Estrogen receptor alpha promoter polymorphism: stronger estrogen action is coupled with lower sperm count

BACKGROUND: Although the importance of estrogens in male reproduction is indisputable, little attention has been paid to the role of estrogen receptor (ER) gene mutations in male infertility. Significant correlation between (TA)n repeat allelic variants and lumbar bone mineral density was previously observed in the promoter region of the ERalpha gene, indicating that allelic combinations with higher number of (TA)n repeats are functionally more active genetic variants. METHODS: We studied the (TA)n repeat polymorphism situated in the promoter region of the ERalpha gene in a large group of infertile and normospermic men (n = 347). RESULTS: Although the (TA)n polymorphism failed to show a significant association with male infertility, we found a significant effect of this polymorphism on sperm count. In the group of infertile men, the mean TA repeat number and sperm concentration (P = 0.022) and total sperm number (P = 0.043) were inversely correlated, showing an association between higher TA repeat number (genotype A) and lower sperm production. In line with this observation, normospermic subjects with genotype A had a significantly lower mean sperm concentration with respect to men bearing genotype B with shorter TA alleles (P < 0.05) and a lower total sperm count (P < 0.01). CONCLUSIONS: Our data indicate that specific allelic combinations of the ERalpha, which confer a stronger estrogen effect, may negatively influence human spermatogenesis.     

Association of 5' estrogen receptor alpha gene polymorphisms with bone mineral density,vertebral bone area and fracture risk

This study investigates the influence of genetic variation of the estrogen receptor alpha (ESR1) gene locus on several bone parameters in 2042 individuals of The Rotterdam Study, a prospective population-based cohort study of elderly subjects. We analysed three polymorphic sites in the 5' region of the ESR1 gene; a (TA)(n)-repeat in the promoter region, and molecular haplotypes of the PvuII and XbaI RFLPs in intron 1, and inferred long-range haplotypes (LRH) thereof. We observed only three of the possible four PvuII-XbaI haplotypes in our population. A comparison with other Caucasian populations showed similar haplotype frequencies, while in Asian and African populations these were different. Linkage disequilibrium (LD) analysis between the PvuII-XbaI haplotype and the (TA)(n) repeat showed strong LD between the two sites. Reconstruction of long range haplotypes over the entire 5' region, revealed six frequent LRH. In men, we did not observe an association between the ESR1 polymorphisms studied and bone parameters. In women, we demonstrated an allele dose effect of haplotype "px" (P=0.003) and a low number of (TA)(n) repeats (P=0.008) with decreased lumbar spine bone mineral density (BMD) (4.8% lower BMD in women homozygous for haplotype "px", representing 28% of the population, compared with homozygous non-carriers) and decreased vertebral bone area (2.3% difference between extreme genotypes; P=0.016). Most importantly, we found an increased vertebral fracture risk with evidence for an allele dose effect with an odds ratio of 2.2 (95%CI 1.3-3.5) for haplotype "px", and 2.0 (1.5-3.2) for a low number of (TA)(n) repeats. The ESR1 genotype dependent fracture risk is largely independent of BMD and bone area. Combination of risk alleles at both loci by long-range haplotyping improved the associations slightly, but because of the strong LD between the two polymorphic sites, we were unable to determine if any particular polymorphic site is driving the associations found. We conclude that ESR1 polymorphism in the 5' (promoter) region is associated with vertebral fracture risk, lumbar spine BMD and vertebral bone area in postmenopausal women, but not in men. The molecular mechanism underlying this association needs further study.     

Association of repeat polymorphisms in the estrogen receptors alpha, beta, and androgen receptor genes with knee osteoarthritis

Genetic factors have been shown to play an important role in the etiology of osteoarthritis (OA). To elucidate the possible role of genetic variation in the estrogen receptors alpha and beta (ER-alpha, ER-beta) and androgen receptor (AR) genes with knee OA, the -1174(TA)(n), c.1092+3607(CA)(n), and c.172(CAG)(n) repeat polymorphisms of ER-alpha, ER-beta, and AR genes were studied. A case-control cohort of 158 patients with idiopathic knee OA and 193 controls were used. A significant difference was observed in the frequency distribution of -1174(TA)(9-25) and c.1092+3607(CA)(13-27) repeat polymorphisms of the ER-alpha and ER-beta genes between OA patients and controls (p<0.005 and p<0.0001, respectively). A significantly increased odds ratio (OR) for knee OA was observed in individuals having long alleles (LL) genotype for ER-alpha gene and LL and one short and one long allele (SL) genotypes for ER-beta gene compared to individuals with the short alleles (SS) genotype (95% CI 1.03-3.5; p=0.04 and CI 2.4-8.3 and 2.5-7.5; p < 0.001, respectively). When ORs were adjusted for various risk factors, it was observed that women with LL genotypes for ER-beta and AR genes showed significantly increased risk for OA development (p=0.002 and 0.001). An association between c.1092+3607(CA)(13-27) and c.172(CAG)(8-34) repeat polymorphisms of the ER-beta and AR genes and knee OA was found in individuals of Greek descent.     

Association between the estrogen receptor TA polymorphism and Harm avoidance

In the last decade a large number of studies focused on the recognition of gene variants modulating temperamental traits. The gene coding for the estrogen receptor alpha (ESR1) appears to be an interesting candidate and it has been found to be linked to Harm avoidance (HA). The aim of the present study was to investigate whether the ESR1 TA dinucleotide repeat polymorphism is associated with HA temperamental trait in a sample of Caucasian University students. One hundred ninety healthy subjects were genotyped for ESR1 TA dinucleotide repeat polymorphism and were administered the Temperament and Character Inventory (TCI). ESR1 TA repeat lengths were dichotomized into short and long categories. ANOVA was used to examine the influence of ESR1 variants (short/long) on the means of the TCI HA scores. HA was significantly associated with age and gender in our sample, being higher in older and female subjects. In the global sample as well as in men and women separately, individuals carrying the S/S variant showed significantly higher HA scores. Further analysis on the HA subscales revealed that specific differences could exist between men and women. Our results further suggest a possible role of ESR1 variants on HA. Further research is needed to replicate our findings as well as to better explore the neuro-biological mechanisms of the modulation of ESR1 on HA.     

Estrogen receptor 1 gene (TA)n polymorphism is associated with lone atrial fibrillation in men

Aim

To determine the association between the number of thymine-adenine (TA)n dinucleotide repeats in the promoter region of the gene coding for the estrogen receptor alpha (ESR1) and the prevalence of lone atrial fibrillation (AF) in men.

Methods

We conducted a case-control study involving 89 men with lone AF and 166 healthy male controls. The ESR1 genotype was established by polymerase chain reaction and capillary electrophoresis. To assess the association of ESR1 genotype with AF, logistic regression models were built with AF as outcome.

Results

Men with lone AF had significantly greater number of (TA)n repeats of single alleles than controls (mean ± standard deviation, 19.2 ± 4.2 vs 18 ± 4.3, P = 0.010). After adjustment for other factors, a unit-increase in (TA)n repeat number was associated with a significantly greater likelihood of AF (odds ratio 1.069; 95% confidence interval 1.024-1.116, P = 0.002).

Conclusions

Our results indicate that a greater number of (TA)n repeats in the promoter region of ESR1 is associated with a significantly increased likelihood of lone atrial fibrillation in men.Atrial fibrillation (AF) is considered the most common sustained arrhythmia of clinical importance (1). Even if corrected for etiological factors such as ischemic and hypertensive heart disease, its prevalence in men is 1.5 times higher than in women (1). lone AF is defined as a normal echocardiogram and no clinical history of known etiological factors for AF and it occurs in the normal heart without any known causal factor (2). It has similar sex prevalence as AF, and such prevalence may indicate the effects of sexual hormones on cardiac electrophysiology through the corresponding intracellular steroid receptors (3).Genetic determinants of AF have been explored using different methods, ranging from candidate gene studies investigating rare mutations (4) with alterations in cardiomyocite structure and function (mostly ion channel alterations) to genome-wide association studies examining subtle effects of single nucleotide polymorphisms (5). Nucleotide polymorphisms have been widely investigated, mostly those affecting ion channel function, cardiac renin-angiotensin-aldosterone system, inflammatory responses, and cardiac connexins (6-12)Less attention, however, has been paid to the association of AF and nucleotide polymorphisms of cardiac sexual steroid receptors. Sexual steroid hormones exert complex genomic and non-genomic cardiac effects through corresponding receptors (13). The gene coding for the estrogen receptor α (ESR1) is located on chromosome 6 (6q25–27). It comprises eight exons and has a polymorphic thymine-adenine (TA) region located 1174 base pairs (bp) upstream from the exon 1 in the genes promoter region. Out of many ESR1 polymorphisms, alleles with a larger number of (TA)n repeats have received the most research attention, making it one of the most promising research targets (14). A previous study suggested a positive correlation between homozygosity for longer alleles (≥19 TA repeats) and AF (15). Therefore, we aimed to examine the association between the actual number of (TA)n repeats and lone AF in men using a case-control design.     

A HSV-1 variant (1720) generates four equimolar isomers despite a 9200-bp deletion from TRL and sequences between 9200 np and 97,000 np in inverted orientation being covalently bound to sequences 94,000–126,372 np

The genome structure of a spontaneously generated HSV-1 strain 17 variant, 1720, has been determined by restriction endonuclease and Southern blot analysis. The short segment of 1720 is unaltered compared to the parental strain 17 genome, whereas the long segment is extensively rearranged. Almost all of TR_L (approximately 9.2 kb) has been deleted and consequently IR_L is converted into unique sequence. Sequences from approximately 9200 nucleotide position (np) to 97,000 np are present in inverted orientation, covalently bound to sequences in the prototype orientation from approximately 94,000 np to the L/S junction at 126,372 np. Thus, sequences from 94,000 np to 97,000 np are now diploid, with one copy in the normal orientation and location, and the other at the long terminus as an inverted repeat; no inversion of the intervening unique sequences occurs about this novel inverted repeat. In contrast, normal inversions of the long and short segments occur to give four equimolar genomic isomers, indicating that the novel long terminus has gained an a sequence. The duplication of sequences between 94,000 np and 97,000 np results in a genome containing two copies of UL43 and one complete and one partial copy each of genes UL42 and UL44 encoding the 65 kD DNA-binding protein and glycoprotein C, respectively.The variant has been shown to grow normally in vitro following high multiplicity infection.     

The role of HLA-DRB1 alleles on susceptibility of Chinese patients with anti-GBM disease

Anti-glomerular basement membrane (GBM) disease, a rare autoimmune disorder, is associated with HLA-DR15 genotype in Caucasian and Japanese populations. But the distribution of HLA-DRB1 alleles in Chinese patients with anti-GBM disease and their association with clinical characteristics of anti-GBM disease are to be determined. The present study analyzed the HLA-DRB1 alleles by sequence based typing in 44 Chinese patients with anti-GBM disease and 200 healthy controls. The effects of DRB1 alleles on susceptibility to anti-GBM disease were examined by a relative predispositional effects (RPEs) method. The clinical and pathological data of the patients were collected and analyzed. The DRB11501 allele was significantly associated with anti-GBM disease (p = 1.597 × 10⁻⁷). The RPEs test also showed a significant increased frequency of DRB10404 in anti-GBM disease (p = 0.037). Interestingly, the patients with DRB11501 or 0404 had more crescent formation in glomeruli than those without the two alleles (p = 0.021). But the DRB10404 was rare in both patients and control groups, which indicates that the importance of the 0404 allele is limited in anti-GBM disease. We conclude that the HLA-DRB11501 allele is a genetic marker for susceptibility to anti-GBM disease.     

Endothelial nitric oxide synthase genotype modulates the improvement of coronary blood flow by pravastatin: a placebo-controlled PET study

The objective was to study whether coronary blood flow or its response to pravastatin are affected by genetic variation in the endothelial nitric oxide synthase (eNOS) gene. Vascular endothelial nitric oxide maintains endothelium-dependent vasodilatation and also mediates antithrombotic actions. Its formation is catalyzed by eNOS, a constitutive enzyme, which has a polymorphic site in intron 4 (4a/b). Some clinical studies have suggested an association of the rare a-allele of eNOS with coronary artery disease and myocardial infarction. We carried out a double-blind placebo-controlled study involving 43 men (aged 35+/-4 years), who were randomized to receive either 40 mg/day pravastatin ( n=21) or placebo ( n=22) for 6 months. Myocardial blood flow was measured by positron emission tomography (PET) using (15)O-labeled water. PET was performed at rest and after stimulation by adenosine infusion. PET and lipid analyses were carried out at baseline and after 6 months. eNOS genotyping was done by PCR. At baseline there were no differences in basal or adenosine-stimulated coronary blood flow between subjects with either eNOS bb or ba genotypes. At the end of the study genotypes reacted differently between pravastatin and placebo groups with respect to the change in adenosine-stimulated flow (ANCOVA P=0.008). More specifically, after pravastatin treatment the adenosine-stimulated flow increased by 54.5% in men with the eNOS ba genotype, whereas in the men with the bb genotype no significant change in flow was observed ( P=0.002 for ba versus bb). In the placebo group there were no significant changes in blood flow from the baseline values ( P=0.916 for ba versus bb). After pravastatin treatment both genotype groups showed a similar decrease in serum total cholesterol and low-density lipoprotein cholesterol ( P<0.00001 for both). Our results suggest that adenosine-stimulated myocardial perfusion improves after treatment with pravastatin in subjects with the eNOS ba genotype but not in those with the bb genotype. This effect is not dependent on the decrease of serum cholesterol.     

Regulation of myocardial oxygen consumption by perfusion pressure in isolated fibrillating canine heart

In order to evaluate whether perfusion pressure or coronary flow affect myocardial oxygen metabolism, oxygen consumption of the isolated fibrillating blood-perfused canine heart was investigated at perfusion pressures of 100, 150, and 200 mm Hg. To obtain different coronary flow rates at a given coronary perfusion pressure, -adrenergic blockade by phenoxybenzamine (10 mg/kg b.w.) was applied, resulting in an increase in coronary flow and a decrease in myocardial oxygen extraction. Myocardial oxygen consumption was increased by elevation of perfusion pressure in both the control and phenoxybenzamine-pretreated group. At the same level of perfusion pressure there was no significant difference between the oxygen consumption of control and phenoxybenzaminepretreated preparations. It can be concluded that in the isolated fibrillating canine heart oxygen consumption is primarily regulated by perfusion pressure, and is independent from coronary blood flow.     

Oestrogen receptor-β CA repeat polymorphism is associated with incidence of colorectal cancer among females

Honma N, Arai T, Takubo K, Younes M, Tanaka N, Mieno M N, Tamura K, Ikeda S, Sawabe M & Muramatsu M
(2011) Histopathology 59 , 216–224 Oestrogen receptor‐β CA repeat polymorphism is associated with incidence of colorectal cancer among females Aims: Increasing evidence suggests an association between oestrogens and colorectal cancer. Oestrogen receptor beta, ER‐β, putatively plays a pathobiological role in colorectal cancer as colorectal epithelial cells frequently express ER‐β. The aim was to elucidate the association of the dinucleotide (CA) repeat polymorphism of the ER‐β gene (ESR2) with colorectal cancer. Methods and results: Deoxyribonucleic acids extracted from the renal cortex of 1488 Japanese autopsies with complete clinical/pathological data were studied. CA repeat polymorphism was determined by polymerase chain reaction using fluorescein‐labelled primers. Patients were divided into three genotype groups according to the number of CA repeats of each allele (S < 22, L ≥ 22); SS (with two S alleles), SL (with one each S and L allele) and LL (with two L alleles). The presence/absence of colorectal cancers was determined by examining the clinical records and autopsy material. The incidence of colorectal cancer was significantly different according to the ESR2 CA repeat genotype only among females (SS, 37/202 = 18.3%; SL, 19/332 = 5.7%; LL, 5/155 = 3.2%, P < 0.0001). Immunohistochemically, cancers in females with the SS genotype, but not the SL genotype, frequently expressed the C‐terminus portion of ER‐β1 (wild‐type ER‐β). Conclusions: A role for ESR2 CA repeat polymorphism in the pathogenesis of colorectal cancer among females is suggested.     

The importance of the perfusion pressure in the coronary arteries for the contractility and the oxygen consumption of the heart

Summary The influence of increasing perfusion pressure in the coronary arteries on cardiac contractility and oxygen consumption was studied in isovolumetrically working, empty beating, and potassium arrested guinea-pig hearts. Raising the coronary perfusion pressure from 60 to 80 cm H₂O increased left ventricular peak systolic pressure by 19.4±2.8%, coronary flow by 47.7±8.0% and oxygen consumption by 32.7±6.2% (N=17).At a constant perfusion pressure hypoxia increased the coronary flow by 111.8±16.4% (N=19), but did not alter the contractility of the heart or its oxygen consumption.Increasing pressure without changing flow, raised pressure in the left ventricle by 26.5±4.8% and myocardial oxygen consumption by 20.3±3.4% (N=14). The end-diastolic pressure and the heart rate remained unchanged in all experiments.From these findings it may be concluded that the pressure in the coronary vessels — independent of the flow rate — exercises a positive inotropic effect, thereby increasing metabolism. This can be explained by increased fibre tension, caused by an extension of the coronary vessels, the so-called garden-hose-effect.Partially delivered during the 31st Meeting of the Deutsche Physiologische Gesellschaft in Würzburg, 1966 [2].     

Lack of association of polymorphisms of the lymphotoxin α gene with myocardial infarction in Japanese

Vascular inflammation plays an important role in the development of myocardial infarction (MI). Lymphotoxin (LTA) is a cytokine with multiple functions in regulation of the immune system and inflammatory reactions. The aim of this study was to examine whether polymorphisms of the LTA gene are associated with the risk of MI in Japanese men and women. A case-control association study was performed for the 252AG and 804CA polymorphisms of the LTA gene and the prevalence of MI. The study population comprised 3,689 unrelated Japanese individuals (2,486 men, 1,203 women), including 1891 patients with MI (1,493 men, 398 women) and 1798 control subjects (993 men, 805 women). Among the control subjects 257 individuals (108 men, 149 women) who had none of the conventional risk factors for coronary artery disease (CAD) were defined as low-risk controls. Genotypes for the two polymorphisms were determined with a fluorescence-based allele-specific DNA primer assay system. Among all study subjects the 252AG and 804CA polymorphisms exhibited linkage disequilibrium. No association of either polymorphism with MI was detected in men or in women in comparisons with total control or low-risk control subjects. However, each of the two polymorphisms was associated with the prevalence of type 2 diabetes mellitus both in men with MI and in those without MI in a recessive genetic model. No association was detected between the polymorphisms and other conventional risk factors for CAD. The LTA gene thus does not appear to be a susceptibility locus for MI in Japanese men or women, although it might affect susceptibility to type 2 diabetes in Japanese men.Abbreviations BMI Body mass index - CAD Coronary artery disease - HLA Human leukocyte antigen - LTA Lymphotoxin - MI Myocardial infarction - PCR Polymerase chain reaction - TNF Tumor necrosis factor     

Coronary artery wall atherosclerosis in relation to the estrogen receptor 1 gene polymorphism: an autopsy study

Estrogen receptors (ESR) 1 and 2 are expressed in the normal and atherosclerotic arteries mediating the atheroprotective action of estrogen to artery wall cells. Whether variants of these receptor genes associate with autopsy-verified coronary artery wall atherosclerosis is not known. This study investigated whether variants of the ESR1 gene are associated with autopsy-verified coronary artery wall atherosclerosis and thrombosis. Coronary arteries were taken from 300 white Finnish male autopsy cases aged 33-69 years included in the Helsinki Sudden Death Study. Areas of coronary wall covered with fatty streaks, fibrotic, calcified, and complicated lesions were measured using computer-assisted planimetry and related to ESR1 PvuII genotypes (P/P, P/p, and p/p) determined by PCR. The mean area of complicated lesions of three major coronaries and the presence of coronary thrombosis were significantly associated with the ESR1 genotype in men aged 53 years or older (median age as a cut off point). No such association was found in men aged under 53 years. After adjusting for age and body mass index the men aged 53 years or over with P/p and P/P genotype had areas of complicated lesions on average two- and fivefold larger than subjects with the p/p genotype. The age and body mass index adjusted odds ratios for coronary thrombosis were 6.2 for P/p and 10.6 for P/P compared to men with the p/p genotype. After additional adjustment for diabetes and hypertension the ESR1 genotype persisted as an independent predictor of complicated lesions ( P=0.007) and coronary thrombosis. In conclusion, the ESR1 gene is a potential candidate behind the pathogenesis of acute coronary events.     

Thermostable antigens of malignant tumors and normal tissues of experimental animals

Thermostable antigens (TA) were found by the gel precipitation test and by immunoelectrophoresis in malignant tumors of muscle tissue induced by dimethylbenzanthracene, and in the amniotic fluid of 8–12-day embryos and certain normal organs of adult Wistar rats. Relative tissue specificity of these antigens was demonstrated, on the one hand, for tumors, amniotic fluid, and the uterus, and on the other hand for the lung, spleen, and serum. TA detected in tumors and amniotic fluid by immunoelectrophoresis are located in the zones of - and ₁-globulins.Research Laboratory of Experimental Immunobiology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR N. N. Zhukov-Verezhnikov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 85, No. 6, pp. 726–728, June, 1978.     

A comparison of the anti-inflammatory activities of conjugated estrogens and 17-β estradiol

Objective and design: Unregulated chronic inflammatory process partly due to an estrogen deficiency may render postmenopausal women vulnerable to degenerative conditions such as arthritis, osteoporosis, atherosclerosis, and Alzheimers disease. Current confusion regarding therapeutic efficacy of estrogen replacement therapy may be due to different estrogen formulations used, short term therapy, as well as advanced stage of the disease. Materials and methods: We compared anti-inflammatory activities of two major estrogen preparations, conjugated equine estrogen (CEE) and 17- estradiol, using an animal model (rat mesentery) of in vivo inflammatory reaction to intravenously infused amyloid-, examined by video recording and subsequently analyzed by transmission electron microscopy. Cellular markers of inflammation were monitored: leukocyte migration, platelet activation, mast cell activation/degranulation, and endothelial disruption. Results: Low doses of CEE (0.3 mg/kg for 3 weeks) demonstrated significant anti-inflammatory activity, whereas even at high doses (2.0 mg) 17- estradiol had only minimal activity. Conclusion: CEE, a mixture of several compounds, may have some component(s) with significant anti-inflammatory activity. The anti-inflammatory activity of CEE may have a role in prevention of several degenerative diseases associated with menopause. Received 18 February 2003; returned for revision 25 March 2003; accepted by J. S. Skotnicki 1 June 2003     

Function associated transforming growth factor-β gene polymorphism in chronic beryllium disease

Chronic beryllium disease (CBD) is a rare occupational, granulomatous lung disease clinically resembling sarcoidosis. The immune response to beryllium is thought to depend on genetic susceptibility. Although a glutamic acid in position 69 of the human leukocyte antigen-DP chain (HLA-DPB1-Glu69) is associated with the development of CBD, it cannot fully explain susceptibility. It is likely that additionally other genes are involved in regulating the immune and inflammatory response in the pathogenesis of this disease. Functional gene polymorphisms (PMs) of the tumor necrosis factor (TNF)A and transforming growth factor (TGF) ₁ genes are suspected to modify the course of granulomatous disorders. We analyzed the TGF-₁ (codon 25) PM in 59 patients with CBD and 164 matched healthy controls, from two groups of European/Israeli and United States origin. Additionally, patients were genotyped for HLA class II gene variants and the TNFA (–308) PM. The most significant results were found for the TGF-₁ (codon 25) PM with a shift towards the low producing non-GG genotypes in the subgroup of European and Israeli patients with CBD (62.50% vs. 13.82% in healthy controls; P<0.001). This phenomenon was not observed in the group from the United States. Moreover, TGF-₁ (codon 25) PM genotype frequencies from United States CBD patients differed significantly from those of European and Israeli patients. In contrast, increased frequencies for the high producing TNFA2 allele were found only in the patients from the United States (28.20% vs. 8.96% in healthy controls; P<0.005) but not in the group of Europe and Israel. In conclusion, the increase in TGF-₁ (codon 25) PM genotype frequency associated with a low TGF- release suggests that immunoregulatory cytokines such as TGF- are involved in the pathogenesis of CBD. Moreover, based on the interaction of gene PMs associated with the control of the immune response, such as TNF- and TGF-₁, with a specific immune response gene such as HLA-DPB1-Glu69 or other HLA-class II PMs driving the immune response to Be, the present data suggest that a combination of different genetic backgrounds determine susceptibility for the same immunopathological reaction and disease.     

Interaction effects between estrogen receptor α gene,vitamin D receptor gene,age, and sex on bone mineral density in Chinese

We evaluated the interaction effects between the estrogen receptor gene (ER-), vitamin D receptor gene (VDR), age and sex on bone mineral density (BMD) in a sample of 340 unrelated males and 297 unrelated females from 401 Chinese nuclear families. Polymorphisms of PvuII and XbaI in the ER- gene and ApaI in the VDR gene were detected by RFLP, and ER- genotype was defined by the haplotype reconstructed according to the two loci. In the females, significant ER-VDR gene interaction (P<0.05) was found on the lumbar spine BMD. Such interaction might account for approximately 1.0% of the BMD variation. At the femoral neck and trochanter, significant ER-age interaction effects were observed, which might explain 0.3% BMD variation for both skeletal sites. In the males, significant VDR-age interaction was found on femoral neck BMD (P<0.05), and it accounted for 0.6% BMD variation. These interaction effects were largely dependent on gender groups, suggesting there may exist ER-VDR-sex, ER-age-sex, and VDR-age-sex complex interactions in our Chinese sample.     

Serum IgG2 Concentration Is Associated with Gm-Allotypes of IgG2 But Not with the R131H Polymorphism of Human Fcγ Receptor Type IIa

Serum concentrations of immunoglobulins IgG, IgG1, and IgG2 were determined in 62 Finnish subjects who were also typed for Gm(n) allele of IgG2 and R131 and H131 alleles of the Fc receptor IIa. Statistically significant G2m-allotype-associated differences in serum concentrations of IgG2 were found; the mean concentration of IgG2 was high in Gm(n)-positive homozygotes (3.9 g/liter) and low in Gm(n)-negative individuals (2.6 g/liter; P = 0.0036), which is in accordance with previous reports. Contrary to an earlier report, no statistically significant R131/H131-allotype-associated differences were found in serum concentrations of IgG2, not even in the case where the IgG2 concentration was calculated relative to the IgG1 or IgG concentration (IgG2/IgG1 or IgG2/IgG). The gene frequencies of R131 and H131 alleles were 0.516 and 0.484, respectively, which did not differ significantly from those reported earlier for Finnish or other Caucasian populations.     

Molecular analysis of the IVS8-T splice variant 5T and M470V exon 10 missense polymorphism in Iranian males with congenital bilateral absence of the vas deferens

Congenital bilateral absence of the vas deferens (CBAVD) is responsible for 2-6% of male infertility in which mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene have been identified. To investigate CBAVD at the molecular level in Iran, we have characterized the mutations in the CFTR gene in 106 patients with this condition. None had clinical manifestations of cystic fibrosis (CF). We also analysed a DNA variant (the 5T allele) in a noncoding region of CFTR, which causes reduced levels of the normal CFTR protein and M470V exon 10 missense polymorphism. Five of the 106 patients with CBAVD had mutations in both copies of the CFTR gene, and none of them had the 5T allele. Eighty-five patients had a mutation in at least one copy of CFTR, and of these patients, 46 had one 5T allele (in 11 cases, two alleles and in 35 cases, just one allele of 5T was detected). In 21 patients, no CFTR and 5T mutations were found (19.81%). 5T/M470 genotype was found in 19 patients, 5T/V470 was found in 3 and 5T with heterozygote form of M470V was found in 24 CBAVD patients. In CBAVD patients, 28 F508del carriers were identified. Most of our patients with CBAVD have mutations in the CFTR gene. The combination of the 5T allele in one copy of the CFTR gene with a CF mutation in the other copy is the most common cause of CBAVD in Iran. The 5T allele mutation has a wide range of clinical presentations and revealed a high frequency, occurring in patients with CBAVD or moderate forms of CF and infertile men.     

The effect of beta-adrenergic blockade on leg blood flow with repeated maximal contractions of the triceps surae muscle group in man

Summary The effect of -adrenergic blockade on torque output and leg blood flow was examined in seven healthy young men during repeated maximal isometric voluntary contractions of the triceps surae muscle group. Exercise was performed in either a bent- or straight-leg position during each of four drug treatments: placebo, propranolol, metoprolol, oxprenolol. Contractions were sustained for 5 s with 5 s relaxation for a total of 10 min followed by a 10-min recovery. Leg blood flow was measured during the 5 s relaxation separating contractions using strain gauge plethysmography. Torque output decreased during the 10-min contractions with no differences between the four drug treatments. Leg blood flow was lower with -blockade during the initial stages of exercise and recovery in the bent-leg position but no differences were observed after 3 min exercise or recovery. Leg blood flow in the straight-leg position was not different between any of the four drug treatments, but it was significantly less than in bent-leg exercise. The lower blood flows during the initial stages of exercise in the -blocked conditions probably reflect a slowing of the central cardiovascular response because of ₁-receptor blockade of the heart rather than on the ₂-receptors effects on peripheral vacular resistance. It is concluded that local vasodilator substances released from the working muscle may play a more important role than ₂-receptor stimulation of smooth muscle in skeletal muscle resistance vessels in regulating local muscle blood flow during maximal exercise of the triceps surae muscle group.