The aim of this study was to examine whether the well-established effect of the common TaqIB polymorphism in intron 1 of the gene for cholesterol ester transfer protein (CETP) on high density lipoprotein cholesterol (HDL-C) concentration and increased risk of myocardial infarction (MI), could be explained by the recently identified -629C>A functional polymorphism in the promoter. Non-fatal MI cases (388 male) and a control group of 794 healthy men were recruited from the 30 year long prospective Reykjavik Study. In the healthy men the frequency of the TaqIB B2 allele was 0.47 (95% CI: 0.44-0.50) and there was a strong allelic association with the -629A allele (D=-0.21, P
Seventy-six Neisseria gonorrhoeae isolates, isolated between 1940 and 1987, and seven Neisseria meningitidis isolates, isolated between 1963 and 1987, were screened for the presence of acquired mef(A), erm(B), erm(C), and erm(F) genes by using DNA-DNA hybridization, PCR analysis, and sequencing. The mef(A), erm(B), and erm(F) genes were all identified in a 1955 N. gonorrhoeae isolate, while the erm(C) gene was identified in a 1963 N. gonorrhoeae isolate. Similarly, both the mef(A) and erm(F) genes were identified in a 1963 N. meningitidis isolate. All four acquired genes were found in later isolates of both species. The mef(A) gene from a 1975 N. gonorrhoeae isolate was sequenced and had 100% DNA and amino acid identity with the mef(A) gene from a 1990s Streptococcus pneumoniae isolate. Selected early isolates were able to transfer their acquired genes to an Enterococcus faecalis recipient, suggesting that these genes are associated with conjugative transposons. These isolates are the oldest of any species to carry the mef(A) gene and among the oldest to carry these erm genes.
Recent findings among boys show that interactions between a polymorphism in the monoamine oxidase A gene promoter region (MAOA-LPR) and psychosocial factors predict criminal activity. The objective of this study was to investigate whether this finding could be extended to adolescent girls. One hundred nineteen female adolescents were recruited among respondents to a cross-sectional study of the total population of 16- and 19-year old girls. These girls constituted a randomly selected sub-sample from groups representing different degrees of risk behavior. The subjects filled in a questionnaire and were interviewed and genotyped with regard to MAOA-LPR. The results indicate that the long, (4-repeat) allele confer an increased risk for criminal behavior in the presence of psychosocial risk. Among girls without social risk, MAOA-LPR genotype was of no importance for criminal behavior. The present results suggest that previous observations on adolescent males, which demonstrate that the short MAOA-LPR genotype and psychosocial adversity interact to predict criminal activity, may not be applicable to females.
Autoimmune Addison's Disease (AAD) is an endocrine and immunological disease of uncertain pathogenesis resulting from the immune system's destruction of the hormone producing cells of the adrenal cortex. The underlying molecular mechanisms are largely unknown, but it is commonly accepted that a combination of genetic susceptibility and environmental impact is critical. In the present study, we identified multiple hypomethylated gene promoter regions in patients with isolated AAD using DNA isolated from CD4+ T cells. The identified differentially methylated regions were distributed evenly across the 10.5-kb-promoter regions covered by the array, and a substantial number localized to promoters of genes involved in immune regulation and autoimmunity. This study reveals a hypomethylated status in CD4+ T cells from AAD patients and indicates differential methylation of promoters of key genes involved in immune responses.
AIMS: To examine whether polymorphic variants of the HTR2C gene are associated with diagnosis of alcohol dependence. METHODS: We compared allele frequencies of five HTR2C promoter polymorphisms in a Nordic population of alcohol dependent individuals (Males: n = 309; Females: n = 127) and ethnically matched controls (Males: n = 83; Females: n = 190) in whom alcohol dependence was established, or any diagnosis of substance disorder was excluded, respectively. Patients were further subtyped into Type I (late onset) and Type II (early onset) alcoholics. RESULTS: None of the individual polymorphisms indicated significant association with alcohol dependence. A common promoter haplotype (GAGG) exhibited different distribution frequencies between males and females (Type I), however on Bonferroni's multiple-testing correction, this observation proved to be insignificant. CONCLUSIONS: Although we report a lack of association between alcohol dependence and five common promoter polymorphisms, and the constituted haplotypes, the analysis tends to indicate gender and sub-type differences. We suggest that a follow up study with larger sample numbers should be performed to improve the power to detect the genetic influences of HTR2C in alcohol dependence.
Loss of heterozygosity (LOH) at the distal half of chromosome arm 11q is frequent in a variety of human tumors, including breast cancer, and is often associated with poor prognosis. In an ongoing attempt to locate and characterize the main target genes within this chromosome region, we first looked for aberrations in known genes either suggested to be involved in tumorigenesis or shown to suppress tumor formation. We examined 31 primary breast tumors showing LOH in 11q21-24 for mutations in the MRE11A, CHK1, PPP2R1B, and TSLC1 genes. The absence of intragenic alterations related to cancer led us next to evaluate possible gene silencing resulting from promoter region CpG hypermethylation, using the bisulfite sequencing technique. In addition to the four genes mentioned above, we also analyzed the ATM gene, which had been investigated for certain germline mutations in an earlier study. Only the TSLC1 promoter region exhibited aberrant methylation patterns, and altogether 33% (10/30) of the successfully analyzed tumors showed evidence of elevated levels of TSLC1 CpG methylation. Ten percent (3/30) of the tumors showed significantly increased methylation. Thus, as has been shown in lung and some other forms of cancer, hypermethylation of the TSLC1 promoter region is also frequently a second hit along with LOH in breast cancer.
Alterations in monoamine oxidase A (MAOA) expression and enzyme activity may be associated with alcoholism and impulsive behavior. Therefore, functional polymorphisms in the MAOA gene would be good candidates to consider in the interindividual differences that exist in the susceptibility to alcoholism. One variant that has been considered as a candidate in alcoholism is a repeat polymorphism in the MAOA gene promoter. We analyzed a cohort of Finnish males with either type 1 or type 2 alcoholism, as well as controls, for differences in the distribution of MAOA promoter alleles. Based on other studies, we postulated that type 2 alcoholism, which is associated with antisocial behavior, but not type 1 alcoholism, would be correlated with the inheritance of the low promoter activity allele. However, we failed to find a difference in allele distribution in type 1 and type 2 alcoholics. In addition, there was no difference in the allele distribution when each group of alcoholics was compared with controls. However, when both groups of alcoholics were pooled and compared with controls, the difference in allele distribution reached a trend towards significance. Our results suggest a minimal association between the MAOA low activity promoter alleles and alcoholism, regardless of the presence or absence of antisocial behavior. Interestingly, approximately 3% of type 2 alcoholics were found to be heterozygous for the MAOA promoter polymorphism. Since MAOA is X-linked, the heterozygotes are probable cases of Klinefelter's syndrome (47,XXY) suggesting that X-chromosome aneuploidy may increase the risk for developing type 2 alcoholism.
The distribution of the allel variants of the promoter area (C = 590T) of the interleukin-4 (IL-4) gene in HIV-infected and relatively healthy representatives of the Caucasoid population has been studied. The relationship between the genotypes of this polymorphism and the production of IL-4 by mononuclear cells of peripheral blood as well as distribution of IL-4 genotypes among males and females is analyzed. The occurrence of the homozygous combination of the allel variant C/C of the promoter of IL-4 has been shown to prevail almost twofold over the occurrence of the variant C/T among healthy donors and HIV-infected patients. Sexual differences play an essential role in the character of inheriting the allel variants of the genes of IL-4, the presence of the homozygous variant C/C or T/T being a risk factor of HIV infection in males. As revealed in this study, in the peripheral blood of healthy donors mononuclear cells having genotype C/C differ from cells with the heterozygous variant C/T in higher spontaneous production of IL-4 and, simultaneously, in lower capacity for the activation of its production in response to stimulation with mitogen. In HIV-infected patients mononuclear cells differ in higher spontaneous production of IL-4 in comparison with controls. We may thus infer that the human genotype controlling the initial level of the production of IL-4 by lymphocytes Th2 may influence the intensity of antibody production in the process of infection.
National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, 5 Dongdan 3 Tiao, Beijing 100005, PR China. firstname.lastname@example.org
OBJECTIVES: Apolipoprotein M plays an important role in the formation of prebeta-HDL and cholesterol efflux to HDL. In the present study, we investigate the potential association between the ApoM promoter polymorphisms and type 1 diabetes. DESIGN AND METHODS: The study was conducted in Peking Union Medical College, Beijing, China and Karolinska Institutet, Stockholm, Sweden. Two populations, including 493 Han Chinese subjects (177 T1D patients/316 controls) and 225 Swedish (124/101), are enrolled in the present study. Three single nucleotide polymorphisms (SNP) C-1065A, T-855C and T-778C in the promoter region of the ApoM gene are genotyped using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol. Promoter activity was measured by reporter gene assay. RESULTS: SNP T-778C was strongly associated with T1D in both Han Chinese (p=0.002, OR=2.188, CI 95%=1.338-3.581) and Swedish (p=0.021, OR=2.865, CI 95%=1.128-7.278) populations. The luciferase activity of -778C promoter was 1.41 times as high as that of -778T promoter (9.90+/-1.92 vs. 7.04+/-0.76, p=0.001). CONCLUSIONS: Allele C of SNP T-778C may increase promoter activity and confer the risk susceptibility to the development of T1D.
There were analyzed associating of functional polymorphism of the promoter regions of genes MMP2 C--1306T, MMP 9 C--1562 T, MMP3 5A--1171 6A in a group of healthy women and breast cancer patients in order to identify informative markers associated with the risk of developing the disease. The study included 395 DNA samples from women with breast cancer and 329 healthy women. Genotyping of polymorphisms was carried out by restriction analysis of amplification products (RFLP-analysis). Among female patients there was revealed significantly seldom a carrier of 6A6A MMP3-1117 and MMP 9-1562TT genotypes and also significantly increased the frequency of MMP3 5A6A genotype. The risk of lymph node metastasis reduced in patients with MMP9-1562CC genotype. Conversely heterozygosis at this position could be regarded as risk factor for metastasis. It was revealed associating of MMP3 5A6A genotype with the degree of malignancy.