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PubMed2003

Angiotensin-converting enzyme gene polymorphisms in patients with pulmonary sarcoidosis: impact on disease severity.

Angiotensin converting enzyme (ACE) is a metallopeptidase with a key function in the regulation of blood pressure and volume. The ACE1 gene, on chromosome 17, contains a insertion/deletion (I/D) polymorphism in intron 16. The D allele of this polymorphism is linked with raised serum ACE (sACE) levels. Sarcoidosis is a systemic disease of granulomatous inflammation that primarily affects the lung and lymph system. It is often accompanied by elevated sACE related to ACE production from granuloma cells. The ACE I/D polymorphism has been tested for association or linkage with the risk of sarcoidosis. Though published results are conflicting, there seems to be suggestive evidence of a minor pro-inflammatory influence of the ACE D allele in sarcoidosis. At present, a more accurate interpretation of sACE levels in diagnosis and monitoring of sarcoidosis seems to be the main value of ACE I/D genotyping.

Animals↗

PubMed2003

[The association between glucocorticoid receptor gene G1666T polymorphism and cerebral infarction in Chinese].

OBJECTIVE: To ascertain whether the human glucocorticoid receptor (GR) gene polymorphism is associated with cerebral infarction (CI) and essential hypertension (EH) in Chinese. METHODS: This is a case-control study of Chinese DNA samples abstracted from 163 subjects. The samples were analysed by a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to determine the intron 4 variant of human GR gene. RESULTS: By analysis of the samples from both sexes as a whole, no association was observed between the EH+CI group and control group, and between the CI group and control group. However, by analysis of the samples from the females, weak association was observed between the EH+CI group and control group, and between the CI group and control group; the frequency of allele G was 0.64 for the EH+CI group, 0.69 for CI group and 0.46 for control group. CONCLUSION: The G allele may be a predisposing gene marker, GR gene intron 4 polymorphism contributes to the development of CI in females.

Asian People↗

PubMed2005

[Whole exon 5 and intron 5 replaced by RHD/CE in partial D phenotype DVa (Hus)].

The study was purposed to analyze DNA and allele structure of the partial D phenotypes D(Va) and D(VI) of the Rhesus blood group in Chinese. Through polymerase chain reaction (PCR) and direct genomic DNA sequencing, the RHD gene was detected in three weak D individuals identified serologically. The results showed that among the three weak D individuals, one was identified as partial D phenotype D(Va) (Hus) type and genotyped DccEe; another two were testified as D(VI) III type and genotyped DCcee. Moreover, the breakpoints of the replaced region by RHCE in D(Va) (Hus) were 5' end of the exon 5 and 3' end of the intron 5, and there were 7 novel polymorphisms in intron 5: 23-25(GCA)2, 98G>A, 168-169insG, 205-206insT, 494-495insA, 1256-1257insC, 1347G>T. In conclusion the whole exon 5 and intron 5 are replaced by RHCE in D(Va) (Hus) detected in Chinese.

China↗

PubMed2004

[Correlation analysis between single nucleotide polymorphism of the leptin receptor intron 8 and fatness traits in chickens].

Leptin receptor plays an important role in leptin functioning signal transduction and it may have direct effects on the deposition of adipose tissues and the body weight, the leptin receptor (OBR) gene, therefore, can be considered as a candidate gene in the study of fat deposition of the chicken. The function of OBR gene has been intensively studied in mammals, but study of OBR gene in the chicken is still rare. In this paper, the NEAU divergent selection broiler lines for abdominal fat were used. Body weight and fatness traits were measured in the sixth generation broiler population of the two lines at 7 week of age. Two pairs of primers for intron 8 of OBR gene were designed according to the database of chicken genomic sequence (Accession No. AF222783). The SNP was detected by DNA sequencing, and PCR-SSCP method was then developed to screen the population. The correlation analysis between the polymorphisms of the intron 8 of OBR gene and growth and fatness traits in the population was carried out using the appropriate statistical model. Two SNPs were found in the population. Those were T500C and G659A. The least square analysis showed that BB genotype birds had significant higher (P < 0.05) abdominal fat weight and percentage of abdominal fat than AA and AB genotype birds, and AA genotype birds had significant lower (P < 0.05) weights of livers than AB and BB genotype birds at the same time. From these results we can putatively drew the conclusion that OBR gene may be a major gene to affect the fatness traits or linked to the major gene, and the two polymorphisms found in OBR gene intron 8 region could be used to select the chicken for low abdominal fat in molecular marker-assisted selection programs.

Adipose Tissue↗

PubMed2003

Polymorphisms within the promoter and the intron 2 of the serotonin transporter gene in a population of bulimic patients.

The serotonin transporter (5-HTT) gene is a firm candidate to explain eating disorders. In this association study, two different polymorphisms were analysed: a variable number of tandem repeat (VNTR) polymorphism in intron 2 and a deletion/insertion polymorphism (5-HTTLPR) in the promoter region. The hypothesis that these gene polymorphisms may be a susceptibility factor in bulimia nervosa (BN) was explored in a female population of 102 purgative bulimics. BN patients who have suffered preceding anorexia nervosa (AN) episodes formed the so-called previous AN bulimic patient group. In our sample of normal-eater controls and purging type bulimics, regardless of whether or not the BN patients had suffered prior AN episodes, no differences were found considering the frequencies of genotypes, alleles or haplotypes of both polymorphic regions of the 5-HTT gene.

Adolescent↗

PubMed2004

Allelic length of a CA dinucleotide repeat in the egfr gene correlates with the frequency of amplifications of this sequence--first results of an inter-ethnic breast cancer study.

Overexpression of the epidermal growth factor receptor (EGFR) is a common finding in invasive breast cancer and represents a potential target for new treatment options. However, little is known about the parameters that might indicate a potential clinical response for these anti-EGFR-based therapies. In order to gain further insights into the interplay between the length of a CA-SSR I repeat in intron 1 of egfr, copy numbers of this untranslated regulatory sequence, and protein expression, the present study investigated breast cancers from Germans and Japanese patients by microsatellite analysis, quantitative 5' nuclease assay by egfr enzyme-linked immunosorbent assay (ELISA), and comparative genomic hybridization (CGH). Japanese breast cancer patients displayed significantly longer alleles for the CA-SSR I repeat (p < 0.001), associated with significantly lower EGFR expression (mean 65 versus 36 fmol/mg membrane protein). Allelic imbalance (restricted to CA-SSR I) was observed in 55% of the informative Japanese breast cancers compared with only 34% of the German breast cancer reference group. Using a quantitative 5' nuclease assay for egfr, a significantly higher percentage of Japanese breast cancer patients revealed amplifications of the CA-SSR I repeat (p < 0.01). Japanese patients with these amplifications were characterized by a significantly higher EGFR content compared with the German breast cancer patients (p < 0.05). These data show, on the one hand, that the correlation of EGFR overexpression and an inherited CA repeat polymorphism within intron 1 of egfr is a general finding in breast cancer, as has been shown previously. On the other hand, the data demonstrate clearly for the first time an interaction between the length of a polymorphism in intron 1 of egfr as an inherited genetic factor and the frequency of egfr amplification, as an acquired genetic factor, both factors contributing to EGFR overexpression in breast cancer. This new knowledge about mechanisms of regulation of EGFR expression might serve as an additional basis for evaluating anti-EGFR-based therapies.

Alleles↗

PubMed2003

[The association between polymorphism of endothelial nitric oxide synthase gene and cirrhotic portal hypertension].

OBJECTIVE: To study whether the liver cirrhosis and portal hypertension are associated with a -786T-->C mutation at promoter and VNTR polymorphism in intron 4 and a 894 G-->T mutation at exon 7 of the eNOS. METHODS: A case control study of 106 patients with liver cirrhosis due to HBV was performed in comparison with 108 controls with the help of PCR-SSCP or RFLP. RESULTS: There was no difference in the gene frequency of allele G of promoter between LC(+) group and other groups. The frequencies of the T and TG genotype at exon7 and the a allele and ab genotype in intron 4 were significantly higher in portal hypertension group (LC(+)) than in liver cirrhosis group alone and control group (P < 0.05). Patients of the liver cirrhosis with coexistence of the T and a alleles had a higher incidence of portal hypertension (P < 0.05) than those with only one of the two alleles or without any of the two alleles. Multivariate logistic regression analysis revealed that VNTR polymorphism in intron 4 and 894 G-->T mutation at exon 7 of the eNOS gene are independent risk factors for the occurrence of portal hypertension in patients with liver cirrhosis. CONCLUSION: The T allele at exon 7 and a allele in intron 4 are associated with the occurrence of portal hypertension in patients with liver cirrhosis. The ocurrence of portal hypertension with liver cirrhosis is higher in patients who have both T and a allele than patients who have either T or a allele alone, which is an independent risk in occurrence of portal hypertension, respectively. TGab may be susceptibility genotype of portal hypertension.

Adult↗

PubMed2004

Body mass index but not a polymorphism of the interleukin-1 receptor antagonist (IL-1 RA) gene is associated with age at natural menopause.

BACKGROUND: A genetic component of the onset of menopause has been described and several candidate genes have been identified. We hypothesized that carriage of a polymorphism of the interleukin-1 receptor antagonist gene (IL-1 RA) is associated with an early age at menopause. METHODS: In a prospective cohort study, 90 consecutive postmenopausal Caucasian women were genotyped by PCR for the presence of an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA. RESULTS: We found that 36/90 (40%) women were homozygous for the wild-type allele 1 and 49/90 (54%) women were heterozygous for any of the variant alleles (1/2 [n = 44], 1/3 [n = 3], 2/3 [n = 2]). Two women (2%) were homozygous carriers of the variant allele 2. The wild-type allele 1 was identified on 119 of 180 chromosomes for an allele frequency of 0.66. The polymorphic alleles 2 and 3 were present on 56 and 5 chromosomes, respectively (allele frequencies 0.31 and 0.03, respectively). No correlation between the IL-1 RA genotype and the age at menarche and menopause, the length of the reproductive period, and the number of deliveries and miscarriages was ascertained. As to allele frequencies, homozygous and heterozygous carriers of the variant allele 2 had a median age at menopause of 50 (range 40-48) years, compared to 49.5 (range 39-56) years for women with no allele 2 (p value 0.41). Women with at least one allele 2 had a median age at menarche of 13 (range 10-16) years, compared to 13 (range 10-17) years for women with no allele 2 (p value 0.1). Decreasing body mass index, but not smoking, was correlated with an increasing age at natural menopause (r = -0.23, p = 0.04). CONCLUSIONS: Our preliminary data suggest that an 86-base pair tandem repeat polymorphism in intron 2 of IL-1 RA does not modulate the onset and cessation of menses in this cohort of Caucasian women.

Adult↗

PubMed2001

Gene polymorphisms of immunoregulatory cytokines and angiotensin-converting enzyme in Wegener's granulomatosis.

Wegener's granulomatosis is a granulomatous and vasculitic disease of unknown origin. Gene polymorphisms are known to affect phenotypes of numerous diseases. Polymorphisms within the angiotensin-converting enzyme (ACE), transforming growth factor-beta1 (TGF-beta1), and interleukin-10 (IL-10) genes are suspected to modify the course of granulomatous disorders. We examined whether the genotype frequencies of the named polymorphisms differ in Wegener's granulomatosis from those in healthy controls. Thirty-nine patients with Wegener's granulomatosis were genotyped for the deletion/insertion polymorphism in intron 16 of the ACE gene, a biallelic polymorphism in codon 25 of the TGF-beta1 gene and a biallelic polymorphism at position -1082 of the IL-10 gene and compared with healthy blood donors. For the ACE polymorphism no significant differences were detected neither in the allele frequencies nor in the genotype frequencies. For TGF-beta1 a trend to genotype CG was found. The most interesting result was the observed, significant shift to genotype AA of the IL-10 polymorphism in Wegener's granulomatosis. IL-10 and TGF-beta1, immunoregulatory cytokines capable of down-regulating T helper cell type 1 response, showed a significant shift or a trend, respectively towards genotypes associated with reduced cytokine release, leading to the hypothesis that different immunoregulatory cytokine patterns dependent on gene polymorphisms might be involved in the pathogenesis of Wegener's granulomatosis.

Adult↗

PubMed2004

A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus in Germans.

BACKGROUND: CYP27B1 hydroxylase catalyzes the conversion of 25 hydroxyvitamin D(3) (25OHD(3)) to 1,25(OH)(2)D(3), the most active natural vitamin D metabolite, which plays a role in the regulation of immunity and cell proliferation. We therefore investigated two single nucleotide polymorphisms in the CYP27B1 hydroxylase gene for an association with Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus. METHODS: Patients with Addison's disease (n=124), Hashimoto's thyroiditis (n=139), Graves' disease (n=334), type 1 diabetes mellitus (n=252) and healthy controls (n=320) were genotyped for the promoter (-1260) C/A polymorphism and for the intron 6 (+2838) C/T polymorphism of the CYP27B1 gene. Patients and controls were compared using genotype-wise and allele-wise X(2) testing. RESULTS: A significant association was found between allelic variation of the promoter (-1260) C/A polymorphism and Addison's disease, Hashimoto's thyroiditis, Graves' disease and type 1 diabetes mellitus (P=0.0062, P=0.0173, P=0.0094 and P=0.0028 respectively). Significant differences were also observed for the intron 6 (+2838) C/T polymorphism (P=0.0058) in Hashimoto's thyroiditis but not for the other autoimmune endocrine diseases. CONCLUSIONS: The CYP27B1 promoter (-1260) C/A polymorphism appears to be associated with endocrine autoimmune diseases but the CYP27B1 intron 6 (+2838) C/T polymorphism appears to be associated only with Hashimoto's thyroiditis. These results imply a regulatory difference of the CYP27B1 hydroxylase to predispose to endocrine autoimmunity.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed2006

Identification of adiponectin and its receptors in human osteoblast-like cells and association of T45G polymorphism in exon 2 of adiponectin gene with lumbar spine bone mineral density in Korean women.

OBJECTIVE: The role of adiponectin in bone metabolism has been recently reported in in vitro and in vivo studies. There has been no report on the association of adiponectin gene polymorphism and bone mineral density (BMD). Therefore, we investigated whether two single nucleotide polymorphisms (SNPs), T45G and G276T, in the adiponectin gene were related to BMD in Koreans. We also report on the identification of adiponectin and its receptors 1 and 2 in human osteoblast-like cell lines. PATIENTS AND MEASUREMENTS: MG-63 cells were cultured and osteogenic and adipogenic differentiations from human mesenchymal stem cells (hMSCs) were performed. RNA was then extracted from the cultured cells and reverse transcriptase-polymerase chain reaction (RT-PCR) was performed using primers for adiponectin and for the adiponectin receptor genes. In 249 female and 80 male subjects, measurements were made of their lumbar spine and femoral neck BMDs, and biochemical markers of bone turnover. The genotyping of the T45G polymorphism in exon 2 and the G276T polymorphisms in intron 2 in the adiponectin gene was performed using an allelic discrimination assay with a TaqMan probe. Analyses were performed separately in each cohort. RESULTS: We found that the mRNAs for adiponectin and for adiponectin receptor 1 (AdipoR1) and 2 (AdipoR2) were expressed in the MG-63 cells. Sequencing of the PCR products revealed that they were identical to human adiponectin, AdipoR1 and AdipoR2, respectively. mRNAs for adiponectin, AdipoR1 and AdipoR2 were also expressed in the osteoblastic and adipogenic cell lines differentiated from hMSCs. For the polymorphism study, the frequencies of T45G and G276T in the adiponectin gene were in compliance with Hardy-Weinberg equilibrium and the two polymorphisms were in complete linkage disequilibrium (D' = -1.0, P < 0.001). In the female cohort, subjects with G alleles at the T45G locus had significantly lower lumbar spine BMD than those subjects with the TT genotype. Although BMD levels showed no association with the G276T locus, the GT genotype group showed significantly higher urine deoxypyridinoline levels than other genotype groups. In the male cohort, no association was observed between adiponectin genotypes and BMD levels. CONCLUSIONS: We observed the expression of adiponectin, AdipoR1 and AdipoR2 in the MG-63 cell line and the osteoblastic cell line differentiated from hMSCs. T45G polymorphism in exon 2 of the adiponectin gene is associated with lumbar spine BMD and G276T polymorphism in intron 2 of the adiponectin gene is associated with the urine deoxypyridinoline level in Korean women. Additional studies are needed to elucidate the precise contribution of adiponectin to bone mineral metabolism.

Absorptiometry, Photon↗

PubMed2000

Identification of novel human GH-1 gene polymorphisms that are associated with growth hormone secretion and height.

Height, which is partially determined by GH secretion, is genetically influenced. The purpose of this study was to identify polymorphisms in the GH-1 gene, which are associated with altered GH production. The subjects included prepubertal short children with GH insufficiency without gross pituitary abnormalities (n = 43), short children with normal GH secretion (n = 46), and normal adults (n = 294). A polymorphism in intron 4 (P-1, A or T at base 1663) was identified. Two additional polymorphic sites (P-2, T or G at base 218, and P-3, G or T at base 439) in the promoter region of the GH-1 gene were also identified and matched with the P-1 polymorphism (A or T, respectively) in more than 90% of the subjects. P-1, P-2, and P-3 were considered to be associated with GH production, and the results of P-2 are explained as a representative in this abstract. For example, the allele frequency of T at P-2 in prepubertal short children with GH insufficiency without gross pituitary abnormalities (58.1%) was significantly different from that in short children with normal GH secretion and normal adults (37.0% and 43.5%, respectively; P < 0.001). Furthermore, significant differences were observed in maximal GH peaks in provocative tests (11.1 vs. 18.2 ng/mL, P = 0.006), insulin-like growth factor I SD scores (SDS) (-2.4 vs. -0.8, P < 0.0001), and height (Ht) SDS (-3.7 vs. -3.0, P = 0/001) in children with the T/T or G/G genotypes at P-2, respectively. In the entire study group, significant differences in insulin-like growth factor SDS (T/T, -0.9; G/G, -0.2; P = 0.0009) and Ht SDS (T/T, -1.0; G/G, -0.4; P = 0.022) were observed between the T/T and G/G genotypes at P-2. These data indicate that GH secretion is partially determined by polymorphisms in the GH-1 gene, which explain some of the variations in GH secretion and Ht.

Adult↗

PubMed2004

DNA sequence analysis of monoamine oxidase B gene coding and promoter regions in Parkinson's disease cases and unrelated controls.

The allele G of the intron 13 G/A polymorphism of the monoamine oxidase B gene (MAO-B) has been associated with Parkinson's disease (PD) in several studies. Apart from a potential direct effect on splicing processes, the association of this intronic polymorphism with PD is due possibly to linkage disequilibrium with other mutations in the coding or promoter regions of the gene. We addressed this latter hypothesis by determining the DNA sequence of the entire MAO-B coding region comprising 15 exons and partial intronic sequences flanking each exon, in 33 cases with idiopathic PD and 38 unrelated controls. The promoter region of MAO-B gene up to base -1,369 from ATG (start point of mRNA translation) was also sequenced to identify variants with potential functional effects on gene transcription. In the promoter region, a new polymorphism consisting of a C to T single base change was detected in position -1,114 from ATG, with an allelic frequency of 3.5%, but it was not associated with PD risk. No commonly occurring (>10%) polymorphisms were found in the exons or the intronic sequences flanking the exons, although several rare variants were detected in the coding and promoter regions.

Aged↗

PubMed1997

Association of DNA polymorphism in the first intron of the tyrosine hydroxylase gene with disturbances of the catecholaminergic system in schizophrenia.

We examined whether there are clinical or biological differences in chronic schizophrenic patients sharing a rare variant allele (a perfect ten tetranucleotide repeats allele of the human TH01 microsatellite) in the tyrosine hydroxylase (TH) gene. For that purpose, clinical parameters (PANSS subscores) and plasma measurements (homovanillic acid and 3-methoxy-4-hydroxy-phenylglycol (MHPG)) were analyzed in five schizophrenic patients sharing the rare allele and 19 schizophrenic patients who did not possess this allele. The mean concentration of plasma HVA and plasma MHPG were significantly lower in the group of schizophrenic patients sharing the rare allele. No other group differences were observed between both groups. These results suggest that this TH gene polymorphism may be associated with disturbances of the catecholaminergic pathway.

Adult↗

PubMed2005

Partial molecular characterization, polymorphism and chromosomal localization of the porcine PSMD4 gene.

The complete coding sequence of porcine PSMD4 gene encoding proteasome 26S non-ATPase subunit 4 was obtained by the reverse transcriptase-polymerase chain reaction (RT-PCR) and deposited in GenBank nucleotide database (AY704418). The nucleotide sequence and the predicted protein sequence shared the high sequence identity with their mammalian counterparts. A G/A single nucleotide polymorphism in intron 9 detected as Hin6I PCR-restriction fragment length polymorphism (PCR-RFLP) shows allele frequency differences between Meishan, Erhualian, Tibetan, Large White and Duroc breeds. Analyses of somatic cell hybrid panel (SCHP) and radiation hybrid (IMpRH) panel revealed that PSMD4 gene maps to SSC 4q21-q23 and closely linked the SW512 (14 cR, LOD = 19.47).

Amino Acid Sequence↗

PubMed1998

Polymorphism of the apolipoprotein E and angiotensin I converting enzyme genes in Japanese patients with myocardial infarction.

OBJECTIVE: To investigate the genetic contribution for myocardial infarction. METHODS: We investigated common polymorphisms of apolipoprotein E gene and angiotensin converting enzyme (ACE) gene in Japanese population. Subjects were 422 healthy people and 254 patients with myocardial infarction. We evaluated the 287 base pair (bp) insertion (I)/deletion (D) polymorphism in intron 16 of the ACE gene and a polymorphism in the apolipoprotein E gene by using the polymerase chain reaction. RESULTS: The ACE genotype prevalences for II, ID, and DD were 36.2, 46.1, and 17.7%, respectively, among the myocardial infarction patients. The prevalence of the D allele of the ACE gene among the myocardial infarction patients (0.593) exceeded that among the healthy controls (0.407). The prevalences of the epsilon 2, epsilon 3, and epsilon 4 alleles of the apolipoprotein E genotype among healthy controls were 0.024, 0.882, and 0.094, and those among survivors of myocardial infarction were 0.024, 0.834, and 0.142, respectively. Myocardial infarction patients had an excessive prevalence of the apolipoprotein E epsilon 4 allele (P < 0.05). Multiple regression analysis demonstrated that the independent risk factors for developing myocardial infarction were age, DD genotype of ACE gene, and apolipoprotein E epsilon 4 allele. Stenotic coronary vessels in myocardial infarction patients did not differ significantly among the patients with various ACE and apolipoprotein E genotypes in the present study. CONCLUSIONS: Among the Japanese, apolipoprotein E epsilon 4 carriers and subjects with ACE DD genotype are at an increased risk of myocardial infarction.

Aged↗

PubMed2003

Identification of the BclI polymorphism in the glucocorticoid receptor gene: association with sensitivity to glucocorticoids in vivo and body mass index.

OBJECTIVE: Sensitivity to glucocorticoids differs between individuals, partially due to genetic variation in the glucocorticoid receptor (GR) gene. We studied the sequence alteration of a previously described intronic BclI polymorphism of the GR gene, and investigated whether there was an association with sensitivity to glucocorticoids and anthropometric parameters in a group of healthy elderly individuals. DESIGN AND MEASUREMENTS: In study group 1, two overnight dexamethasone suppression tests (DSTs) were performed: with 1 mg dexamethasone, and 2.5 years later with 0.25 mg dexamethasone. Anthropometric parameters were measured in a larger population (study group 2), as well as in a third study group, in which we also measured body composition by dual-energy X-ray absorbtiometry (DEXA) scans. SUBJECTS: Groups 1 and 2, respectively, 191 and 1963 male and female participants of the Rotterdam study, a population-based study in Dutch elderly. Study group 3: 370 elderly males (mean age 77.8 +/- 0.2 years) from Zoetermeer, the Netherlands. RESULTS: We identified the BclI restriction site polymorphism as a C/G substitution in intron 2, 646 nucleotides downstream from exon 2. After both 1 mg and 0.25 mg DST, heterozygous (CG) and homozygous G-allele carriers (GG) had lower cortisol levels than CC-carriers (P = 0.01 and P = 0.02, respectively). In study group 2, we found a lower body mass index (BMI; P = 0.006) and waist-hip ratio (WHR; P = 0.02) in G-allele carriers. In study group 3, again we found a lower BMI (P = 0.05) in G-allele carriers. No differences were found in fat mass. However, lean mass tended to be lower in G-allele carriers (P = 0.07). CONCLUSIONS: We characterized a BclI-RFLP (restriction fragment length polymorphism) of the GR gene as a C/G polymorphism in intron 2 of which the G-allele was associated with hypersensitivity to glucocorticoids. This resulted in a lower BMI in older individuals in general, while our study in elderly males suggests that the lower BMI is probably due to a greater loss of lean mass during the ageing process.

Aged↗

PubMed2004

Differential contribution of IL-1Ra isoforms to allele-specific IL-1Ra mRNA accumulation.

The interleukin-1 (IL-1) receptor antagonist (IL-1Ra) gene produces two isoforms of IL-1Ra, intracellular (icIL-1Ra) and secreted (sIL-1Ra). Distinct promoter regions control synthesis of each isoform. Five alleles of this gene, defined by sIL-1Ra intron 2 polymorphism, have been described. Although differences in IL-1Ra protein production have been demonstrated in various tissues and cells obtained from individuals carrying allele 1 vs. allele 2, the underlying mechanisms of this discrepancy remain poorly understood. We hypothesize that one mechanism contributing to differences in protein levels may be allele-specific accumulation of icIL-1Ra or sIL-1Ra mRNA. Quantification of allele-specific differences in mRNA accumulation in colonic biopsies and peripheral blood mononuclear cells (PBMC) of heterozygous individuals shows that the amount of allele 1-specific icIL-1Ra mRNA averaged four times higher relative to allele 2. In transfection assays, gene expression directed by the allele 1-specific icIL-1Ra promoter fragment was found to be greater than that directed by the allele 2 promoter, suggesting that icIL-1Ra promoter activity contributes to the disparity in the allele-specific icIL-1Ra mRNA accumulation. Our data show that differences in the transcriptional regulation of icIL-1Ra alleles 1 and 2 may be involved in the production of icIL-1Ra protein. Disregulated icIL-1Ra production may play a role in chronic inflammatory diseases where the balance between IL-1 and IL-1Ra has been implicated as a key pathogenic mechanism.

Alleles↗