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PubMed2004

Matrix metalloproteinase-1 polymorphism of promoter region in sarcoidosis and tuberculosis patients.

BACKGROUND AND AIM OF THE WORK: Matrix metalloproteinases (MMPs) are associated with several diseases. MMP-1 is one of the interstitial collagenases and the most highly expressed. Recent studies have found that a single nucleotide polymorphism located in the promoter region of the MMP-1 gene affects transcriptional activity. This polymorphism, 1G/2G, has been reported to associate with several malignant tumors and lung diseases. In this study, we investigated whether this polymorphism is associated with sarcoidosis or tuberculosis. METHODS: Polymerase chain reaction-restriction fragment length polymorphism was used to determine the MMP-1 genotypes of 103 sarcoidosis patients, 105 tuberculosis patients and 106 healthy control subjects. RESULTS: We found no differences in genotype distributions and allele frequency between sarcoidosis or tuberculosis patients and healthy control subjects. In sarcoidosis patients with ocular involvement, a significant increase in 1G/1G or 1G/2G genotype was observed compared with patients without (p = 0.009, odds ratio (OR) = 3.22, 95% confidence interval (CI): 1.34-7.71). In sarcoidosis patients with three or more organs involved, 1G/1G type tended to increase compared with patients without (p = 0.035, OR = 5.17, 95% CI: 1.12-23.9). In tuberculosis patients with cavity formation, an increasing trend of 1G/1G type was observed compared with patients without (p = 0.064, OR = 7.69, 95% CI: 0.89-66.3). CONCLUSIONS: Although MMP-1 polymorphism was not associated with onset risk of sarcoidosis and tuberculosis, the clinical characteristics of both diseases were affected by this polymorphism.

Adult↗

PubMed1991

Human T-cell receptor V alpha gene polymorphism.

Polymorphism in the germline repertoire of T-cell receptor (TCR) variable alpha and beta (V alpha and V beta) genes could alter the relative abilities of individuals in a population to respond to particular antigens. Variation in the number of germline V alpha and V beta gene segments has been reported in wild mice and in different inbred mouse strains. A previous study of the human V beta gene germline repertoire failed to reveal a similar degree of polymorphism in the numbers of V beta gene segments. We have now carried out a survey of 10 different V alpha gene segment subfamilies containing approximately 23 V alpha gene segments in a panel of 120 unrelated individuals by hybridization and failed to find any evidence for V alpha repertoire polymorphism. To determine if significant germline polymorphism does occur in humans at the level of individual V gene segments, we determined the nucleotide sequences of eight copies of the V alpha 21 gene segment derived from seven unrelated individuals. Polymorphic differences between these sequences defined three different alleles. One of these alleles contains a frameshift mutation which would cause premature termination of the protein product. The presence of this null allele among the eight sequences determined suggests that functionally relevant germline polymorphism of human TCR V gene segments may occur by mechanisms other than gene duplication or deletion.

Amino Acid Sequence↗

PubMed1992

A minisatellite and a microsatellite polymorphism within 1.5 kb at the human muscle glycogen phosphorylase (PYGM) locus can be amplified by PCR and have combined informativeness of PIC 0.95.

We sequenced a genomic clone (pMCMP1), previously reported to detect a VNTR polymorphism at the PYGM locus, and found a dinucleotide repeat segment (CA)14(GA)25 and a complex (AT)-repeat-rich segment containing 63 repeats spanning 160 bp. Resolution of PCR-amplified genomic DNA from the (CA)(GA) repeat region on DNA sequencing gels revealed a highly informative polymorphism with alleles differing by 2-bp intervals and ranging in size from 156 to 190 bp. Among three racial groups, a total of 18 alleles were observed. Fourteen alleles were observed in Caucasians (PIC 0.89), 12 alleles in American Blacks (PIC 0.89), and 9 alleles in Pima Indians (PIC 0.73). PCR amplification of the (AT) repeat region and resolution of the products on DNA sequencing gels revealed a complex variable length polymorphism with alleles distributed in size from 367 to 970 bp. Twenty-eight alleles were found in American Blacks (PIC 0.94), 6 alleles in Pima Indians (PIC 0.70), and 11 alleles in Caucasians (PIC 0.71). Comparison of the previously described VNTR RFLP alleles visualized by Southern hybridization to the PCR products described in this report demonstrated that the polymorphism described in both assays was identical. However, a larger number of alleles could be detected from the PCR-amplified products. Combined informativeness, PIC 0.95, for the two polymorphisms was determined from haplotype analysis of 100 Caucasian chromosomes. Therefore, for genotyping purposes, informativeness is maximized from using both polymorphisms.

Asian People↗

PubMed2006

Genotyping of eight polymorphic genes encoding drug-metabolizing enzymes and transporters using a customized oligonucleotide array.

Polymorphisms in drug-metabolizing genes may lead to the production of dysfunctional proteins and consequently affect therapeutic efficacy and toxicity of drugs. Different frequencies of polymorphic alleles among the races have been postulated to account for the observed ethnic variations in drug responses. In the current study, we aimed to estimate the frequencies of 14 polymorphisms in eight genes (TPMT, NQO1, MTHFR, GSTP1, CYP1A1, CYP2D6, ABCB1, and SLC19A1) in the Singapore multiracial populations by screening 371 cord blood samples from healthy newborns. To improve genotyping efficacy, we designed an oligonucleotide array based on the principle of allele-specific primer extension (AsPEX) that was capable of detecting the 14 polymorphisms simultaneously. Cross-validation using conventional polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP) assays demonstrated 99% concordant results. Measurements on the fluorescent intensity displayed clear distinctions among different genotypes. Statistical analyses showed significantly different allele distributions in several genes among the three races, namely Chinese, Malays, and Indians. Comparing the allelic frequencies in Chinese with previous studies in Caucasian populations, NQO1 609C>T and SLC19A1 80G>A were distinctly different, whereas close similarity was observed for MTHFR 677C>T. We have demonstrated an array-based methodology for rapid multiplex detection of genetic polymorphisms. The allelic frequencies reported in this study may have important therapeutic and prognostic implications in the clinical use of relevant drugs.

Alleles↗

PubMed2006

HindIII(+/-) polymorphism of the Y chromosome, blood pressure, and serum lipids: no evidence of association in three white populations.

BACKGROUND: Male sex is associated with elevated levels of cardiovascular risk factors, including higher blood pressure (BP). Genetic variants on the Y chromosome may contribute to explain the sexual dimorphism in cardiovascular diseases. Among them, the HindIII(+/-) polymorphism of the male-specific region of the Y chromosome has been associated with BP and serum cholesterol levels, with conflicting results. We evaluated the association between the HindIII(+/-) polymorphism, prevalence of hypertension, BP, and serum lipid levels in a large sample of white men and the previously reported epistatic interaction between HindIII(+/-) and the -344C/T polymorphism of the aldosterone synthase gene (CYP11B2) on BP. METHODS: From three European populations (UK n = 422; Belgium n = 313; Italy n = 1248) 1983 white men were phenotyped for BP and serum lipids and genotyped for HindIII(+/-) site and for -344C/T polymorphism in the promoter of CYP11B2 by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: A higher frequency of the HindIII (+) was found in Italians (63%) as compared to both British (31%) and Belgians (28%) (P < .0001). We found no evidence of association of the HindIII(+/-) site with prevalence of hypertension, BP, and serum lipids in any of the three European populations examined and in the entire sample. Finally, we did not observe any interaction between the HindIII(+/-) polymorphism and the -344C/T variant of CYP11B2 on BP. CONCLUSIONS: Our data do not support the hypothesis that the HindIII(+/-) site of the Y chromosome is a marker of cardiovascular risk in white men, highlighting the need for replication in genetic association studies.

Adult↗

PubMed2004

Polymorphisms of the porcine androgen receptor gene affecting its amino acid sequence and expression level.

Diverse physiological effects of the androgen receptor (AR), a nuclear transcription factor, and its mapping position within a quantitative trait loci (QTL) region on chromosome X propose it as an interesting candidate gene for pig reproduction and performance. Therefore, the aims of this study were isolation of the gene and detection of polymorphisms as a tool for association study and analysis of functional properties of the porcine AR. The mRNA and promoter sequences were obtained and screened for polymorphisms. Based on comparative sequencing, eight single nucleotide polymorphisms (SNPs), TG- and T-insertion/deletetion polymorphisms (INDELs) upstream transcription initiation sites, three SNPs in the 5'-untranslated region (UTR), one microsatellite (CCTTT)n in the intron of 5'-UTR, and a CAG-INDEL in exon 1 were detected. Two haplotypes originated from Duroc and Berlin Miniature Pig were segregating in the DUMI-F2 resource population. Characterization of the porcine AR promoter showed two conserved transcription start sites, a consensus sequence of GC-box and a homopurine/homopyrimidine stretch at similar locations compared to the human, rat and mouse as well as sequences similar to androgen response elements (ARE). The AR mRNA expression levels determined by real-time RT-PCR in various tissues of female pigs were high in ovary (100%) and adrenal gland (83.9% relative to ovary), moderate in uterus (61.6%) and liver (47.4%), and low in pituitary gland (1.3%) as well as in tonsil, muscle, mammary gland, leukocyte and jejunum (less than 1%). Detection of the AR mRNA transcripts in liver revealed that hemizygous males carrying the AR haplotype descended from Berlin Miniature pig had higher relative AR expressions than did those with the Duroc haplotype. Here we showed that the porcine AR is a highly polymorphic gene. Polymorphisms identified in the present study affect the predicted amino acid sequence as well as consensus transcription factor binding sites and are associated with the allele-specific differences of the AR mRNA transcript level in liver, reinforcing AR as a potential candidate gene for traits related to pig reproduction and performance.

5' Untranslated Regions↗

PubMed2004

Identification of polymorphisms in the promoter region of the human NRF2 gene.

Transcription factor Nrf2 regulates the basal and inducible expression of detoxifying and antioxidant genes. Recent studies using nrf2-null mice suggest that Nrf2 dysfunction might be involved in the pathogenesis of human diseases. To gain insight into the relationship between impairment in the NRF2 gene and human diseases, we attempted to identify polymorphisms in the human NRF2 gene. We determined the structure of the NRF2 gene and found three single nucleotide polymorphisms and one triplet repeat polymorphism in its regulatory region. These results provide a molecular basis for the genetic analysis of the NRF2 gene. The frequency of each polymorphism was examined in two groups of patients with systemic lupus erythematosus and chronic obstructive pulmonary disease. This study did not reveal a close connection between the risk of these diseases and the polymorphisms. However, available lines of evidence suggest the importance of examining the link between NRF2 polymorphisms and other oxidative stress-related diseases.

Base Sequence↗

PubMed2005

The G-113A polymorphism in CYP1A2 affects the caffeine metabolic ratio in a Chinese population.

OBJECTIVE: This study was designed to better understand genetic variation in the cytochrome P450 (CYP) gene CYP1A2 and its impact on CYP1A2 activity in Chinese subjects. METHODS: CYP1A2 genetic polymorphisms were screened by direct sequencing in 27 selected Chinese subjects. Plasma 1,7-dimethylxanthine/caffeine ratios 5 hours after a 100-mg caffeine administration, used as an index of CYP1A2 in vivo activity, were determined in 422 healthy subjects. Five single-nucleotide polymorphism markers, including G-860A (CYP1A2*1C), T-3594G, G-3113A, A-163C (CYP1A2*1F), and C5347T (CYP1A2*1B), were selected and genotyped by either polymerase chain reaction-restriction fragment length polymorphism or direct sequencing. RESULTS: Thirteen polymorphisms and 2 linkage disequilibrium blocks with a boundary around -2467 were identified at this locus. The allele frequency for -3860A, -3594G, -3113A, -163C, and 5347T was 0.21, 0.15, 0.10, 0.36, and 0.14, respectively, in the CYP1A2-phenotyped cohort. A significant difference in CYP1A2 activity was observed among genotypes of polymorphism G-3113A (P = .038), and CYP1A2 activity in subjects carrying the AA genotype was lower than that in those carrying the GA (P = .096) and GG genotypes (P = .036): -0.45 +/- 0.05 (mean +/- SD), -0.32 +/- 0.16, and -0.29 +/- 0.16, respectively. Further analysis based on haplotype pairs found a 1.92-fold variation (95% confidence interval, 1.13-2.71) in mean CYP1A2 activity between haplotype pairs 13 and 15, and the difference was significant (-0.19 +/- 0.15 versus -0.45 +/- 0.05, P = .016). As compared with haplotype pair 10, haplotype pairs 9 and 15 and most haplotype pairs heterozygous for the haplotype with an A allele at -3113, including pairs 5, 8, and 12, also showed significantly lower CYP1A2 activity (P = .015, .048, .008, .024, and .014 for pairs 5, 8, 9, 12, and 15, respectively). In addition, haplotype pairs 5, 9, and 12 also showed significantly lower CYP1A2 activity than pair 13 (P = .034, .020, and .037 for pairs 5, 9, and 12, respectively). CONCLUSIONS: The G-3113A polymorphism is associated with decreased CYP1A2 activity, haplotype pairs 10 and 13 are responsible for high CYP1A2 activity, and haplotype pairs 5, 8, 9, 12, and 15 are responsible for low CYP1A2 activity in Chinese subjects.

Adolescent↗

PubMed2006

Two germ line polymorphisms of the tumour suppressor gene p53 may influence the biology of chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is characterised by the accumulation of mature B lymphocytes. Defects in the tumour suppressor gene p53 pathway are known to be important in CLL and p53 inactivation is associated with a particularly aggressive form of CLL. A single nucleotide polymorphism (SNP) in codon 72 of TP53 leads to a single amino acid change leading to a change in apoptotic potential and alters prognosis in squamous carcinomas. A polymorphism within intron 6 of TP53 has been postulated to alter the susceptibility to lung cancer. Our study looked at the influence of these two polymorphisms in a cohort of approximately 200 CLL patients. The codon 72 polymorphism A2/A2 genotype (homozygous arginine) was associated with an increased susceptibility to CLL and CD38 negativity but did not appear to influence other biological behaviour or clinical response. The intron 6 polymorphism A2/A2 genotype was strongly associated with early stage disease, CD38 negativity and a longer time to first treatment. The effect on time to treatment did not retain significance in multivariate analysis and the polymorphism did not predict for overall survival (OS). Detailed investigation of the complete TP53 genotype is warranted to further characterise the role of SNPs in p53 and their influence on CLL.

Adult↗

PubMed2006

Association of TNF-alpha polymorphism with susceptibility to and severity of non-small cell lung cancer.

BACKGROUND: Genetic polymorphisms in the promoter region of the tumor necrosis factor-alpha (TNF-alpha) gene are involved in the regulation of expression levels and have been associated with various inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter region of the TNF-alpha gene (-308 G/A and -238 G/A) for their role in the susceptibility to and severity of non-small cell lung cancer (NSCLC), by means of an allelic association study. METHODS: Using a case-control study design, lung cancer patients (n = 202) and appropriate age- and sex-matched controls recruited from the health check-up unit (n = 205) were subjected to genotype analysis for these polymorphisms, using a high-throughput allelic discrimination method. RESULTS: Genotype was analyzed using the polymerase chain reaction-restriction fragment length polymorphism technique with genomic DNA isolated from peripheral blood lymphocytes. Overall, the distribution of the genotype frequencies of TNF-alpha-308 A/G and -238 A/G were significantly different between the lung cancer patients and the healthy controls, and also different between patients with lung cancers of various stages (p < 0.0001). Logistic regression analysis revealed that higher odds ratios (ORs) for lung cancer were seen for individuals with TNF-alpha-308 AA/GA genotypes against GG genotype (an OR of 3.75, 95% CI 2.38-5.92, p < 0.0001), and lower ORs were seen for individuals with TNF-alpha-238 AA/GA genotypes against GG genotype (an OR of 0.26, 95% CI 0.13-0.50, p < 0.0001). The patients carrying a homologous AA or heterologous GA genotype at TNF-308 (p = 0.017), or a homologous GG genotype at TNF-238 (p = 0.001), had a tendency to advanced disease. CONCLUSIONS: A significant association between the 308 G/A and 238 G/A polymorphisms in the promoter region of TNF-alpha and the susceptibility to lung cancer was demonstrated. Also, these two polymorphisms were associated with the severity of lung cancer. The -308 A allele has a promotive effect for lung cancer development and progression, whereas the -238 A allele has a protective function against lung cancers.

Adenocarcinoma↗

PubMed2006

Polymorphisms of insulin receptor substrate 1 and beta3-adrenergic receptor genes in gestational diabetes and normal pregnancy.

Gestational diabetes mellitus (GDM) is considered an important risk factor for the development of type 2 diabetes mellitus. We studied possible relations between GDM and both insulin receptor substrate 1 (IRS-1) (Gly972Arg) and beta3-adrenergic receptor (ADRB3 Trp64Arg, beta3-AR) gene mutations, considered potential modifying factors in the etiology of type 2 diabetes mellitus. We evaluated the 2 gene mutations in late gestation in 627 pregnant women, all studied using the glucose challenge test, followed (in positive tests) by the oral glucose tolerance test (100 g, Carpenter and Coustan [J Obstet Gynecol. 1982;144:768-773] criteria) We diagnosed 309 women with GDM, 41 with gestational impaired glucose tolerance and 277 normal pregnant women. Age, family history of diabetes, prepregnancy body mass index, weight gain during pregnancy, plasma glucose levels, hemoglobin A1c, islet autoantibody levels, and insulin treatment during pregnancy were all evaluated. All pregnant women were genotyped for IRS-1 (Gly972Arg) and beta3-AR (ADRB3 Trp64Arg) polymorphisms. The frequency of IRS-1 gene polymorphism was significantly higher in women with GDM than in women with a normal glucose tolerance (NGT) (P = .039), and there was a significant trend (P = .032) in the increasing frequency of mutant allele Arg from NGT > gestational impaired glucose tolerance > GDM. The search for beta3-AR gene polymorphism showed no significant differences between women with GDM and women with NGT. The X-Arg genotype of IRS-1 was significantly associated with a positive family history of diabetes in NGT (P = .006) and neared significance in GDM (P = .057). Moreover, we found that NGT carriers of both polymorphisms had a higher prepregnancy body mass index than carriers of the IRS-1 variant alone (P = .0034), the beta3-AR variant alone (P = .039), or neither (P = .048), suggesting a possible synergistic effect of the 2 gene polymorphisms. These results suggest that the IRS-1 genetic polymorphism is involved in the occurrence of gestational diabetes, as well as type 2 diabetes mellitus.

Adult↗

PubMed2006

Nucleotide polymorphisms associated with Internal Transcribed Spacer (ITS) regions of ocular isolates of Aspergillus flavus.

PURPOSE: To analyse the genetic similarity among ocular isolates of Aspergillus flavus by Polymerase chain reaction based Restriction Fragment Length Polymorphism (PCR-RFLP) and DNA sequencing. MATERIALS AND METHODS: Seven ocular isolates of A. flavus from 5 patients (3 from paient 1, and four isolates from patients no. 2, 3, 4, and 5 respectively) consisting of 2 Aqueous Humor (AH), 2 Vitreous fluid (VF), 1 eviscerated material, 1 corneal button were included in the study. The three specimens from 1 were one each of AH, VF and corneal button. The fungal isolates were amplified using primers targeting ITS region and the amplicons were subjected to PCR-RFLP using Hae-III enzyme and DNA sequencing to analyse the genetic similarity. RESULTS: A. flavus isolates yielded a specific product of 595 bp after amplification. All the seven A. flavus isolates showed similar pattern of digestion with Hae-III . However, DNA sequencing of ITS amplicons revealed 97.7% genetic similarity and 2.3% dissimilarity with nucleotide polymorphisms -- single, double and multiple pertaining to inversion, substitution, insertion and deletion in comparison with that of standard strain of A. flavus ATCC 16883 [Accession Number ]. A. flavus isolated from AH, VF and corneal button from the same patient showed similar nucleotide polymorphisms as against other isolates which exhibited distinct polymorphisms. This pattern of nucleotide polymorphisms in A. flavus isolates is novel and first time reported in literature to the best of our knowledge. CONCLUSION: DNA sequencing proves to be a useful molecular tool in screening for nucleotide polymorphisms among fungal isolates.

Aqueous Humor↗

PubMed2006

Tumour necrosis factor gene complex polymorphisms in chronic obstructive pulmonary disease.

We aimed to examine the role of tumour necrosis factor gene complex polymorphisms in subjects with chronic obstructive pulmonary disease (COPD). We hypothesized that individuals possessing polymorphic variants associated with higher tumour necrosis factor (TNF) secretion would be more susceptible to and/or have more severe disease. Patients with COPD and population controls underwent detailed clinical phenotyping. Genotyping for the tumour necrosis factor-308 and the lymphotoxin alpha NcoI (LTalpha polymorphisms was carried out by 'blinded' laboratory staff. Three hundred and sixty one individuals (220 cases and 141 controls) were recruited. We showed an association between the LTalphaNcol polymorphism and forced vital capacity (FVC) in a population of older adults with and without COPD. The LTalphaNcol*2 allele was associated with poorer lung function, under a codominant model, with a fall in FVC (expressed as a percentage of its predicted value) of 3.7% for each copy of the LTalphaNcol*2 allele possessed (for FVC, regression coefficient (95% CI)=-3.73(-7.01 to -0.44), P=0.026; for FEV(1) regression coefficient=-3.56(-7.80 to 0.70), P=0.101. However, there was no difference in genotype distribution between the case and control populations. This study adds weight to the suggestion that the TNF gene complex is involved in physiological alterations (FVC) that may affect the development and severity of COPD. The absence of a significant association between the TNF gene-complex polymorphisms in this study does not rule out a modest effect of these polymorphisms on the risk of COPD, as much larger studies are needed to detect modest gene effects on binary disease endpoints.

Aged↗

PubMed2004

Allele frequencies of two polymorphisms associated with the factor IX gene in Iranian population.

Indirect genetic diagnosis using polymorphic DNA markers can be useful in large-scale screening programs, which is technically simpler, more rapid and amenable. The main objective of this study was to test the informativeness of two common intragenic markers (TaqI and XmnI) in Iranian haemophilia B families to detect the carriers by using a strategy that would be accurate and informative, yet less expensive compared to direct mutation analysis. The efficacy of these sites has been examined in 50 unrelated Iranian haemophilia B families and 50 normal females. The method used was polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP), which is economical and the enzymes XmnI and TaqI are cheap enough to be accessible in most of laboratories in developing countries. Our results show that 25% of X-chromosomes had the restriction site for TaqI enzyme. The XmnI site was 21%. The heterozygosity rates for TaqI and XmnI polymorphisms were 37% and 38%, respectively. Using the two polymorphisms together, the informative rate reached 46%. Taking advantage of TaqI and XmnI polymorphisms, carrier detection was performed for seven females with unknown status in five haemophilia B families (including one large extended family) with positive history. Six of the girls were normal and one was haemophilia B carrier. Therefore, carrier detection might be possible for informative Iranian haemophilia B families in the familial cases. Additionally, similarities in term of heterozygosity rates for these two polymorphic sites were seen between some European and Iranian populations.

Alleles↗

PubMed2005

Association of polymorphisms in CYP17A1, MTP, and VLDLR with bone mineral density in community-dwelling Japanese women and men.

We examined whether a -34T --> C polymorphism of the gene for cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), a -493G --> T polymorphism of the microsomal triglyceride transfer protein gene (MTP), and a CGG repeat polymorphism of the very low density lipoprotein receptor gene (VLDLR) were associated with bone mineral density (BMD) in community-dwelling Japanese women and men. The -34T --> C polymorphism of CYP17A1 was associated with BMD in postmenopausal women, with the CC genotype being related to increased BMD. The -493G --> T polymorphism of MTP was associated with BMD in premenopausal women, with the TT genotype being related to increased BMD. The CGG repeat polymorphism of VLDLR was associated with BMD in men, with two (CGG)(n > or= 8) alleles being related to increased BMD. These results suggest that CYP17A1 and MTP are susceptibility loci for increased BMD in postmenopausal and premenopausal Japanese women, respectively, and that VLDLR constitutes such a locus in Japanese men.

Asian People↗

PubMed2001

A new DNA polymorphism in the 5' untranslated region of the human SREBP-1a is related to development of atherosclerosis in high cardiovascular risk population.

Sterol-regulatory element binding proteins (SREBPs) are ubiquitous transcription factors that regulate the genes encoding key proteins in the control of cholesterol homeostasis. We looked for mutations or polymorphisms within the sequences of the SREBP-1a gene critical for the synthesis and/or activity of the protein in 204 asymptomatic men. A single G deletion at base pair -36 of the translation initiation site (designated G-) was found using single-strand conformation polymorphism (SSCP), in addition to three rare variants. This new marker was then assessed for its influence on the lipid parameters of 812 men at high cardiovascular risk, and on the presence of echographic atherosclerotic plaque in their peripheral arteries. The allelic frequency of the -36delG polymorphism was 0.58. At least one plaque was found in the carotid in 24% of subjects, in the femoral arteries of 48%, and in the aorta of 25%. There were significant associations between the -36delG polymorphism and mean total cholesterol (p=0.02) and LDL-cholesterol (P=0.02). There was a graded relationship between the G- allele and the presence of carotid plaque (r=0.084, P=0.02). In addition, there was a statistically significant interaction between the -36delG genotype and the apoE phenotype for plasma LDL-cholesterol (P=0.04) and apoB (P=0.05), suggesting a gene-gene interaction. Stepwise multiple regression analysis for lipid traits, risk factors, and apoE phenotype showed an independent association between carotid plaque and the -36delG polymorphism (beta=0.311, P=0.03). Thus, we have identified a new polymorphism in the 5' untranslated region of the SREBP-1a gene, and demonstrated its association with an atherogenic lipid profile and echographic plaques.

5' Untranslated Regions↗

PubMed1996

Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol.

A common MspI polymorphism (G/A) in the promoter region of the APOA1 gene (-75 bp) has been shown to be associated with plasma apo A-I and HDL-C variation in several, but not all, studies. Recently another MspI polymorphic site (+/-) in the 5'region of APOA1 (+83 bp) has been identified which may also be relevant to HDL metabolism. This study was undertaken to elucidate the individual and combined effects of these two polymorphisms on plasma apo A-I and HDL-C levels in a cohort of 534 normoglycemic US Whites from the San Luis Valley, Colorado. Both polymorphisms were in strong linkage disequilibrium (P < 0.005); of the expected four haplotypes (G+, G-, A+, A-) the A- was not observed in this sample. Single site RFLP analysis revealed an independent and significant effect associated with each polymorphism on plasma apo A-I variation but not on HDL-C variation. Further analyses showed that the genotype effects of both polymorphisms were confined to non-smokers only. Haplotype analysis, combining both RFLPs, was more informative as this explained almost twice the amount of phenotypic variation in plasma apo A-I compared to single RFLP analysis in non-smokers. Compared to the most common haplotype (G+), the A+ and G- haplotypes were associated with increased plasma apo A-I levels by 6.7 mg/dl and 22.0 mg/dl, respectively in non-smoking men, and by 4.6 mg/dl and 15.1 mg/dl in non-smoking women, respectively. These data indicate that haplotype analysis in this region may be important to elucidate the functional significance of the APOA1 gene in HDL metabolism.

Adult↗

PubMedDate not supplied

Polymorphisms in the human homologue of the drosophila Indy (I'm not dead yet) gene.

Insertion of a P element in one copy of the Drosophila Indy gene results in a significant increase in Drosophila lifespan. In order to examine whether mutations or polymorphisms in the human Indy gene promoted human longevity, the Indy gene was sequenced in 13 subjects of age 90-99, 12 subjects between age 38-49 and 18 subjects <age 23. Three coding region polymorphisms resulting in an amino acid change, F62L, V80L and I550V, two silent coding region polymorphisms, A99A and I551I, and three intron polymorphisms, IVS2+10 C deletion, IVS9+40T/A and IVS10+38C/T were identified. The I550V polymorphism occurred in whites, Hispanics, Asians and African-Americans at allele frequencies of 0.3514, 0.5104, 0.4274 and 0.5375, respectively. The I550V polymorphism was genotyped in 2366 subjects and examined for its association with age and weight.

Adult↗

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