Biomedical subjects

C Yung Yu

Publications and source records attributed to C Yung Yu.

15 recordsLinked to original sources

PubMed2006

Fluctuation in self-perceived stress and increased risk of flare in patients with lupus nephritis carrying the serotonin receptor 1A -1019 G allele.

OBJECTIVE: Stress is believed to be a risk factor for systemic lupus erythematosus (SLE) flare. Two serotonin-related gene polymorphisms, the serotonin receptor 1A (5-HT1A) polymorphism at -1019C>G and the serotonin transporter LS polymorphism, have been reported to affect stress-related behaviors. The purpose of this study was to assess the relationship between self-perceived stress (SPS), variability in SPS, and the 2 serotonin-related gene polymorphisms as risk factors for SLE flare. METHODS: Seventy-seven SLE patients (50 with lupus nephritis) were evaluated every 2 months (mean +/- SD total followup 18.5 +/- 8.5 months), and patients recorded their daily SPS levels (0-10 scale). Values for mean SPS and coefficient of variation (CV) for SPS were calculated from the 60-day block of daily measurements between study visits. Serotonin-related gene polymorphism genotypes were determined by polymerase chain reaction-based methods. RESULTS: Of the 77 patients, 53 experienced 80 flares of SLE (32 renal flares) based on prespecified criteria. Multivariate analysis revealed that whereas neither the serotonin-related gene polymorphisms nor the mean SPS was predictive of an SLE flare, an increased CV for SPS was predictive (P = 0.0031). Interaction between the CV for SPS and the 5-HT1A -1019C>G polymorphism was also found to be a predictor of SLE flare (P = 0.0039). Subset analysis revealed that only in lupus nephritis patients were increasing CVs for SPS (P = 0.0002) and the interaction between CVs for SPS and 5-HT1A (P < 0.0001) predictive of a flare. Odds ratio curves demonstrated that the predictive effect of increasing CVs for SPS required the presence of the 5-HT1A -1019 G allele, but appeared to be independent of the G allele number. CONCLUSION: Fluctuation in the level of SPS is a risk factor for the onset of flare in SLE patients with major renal manifestations when it occurs on the background of a stress-related susceptibility gene (the 5-HT1A -1019 G allele).

Adult↗

PubMed2006

Three distinct profiles of serum complement C4 proteins in pediatric systemic lupus erythematosus (SLE) patients: tight associations of complement C4 and C3 protein levels in SLE but not in healthy subjects.

The serial changes of serum complement proteins C4 and C3 in SLE were characterized in 33 pediatric SLE patients with defined C4 genotypes. Three distinct groups of C4 protein profiles were observed. The first group was characterized by persistently low C4 levels (<10 mg/dL) throughout the course of the study. Patients with this profile had mild disease manifestations and low to medium copy numbers of C4 genes. The second group featured periodic fluctuations of serum C4 protein concentrations above and below 10 mg/dL, paralleled with ups and downs of SLE disease activities. Most patients with the second profile had unequal copy numbers of C4A and C4B genes and relatively severe disease. The third group had normal serum C4 levels (>15 mg/dL) most of the time and occasionally low C4 and C3 levels that were mostly coincident with disease flares prior to effective medical treatment. Most patients in this group

Adolescent↗

PubMed2005

Association analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in systemic lupus erythematosus families: increased T allele frequency in systemic lupus erythematosus patients with autoimmune thyroid disease.

OBJECTIVE: Recent case-control studies show associations of the minor T allele (of the C1858T single-nucleotide polymorphism corresponding to the R620W amino acid substitution) of PTPN22 with multiple autoimmune diseases, including systemic lupus erythematosus (SLE). We performed family-based association studies of this polymorphism in 4 independent cohorts containing SLE patients and their parents and/or other family members. METHODS: A total of 2,689 individuals from 902 independent Caucasian families with SLE were genotyped using polymerase chain reaction pyrosequencing (cohorts 1 and 2) and the Sequenom MassArray system (cohorts 3 and 4). The transmission disequilibrium test (TDT) and the pedigree disequilibrium test (PDT) were conducted to assess the evidence of association. RESULTS: The 1858 C > T allele frequencies of the parents showed no deviation from Hardy-Weinberg equilibrium within each cohort. No evidence of preferential transmission of the T allele from heterozygous parents to their affected offspring was observed in each of the 4 cohorts or in the combined sample. Consistent with the TDT result, the PDT analysis revealed no significant association between the T allele and SLE. In 54 of the 661 SLE patients (cohorts 1 and 3) with documented autoimmune thyroid disease, the T allele frequency was higher than in individuals with SLE alone (16.7% versus 8.5%; P = 0.008, odds ratio 2.16 [95% confidence interval 1.25-3.72]). CONCLUSION: The R620W polymorphism of the PTPN22 gene is not a major risk allele for SLE susceptibility in our sample of Caucasian individuals from northern America, the UK, or Finland, but it appears to be a risk factor for the concurrent autoimmune diseases of autoimmune thyroid disease and SLE.

Arginine↗

PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗

PubMed2004

Complete complement components C4A and C4B deficiencies in human kidney diseases and systemic lupus erythematosus.

Although a heterozygous deficiency of either complement component C4A or C4B is common, and each has a frequency of approximately 20% in a Caucasian population, complete deficiencies of both C4A and C4B proteins are extremely rare. In this paper the clinical courses for seven complete C4 deficiency patients are described in detail, and the molecular defects for complete C4 deficiencies are elucidated. Three patients with homozygous HLA A24 Cw7 B38 DR13 had systemic lupus erythematosus, mesangial glomerulonephritis, and severe skin lesions or membranous nephropathy. Immunofixation, genomic restriction fragment length polymorphisms, and pulsed field gel electrophoresis experiments revealed the presence of monomodular RP-C4-CYP21-TNX (RCCX) modules, each containing a solitary, long C4A mutant gene. Sequencing of the mutant C4A genes revealed a 2-bp, GT deletion in exon 13 that leads to protein truncation. The other four patients with homozygous HLA A30 B18 DR7 had SLE, severe kidney disorders including mesangial or membranoproliferative glomerulonephritis, and/or Henoch Schoenlein purpura. Molecular genetic analyses revealed an unusual RCCX structure with two short C4B mutant genes, each followed by an intact gene for steroid 21-hydroxylase. Nine identical, intronic mutations were found in each mutant C4B. In particular, the 8127 g-->a mutation present at the donor site of intron 28 may cause an RNA splice defect. Analyses of 12 complete C4 deficiency patients revealed two hot spots of deleterious mutations: one is located at exon 13, the others within a 2.6-kb genomic region spanning exons 20-29. Screening of these mutations may facilitate epidemiologic studies of C4 in infectious, autoimmune, and kidney diseases.

Adolescent↗

PubMed2004

Sex, MHC and complement C4 in autoimmune diseases.

Autoimmune diseases are estimated to affect 10-50 million people in the United States, and untold millions worldwide. Nearly 80% of all people with autoimmune diseases are women, and a strong association of these diseases with MHC genes has been known for some time. However, very little is known about what causes autoimmune diseases or the factors that lead to disease recurrence. The sex-associated differences in multiple sclerosis (MS) and the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), are associated with MHC genetic background, sex hormone levels and cytokine production. The implication of these factors has aided the identification of new autosomal genetic susceptibility loci. Complete deficiencies of early complement components are strongly associated with systemic lupus erythematosus (SLE) but the role of complement proteins in SLE is not yet clear. Recent data suggest that quantitative and qualitative diversities of the MHC-linked complement C4 among different ethnic groups can be important in the susceptibility and disease severity of SLE.

Animals↗

PubMed2004

The intricate role of complement component C4 in human systemic lupus erythematosus.

It was observed about 50 years ago that low serum complement activity or low protein concentrations of complement C4 concurred with disease activities of systemic lupus erythematosus (SLE). Complete deficiencies of complement components C4A and C4B, albeit rare in human populations, are among the strongest genetic risk factors for SLE or lupus-like disease, across HLA haplotypes and racial backgrounds. However, whether heterozygous or partial deficiency of C4A (C4AQ0) or C4B (C4BQ0) is a predisposing factor for SLE has been a highly controversial topic. In this review we critically analyzed past epidemiologic studies on deficiency of C4A or C4B in human SLE. Cumulative results from more than 35 different studies revealed that heterozygous and homozygous deficiencies of C4A were present in 40-60% of SLE patients from almost all ethnic groups or races investigated, which included northern and central Europeans, Anglo-Saxons, Caucasians in the US, African Americans, Asian Chinese, Koreans and Japanese. In addition, French SLE and control populations had relatively low frequencies of C4AQ0, but the difference between the patient and control groups was statistically significant. The relative risk of C4AQ0 in SLE varied between 2.3 and 5.3 among different ethnic groups. In Caucasian and African SLE patients, the two major causes for C4AQ0 are (1) the presence of a mono-S RCCX (RP-C4-CYP21-TNX) module with a single, short C4B gene in the major histocompatibility complex; and (2) a 2-bp insertion into the sequence for codon 1213 at exon 29 of the mutant C4A gene. Both mono-S structures and 2-bp insertion in exon 29 are absent or extremely rare in the C4AQ0 of Oriental SLE patients. The highly significant association of C4AQ0 with SLE across multiple HLA haplotypes and ethnic groups, and the presence of different mechanisms leading to a C4A protein deficiency among SLE patients suggested that deficiency or low expression level of C4A protein is a primary risk factor for SLE disease susceptibility per se. On the other hand, Spanish, Mexican, Australian Aborigine SLE patients had increased frequencies of C4B deficiency instead of C4A deficiency. Such observations underscore the importance of both C4A and C4B proteins in the fine control of autoimmunity. Different racial and genetic backgrounds could change the thresholds for the requirement of C4A or C4B protein levels in immune tolerance and immune regulation. Most past epidemiological studies of C4 in human SLE did not consider the polygenic and gene size variations of C4A and C4B. In addition, many studies were overly dependent on phenotypic observations or methods that did not distinguish differential C4A and C4B protein expression caused by unequal gene number or different gene size from the absence of a functional C4A or C4B gene. For further longitudinal studies on clinical manifestations of SLE, it would be informative to stratify the patients with accurately defined C4A and C4B genotypes. Likewise, elucidation of epistatic genetic factors interacting with C4AQ0 would provide important insights into the intricate roles of C4 in SLE disease susceptibility and pathogenesis.

Alleles↗

PubMed2003

Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index.

Among the genes and proteins of the human immune system, complement component C4 is extraordinary in its frequent germline variation in the size and number of genes. Definitive genotypic and phenotypic analyses were performed on a central European population to determine the C4 polygenic and gene size variations and their relationships with serum C4A and C4B protein concentrations and hemolytic activities. In a study population of 128 healthy subjects, the number of C4 genes present in a diploid genome varied between two to five, and 77.4% of the C4 genes belonged to the long form that contains the endogenous retrovirus HERV-K(C4). Intriguingly, higher C4 serum protein levels and higher C4 hemolytic activities were often detected in subjects with short C4 genes than those with long genes only, suggesting a negative epistatic effect of HERV-K(C4) on the expression of C4 proteins. Also, the body mass index appeared to affect the C4 serum levels, particularly in the individuals with medium or high C4 gene dosages, a phenomenon that was dissimilar in several aspects from the established correlation between body mass index and serum C3. As expected, there were strong, positive correlations between total C4 gene dosage and serum C4 protein concentrations, and between serum C4 protein concentrations and C4 hemolytic activities. There were also good correlations between the number of long genes with serum levels of C4A, and the number of short genes with serum levels of C4B. Thus, the polygenic and gene size variations of C4A and C4B contribute to the quantitative traits of C4 with a wide range of serum protein levels and hemolytic activities, and consequently the power of the innate defense system.

Adult↗

PubMed2003

Dancing with complement C4 and the RP-C4-CYP21-TNX (RCCX) modules of the major histocompatibility complex.

The number of the complement component C4 genes varies from 2 to 8 in a diploid genome among different human individuals. Three quarters of the C4 genes in Caucasian populations have the endogenous retrovirus, HERV-K(C4), in the ninth intron. The remainder does not. The C4 serum proteins are highly polymorphic and their concentrations vary from 100 to approximately 1000 microg/ml. There are two distinct classes of C4 protein, C4A and C4B, which have diversified to fulfill (a) the opsonization/immunoclearance purposes and (b) the well-known complement function in the killing of microbes by lysis and neutralization, respectively. Many infectious and autoimmune diseases are associated with complete or partial deficiency of C4A and/or C4B. The adverse effects of high C4 gene dosages, however, are just emerging, as the concepts of human C4 genetics are revised and accurate techniques are applied to distinguish partial deficiencies from differential expression caused by unequal C4A and C4B gene dosages and gene sizes. This review attempts to dissect the sophisticated genetics of complement C4A and C4B. The emphases are on the qualitative and quantitative diversities of C4 genotypes and phenotypes. The many allotypic variants and the processed products of human and mouse C4 proteins are described. The modular variation of C4 genes together with the serine/threonine nuclear kinase gene RP, the steroid 21-hydroxylase CYP21, and extracellular matrix protein TNX (RCCX modules) are investigated for the effects on homogenization of C4 protein polymorphisms, and on the unequal genetic crossovers that knocked out the functions of CYP21 and/or TNX. Furthermore, the influence of the endogenous retrovirus HERV-K(C4) on C4 gene expression and the dispersal of HERV-K(C4) family members in the human genome are discussed.

Animals↗

PubMed2003

Relationship between complement components C4A and C4B diversities and two TNFA promoter polymorphisms in two healthy Caucasian populations.

The RP-C4-CYP21-TNX (RCCX) modules and the tumor necrosis factor (TNF) gene cluster are probably the most polymorphic genomic regions in the human central major histocompatibility complex (MHC). Using definitive methods for genotypic and phenotypic analyses of complement components C4A and C4B, determination of the RCCX length variants, and SSP-PCR/RFLP analyses of TNFA promoter polymorphisms at positions -308 and -238, we studied the complex relationships between the C4 and TNFA polymorphisms in two normal Caucasian populations. The patterns of the RCCX modular structures and the allelic frequency of -308A TNFA (TNF2) were similar between the Budapest (n = 125) and the Ohio (n = 80) Caucasians. However, the frequency of the -238A allele was significantly higher in the Ohio (11.3%) than in the Budapest (1.6%) study population (p < 0.0001). Marked features were found in the RCCX length variants in the TNF2 carriers and noncarriers. Strong associations were found between the C4AQ0 B1 haplotype from the monomodular short (mono-S) RCCX structure and the TNF2 allele, and between the C4A6 B1 haplotype from the bimodular long-short (LS) structure of the RCCX and the TNFA -238A allele. However, 36%-46% of the TNF2 carriers did not associate with a mono-S in both study cohorts, and 57.1% of the TNFA -238A carriers in Ohio did not associate with C4A6, which has a defective complement C5 convertase activity. The carriers of TNF2 allele had significantly lower C4A serum concentration (0.17 +/- 0.08 g/l) than noncarriers (0.23 +/- 0.09 g/l) (p < 0.001). The lowest C4A serum levels were found in TNF2 carriers with mono-S structures (0.14 +/- 0.06 g/l). In essence, our results demonstrated the heterogeneities of the TNFA promoter polymorphisms, and the linkage disequilibrium of TNFA -308A and -238A alleles with complement C4A deficiency and impaired C4A protein function, respectively.

Blotting, Southern↗

PubMed2002

Genetic sophistication of human complement components C4A and C4B and RP-C4-CYP21-TNX (RCCX) modules in the major histocompatibility complex.

Human populations are endowed with a sophisticated genetic diversity of complement C4 and its flanking genes RP, CYP21, and TNX in the RCCX modules of the major histocompatibility complex class III region. We applied definitive techniques to elucidate (a) the complement C4 polymorphisms in gene sizes, gene numbers, and protein isotypes and (b) their gene orders. Several intriguing features are unraveled, including (1) a trimodular RCCX haplotype with three long C4 genes expressing C4A protein only, (2) two trimodular haplotypes with two long (L) and one short (S) C4 genes organized in LSL configurations, (3) a quadrimodular haplotype with four C4 genes organized in a SLSL configuration, and (4) another quadrimodular structure, with four long C4 genes (LLLL), that has the human leukocyte antigen haplotype that is identical to ancestral haplotype 7.2 in the Japanese population. Long-range PCR and PshAI-RFLP analyses conclusively revealed that the short genes from the LSL and SLSL haplotypes are C4A. In four informative families, an astonishingly complex pattern of genetic diversity for RCCX haplotypes with one, two, three and four C4 genes is demonstrated; each C4 gene may be long or short, encoding a C4A or C4B protein. Such diversity may be related to different intrinsic strengths among humans to defend against infections and susceptibilities to autoimmune diseases.

Arthritis, Juvenile↗

PubMed2002

Determining the one, two, three, or four long and short loci of human complement C4 in a major histocompatibility complex haplotype encoding C4A or C4B proteins.

The complex genetics of human complement C4 with unusually frequent variations in the size and number of C4A and C4B, as well as their neighboring genes, in the major histocompatibility complex has been a hurdle for accurate epidemiological studies of diseases associated with C4. A comprehensive series of novel or improved techniques has been developed to determine the total gene number of C4 and the relative dosages of C4A and C4B in a diploid genome. These techniques include (1) definitive genomic restriction-fragment-length polymorphisms (RFLPs) based on the discrete duplication patterns of the RCCX (RP-C4-CYP21-TNX) modules and on the specific nucleotide changes for C4A and C4B isotypes; (2) module-specific PCR to give information on the total number of C4 genes by comparing the relative quantities of RP1- or TNXB-specific fragments with TNXA-RP2 fragments; (3) labeled-primer single-cycle DNA polymerization procedure of amplified C4d genomic DNA for diagnostic RFLP analysis of C4A and C4B; and (4) a highly reproducible long-range-mapping method that employs PmeI-digested genomic DNA for pulsed-field gel electrophoresis, to yield precise information on the number of long and short C4 genes in a haplotype. Applications of these vigorously tested techniques may clarify the roles that human C4A and C4B gene-dosage variations play in infectious and autoimmune diseases.

Alleles↗

PubMed2002

The molecular basis of complete complement C4A and C4B deficiencies in a systemic lupus erythematosus patient with homozygous C4A and C4B mutant genes.

The disease course of a complete C4-deficient patient in the U.S. was followed for 18 years. The patient experienced multiple episodes of infection, and he was diagnosed with systemic lupus erythematosus at age 9 years. The disease progressed to WHO class III mild lupus nephritis and to fatal CNS vasculitis at age 23 years. Immunochemical experiments showed that the patient and his sibling had complete absence of C4A and C4B proteins and were negative for the Rodgers and Chido blood group Ags. Segregation and definitive RFLP analyses demonstrated that the patient and his sibling inherited two identical haplotypes, HLA A2 B12 DR6, each of which carries a defective long C4A gene and a defective short C4B gene. PCR and DNA sequencing revealed that the mutant C4A contained a 2-bp insertion in exon 29 at the sequence for codon 1213. The identical mutation was absent in the mutant C4B. The C4B mutant gene was selectively amplified by long range PCR, and its 41 exons were completely sequenced. The C4B mutant had a novel single C nucleotide deletion at the sequence for codon 522 in exon 13, leading to frame-shift mutation and premature termination. Thus, a multiplex PCR is designed by which known mutations in C4A and C4B can be elucidated conveniently. Among the 28 individuals reported with complete C4 deficiency, 75-96% of the subjects (dependent on the inclusion criteria) were afflicted with autoimmune or immune complex disorders. Hence, complete C4 deficiency is one of the most penetrant genetic risk factors for human systemic lupus erythematosus.

Adult↗

PubMed2000

Deficiencies of human complement component C4A and C4B and heterozygosity in length variants of RP-C4-CYP21-TNX (RCCX) modules in caucasians. The load of RCCX genetic diversity on major histocompatibility complex-associated disease.

The complement component C4 genes located in the major histocompatibility complex (MHC) class III region exhibit an unusually complex pattern of variations in gene number, gene size, and nucleotide polymorphism. Duplication or deletion of a C4 gene always concurs with its neighboring genes serine/threonine nuclear protein kinase RP, steroid 21-hydroxylase (CYP21), and tenascin (TNX), which together form a genetic unit termed the RCCX module. A detailed molecular genetic analysis of C4A and C4B and RCCX modular arrangements was correlated with immunochemical studies of C4A and C4B protein polymorphism in 150 normal Caucasians. The results show that bimodular RCCX has a frequency of 69%, whereas monomodular and trimodular RCCX structures account for 17.0 and 14.0%, respectively. Three quarters of C4 genes harbor the endogenous retrovirus HERV-K(C4). Partial deficiencies of C4A and C4B, primarily due to gene deletions and homoexpression of C4A proteins, have a combined frequency of 31.6%. This is probably the most common variation of gene dosage and gene size in human genomes. The seven RCCX physical variants create a great repertoire of haplotypes and diploid combinations, and a heterozygosity frequency of 69.4%. This phenomenon promotes the exchange of genetic information among RCCX constituents that is important in homogenizing the structural and functional diversities of C4A and C4B proteins. However, such length variants may cause unequal, interchromosomal crossovers leading to MHC-associated diseases. An analyses of the RCCX structures in 22 salt-losing, congenital adrenal hyperplasia patients revealed a significant increase in the monomodular structure with a long C4 gene linked to the pseudogene CYP21A, and bimodular structures with two CYP21A, which are likely generated by recombinations between heterozygous RCCX length variants.

Adrenal Hyperplasia, Congenital↗

PubMed2000

The human and mouse MHC class III region: a parade of 21 genes at the centromeric segment.

The human major histocompatibility complex (MHC) class III region contains 57-60 structural genes spanning 654-759 kb of genomic DNA. Analysis of the sequence identities of the human and mouse genomic regions between NOTCH4 and complement C2 yields important information on the locations of the coding and regulatory sequences. It also provides insights into the relationship between protein function and level of sequence conservation, and on the clustering of genes with related functions.

Animals↗