyped with 451 microsatellite markers spaced approximately 8.1 cM apart across the human genome. Two point and multipoint linkage analyses were carried out using the variance component method. RESULTS: The strongest linkage signal was obtained on Xq27 with two point LOD scores of 4.30 for wrist BMD, and 2.57 for hip BMD, respectively. Another important region was 11q23, which achieved a maximum LOD score of 3.13 for spine BMD in multipoint analyses, confirming the results on this region in two earlier independent studies. Suggestive linkage evidence was also found on 7p14 and 20p12. CONCLUSIONS: Together with the findings from other studies, the current study has further delineated the genetic basis of bone mass and highlights the importance of increasing sample size to confirm linkage findings and to identify new regions of linkage.
Osteoporosis is one of the most common bone-related disorders in the elderly. It is a complex disease, and largely determined genetically. Traditional gene expression studies have shown that osteoporosis has complex regulating mechanisms which are controlled by multiple inherent factors, such as hormones, cytokines, various receptors, etc. The complex nature of osteoporosis, and the large number of genes involved in its onset and development, suggest the use of the state of the art microarray technique as a powerful tool to unravel mechanisms underlying etiology of osteoporosis.
Sprague-Dawley rats were pretreated with whole body hyperthermia (rectal 42 degrees C) for 15 min, 24 h before the experiments, and then the left main coronary artery of rat hearts was subjected to a 60 min occlusion followed by 3 h reperfusion. Myocardium injury degree was evaluated by measurement of infarct size and serum creatine kinase (CK) activity. Plasma concentrations of calcitonin gene-related peptide (CGRP), and the expression of alpha- and beta-CGRP mRNA in dorsal root ganglia were determined by radioimmunoassay and semi-quantitative reverse-transcription polymerase chain reaction, respectively. Hyperthermia treatment significantly reduced infarct size and CK release concomitantly with a dramatic increase in plasma concentrations of CGRP and the expression of alpha-CGRP mRNA, but not beta-CGRP mRNA, which was completely abolished by pretreatment with capsazepine (38 mg/kg, s.c.), a competitive vanilloid receptor 1 antagonist. These results suggests that vanilloid receptor 1 on capsaicin-sensitive sensory nerves plays an important role in the modulation of the delayed cardioprotection induced by heat stress in rats.
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Bone mineral density (BMD) is an important risk factor for osteoporosis and has strong genetic determination. While average BMD differs among major ethnic groups, several important candidate genes have been shown to underlie BMD variation within populations of the same ethnicity. To investigate whether important candidate genes may contribute to ethnic differences in BMD, we studied the degree of genetic differentiation among several important candidate genes between two major ethnic groups: Caucasians and Chinese. The genetic variability of these two populations (1131 randomly selected individuals) was studied at six restriction sites exhibiting polymorphisms of five important candidate genes for BMD: the BsaHI polymorphism of the calcium-sensing receptor (CASR) gene, the SacI polymorphism of the alpha2HS-glycoprotein (AHSG) gene, the PvuII and XbaI polymorphisms of the estrogen receptor alpha (ESR1) gene, the ApaI polymorphism of the vitamin D receptor (VDR) gene, and the BstBI polymorphism of the parathyroid hormone (PTH) gene. The two ethnic groups showed significant allelic and genotypic differentiation of all the polymorphisms studied. The mean FST was 0.103, which significantly differed from zero (P < 0.01). The Chinese population had lower mean heterozygosity (0.331) than the Caucasian one (0.444); the CASR-BsaHI and PTH-BstBI polymorphisms contributed most significantly to this difference. Analysis of the intra- and inter-population variability suggests that various types of natural selection may affect the observed patterns of variation at some loci. If some of the candidate genes we studied indeed underlie variation in BMD, their population differentiation revealed here between ethnic groups may contribute to understanding ethnic difference in BMD.
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