Biomedical subjects

H W Deng

Publications and source records attributed to H W Deng.

At least 19 recordsLinked to original sources

PubMed2004

Complex segregation analyses of bone mineral density in Chinese.

China has the largest population in the world; approximately 7% of the total population suffers from primary osteoporosis. Osteoporosis is mainly characterized by low bone mineral density (BMD). In the present study, familial correlation and segregation analyses for spine and hip BMDs have been undertaken for the first time in a Chinese sample composed of 401 nuclear families with a total of 1260 individuals. The results indicate a major gene of additive inheritance for hip BMD, whereas there is no evidence of a major gene influencing spine BMD. Significant familial residual effects are found for both traits, and heritability estimates (+/-SE) for spine and hip BMDs are 0.807(0.099) and 0.897(0.101), respectively. Sex and age differences in genotype-specific average BMD are also observed. This study provides the first evidence quantifying the high degree of genetic determination of BMD variation in the Chinese.

Age Factors↗

PubMed2004

Gene mapping and identification for osteoporosis.

Osteoporosis is a disease characterized by fragile bones and high susceptibility to low trauma fractures. It is a serious health problem, especially in elderly women. Bone mineral density (BMD) has been employed most commonly as the index for defining and studying osteoporosis. In this presentation, we use examples of our studies in both Caucasians and Chinese to illustrate the approaches used and some main results obtained on 1) characterizing the degree and the inheritance mode of genetic determination of a complex trait such as BMD; 2) identifying and mapping genes for osteoporosis. The purpose of the presentation is to introduce to the medical researchers how and what modern genetics can do to disentangle the mist of an array of genetics factors, the major determinants, for BMD.

Asian People↗

PubMed2003

Association of estrogen receptor alpha and vitamin D receptor gene polymorphisms with bone mineral density in Chinese males.

Osteoporosis is a common health problem not only in females but also in males, however, studies of osteoporosis in males are relatively rare compared to those in females. This is especially true in genetics studies. We evaluated the effects of PvuII and XbaI polymorphisms in the estrogen receptor alpha (ER-alpha) gene and ApaI polymorphism in the vitamin D receptor (VDR) gene on BMD variation in a random sample of 352 unrelated males from 401 Chinese nuclear families. BMD was measured at the lumbar spine (L1-L4) and hip (femoral neck, trochanter, intertrochanteric region). Raw BMD values were adjusted by age, age(2), height, and weight as covariates. We found no significant results for the 3 individual markers on BMD variation, however, ER-alpha haplotype analyses yielded some interesting results. Carriers of haplotype pX had a 4.98% lower BMD at the trochanter (P = 0.02) and 3.55% lower BMD at the lumbar spine (P = 0.09) than non-carriers. PX subjects had a 3.42% higher BMD at the trochanter and 3.26% higher BMD at the lumbar spine than others (P = 0.07 and P = 0.10, respectively). Such results were highly comparable with the significant or nearly significant interactions between ER-PvuII and ER-XbaI on BMD values at the trochanter (P = 0.03) and spine (P = 0.11). No significant results were observed for the interactions between ER-PvuII and VDR-ApaI, between ER-XbaI and VDR-ApaI, and between any of ER-alpha haplotypes and VDR-ApaI locus. Our results suggest that the ER-alpha haplotypes, not individual markers, may be associated with BMD variation at some skeletal sites in our Chinese male samples.

Absorptiometry, Photon↗

PubMed2003

No evidence for linkage and/or association of human alpha2-HS glycoprotein gene with bone mineral density variation in Chinese nuclear families.

Osteoporosis is an important health problem in the world. Alpha2-HS glycoprotein (AHSG) is involved in bone formation and metabolism and has been considered as an important candidate gene for osteoporosis. In this study, we simultaneously tested linkage and/or association of the AHSG gene with the variation of bone mineral density (BMD), an important risk factor for osteoporosis. A sample of 1,260 subjects from 401 Chinese nuclear families (including both parents and their daughters) were studied. The daughters' ages ranged from 20 to 45 years. All the subjects were genotyped by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) at polymorphic Sac I site inside the exon 7 of the AHSG gene. This polymorphism involves a nucleotide substitution of C to G at the middle nucleotide of the codon at amino acid position 238, resulting in the replacement of threonine (ACC) with serine (AGC). BMD was measured at the lumbar spine and hip region by dual-energy X-ray absorptiometry (DXA). Using the QTDT (quantitative trait transmission disequilibrium test), we found no significant results for association or linkage between the AHSG gene and BMD variation at the spine or hip. Our data provided no evidence to support the AHSG gene as a quantitative trait locus (QTL) for the BMD variation in a Chinese population.

Absorptiometry, Photon↗

PubMed2003

Tests of linkage and association of the COL1A2 gene with bone phenotypes' variation in Chinese nuclear families.

In the present study, we simultaneously test linkage and/or association of the collagen type I alpha 2 (COL1A2) gene with bone mineral density (BMD) and bone area. A total of 1280 subjects from 407 Chinese nuclear families (including both parents and their daughters) were genotyped for an intragenic marker MspI in the COL1A2 gene. BMD and bone area at the lumbar spine and hip were measured by dual-energy X-ray absorptiometry. Applying the QTDT (quantitative transmission disequilibrium test) program, we performed tests for population stratification, within-family association (via transmission disequilibrium test), total association, linkage, and linkage while modeling association. Significant or marginal within-family associations were found with BMD at the lumbar spine (P = 0.013), trochanter (P = 0.004), and total hip (P = 0.053) and with bone area at the intertrochanteric region (P = 0.024) and total hip (P = 0.048). The positive associations were confirmed in permutations except for bone area at total hip (P > 0.10). A small proportion (<1%) of the population variance of bone phenotypes can be explained by the MspI polymorphism; however, it may be underestimated given the significant population stratification detected in our sample. Due to the limited number of sib pairs in this sample, we did not find evidence of linkage. In summary, the MspI polymorphism is likely to be in linkage disequilibrium with a nearby functional mutation affecting BMD and bone area.

Adult↗

PubMed2003

Molecular and genetic mechanisms of osteoporosis: implication for treatment.

Osteoporosis is a leading public health problem in our rapidly growing, aging population. It is characterized by reduced bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture risk. Osteoporosis is a complex multifactorial disease, determined by genetic and environmental factors as well as their interactions. A large number of molecular, genetic and environmental factors underlying osteoporosis have been identified in past decades. In this article, we review 1) the molecular mechanisms of several principal systemic and local factors regulating bone metabolism; and 2) the current status of genetic studies searching for genes underlying osteoporosis. Further, we attempt to integrate knowledge from those two fields, and their potential implications for osteoporosis treatment.

Bone Density↗

PubMed2002

Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density.

Bone mineral content (BMC) and/or bone mineral density (BMD, i.e. BMC scaled by bone size) are major determinants for osteoporosis, which is a serious health problem. The major determinant of variation in BMD/BMC is genetic. The few studies now available are inconsistent in the identification and/or even in the existence of major gene(s) for BMD/BMC. In 51 human pedigrees with 941 individuals (526 measured for phenotypes) identified via probands with extreme BMD values, we performed complex segregation analyses to test the existence of a genetic locus with a major effect on BMD/BMC variation. We analyzed BMD and BMC at the spine, hip and wrist jointly by employing, as the study phenotype, factor scores (FS) of the principle component that explains approximately 75% of the total BMD/BMC variation at the three sites. The results indicate that a major gene exists with a codominant effect that is responsible for approximately 16% of the FS variation when adjusted for significant effects of sex, body weight and age. A significant genotype-x-sex-x-age interaction was found, which may explain approximately 14% of the FS variation after adjusting for body weight. Testing of various models did not provide support for shared familial environmental effects but suggested the existence of residual polygenic effects, which may explain approximately 50% of the FS variation when adjusting for sex, body weight and age. This study indicates a promising aspect of studies to identify a major gene for BMD/BMC variation in our pedigrees identified via extreme probands.

Bone Density↗

PubMed2001

Delayed cardioprotection by intestinal preconditioning is mediated by calcitonin gene-related peptide.

Previous studies have shown that nitric oxide and calcitonin gene-related peptide (CGRP) are involved in mediation of the delayed cardioprotection of ischemic or pharmacological preconditioning, and nitric oxide can evoke the release of CGRP. In the present study, we examined the role of CGRP in nitric oxide-mediated delayed cardioprotection by brief intestinal ischemia in rats. The serum concentration of creatine kinase and infarct size were measured after 45-min coronary artery occlusion and 180-min reperfusion. Ischemic preconditioning was induced by six cycles of 4-min ischemia and 4-min reperfusion of the small intestine. Pretreatment with intestinal ischemic preconditioning for 24, 48, or 72 h significantly reduced infarct size and creatine kinase release, and the effects of ischemic preconditioning were completely abolished by L-nitroarginine methyl ester (L-NAME, 10 mg/kg, i.p.), an inhibitor of nitric oxide synthase, or by pretreatment with capsaicin (50 mg/kg, s.c.), which selectively depletes transmitters in capsaicin-sensitive sensory nerves. Intestinal preconditioning caused a significant increase in plasma concentrations of CGRP, and the effect was also abolished by L-NAME or capsaicin. These results suggest that the delayed cardioprotection afforded by intestinal ischemic preconditioning is mediated by endogenous CGRP via the nitric oxide pathway.

Animals↗

PubMed2001

Involvement of calcitonin gene-related peptide in the development of tolerance to nitroglycerin in the rat.

Previous studies have shown that the depressor effect of nitroglycerin is related to stimulation of endogenous calcitonin gene-related peptide (CGRP) release. In the present study, we explored whether endogenous CGRP is involved in the development of tolerance to nitroglycerin in the rat. Tolerance was induced by treatment with nitroglycerin (10 mg/kg, subcutaneous [s.c.]) three times a day for 8 days and confirmed by a reduction in hypotensive responses to intravenous (i.v.) nitroglycerin. Nitroglycerin (30 or 150 microg/kg, i.v.) significantly decreased blood pressure concomitantly with an increase in plasma concentration of nitric oxide (NO) and CGRP, and these effects of nitroglycerin disappeared after pretreatment with nitroglycerin for 8 days. However, the nitroglycerin-induced depressor effect and elevation of NO and CGRP content were restored, partially or completely, 4 or 8 days after nitroglycerin removal in the tolerant rat. The present study suggests that the development of tolerance to nitroglycerin is related to the decreased release of CGRP in the rat.

Animals↗

PubMed2001

The depressor effect of nitroglycerin is mediated by calcitonin gene-related peptide.

Previous investigations have suggested that vasodilator responses to nitroglycerin involve in stimulation of calcitonin gene-related peptide (CGRP) release. Therefore, we tested whether depressor effect of nitroglycerin is mediated by CGRP. A catheter was inserted into the left femoral artery to record blood pressure and drugs were administered through cannulae inserted into the right femoral vein. Nitroglycerin (15, 30, 60, 120 and 150 microg/kg) caused depressor effects in a dose-dependent manner. Nitroglycerin (30 or 150 microg/kg) caused a depressor effect with an increase in plasma concentrations of CGRP. The effects of nitroglycerin were significantly attenuated by methylene blue, an inhibitor of guanylate cyclase, or by pretreatment with capsaicin (50 mg x kg(-1), s.c.), which depletes neurotransmitters in sensory nerves. The present study suggests that the depressor effect of nitroglycerin is related to stimulation of CGRP release in the rat.

Animals↗

PubMed2001

Calcitonin gene-related peptide-mediated ischemic preconditioning in the rat heart: influence of age.

In the present study, we examined whether age-related reduction of ischemic preconditioning is related to calcitonin gene-related peptide (CGRP) release in the rat heart. Thirty minutes of global ischemia and 40 min of reperfusion caused a significant decrease of cardiac function and a marked increase of creatine kinase (CK) release at 2, 6 and 20 months of age. Ischemic preconditioning and pretreatment with CGRP for 5 min significantly improved cardiac function and reduced CK release during reperfusion at 2 and 6 months of age but not at 20 months of age. The content of CGRP in the coronary effluent during ischemic preconditioning was significantly increased in the first cycle at 2, 6 months of age but not at 20 months of age. These results suggest that the protection afforded by ischemic preconditioning is decreased in aging hearts, and the age-related change may be related to reduction of the release and effect of CGRP in the rat heart.

Aging↗

PubMed2001

Monophosphoryl lipid A-induced delayed preconditioning is mediated by calcitonin gene-related peptide.

The delayed preconditioning of the heart by monophosphoryl lipid A is mediated by endogenous nitric oxide (NO), and the cardioprotection afforded by nitroglycerin is related to stimulation of calcitonin gene-related peptide (CGRP) release. The objective of this study was to explore whether improvement of preservation with cardioplegia by monophosphoryl lipid A is mediated by CGRP. In addition, we examined the effect of monophosphoryl lipid A on the tumor necrosis factor-alpha (TNF-alpha) content of myocardial tissues. The isolated rat heart was perfused in the Langendorff mode. Heart rate, coronary flow, left-ventricular pressure, and its first derivatives (+/-dp/dt(max)) were recorded, and plasma levels of NO and CGRP, the release of creatine kinase in coronary effluent and the content of TNF-alpha in myocardial tissues were measured. Hypothermic ischemia for 4 h caused a decline in cardiac function, and an increase in the release of creatine kinase and in the content of TNF-alpha. Pretreatment with monophosphoryl lipid A (500 microg/kg, i.p.) for 24 h improved the recovery of cardiac function and reduced the release of creatine kinase concomitantly with a decrease in the content of cardiac TNF-alpha. Monophosphoryl lipid A markedly increased plasma concentrations of CGRP and NO. After pretreatment with L-nitroarginine methyl ester (L-NAME), the cardioprotection and the increased release of NO and CGRP induced by monophosphoryl lipid A were abolished. Capsaicin also abolished the cardioprotection and the increased release of CGRP induced by monophosphoryl lipid A, but did not affect the content of NO. The results suggest that monophosphoryl lipid A-induced preconditioning enhances preservation with cardioplegia and that the protective effects of monophosphoryl lipid A are related to stimulation of CGRP release.

Animals↗

PubMed2001

A general and accurate approach for computing the statistical power of the transmission disequilibrium test for complex disease genes.

Transmission disequilibrium test (TDT) is a nuclear family-based analysis that can test linkage in the presence of association. It has gained extensive attention in theoretical investigation and in practical application; in both cases, the accuracy and generality of the power computation of the TDT are crucial. Despite extensive investigations, previous approaches for computing the statistical power of the TDT are neither accurate nor general. In this paper, we develop a general and highly accurate approach to analytically compute the power of the TDT. We compare the results from our approach with those from several other recent papers, all against the results obtained from computer simulations. We show that the results computed from our approach are more accurate than or at least the same as those from other approaches. More importantly, our approach can handle various situations, which include (1) families that consist of one or more children and that have any configuration of affected and nonaffected sibs; (2) families ascertained through the affection status of parent(s); (3) any mixed sample with different types of families in (1) and (2); (4) the marker locus is not a disease susceptibility locus; and (5) existence of allelic heterogeneity. We implement this approach in a user-friendly computer program: TDT Power Calculator. Its applications are demonstrated. The approach and the program developed here should be significant for theoreticians to accurately investigate the statistical power of the TDT in various situations, and for empirical geneticists to plan efficient studies using the TDT.

Adult↗

PubMed2001

Effect of polygenes on Xiong's transmission disequilibrium test of a QTL in nuclear families with multiple children.

The transmission disequilibrium test (TDT), originally developed for mapping disease genes, has recently been extended to identify quantitative trait loci (QTL). For quantitative traits important for human health, generally multiple QTLs are involved. In the investigation of the statistical properties of the TDT, background polygenes (QTLs other than the QTL under test) generally have not been explicitly considered. The effects of background polygenes on the statistical properties of the TDT are thus largely unknown. Investigation of these effects will provide more realistic analyses of the statistical properties of the TDT under biologically plausible situations, and thus provide more accurate guidelines on the application of the TDT in practice. A general TDT (TDT(G)) has been developed to test linkage of a QTL in nuclear families that may be composed of more than one heterozygous parent and multiple children. Using the TDT(G) as an example, we develop an analytical method to investigate the effects of background polygenes on the power of the TDT. The accuracy of our analytical method is validated by computation simulations. We found that the power of the TDT(G) is increased with background polygenes when more than one child is employed in nuclear families, and the effect is stronger with more children per family recruited for study. The power of the TDT(G) increases dramatically when the number of children recruited from each nuclear family increases from one to two or from two to three. The type one error rate is not affected by the presence of background polygenes. The results of this study should be of theoretical significance in generalizing the investigation of the TDT to biologically plausible situations with background polygenes. They should also be of practical values in providing guidance on the recruitment of nuclear families with multiple children with the TDT(G).

Computer Simulation↗

PubMed2001

On the mechanism of the protective effects of nitroglycerin and nicorandil in cardiac anaphylaxis.

Previous investigations have shown that nitric oxide donors and nicorandil can suppress allergic reaction. In the present study, the protective effects of nitroglycerin and nicorandil on cardiac anaphylaxis were examined. Presensitized guinea-pig hearts challenged with specific antigen caused a marked decrease in coronary flow (CF), left ventricular pressure (LVP) and its derivatives (+/-dp/dtmax), increase in heart rate, and prolongation of P-R interval. Nitroglycerin (300 nM) or nicorandil (100 microM) markedly increased the content of calcitonin gene-related peptide (CGRP) concomitant with a significant improvement of the cardiac dysfunction and alleviation of the extension of P-R interval. Nicorandil at a concentration of 100 microM also inhibited the sinus tachycardia and histamine release. The protection afforded by nitroglycerin was abolished by glibenclamide, a blocker of ATP-sensitive potassium channels, or by CGRP8-37, the selective CGRP receptor antagonist, or by pretreatment with capsaicin, which depletes endogenous CGRP. The inhibitory effect of nicorandil on cardiac anaphylaxis was abolished only by glibenclamide but not by pretreatment with capsaicin. These results suggest that nitroglycerin and nicorandil possess a protection of cardiac anaphylactic injury. The present study also suggests that the protective effect of nitroglycerin may be related to stimulation of CGRP release and opening the KATP channel, and that the effect of nicorandil is mainly due to the activation of the KATP channel.

Anaphylaxis↗

PubMed2001

Improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning is mediated by calcitonin gene-related peptide.

Improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning was studied in the isolated rat heart. The isolated rat heart was arrested using St. Thomas Hospital solution, and then reperfused with normothermic Krebs-Henseleit solution for 40 min after a 4-h hypothermic ischemic period. Heart rate, coronary flow, left ventricular pressure and the maximum value of the first derivatives of left ventricular pressure (+/-dp/dt(max)) were recorded, and plasma concentrations of CGRP-like immunoreactivity (CGRP-LI) and nitric oxide (NO), tumor necrosis factor-alpha (TNF-alpha) in myocardial tissues, and creatine kinase in coronary effluent were measured. Delayed preconditioning was induced by i.v. injection of nitroglycerin 24 h before the experiment. Nitroglycerin (60 microg/kg or 120 microg/kg) caused an improvement of cardiac function, a decrease in the release of creatine kinase in coronary effluent and a decrease in the content of TNF-alpha in myocardial tissues. Nitroglycerin significantly increased plasma concentrations of CGRP and NO. After pretreatment with capsaicin, which depletes neurotransmitters in sensory nerves, or methylene blue, a selective guanylate cyclase inhibitor, the protection and the elevated release of CGRP induced by nitroglycerin were abolished. The present study suggests that improvement of preservation with cardioplegic solution by nitroglycerin-induced delayed preconditioning is due to stimulation of CGRP release in the rat heart, and that the protection of CGRP-mediated nitroglycerin is related to inhibition of TNF-alpha production.

Animals↗

PubMed2001

LOD score exclusion analyses for candidate genes using random population samples.

While extensive analyses have been conducted to test for, no formal analyses have been conducted to test against, the importance of candidate genes with random population samples. We develop a LOD score approach for exclusion analyses of candidate genes with random population samples. Under this approach, specific genetic effects and inheritance models at candidate genes can be analysed and if a LOD score is < or = - 2.0, the locus can be excluded from having an effect larger than that specified. Computer simulations show that, with sample sizes often employed in association studies, this approach has high power to exclude a gene from having moderate genetic effects. In contrast to regular association analyses, population admixture will not affect the robustness of our analyses; in fact, it renders our analyses more conservative and thus any significant exclusion result is robust. Our exclusion analysis complements association analysis for candidate genes in random population samples and is parallel to the exclusion mapping analyses that may be conducted in linkage analyses with pedigrees or relative pairs. The usefulness of the approach is demonstrated by an application to test the importance of vitamin D receptor and estrogen receptor genes underlying the differential risk to osteoporotic fractures.

Alleles↗

PubMed2001

The power of the transmission disequilibrium test (TDT) with both case-parent and control-parent trios.

The transmission disequilibrium test (TDT) customarily uses affected children and their parents (often case-parent trios, TDTD). Control-parent trios are necessary to guard against spurious significant results due to segregation distortion but are not generally utilized in the identification of disease susceptibility loci (DSL). Controls are often easy to recruit and the TDT can easily be extended to include control-parent trios into the analyses with unrelated case-parent trios. We present an extension of the TDT (TDTDC) that incorporates unrelated cases and controls and their parents into a single analysis. We develop a simple and accurate analytical method for computing the statistical power of various TDT (e.g. the TDTD, TDTDC, TDTDC and TDTC that employ control-parent trios only) under any genetic model. We investigated the power of these TDT, and particularly compared the relative power of the TDTD and TDTDC. We found that the TDTDC is almost always more powerful than the TDTC and TDTD. The relative power of the TDTDC and TDTD depends largely upon a number of parameters identified in the study. This study provides a basis for efficient use of control-parent trios in DSL identification.

Case-Control Studies↗