Transforming growth factor beta1 gene polymorphism in rheumatoid arthritis

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease and synovial cells, antigen presenting cells, lymphocytes, and their cytokines might be associated with the disease. Transforming growth factor beta1 (TGFbeta1) has been reported to have important roles in unresolved inflammation, immune suppression, fibrosing processes, and angiogenesis. TGFbeta1 is highly expressed in joints in RA and is considered to be a regulator of anti-inflammation in RA. Polymorphisms of TGFbeta1 have been reported to be associated with the production of TGFbeta1 protein, and to increase the risk of acquiring several diseases. It was speculated that these polymorphisms might also be involved in RA, and therefore the TGFbeta1 codon 10 T869C polymorphism in a series of patients and controls was investigated. METHOD: A total of 155 patients with RA and 110 healthy subjects were studied. DNA was extracted from peripheral leucocytes and TGFbeta1 codon 10 T869C polymorphism was determined by polymerase chain reaction restriction fragment polymorphism. RESULTS: A significantly higher proportion of patients with RA with the T allele (CT type or TT type) was found compared with the CC type (p=0.039). CONCLUSION: The T allele, previously reported to be linked with production of TGFbeta1, may be associated with an increased risk of RA.     

The Q223R polymorphism of the leptin receptor gene is significantly associated with obesity and predicts a small percentage of body weight and body composition variability

Genetic variation at the leptin receptor gene locus may play an important role in the pathophysiology of human obesity, a leptin-resistant state. Previous studies exploring potential associations between leptin receptor gene polymorphisms and obesity have reported conflicting results. The aim of this study was to evaluate a genetically homogeneous population for associations between body composition variables and three common leptin receptor gene polymorphisms (K109R, Q223R, and K656N) that have potential functional significance as well as to assess the contributions of these polymorphisms to the variability of obesity. One hundred and eighteen consecutively enrolled subjects (62 women: mean age, 17.5 +/- 1.6 yr; body mass index range, 16.2-30.1; 56 men: mean age, 17.8 +/- 1.8 yr; body mass index range, 15.4-35.9) were genotyped for the three polymorphisms, and their body mass index, sum of 4 skinfolds, fat-free mass, percent fat mass, serum leptin levels, caloric intake, fat intake, and exercise patterns were determined. Allele frequencies were estimated by the gene-counting method, and genotype distributions between 89 normal weight (body mass index, < or =25 kg/m(2)) and 29 overweight-obese (body mass index, >25 kg/m(2)) subjects were compared using chi(2) test (using codominant, dominant, and recessive models). Analysis of covariance was also performed to evaluate associations between the polymorphisms and body composition variables after controlling for potential confounders. For the Q223R polymorphism, there was a higher prevalence of the R223 allele in the homozygous form among overweight-obese subjects vs. normal weight subjects (20.7% vs. 4.5%; P = 0.01). Furthermore, simple and multiple regression analyses revealed that the R223 allele in the homozygous form is a significant predictor of both body mass index (P = 0.015) and percent fat mass (P = 0.02) even after adjusting for age and gender and explains 4.5% of the variance in percent fat mass and 5% of the variance in body mass index. There was no significant difference in allele frequencies or genotype distributions for the K109R or K656N polymorphisms. These findings support the hypothesis that the Q223R polymorphism (but not the K109R or K656N polymorphism) of the leptin receptor gene is associated with obesity and predicts a small percentage of body weight and body composition variability in a genetically homogeneous population.     

The Q/E27 polymorphism in the beta2-adrenoceptor gene is associated with increased body weight and dyslipoproteinaemia involving triglyceride-rich lipoproteins

OBJECTIVES: To investigate whether a substitution of glutamine by glutamic acid at amino acid position 27 (Q/E27) and an arginine to glycine transition at amino acid 16 (R/G16) in the beta2-adrenoceptor gene are associated with lipid and lipoprotein disturbances and/or increased body weight in men. DESIGN: Population-based study. SETTING: Department of medicine at a university hospital. SUBJECTS: A total of 180 healthy men, aged 30-45 years, were recruited at random from a register containing all permanent residents in Stockholm County (response rate of 70%). MAIN OUTCOME MEASURES: Frequency of beta2-adrenoceptor genotypes and alleles in relation to plasma lipid and lipoprotein levels and body mass index. RESULTS: Individuals carrying the E27 allele and/or the G16 allele had significantly higher body mass index (BMI). Furthermore, carriers of the E27 allele had significantly higher plasma concentrations of cholesterol, triglycerides, VLDL cholesterol and VLDL triglycerides than did subjects homozygous for the Q allele. CONCLUSION: The E27 allele of the beta2-adrenoceptor gene is associated with slightly to moderately elevated BMI and dyslipoproteinaemia involving triglyceride-rich lipoproteins in healthy younger and middle-aged men.     

Transforming growth factor beta1 gene polymorphism in patients with systemic sclerosis

OBJECTIVE: To determine whether transforming growth factor beta1 (TGFbeta1) gene DNA polymorphism is associated with pathogenesis in the fibrosis of patients with systemic sclerosis (SSc). METHODS: Eighty-seven Japanese patients with SSc including 30 with diffuse type and 57 with limited type together with 110 unrelated controls were investigated. Pulmonary fibrosis was determined in 34 SSc patients using high-resolution chest computed tomography. TGFbeta1 genetic polymorphisms were analyzed in 2 loci; T869C (Leu10Pro) in codon 10 at exon 1, and C-509T in the promoter region using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Neither the genotype of T/C polymorphism in T869C nor C/T polymorphism in C-509T revealed any difference in distribution between SSc and controls. In the group of SSc patients with pulmonary fibrosis, a weak but significantly high frequency (p = 0.05) of TC+CC (the presence of C allele) in T869C, and CT+TT (the presence of T allele) in C-509T was found. Compared with controls, the pulmonary fibrosis group showed no difference in the highly frequent alleles. CONCLUSION: Our results suggest that TGFbeta1 polymorphisms do not play a role in the pathogenesis of SSc, even though there remains the possibility of a risk factor for genetic susceptibility to pulmonary fibrosis.     

Body weight changes and the A-6G polymorphism of the angiotensinogen gene

BACKGROUND: The objective of the study was to analyze the relationship of polymorphisms of the angiotensinogen gene with changes in body weight during 3 y of antihypertensive treatment, in a group of young adults with essential hypertension. METHODS: Essential hypertensives, less than 50 y old, never previously treated with antihypertensive drugs and in the absence of diabetes mellitus were included. After the initial evaluation, patients were treated using only non-pharmacological measures (n=29), beta-blockers (n=40) or angiotensin-converting enzyme inhibitors (n=66). Resting blood pressure, biochemical profile and body weight at the beginning and yearly were measured. The polymorphism A-6G of the angiotensinogen gene located in the promoter region was analyzed. RESULTS: One-hundred and thirty-five patients were included. Genotypes of the A-6G polymorphism of the AGT gene were in Hardy-Weinberg equilibrium (AA 34, AG 63, GG 38). No significant differences were observed among genotypes in terms of age, body mass index, body weight, systolic or diastolic blood pressure. No significant differences in the genotype distribution or in the allele frequencies were observed, although the A allele was most frequent among the obese subjects. During the 3 y of antihypertensive treatment, there was a trend to increase weight despite the dietary recommendations. The slopes of body weight over time, adjusted by age and baseline BMI, differed significantly among the homozygote genotypes (P=0.006). The highest were for those with the AA genotype and the lowest for the GG genotype (1.180+/-0.25 and -0.128+/-0.24 kg/y; P=0.0001). The influence of the genotype in the changes on body weight remained significant after considering its interaction with the kind of antihypertensive treatment, although among subjects carrying the AA genotype those treated with ACEi showed the least body weight change. Furthermore, A-6G genotypes had the largest influence on weight changes, accounting for 19% of the variance, when age, sex and initial body mass index were included in the model. CONCLUSIONS: In a group of young adult hypertensive subjects, there was a trend to increase weight despite dietary recommendations. Subjects with the AA genotype were those with the largest weight gain, but this effect was modified by the antihypertensive treatment.     

Associations between a polymorphism in the 11 beta hydroxysteroid dehydrogenase type I gene and body composition

We investigated 11 beta hydroxysteriod dehydrogenase type 1 (11betaHSD-1) sequence variants in 103 healthy overweight (BMI >2 s.d.) and 160 nonoverweight (BMI -2 to +2 SD) children to examine the associations between body composition and 11betaHSD-1 polymorphisms. A total of 4.3% of children were homozygous and 30.0% heterozygous for an adenine insertion in intron 3 (ins4436A). By ANCOVA (adjusting for age, sex, race, and height), BMI-s.d. differed according to ins4436A genotype (P<0.005), with the greatest BMI-SD for ins4436A homozygotes (mean +/-s.d., 3.4+/-3.4, vs heterozygotes, 0.8+/-5.5, or wild-type, 1.8+/-7.5). Homozygotes also had greater waist circumference, waist-to-hip ratio, and insulin resistance indices than heterozygote or wild-type children (all P<0.05), but no significant differences in trunk fat by DXA, or in serum lipids. We conclude an intronic 11betaHSD-1 gene polymorphism is associated with greater body mass, altered body composition, and insulin resistance in children. 11betaHSD-1 may be one of the genes relevant for pediatric-onset obesity and its complications.     

The role of interleukin-1beta gene polymorphism in the gastric carcinogenesis]

BACKGROUND/AIMS: This study was aimed to investigate the polymorphism of interleukin-1beta(IL-1B) and IL-1 receptor antagonist (IL-1RN) gene and the relationship between genotypes and development of gastric adenocarcinoma in Korean, and to investigate the role of Helicobacter pylori (H. pylori) infection. METHODS: The study population comprised of 258 patients with gastric adenocarcinoma. They were classified according to Lauren's classification and the status of H. pylori infection. Genomic DNA was extracted from the gastric tissue. As a control, genomic DNA from peripheral lymphocyte of 100 healthy individuals was used. The amplified products of -511 bp and -31 bp fragments in the IL-1B by PCR were digested by restriction enzyme and separated for RFLP. Variable number tandem repeats were amplified and subjected to RFLP of IL-1RN. RESULTS: There was no significant difference in the genotype of IL-1B-511T and IL-1B-31C between the adenocarcinoma group and the control group. IL-1RN allele 1 homozygote in the intestinal type showed high frequency of 91.7% (p=0.007). In the H. pylori-positive group of the adenocarcinoma, the frequency of IL-1B-31C was significantly higher than that of H. pylori-negative group (p=0.045). CONCLUSIONS: The single nucleotide polymorphism of IL-1B-31C may contribute to the development of the gastric adenocarcinoma in the H. pylori-positive population.     

beta2- and beta3-Adrenoceptor polymorphisms relate to subsequent weight gain and blood pressure elevation in obese normotensive individuals.

High blood pressure (BP) is a major determinant of cardiovascular events in obesity. The beta2- and beta3-adrenoceptor polymorphisms are associated with obesity and hypertension. In the present study, we examine the relationships of beta2- and beta3-adrenoceptor polymorphisms with further weight gain-induced BP elevation in obese subjects. Changes in BP, body weight, total body fat-mass, waist-to-hip ratio, plasma norepinephrine (NE) and leptin levels, and beta2(Arg16Gly)- and beta3(Trp64Arg)-adrenoceptor polymorphisms were measured periodically over a 5-year period in 55 entry obese (body mass index [BMI]> or =25.0 kg/m(2)) normotensive (BP<140/90 mmHg) men. BP elevation and weight gain were defined as > or =10% increases from entry levels over 5 years in mean BP or BMI. Obese subjects with weight gain, BP elevation or weight gain-induced BP elevation had higher frequencies of the Gly16 allele of Arg16GIy and Arg64 allele of Trp64Arg. Subjects carrying the Gly16 or Arg64 alleles had significantly greater total fat-mass and waist-to-hip ratio at entry and over a 5-year period compared to the subjects who did not carry these polymorphisms. Subjects carrying the Gly16 allele had similar levels of plasma NE, higher levels of plasma leptin and a lower slope of the regression lines between plasma leptin and NE levels. Those carrying the Arg64 allele had higher plasma NE levels at entry and over a 5-year period compared to the subjects without the Arg64 allele, but plasma leptin levels and slopes were similar. The findings demonstrate that the Arg64 allele of the beta3-adrenoceptor polymorphisms relates to weight gain-induced BP elevation accompanying high plasma NE (heightened sympathetic activity) in obese men. The Gly16 allele of the beta2-adrenoceptor polymorphisms links to weight gain-induced BP elevation associated with leptin resistance. beta2- and beta3-adrenoceptor polymorphisms could predict the future BP elevation and further weight gain-induced BP elevation in originally obese subjects.     

Interleukin-1β gene polymorphism associated with hepatocellular carcinoma in hepatitis B virus infection

AIM: To examine the effect of interleukin-1-beta (IL-1beta) promoter region C-511T and IL-1 receptor antagonist (IL-1RN) polymorphism among the patients with chronic hepatitis B virus (HBV) infection (HCC and non-HCC). METHODS: Genomic DNA from 136 Thai patients with chronic HBV infection (HCC=46 and non-HCC=90) and 152 healthy individuals was genotyped for IL-1beta gene polymorphism (-511) using polymerase chain reaction with sequence specific primers (PCR-SSP). The variable number of tandem repeats (VNTR) of IL-1RN gene was assessed by a PCR-based assay. The association between these genes and status of the disease was evaluated by chi2 test. RESULTS: IL-1B-511 genotype C/C was found to be significantly different in patients with HCC when compared with healthy individuals (P=0.036, OR=2.29, 95%CI=1.05-4.97) and patients without HCC (P=0.036, OR=2.52, 95%CI=1.05-6.04). Analysis of allele frequencies of IL-1B-511 showed that IL-1B-511 C allele was also significantly increased in patients with HCC, compared to that in healthy control (P=0.033, OR=1.72, 95%CI=1.04-2.84). However, no significant association in IL-1RN gene was found between the two groups. CONCLUSION: IL-1B-511C allele, which may be associated with high IL-1B production in the liver, is a genetic marker for the development of HCC in chronic hepatitis B patients in Thai population.     

The Trp(64)Arg polymorphism of the beta(3)-adrenergic receptor gene is not associated with body weight or body mass index in Japanese: a longitudinal analysis

The beta(3)-adrenergic receptor (ADRB3) is expressed mainly in visceral adipose tissue and is thought to contribute to lipolysis and the delivery of free fatty acids to the portal vein. Although many studies have examined the relationship between the Trp(64)Arg mutation of ADRB3 and obesity, the results have been inconsistent. We examined the cross-sectional relationship of ADRB3 variants with indexes of obesity, and their longitudinal changes over 10 yr, in men and women, aged 40-69 yr, who were randomly selected from the Japanese rural population. The study considered both dietary energy intake and physical activity levels. Among the 746 participants, the genotype frequencies of the Trp(64)Trp, Trp(64)Arg, and Arg(64)Arg variants were 483, 224, and 39, respectively. The cross-sectional analysis showed no significant differences in height, weight, body mass index, blood pressure, serum total and high density lipoprotein cholesterols, and hemoglobin A(1c) among the genotype groups even after adjustments for gender, age, smoking, alcohol drinking, physical activity, and energy intake. No significant differences in the weight changes between the genotype groups were evident in the longitudinal analysis. We conclude that the Trp(64)Arg mutation of ADRB3 has little or no influence on either body weight or body mass index in the general Japanese population.     

Significant association between a silent polymorphism in the neuromedin B gene and body weight in German children and adolescents

Neuromedin B has been shown to exert an inhibiting effect on food consumption in rats. The corresponding gene NMB maps to chromosome 15q22.3-q23, a region expected to contain a gene for the Bardet-Biedl syndrome type 4 (BSS4). Based on its map position and the putative function of the encoded peptide, NMB can be considered as a candidate gene both for BBS4 and the development of human obesity. To examine its involvement in these phenotypes, we determined the genomic structure of human NMB, and performed a mutation screen in its coding region. In genomic DNA of six BBS4 patients and in a large population sample, two sequence variants were detected: a g.253C→A transversion creating a P73T substitution and a g.401G→A silent mutation changing the stop codon TGA into stop codon TAA. A case-control study with 92 extremely obese patients and 94 underweight students revealed a significant association between the g.401G→A polymorphism and body weight (adjusted p = 0.03), which was confirmed in a validation sample consisting of 95 extremely obese patients, and 95 normal weight and 48 underweight individuals, (Mann-Whitney p = 0.02). These results suggest a contribution of NMB or a gene in its close vicinity to genetic weight control in humans. Received: 15 May 2000 / Accepted: 14 September 2000     

女童婴儿期体重增加可预示儿童期体脂量和月经初潮年龄

儿童肥胖的发病率正在不断上升.对英国Wirral的50455名3～4岁儿童的数据资料进行的分析显示,在1998至2003年间,他们的平均体重指数(BMI)和超重风险均稳步上升.研究表明儿童期肥胖可影响成年后的健康状况,并可预示以后心血管疾病的发生和死亡率.因此,在婴儿早期即开始干预可能有助于预防肥胖及与之相关的代谢异常.     

Immediate, short- and long-term opposite effects of oestradiol-17 beta on glucose metabolism in rat adipocytes: relationship with the biphasic changes in body weight and food intake

The changes in the effects of oestradiol-17 beta on body weight, food intake and [1-14C]glucose oxidation in adipocytes were followed in sham-operated, ovariectomized and adrenalectomized-ovariectomized rats to eliminate effects of endogenous progesterone and corticosterone. During the first 5 days oestradiol induced a dramatic fall in food intake and body weight concomitant with a decrease in glucose oxidation by adipocytes, when tested 12 h and 3 days after the beginning of treatment. In-vitro incubations with oestradiol showed that this was a direct effect of this hormone. On the other hand, from days 5 to 14 of treatment, body weight and food intake increased, though they were still lower than in sham-operated controls. On day 14, as values of treated rats tended to reach those of controls, glucose oxidation in adipocytes was stimulated by oestradiol treatment. An insulin effect was still observable and none of these effects was dependent on the adrenal gland. These biphasic changes in the parameters studied could be closely related; moreover, a relationship with other oestradiol actions on metabolism that are known to be corticosterone-dependent could be eliminated.     

Relationship of RIC-3 gene rs1528133 polymorphism with varying degrees of body weight and eating behavior

AimsThe aim of this study was to determine the allele frequencies of resistance to inhibitors of cholinesterase 3 homologue (RIC-3) gene rs1528133 polymorphism in overweight + obese + morbid obese and non-obese (non-OB) subjects. The effects of rs1528133 genotypes on anthropometric, diabetes and obesity related parameters, self-reported macronutrient intake and drugs were also evaluated. The study was performed on overweight + obese + morbid obese and non-obese subjects.MethodsRIC-3 gene rs1528133 genotypes were determined with qPCR.ResultsThe RIC-3 rs1528133 genotype frequencies were respectively as 89.4% for homozygous wild type (A/A), 10.6% for heterozygous (A/C) genotypes in overweight + obese + morbid obese patients and 92.7% for A/A, 7.3% for A/C genotypes in non-OB subjects. The homozygous mutant genotype (C/C) was not detected in our study population. Genotype frequencies were not significantly different among study groups. Heterozygous genotype carriers for the rs1528133 polymorphism were found to prefer higher glycemic load, fat and protein diet content compared to homozygous wild type genotype carriers (p = 0.0001). The frequency of rs1528133 heterozygous individuals (16.7%) using antihypertensive drugs was lower (p = 0.045) in comparison to wild type genotype carriers (46.9%) in the whole study population.ConclusionsRIC-3 gene rs1528133 variation was not found to be effective over any analyzed obesity related parameter, but associated with higher glycemic load, protein and fat eating behavior and antihypertensive drug use.     

Personality characteristics in adolescence predict long-term changes in body fatness

Five personality characteristics were assessed in 312 adolescent boys and girls, and investigated in relation to the change in body fat percentage over 22 years of follow up. Boys with low levels of Social Inadequacy and girls with high levels of Recalcitrance showed relatively large gains in body fat percentage.