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Different Susceptibilities (different + susceptibility)
Selected AbstractsL-myc Genotype is Associated with Different Susceptibility to Lung Cancer in SmokersCANCER SCIENCE, Issue 1 2002Hiroshi Kumimoto We have shown that L-myc genotype is associated with the risk of esophageal cancer from smoking and heavy drinking. In this study, we have analyzed the relationship between the L-myc genotypes and lung cancer risk from smoking in 191 Japanese lung-cancer patients and 241 non-cancer controls. The odds ratios (ORs) were markedly higher in SS and LS genotypes than in LL genotype; age-sex-adjusted ORs were 3.19, 2.30 and 0.92, respectively. This result suggests that the L-myc polymorphism may affect the induction of lung cancer by smoking. The OR for smoking in SS-genotype patients diagnosed within 2 years was higher than that in other SS patients, suggesting that smoking-related lung cancer in SS genotype might exhibit a poorer prognosis. [source] Peptide signaling paths related to intoxication, memory and addictionADDICTION BIOLOGY, Issue 3 2000William E. M. Lands Many peptides bind to G protein-coupled receptors and activate intracellular signaling paths for adaptive cellular responses. The components of these paths can be affected by signals from other neurotransmitters to produce overall integrated results not easily predicted from customary a priori considerations. This intracellular cross-talk among signaling paths provides a "filter" through which long-term tonic signals affect short-term phasic signals as they progress toward the nucleus and induce long-term adaptation of gene expression which provide enduring attributes of acquired memories and addictions. Peptides of the PACAP family provide intracellular signaling that involves kinases, scaffolding interactions, Ca2 + mobilization, and gene expression to facilitate development of tolerance to alcohol and development of associative memories. The peptide-induced enhancement of NMDA receptor responses to extracellular glutamate also may increase behavioral sensitization to the low doses of alcohol that occur at the onset of each bout of drinking. Because many gene products participate in each signaling path, each behavioral response to alcohol is a polygenic process of many steps with no single gene product sufficient to interpret fully the adaptive response to alcohol. Different susceptibility of individuals to alcohol addiction may be a cumulative result of small differences among the many signaling components. Understanding this network of signals may help interpret future "magic bullets" proposed to treat addiction. [source] Difference in susceptibilities of different cell lines to bilirubin damageJOURNAL OF PAEDIATRICS AND CHILD HEALTH, Issue 1 2000K-C Ngai Objective: To investigate if there are differences in susceptibilities to bilirubin toxicity of different cell lines. Methodology: A modified 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method was adopted to study the cytotoxic effect of bilirubin on several commercially available cell lines including human glioblastoma (ATCC CRL 1690, T98G), human neuroblastoma (ATCC HTB-10, SK-N-MC), human liver (ATCC CCL 13, Chang Liver, HeLa markers) and a mouse fibroblast (ATCC CCL-1, NCTC Colon 929). Results: Cytotoxicity was observed when certain bilirubin:albumin molar ratios were exceeded in the medium of a cell line in culture. Different cells exhibited different susceptibilities to the cytotoxic effects of bilirubin; neuroblastoma and glioblastoma were most susceptible, fibroblasts were the least vulnerable. Conclusions: Our findings have confirmed the clinical impression that different cells sustain different degrees of cytotoxicities caused by bilirubin. [source] Innate immune responses of gingival epithelial cells to nonperiodontopathic and periodontopathic bacteriaJOURNAL OF PERIODONTAL RESEARCH, Issue 6 2007S. Ji Background and Objective:, We have previously reported different susceptibilities of periodontopathic and nonperiodontopathic bacteria to antimicrobial peptides and phagocytosis by neutrophils. Differences between the two groups of bacteria may exist also in their ability to induce immune responses from the host. Therefore, we evaluated the effects of various oral bacteria on innate immune responses by gingival epithelial cells. Material and Methods:, HOK-16B cells were cocultured with live or lysed nonperiodontopathic (n = 3) and periodontopathic (n = 5) bacterial species. The levels of human beta defensin-1, -2 and -3, and of the cathelicidin, LL-37, were examined by real-time reverse transcription-polymerase chain reaction, and the accumulated interleukin-8 and interleukin-1, were measured by enzyme-linked immunosorbent assay. Results:, Nonperiodontopathic bacteria up-regulated some antimicrobial peptides without affecting the levels of cytokines. In the periodontopathic group, the orange-complex bacteria induced antimicrobial peptides and interleukin-8 efficiently, but the red-complex bacteria often demonstrated suppressive effects. In contrast to live bacteria, bacterial lysates had no suppressive effects. In addition, some bacterial lysates demonstrated a reduced ability to induce antimicrobial peptides compared with live bacteria. Conclusion:, The nonperiodontopathic, the orange-complex, and the red-complex bacteria had different effects on the innate immune responses from gingival epithelial cells, which may affect the outcome of their host,microbial interaction in gingival sulcus. [source] Cigarette smoking and aneuploidy in human spermMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 4 2001Qinghua Shi Abstract Cigarette smoke contains chemicals which are capable of inducing aneuploidy in experimental systems. These chemicals have been shown to reach the male reproductive system, increasing oxidative DNA damage in human sperm and lowering semen quality. We have examined the association between smoking and aneuploid sperm by studying 31 Chinese men with similar demographic characteristics and lifestyle factors except for cigarette smoking. None of the men drank alcohol. These men were divided into three groups: nonsmokers (10 men), light smokers (<,20 cigarettes/day, 11 men), and heavy smokers (,,20 cigarettes/day, 10 men). There were no significant differences in semen parameters or in age across groups. Two multi-color fluorescence in situ hybridizations (FISH) were performed: two-color FISH for chromosomes 13 and 21, and three-color FISH for the sex chromosomes using chromosome 1 as an internal autosomal control for diploidy and lack of hybridization. The mean hybridization efficiency was 99.78%. The frequency of disomy 13 was significantly higher in light and heavy smokers than in non-smokers, while no significant differences in the frequency of disomy 21, X or Y were observed across groups. Significant inter-donor heterogeneity in every category of disomic sperm examined was found in both light and heavy smokers, while in nonsmokers only XY disomy showed significant inter-donor differences. Thus, we conclude that cigarette smoking may increase the risk of aneuploidy only for certain chromosomes and that men may have different susceptibilities to aneuploidy in germ cells induced by cigarette smoking. Mol. Reprod. Dev. 59: 417,421, 2001. © 2001 Wiley-Liss, Inc. [source] Relationship between esterase activity and acrinathrin and methiocarb resistance in field populations of western flower thrips, Frankliniella occidentalis,PEST MANAGEMENT SCIENCE (FORMERLY: PESTICIDE SCIENCE), Issue 12 2006Ana C Maymó Abstract The western flower thrips, Frankliniella occidentalis (Pergande), is a serious pest in the south-east of Spain owing to its direct feeding on crops, transmission of the tomato spotted wilt virus and its very high level of resistance to insecticides. Mechanisms of resistance were examined using field populations of F. occidentalis with different susceptibilities to acrinathrin, methiocarb (selective insecticides), endosulfan, metamidophos and deltamethrin (broad-spectrum insecticides). Esterase activity towards ,-naphthyl acetate and p -nitrophenyl acetate in resistant strains was significantly higher than in the reference strain (MLFOM) for both model substrates. This higher activity was significantly correlated with acrinathrin and methiocarb resistance. Copyright © 2006 Society of Chemical Industry [source] Systemic Potato virus YNTN infection and levels of salicylic and gentisic acids in different potato genotypesPLANT PATHOLOGY, Issue 4 2005-Stres, H. Kre Endogenous levels of free and conjugated salicylic (SA) and gentisic (GA) acids, both putative signal molecules in plant defence, were analysed in order to investigate their involvement in the resistance of four potato (Solanum tuberosum) genotypes with different susceptibilities to Potato virus YNTN (PVYNTN) infection: the highly susceptible cv. Igor and its extremely resistant transgenic line, the extremely resistant cv. Sante and the tolerant cv. Pentland Squire. The lowest levels of free and conjugated SA were observed in the extremely resistant cv. Sante, while free GA, which was detected in all the other varieties, was absent. The extremely resistant transgenic cv. Igor contained the highest basal total SA level and the lowest level of total GA of all four cultivars. In susceptible cv. Igor, but not in resistant transgenic cv. Igor, a systemic increase of free SA was measured 1 day postinfection (dpi). Even more significant increases of free and conjugated SA and GA were detected 11 dpi when systemic symptoms appeared. In inoculated but not in upper noninoculated leaves of resistant transgenic cv. Igor, significant increase of SA conjugates occurred, but not before 11 dpi. The increase of SA and GA in susceptible cv. Igor could contribute to the general elevated levels of phenolic compounds as a response to stress caused by virus infection. It appears that basal levels of SA and GA do not correlate with resistance to PVYNTN in potato plants. [source] Glutamine deamidation of a recombinant monoclonal antibodyRAPID COMMUNICATIONS IN MASS SPECTROMETRY, Issue 24 2008Hongcheng Liu Deamidation of glutamine (Gln) proceeds at a much slower rate than deamidation of asparagine (Asn) residues at peptide level. However, deamidation of Gln residues in native proteins may occur faster because of the impact of protein structure and thus plays a significant role in affecting protein stability. Gln deamidation of a recombinant monoclonal IgG1 antibody was investigated in the current study. Deamidation was determined by a molecular weight increase of 1,Da, a retention time shift on reversed-phase chromatography and tandem mass spectrometric (MS/MS) analysis of the peptides. As expected, Gln residues at different locations in the three-dimensional structure had different susceptibilities to deamidation. Gln deamidation was highly pH dependent with the highest level detected in the sample incubated at pH 9, and lowest level at pH 6 in the pH range from 5 to 9. The detection of significant levels of Gln deamidation suggested that it may play an important role in affecting heterogeneity and stability of recombinant monoclonal antibodies. Copyright © 2008 John Wiley & Sons, Ltd. [source] Kinetic bactericidal activity of telithromycin, azithromycin and clarithromycin against respiratory pathogens,APMIS, Issue 10 2005L. DRAGO The present study assessed the comparative in vitro killing kinetics of telithromycin, azithromycin and clarithromycin. Minimal inhibitory concentrations (MIC) and minimal bactericidal concentrations (MBC) were determined against Streptococcus pneumoniae, ,-haemolytic streptococci, Haemophilus influenzae and Moraxella catarrhalis strains characterized by different susceptibilities to ,-lactams and macrolides. For each bacterial species, representative strains were chosen for time-kill studies. Telithromycin showed high activity against all the tested strains with MIC ranging from ,0.004 to 0.5 mg/L for streptococci, from 0.008 to 8 mg/L for H. influenzae, and from 0.008 to 0.5 mg/L for M. catarrhalis. In time-kill studies, telithromycin showed an overall superior bactericidal activity in respect to macrolides, particularly against resistant strains. In conclusion, telithromycin proved to possess bactericidal activity against a wide range of respiratory pathogens, including strains resistant to common macrolides. [source] Purification and partial characterization of glutathione S -transferase from insecticide-resistant field populations of Liposcelis paeta Pearman (Psocoptera: Liposcelididae)ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 2 2009Shuang Wu Abstract Enzymes that possess glutathione S-transferase (GST) activity were purified to homogeneity by glutathione-agarose affinity chromatography from three field populations of Liposcelis paeta (Pearman). These populations were collected from Nanyang city of Henan Province (NY), Wuzhou (WZ) and Hezhou (HZ) cities of Guangxi Province, China, and had different susceptibilities to dichlorvos [LC50s of the NY (281.48,mg/m2), the WZ (285.07,mg/m2), and the HZ (243.52,mg/m2), respectively]. The specific activities of purified enzymes from these three populations increased 32.24-, 99.81-, and 42.52-fold, respectively. Kinetic analyses showed that the catalytic activity of purified GST from NY population towards GSH was much higher than the others, while WZ population reached the highest in V. SDS,polyacrylamide electrophoresis revealed that the purified GST had two subunits with a molecular mass of 23.31 and 20.43,kDa for NY, 53.14 and 20.13,kDa for WZ, and 50.79 and 19.42,kDa for HZ, respectively. The in vitro inhibition studies of GSTs indicated that three kinds of insecticides (chlorpyrifos, carbosulfan, and cypermethrin) and five metallic ions (Zn2+, Ba2+, Ca2+, Hg2+, Mn2+, and Mg2+) all possessed inhibitory effects on purified GST, and ethacrynic acid (EA, a specific inhibitor of GST) expressed inhibitory effects. In the bioassay, three populations of L. paeta had different susceptibilities to different insecticides, even after they were reared on diets consisting of 25% EA. The GST activities of L. paeta from different areas also showed different temperature and pH stabilities. The differences in GST among the three populations may be attributed partially to the differences in control practices for psocids between Henan and Guangxi Provinces. © 2009 Wiley Periodicals, Inc. [source] The D4Mit12 locus on mouse chromosome 4 provides susceptibility to both ,-ray-induced and N-methyl-N-nitrosourea-induced thymic lymphomasCANCER SCIENCE, Issue 8 2003Hiroki Sato Low-penetrance genes control different susceptibilities to ,-ray-induced thymic lymphomas in mouse strains. Our previous genetic analyses with backcross mice between BALB/c and MSM strains and congenic lines localized one such gene near the D4Mit12 locus on chromosome 4. N-Methyl-N-nitrosourea (MNU) is a guanine base-alkylating agent and differs from ,-radiation in its mechanism of mutagenic action. Accordingly, in this study, we examined whether or not the locus also provides susceptibility to MNU-induced thymic lymphomas using 84 offsprings derived from congenic mice for D4Mit12. Association analysis provided a suggestive linkage at D4Mit12 (P=0.0075) and the linkage was sustained by the peak of likelihood ratio statistical values being at the same position as that for the ,-ray-induced lymphomas. The results strongly suggest that the BALB/c allele near D4Mit12 is associated with susceptibility to lymphomas induced by two carcinogenic agents having different mechanisms of mutagenic action. [source] Metabolic fingerprinting allows discrimination between Ulmus pumila and U. minor, and between U. minor clones of different susceptibility to Dutch elm diseaseFOREST PATHOLOGY, Issue 4 2008J. A. Martin Summary Experiments were conducted to test whether Fourier transform-infrared (FT-IR) spectroscopy, coupled with chemometric methods, can distinguish healthy xylem tissues collected from elms known to differ significantly in their susceptibility to Ophiostoma novo-ulmi Brasier. Twig samples from resistant Ulmus pumila L., susceptible U. minor Mill. and resistant U. minor clones were harvested on 1 May, 15 May, 1 June, 1 July and 1 September 2004, and subjected to FT-IR analysis. The application of principal component analysis to the spectral data, followed by discriminant function analysis, discriminated between the three groups of samples in all harvesting dates. The examination of the DF-loading plots allowed the identification of key regions within the spectra for the separation between clusters. The chemical assignments of these key regions allowed the following interpretations to be made: (i) U. pumila tissues contained enhanced levels of starch, cellulose and lignin with respect to U. minor tissues and (ii) resistant U. minor tissues contained enhanced levels of starch, cellulose and pectic polysaccharides with respect to susceptible U. minor tissues. The possible roles of the compositional differences in disease resistance, as well as the potential use of FT-IR spectroscopy and chemometrics as a tool for screening resistant elms are discussed. [source] Interleukin-13 in the skin and interferon-, in the liver are key players in immune protection in human schistosomiasisIMMUNOLOGICAL REVIEWS, Issue 1 2004Alain Dessein Summary:, Immunity against schistosomes includes anti-infection immunity, which is mainly active against invading larvae in the skin, and anti-disease immunity, which controls abnormal fibrosis in tissues invaded by schistosome eggs. Anti-infection immunity is T-helper 2 (Th2) cell-dependent and is controlled by a major genetic locus that is located near the Th2 cytokine locus on chromosome 5q31-q33. Mutations in the gene encoding interleukin (IL)-13 that decrease or increase IL-13 production account, at least in part, for that genetic control. In contrast, protection against hepatic fibrosis is dependent on interferon (IFN)-, and is controlled by a major genetic locus that is located on 6q23, near the gene encoding the IFN-, receptor , chain. Mutations that modulate IFN-, gene transcription are associated with different susceptibility to disease. These data indicate that IL-13 in the skin and IFN-, in the liver are key players in protective immunity against schistosomes. These roles relate to the high anti-fibrogenic activities of IFN-, and to the unique ability of IL-13 in Th2 priming in the skin and in the mobilization of eosinophils in tissues. The coexistence of strong IFN-, and IL-13-mediated immune responses in the same subject may involve the compartmentalization of the anti-schistosome immune response between the skin and the liver. [source] Variation in enterovirus receptor genesJOURNAL OF MEDICAL VIROLOGY, Issue 1 2003Åse Karttunen Abstract The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG),,,Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG),,,Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the ,2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and ,3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. J. Med. Virol. 70:99,108, 2003. © 2003 Wiley-Liss, Inc. [source] Effect of amyloid ,-peptide on permeability transition pore: A comparative studyJOURNAL OF NEUROSCIENCE RESEARCH, Issue 2 2002Paula I. Moreira Abstract A potentially central factor in neurodegeneration is the permeability transition pore (PTP). Because of the tissue-specific differences in pore properties, we directly compared isolated brain and liver mitochondria responses to the neurotoxic A, peptides. For this purpose, the following parameters were examined: mitochondrial membrane potential (,,m), respiration, swelling, ultrastructural morphology, and content of cytochrome c. Both peptides, A,25,35 (50 ,M) and A,1,40 (2 ,M), had a similar toxicity, exacerbating the effects of Ca2+, although, per se, they did not induce (PTP). In liver mitochondria, A, led to a drop in ,,m and potentiated matrix swelling and disruption induced by Ca2+. In contrast, brain mitochondria, exposed to the same conditions, demonstrated a higher capacity to accumulate Ca2+ before the ,,m drop and a slight increase of mitochondrial swelling compared with liver mitochondria. Furthermore, mitochondrial respiratory state 3 was depressed in the presence of A,, whereas state 4 was unaltered, resulting in an uncoupling of respiration. In both types of mitochondria, A, did not affect the content of cytochrome c. The ,,m drop was reversed when Ca2+ was removed by EGTA or when ADP plus oligomycin was present. Pretreatment with cyclosporin A or ADP plus oligomycin prevented the deleterious effects promoted by A, and/or Ca2+. It can be concluded that brain and liver mitochondria show a different susceptibility to the deleterious effect of A, peptide, brain mitochondria being more resistant to the potentiation by A, of Ca2+ -induced PTP. © 2002 Wiley-Liss, Inc. [source] Variety-specific Epidemiology of Cercospora beticola Sacc. and Consequences for Threshold-based Timing of Fungicide Application in Sugar BeetJOURNAL OF PHYTOPATHOLOGY, Issue 4 2010Ulrike Kaiser Abstract In Central Europe, fungicides to control leaf spot disease in sugar beet caused by Cercospora beticola are applied based on thresholds of disease incidence (DI, per cent of infected plants). As variety-specific fungicide application was not analyzed to date, the epidemiology of C. beticola and its effect on white sugar yield (WSY) in varieties with different susceptibility were investigated at seven sites in Germany and Austria in 2004 and 2005. All varieties reached the summary thresholds 5 / 15 / 45% DI in all environments. Fitting a logistic growth curve to DI revealed significant differences among varieties. At high disease pressure, susceptible varieties reached a considerably higher disease severity (DS, per cent of infected leaf area) at harvest and a larger area under disease progress curve (AUDPC) than resistant varieties. Fitting a logistic growth curve to DS showed an increasing differentiation among varieties with time. The growth rate estimated based on the logistic growth curve was the only variable that performed equally well in differentiating varieties under low and high disease pressure. With increasing disease pressure, varieties differed considerably in WSY, but differences between susceptible and resistant varieties were significant only in some environments. The disease-loss relation between AUDPC and relative WSY was variety-specific. Resistant varieties had an approximately identical WSY with and without infection and compensated for negative infection effects even at higher AUDPC. Therefore, at high disease pressure, resistant varieties had a higher relative yield compared to susceptible ones. However, our results indicate that there is no need to develop variety-specific thresholds, but resistant varieties reach the established thresholds later than susceptible ones. Consequently, the time of fungicide application can be delayed in resistant varieties. This will help to reduce the use of fungicides to the bare essentials as requested for the integrated crop protection management. [source] Novel infection strategies of Colletotrichum acutatum on ripe blueberry fruitPLANT PATHOLOGY, Issue 1 2008P. S. Wharton The infection and colonization process of Colletotrichum acutatum on ripe blueberry fruit from two cultivars with different susceptibility to anthracnose were examined using light and confocal laser scanning microscopy. Ripe fruit from susceptible cv. Jersey and resistant cv. Elliott were drop-inoculated with a conidial suspension of C. acutatum, and epidermal peels were evaluated at selected times after inoculation and incubation. Results from pre-penetration studies demonstrated that there were significant differences in the rate of formation of melanized appressoria between the two cultivars, with the rate of formation being faster in the susceptible one. In both cultivars, penetration by the pathogen occurred via appressoria 48 h post-inoculation (hpi). However, in the susceptible cv. Jersey, C. acutatum then adopted an intracellular hemibiotrophic-like infection strategy, whereas in the resistant cv. Elliott subcuticular intramural-like infection occurred. In cv. Jersey by 108 hpi, intracellular growth of the pathogen led to the formation of numerous acervuli, with orange conidial masses. By 120 hpi, the conidial masses had coalesced covering the entire inoculated area. In cv. Elliott, acervuli were not seen until 144 hpi and contained few conidia. These results demonstrate for the first time the ability of C. acutatum to adopt a different infection and colonization strategy depending on the susceptibility of the host tissue being colonized. [source] Structural properties of trimers and tetramers of ribonuclease APROTEIN SCIENCE, Issue 10 2001Arianna Nenci Abstract Ribonuclease A aggregates (dimers, trimers, tetramers, pentamers) can be obtained by lyophilization from 40% acetic acid solutions. Each aggregate forms two conformational isomers distinguishable by different basic net charge. The crystal structure of the two dimers has recently been determined; the structure of the higher oligomers is unknown. The results of the study of the two trimeric and tetrameric conformers can be summarized as follows: (1) RNase A trimers and tetramers form by a 3D domain-swapping mechanism. N-terminal and C-terminal types of domain swapping could coexist; (2) the secondary structures of the trimeric and tetrameric conformers do not show significant differences if compared with the secondary structure of monomeric RNase A or its two dimers; (3) a different exposure of tyrosine residues indicates that in the aggregates they have different microenvironments; (4) the two trimeric and tetrameric conformers show different susceptibility to digestion by subtilisin; (5) dimers, trimers, and tetramers of RNase A show unwinding activity on double-helical poly(dA-dT) , poly(dA-dT), that increases as a function of the size of the oligomers; (6) the less basic conformers are more stable than the more basic ones, and a low concentration in solution of trimers and tetramers favors their stability, which is definitely increased by the interaction of the aggregates with poly(dA-dT) , poly(dA-dT); (7) the products of thermal dissociation of the two trimers indicate that their structures co ld be remarkably different. The dissociation products of the two tetramers allow the proposal of two models for their putative structures. [source] Suggestive linkage of familial primary cutaneous amyloidosis to a locus on chromosome 1q23BRITISH JOURNAL OF DERMATOLOGY, Issue 1 2005M-W. Lin Summary Background, There is a high incidence of primary cutaneous amyloidosis (PCA) in South America, South-east Asia and Taiwan. To date, the aetiology of PCA remains unknown, but it is believed to be multifactorial. Although most cases are sporadic, some patients have a family history. Familial aggregation and different susceptibility to PCA among ethnic groups suggest that genetic factors may play an important role in its pathogenesis. However, no genetic loci for familial PCA (FPCA) have been identified so far. Objectives, In order to identify the susceptibility gene of FPCA, we took a candidate gene approach and performed linkage analysis on chromosome 1q21.3,24.2, including the 1q23.2 region where the gene encoding serum amyloid P component (APCS) is located. Patients and methods, Nine FPCA families including 29 individuals affected with PCA were recruited for this linkage study. Initially, 11 highly polymorphic microsatellite markers spanning the region from 1q21.3 to 1q24.2 were genotyped and revealed a suggestive linkage region. This region was further fine-mapped with seven additional markers. We also re-sequenced the 2·5-kb genomic region of the APCS gene in 29 affected and 42 control individuals. Two-point and multipoint linkage analyses were performed using the LINKAGE program. Nonparametric linkage (NPL) analysis and reconstruction of haplotypes were performed with the GENEHUNTER program. Results, Both two-point and multipoint linkage analysis for all 11 markers generated negative or small positive total lod scores for all nine families. However, when we considered only three families, a maximum two-point total lod score of 2·09 was obtained for the marker D1S2844 at , = 0·01. A plateau of multipoint total lod score between D1S2768 and D1S2878 with a maximum of 2·48 at the marker D1S2844 was observed. A maximum NPL score of 3·11 (P = 0·008) was also obtained for the marker D1S2878. However, re-sequencing of the APCS gene identified no functional mutation. Conclusions, Both parametric and nonparametric linkage evidence suggested that a possible susceptibility locus for a subset of FPCA might exist on chromosome 1q23. This is the first report demonstrating suggestive evidence of linkage of FPCA to a locus in this candidate region. No functional sequence variations of the APCS gene were found to be associated with this disease among the study families. Our data imply the existence of at least one additional locus responsible for FPCA in these families, confirming genetic heterogeneity of this skin disorder. [source] | |||||||||||||||||||||||||