Biomedical subjects

Guanjie Chen

Publications and source records attributed to Guanjie Chen.

15 recordsLinked to original sources

PubMed2007

Refining the impact of TCF7L2 gene variants on type 2 diabetes and adaptive evolution.

We recently described an association between risk of type 2diabetes and variants in the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4), with a population attributable risk (PAR) of 17%-28% in three populations of European ancestry. Here, we refine the definition of the TCF7L2 type 2diabetes risk variant, HapB(T2D), to the ancestral T allele of a SNP, rs7903146, through replication in West African and Danish type 2 diabetes case-control studies and an expanded Icelandic study. We also identify another variant of the same gene, HapA, that shows evidence of positive selection in East Asian, European and West African populations. Notably, HapA shows a suggestive association with body mass index and altered concentrations of the hunger-satiety hormones ghrelin and leptin in males, indicating that the selective advantage of HapA may have been mediated through effects on energy metabolism.

Asian People↗

PubMed2006

Variance components model with disequilibria.

The variance components (VC) model has been popular for genetic analysis. It has received wide applications in a variety of genetic practices, and been extended to various forms for different settings. However, most of the existing VC models are, explicitly or implicitly, under the assumption of the Hardy-Weinberg and/or linkage equilibria, which is impractical in some realistic settings since more or less deviations from this assumption are common. We propose a new VC model that incorporates both these disequilibria, and includes the existing models as special cases. The corresponding variance components are computed for some commonly used relative pairs conditional on the observed marker identity-by-descent data. Parameters can be estimated by the traditional methods such as the maximum likelihood estimate. Simulation studies suggest that this extended model improves inference significantly over the existing models when deviations of these disequilibria are present.

Analysis of Variance↗

PubMed2006

Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis.

OBJECTIVE: Scientific evidence is lacking for the antiarthritic efficacy of turmeric dietary supplements that are being promoted for arthritis treatment. Therefore, we undertook studies to determine the antiarthritic efficacy and mechanism of action of a well-characterized turmeric extract using an animal model of rheumatoid arthritis (RA). METHODS: The composition of commercial turmeric dietary supplements was determined by high-performance liquid chromatography. A curcuminoid-containing turmeric extract similar in composition to these supplements was isolated and administered intraperitoneally to female Lewis rats prior to or after the onset of streptococcal cell wall-induced arthritis. Efficacy in preventing joint swelling and destruction was determined clinically, histologically, and by measurement of bone mineral density. Mechanism of action was elucidated by analysis of turmeric's effect on articular transcription factor activation, microarray analysis of articular gene expression, and verification of the physiologic effects of alterations in gene expression. RESULTS: A turmeric fraction depleted of essential oils profoundly inhibited joint inflammation and periarticular joint destruction in a dose-dependent manner. In vivo treatment prevented local activation of NF-kappaB and the subsequent expression of NF-kappaB-regulated genes mediating joint inflammation and destruction, including chemokines, cyclooxygenase 2, and RANKL. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2), and periarticular osteoclast formation were inhibited by turmeric extract treatment. CONCLUSION: These translational studies demonstrate in vivo efficacy and identify a mechanism of action for a well-characterized turmeric extract that supports further clinical evaluation of turmeric dietary supplements in the treatment of RA.

Animals↗

PubMed2006

Turmeric extracts containing curcuminoids prevent experimental rheumatoid arthritis.

Turmeric has been used for centuries in Ayurvedic medicine as a treatment for inflammatory disorders including arthritis. On the basis of this traditional usage, dietary supplements containing turmeric rhizome and turmeric extracts are also being used in the western world for arthritis treatment and prevention. However, to our knowledge, no data are available regarding antiarthritic efficacy of complex turmeric extracts similar in composition to those available for use as dietary supplements. Therefore, the studies described here were undertaken to determine the in vivo efficacy of well-characterized curcuminoid-containing turmeric extracts in the prevention or treatment of arthritis using streptococcal cell wall (SCW)-induced arthritis, a well-described animal model of rheumatoid arthritis (RA). Arthritic index, a clinical measure of joint swelling, was used as the primary endpoint for assessing the effect of extracts on joint inflammation. An essential oil-depleted turmeric fraction containing 41% of the three major curcuminoids was efficacious in preventing joint inflammation when treatment was started before, but not after, the onset of joint inflammation. A commercial sample containing 94% of the three major curcuminoids was more potent in preventing arthritis than the essential oil-depleted turmeric fraction when compared by total curcuminoid dose per body weight. In conclusion, these data (1) document the in vivo antiarthritic efficacy of an essential oil-depleted turmeric fraction and (2) suggest that the three major curcuminoids are responsible for this antiarthritic effect, while the remaining compounds in the crude turmeric extract may inhibit this protective effect.

Arthritis, Rheumatoid↗

PubMed2006

Genomewide scan and fine mapping of quantitative trait loci for intraocular pressure on 5q and 14q in West Africans.

PURPOSE: High intraocular pressure (IOP) is a major risk factor for glaucoma, one of the leading causes of blindness worldwide. Because it has been demonstrated that African populations are at increased risk for glaucoma, the authors investigated the genetic basis of IOP in a sample of West Africans with type 2 diabetes (T2D) from Ghana and Nigeria. METHODS: Genomewide linkage analysis was conducted for loci linked to IOP (measured by applanation tonometry) in 244 affected sibling pairs with T2D using 372 autosomal short-tandem repeat markers at an average spacing of 9 cM. RESULTS: Multipoint variance components linkage analyses revealed suggestive linkage on chromosome 5 (5q22) with a logarithm of odds (LOD) score of 2.50 (nominal P = 0.0003; empiric P = 0.0004) and on chromosome 14 (14q22) with an LOD score of 2.95 (nominal P = 0.0001; empiric P = 0.0003). Fine mapping at a marker density of 2 cM in the 5q region confirmed the linkage signal, with an increase in peak LOD score to 4.91. CONCLUSIONS: The strong signal on chromosome 5 lies in the region in which a novel gene, WDR36, in the GLC1G locus was recently identified as causative for adult-onset primary open-angle glaucoma and provides additional evidence that chromosome 5 contains susceptibility loci for glaucoma in multiple human populations. The evidence provided in this study is particularly important given the evolutionary history of these West African populations and the recent ancestral relationship to African Americans-a population with one of the highest rates of diabetes and associated complications (including glaucoma) in the world.

Chromosome Mapping↗

PubMed2005

Genome scan linkage analysis comparing microsatellites and single-nucleotide polymorphisms markers for two measures of alcoholism in chromosomes 1, 4, and 7.

BACKGROUND: We analyzed 143 pedigrees (364 nuclear families) in the Collaborative Study on the Genetics of Alcoholism (COGA) data provided to the participants in the Genetic Analysis Workshop 14 (GAW14) with the goal of comparing results obtained from genome linkage analysis using microsatellite and with results obtained using SNP markers for two measures of alcoholism (maximum number of drinks -MAXDRINK and an electrophysiological measure from EEG -TTTH1). First, we constructed haplotype blocks by using the entire set of single-nucleotide polymorphisms (SNP) in chromosomes 1, 4, and 7. These chromosomes have shown linkage signals for MAXDRINK or EEG-TTTH1 in previous reports. Second, we randomly selected one, two, three, four, and five SNPs from each block (referred to as Rep1 - Rep5, respectively) to conduct linkage analysis using variance component approach. Finally, results of all SNP analyses were compared with those obtained using microsatellite markers. RESULTS: The LOD scores obtained from SNPs were slightly higher but the curves were not radically different from those obtained from microsatellite analyses. The peaks of linkage regions from SNP sets were slightly shifted to the left when compared to those from microsatellite markers. The reduced sets of SNPs provide signals in the same linkage regions but with a smaller LOD score suggesting a significant impact of the decrease in information content on linkage results. The widths of 1 LOD support interval of linkage regions from SNP sets were smaller when compared to those of microsatellite markers. However, two linkage regions obtained from the microsatellite linkage analysis on chromosome 7 for LOG of TTTH1 were not detected in the SNP based analyses. CONCLUSION: The linkage results from SNPs showed narrower linkage regions and slightly higher LOD scores when compared to those of microsatellite markers. The different builds of the genetic maps used in microsatellite and SNPs markers or/and errors in genotyping may account for the microsatellite linkage signals on chromosome 7 that were not identified using SNPs. Also, unresolved map issues between SNPs and microsatellite markers may be partly responsible for the shifted linkage peaks when comparing the two types of markers.

Alcoholism↗

PubMed2005

Genetic structure in four West African population groups.

BACKGROUND: Africa contains the most genetically divergent group of continental populations and several studies have reported that African populations show a high degree of population stratification. In this regard, it is important to investigate the potential for population genetic structure or stratification in genetic epidemiology studies involving multiple African populations. The presences of genetic sub-structure, if not properly accounted for, have been reported to lead to spurious association between a putative risk allele and a disease. Within the context of the Africa America Diabetes Mellitus (AADM) Study (a genetic epidemiologic study of type 2 diabetes mellitus in West Africa), we have investigated population structure or stratification in four ethnic groups in two countries (Akan and Gaa-Adangbe from Ghana, Yoruba and Igbo from Nigeria) using data from 372 autosomal microsatellite loci typed in 493 unrelated persons (986 chromosomes). RESULTS: There was no significant population genetic structure in the overall sample. The smallest probability is associated with an inferred cluster of 1 and little of the posterior probability is associated with a higher number of inferred clusters. The distribution of members of the sample to inferred clusters is consistent with this finding; roughly the same proportion of individuals from each group is assigned to each cluster with little variation between the ethnic groups. Analysis of molecular variance (AMOVA) showed that the between-population component of genetic variance is less than 0.1% in contrast to 99.91% for the within population component. Pair-wise genetic distances between the four ethnic groups were also very similar. Nonetheless, the small between-population genetic variance was sufficient to distinguish the two Ghanaian groups from the two Nigerian groups. CONCLUSION: There was little evidence for significant population substructure in the four major West African ethnic groups represented in the AADM study sample. Ethnicity apparently did not introduce differential allele frequencies that may affect analysis and interpretation of linkage and association studies. These findings, although not entirely surprising given the geographical proximity of these groups, provide important insights into the genetic relationships between the ethnic groups studied and confirm previous results that showed close genetic relationship between most studied West African groups.

Africa, Western↗

PubMed2005

A genome wide quantitative trait linkage analysis for serum lipids in type 2 diabetes in an African population.

Lipid abnormalities are strongly linked with coronary heart disease and are common in type 2 diabetes. However, little is known about the genetic determinants of serum lipids in African populations. An autosomal genome scan was performed for linkage to five plasma lipid phenotypes (total cholesterol, triglycerides (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C) and VLDL-cholesterol (VLDL-C)) in the Africa-America Diabetes Mellitus (AADM) study. Two hundred and ninety-five affected sibling pairs with type 2 diabetes mellitus enrolled from Ghana and Nigeria were genotyped for 390 microsatellite markers with an average inter-marker distance of 9cM. Multipoint variance components linkage analysis showed that HDL-C had a LOD score of 4.34 near marker D7S3061 and 3.00 near marker D7S513. Some clustering of linkage evidence to several lipid phenotypes was observed on chromosomes 5 (LDL-C, total cholesterol, VLDL-C), chromosome 7 (HDL-C, TG) and chromosome 19 (total cholesterol, LDL-C, TG). Principal component analysis of the five phenotypes yielded two factors, one (TG, HDL-C and VLDL) of which was linked to QTLs on chromosomes 2, 5 and 7, while the other (total cholesterol and LDL-C) was linked to a different set of QTLs on chromosomes 2, 5 and 18. Several of these regions have been reported to be linked to lipids in other studies. Follow up investigations are warranted in view of the central role serum lipids play in the aetiopathogenesis of cardiovascular disease.

Adult↗

PubMed2005

Calpain-10 gene polymorphisms and type 2 diabetes in West Africans: the Africa America Diabetes Mellitus (AADM) Study.

PURPOSE: To investigate whether the three single nucleotide polymorphisms (SNPs), SNP-43, -56, and -63 of CAPN10 were associated with type 2 diabetes in a West African cohort. METHODS: A total of 347 diabetic subjects and 148 unaffected controls from four ethnic groups in two West African countries were enrolled in this study. After genotyping three SNPs of CAPN10 and one SNP from CYP19, the allele, genotype, and haplotype frequencies as well as the odds ratios were calculated to test their association with type 2 diabetes. RESULTS: None of the alleles or genotypes was associated with type 2 diabetes. Although statistical analysis indicated that haplotype 221 was associated with type 2 diabetes (OR, 3.765; 95% CI, 1.577-8.989) in the two ethnic groups of Nigeria, the same haplotype did not show any association with type 2 diabetes in the two ethnic groups in Ghana (OR, 0.906; 95% CI, 0.322-2.552). CONCLUSION: Considering the relatively low frequency of haplotype 221 and that none of the haplotypes including 221 was associated with any of the diabetes-related quantitative traits tested, it is concluded that SNP-43, -56, and -63 of the CAPN10 gene variants may play a limited role in the risk of type 2 diabetes risks in this cohort of West Africans.

Alleles↗

PubMed2005

A statistical framework for haplotype block inference.

The existence of haplotype blocks transmitted from parents to offspring has been suggested recently. This has created an interest in the inference of the block structure and length. The motivation is that haplotype blocks that are characterized well will make it relatively easier to quickly map all the genes carrying human diseases. To study the inference of haplotype block systematically, we propose a statistical framework. In this framework, the optimal haplotype block partitioning is formulated as the problem of statistical model selection; missing data can be handled in a standard statistical way; population strata can be implemented; block structure inference/hypothesis testing can be performed; prior knowledge, if present, can be incorporated to perform a Bayesian inference. The algorithm is linear in the number of loci, instead of NP-hard for many such algorithms. We illustrate the applications of our method to both simulated and real data sets.

Algorithms↗

PubMed2004

Identifying the susceptibility gene(s) in a set of trait-linked genes using genotype data.

There are generally three steps to isolate a disease linkage-susceptibility gene: genome-wide scan, fine mapping, and, last, positional cloning. The last step is time consuming and involves intensive laboratory work. In some cases, fine mapping cannot proceed further on a set of markers because they are tightly linked. For years, genetic statisticians have been trying different ways to narrow the fine-mapping results to provide some guidance for the next step of laboratory work. Although these methods are practical and efficient, most of them are based on IBD data, which usually can be inferred only from the genotype data with some uncertainty. The corresponding methods thus have no greater power than one using genotype data directly. Also, IBD-based methods apply only to relative pair data. Here, using genotype data, we have developed a statistical hypothesis-testing method to pinpoint a SNP, or SNPs, suspected of responsibility for a disease trait linkage among a set of SNPs tightly linked in a region. Our method uses genotype data of affected individuals or case-control studies, which are widely available in the laboratory. The testing statistic can be constructed using any genotype-based disease-marker disequilibrium measure and is asymptotically distributed as a chi-square mixture. This method can be used for singleton data, relative pair data, or general pedigree data. We have applied the method to simulated data as well as a real data set; it gives satisfactory results.

Chromosome Mapping↗

PubMed2004

A genome-wide search for type 2 diabetes susceptibility genes in West Africans: the Africa America Diabetes Mellitus (AADM) Study.

The incidence of type 2 diabetes is growing rapidly, not only in developed countries but also worldwide. We chose to study type 2 diabetes in West Africa, where diabetes is less common than in the U.S., reasoning that in an environment where calories are less abundant, incident cases of type 2 diabetes might carry a proportionately greater genetic component. Through the Africa America Diabetes Mellitus (AADM) study, we carried out a genome-wide linkage analysis of type 2 diabetes in a cohort of 343 affected sibling pairs (691 individuals) enrolled from five West African centers in two countries (Ghana: Accra and Kumasi; Nigeria: Enugu, Ibadan, and Lagos). A total of 390 polymorphic markers were genotyped, and multipoint linkage analysis was conducted using the GENEHUNTER-PLUS and ASM programs. Suggestive evidence of linkage was observed in four regions on three chromosomes (12, 19, and 20). The two largest logarithm of odds scores of 2.63 and 1.92 for chromosomes 20q13.3 and 12q24, respectively, are particularly interesting because these regions have been reported to harbor diabetes susceptibility genes in several other populations and ethnic groups. Given the history of forced migration of West African populations during the slave trade, these results should have considerable relevance to the study of type 2 diabetes in African Americans.

Africa, Western↗

PubMed2003

Prevalence and determinants of diabetic retinopathy and cataracts in West African type 2 diabetes patients.

OBJECTIVE: To quantify the prevalence of, and risk factors for, diabetic retinopathy and cataracts in patients with type 2 diabetes, and their spouse controls, enrolled from 5 centers in 2 West African countries (Ghana and Nigeria). METHOD: The analysis cohort was made up of 840 subjects with type 2 diabetes, and their 191 unaffected spouse controls, who were enrolled and examined in Lagos, Enugu, and Ibadan, in Nigeria, and in Accra and Kumasi, in Ghana. A diagnosis of diabetic retinopathy was made only where a participant had a minimum of one microaneurysm in any field, as well as exhibiting hemorrhages (dot, blot, or flame shaped), and maculopathy (with or without clinically significant edema). RESULTS: Average duration of diabetes was 7.0 years, and mean age at diagnosis was 46.5 years. Prevalence of diabetic retinopathy was 17.9%. Cataracts were present in 44.9% of the patients with type 2 diabetes, and in 18.3% of spouse controls. The risk of developing retinopathy increased more than 3-fold for patients at the highest fasting plasma glucose (FPG) level (OR=3.4; 95% CI, 1.8-6.3), compared to patients at the lowest FPG level. The odds ratios for persons with diabetes for 10 years or more, compared to persons with diabetes for less than 5 years, was 7.3 (95% CI, 4.3-12.3) for retinopathy, and 2.6 (95% CI, 1.5-4.5) for cataracts. CONCLUSIONS: Cataracts were a more important cause of vision impairment than was diabetic retinopathy in this cohort. The prevalence of cataracts in patients with diabetes was more than twice that of their spouse controls, indicating that type 2 diabetes is an important risk factor for cataract formation. Individuals who developed type 2 diabetes at an earlier age were more likely to develop both diabetic retinopathy and cataracts. A strong positive association was observed between FPG level, duration of diabetes, and risk of retinopathy and cataracts. The low prevalence of retinopathy and cataracts observed within the first 5 years of diagnosis of diabetes in this cohort, suggests that intensive blood glucose control may reduce the risk of the development and progression of retinopathy and cataracts. In this regard, early eye examination, preferably at first presentation of elevated blood glucose, is highly recommended.

Adult↗

PubMed2002

Parathyroid hormone-related protein induction in focal stroke: a neuroprotective vascular peptide.

Parathyroid hormone-related protein (PTHrP) is a multifunctional peptide that enhances blood flow in non-central nervous system (CNS) vascular beds by causing vasodilation. PTHrP expression is induced in non-CNS organs in response to ischemia. Experiments were therefore undertaken to determine whether PTHrP can be induced in brain in response to ischemic injury and whether PTHrP can act locally as a vasodilator in the cerebral vasculature, an effect that could be neuroprotective in the setting of stroke. PTHrP expression was examined by Northern analysis and immunohistochemical staining in male Sprague-Dawley rats subjected to permanent middle cerebral artery occlusion (MCAO). Vasodilatory effects of superfused PTHrP(1-34) on pial arterioles were determined by intravital fluorescence microscopy. Effects of PTHrP(1-34) peptide administration on MCAO infarction size reduction were assessed. PTHrP expression was induced in the ischemic hemisphere as early as 4 h after MCAO and remained elevated for up to 24 h. Increased immunoreactive PTHrP at sites of ischemic tissue injury was located in the cerebral microvessels. Superfusion with PTHrP(1-34) peptide for up to 25 min increased pial arteriolar diameter by 30% in normal animals. In animals with permanent MCAO, PTHrP(1-34) peptide treatment significantly decreased cortical infarct size (-47%). In summary, PTHrP expression increases at sites of ischemic brain injury in the cerebrovasculature. This local increase in PTHrP could be an adaptive response that enhances blood flow to the ischemic brain, thus limiting cell injury.

Animals↗

PubMed2002

A genome-wide scan for obesity in African-Americans.

A genome-wide scan using 387 short tandem repeat markers was conducted for obesity among 618 black individuals from 202 families residing in a suburb of Chicago. Evidence for linkage was evaluated with BMI and percent body fat (PBF) using a variance component analysis approach. Suggestive evidence for linkage was found for BMI on chromosome 5 (logarithm of odds [LOD] score = 1.9) and PBF on chromosome 6 (LOD score = 2.7). One additional region on chromosome 3 was linked to these phenotypes at a lower level of significance (LOD score = 1.8 and 0.95 for BMI and PBF, respectively); the linked marker on this chromosome lies in the same region implicated as harboring obesity genes in a previous study of a white population. The replication of linkage evidence using different ethnic groups reinforces the potential significance of this latter candidate region.

Adipose Tissue↗