Association of the ins/del polymorphisms of uncoupling protein 2 (UCP2) with BMI in a Korean population

To elucidate the potential impact of the variants of the UCP2 gene on obesity phenotypes, we have genotyped four polymorphisms in UCP2 among 988 Korean subjects using TaqMan^® methods, and three common haplotypes with frequency greater than 0.1 were constructed in the Korean population. No significant associations were detected with the risk of metabolic syndrome by logistic regression analyses. However, the 45 base-pair ins/del polymorphism (+3474 ins/del) in the 3′ untranslated region (3′ UTR) showed significant association with body mass index (P = 0.007, P^corr = 0.02) and waist circumference (P = 0.005). Further subgroup analysis revealed that the genetic effects were more apparent among female subjects. In addition, a summary of the controversial genetic effects on obesity mediated by UCP2 polymorphisms from previous studies is also given. Our results suggest that subjects with a 45 bp insertion allele of UCP2+3474 ins/del might have a higher risk of developing obesity, although the biological effects of this variant are not completely known.     

ABCB1 基因单核苷酸多态性rs2235048 与氯吡格雷抵抗的相关关系

目的:探讨ABCB1基因单核苷酸多态位点rs2235048在中国汉族人群中的分布及其与氯吡格雷抵抗(Clopidogrelresistance,CR)发生的相关关系。方法:采用光学比浊法测定20μmol/L ADP诱导的残余血小板聚集率(Residual plateletagglutination,RPA)。当RPA≥70%时,即为CR。所有入选患者分为CR组和氯吡格雷非抵抗组(Non-clopidogrel resistance,NCR)。采用焦磷酸测序法测定ABCB1基因rs2235048单核苷酸多态位点在CR组和NCR组的基因型及等位基因分布频率。结果:ABCB1基因rs2235048多态在CR组和NCR组基因型分布频率符合Hardy-Weinberg平衡。在CR组和NCR组中,ABCB1基因rs2235048多态的基因型频率分布无统计学差异(P=0.527,X2=1.281);T、C等位基因频率在两组间分布频率也没有统计学差异(P=0.740,OR=0.958,95%CI=0.742～1.236)。结论:对PCI术后服用氯吡格雷的冠心病患者进行分析发现,ABCB1基因单核苷酸多态位点rs2235048与冠心病患者CR的发生无相关关系。     

ABCB1基因多态性与难治性癫痫

近年来,难治性癫痫的病因与多药耐药基因以及多药耐药基因与抗癫痫治疗的因果关系越来越受到关注。P糖蛋白(P-glycopretein,P-gp)是由ATP结合盒B亚家族成员1转运蛋白基因(ATP-binding cassette subfamily B member 1 transporter gene,ABCB1)编码的产物。它不仅可以限制抗癫痫药物(antiepileptic drug,AED)的消化道吸收,而且可以在细胞和亚细胞水平调控药物在中枢神经系统的运输过程。除了生理和环境因素的影响,P-gp的功能和表达的变化可能主要取决于ABCB1基因的多态性,这是目前研究得最广泛、最深入的多药耐药机制。本文就目前ABCB1基因多态性与难治性癫痫的相关性研究进展作一综述。     

Colorectal cancer susceptibility: apparent gender-related modulation by ABCB1 gene polymorphisms

Background

The ATP-binding cassette transporter B1 (ABCB1) gene codes for a membrane efflux pump localized in epithelial cells. Together with other Permeability-glycoproteins in the small and large intestine, its product represents a barrier against xenobiotics, bacterial toxins, drugs and other substances introduced with diet, including carcinogens. The aim of this investigation was to verify the possible contribution of ABCB1 single nucleotide polymorphisms (SNPs) to the genetic risk of colorectal cancer (CRC).

Results

DNA obtained from the peripheral blood of 98 CRC patients and 100 healthy controls was genotyped for the three selected SNPs: 1236C > T (rs1128503), 2677G > T/A (rs2032582), and 3435C > T (rs1045642). Molecular data were analyzed to asses allele and haplotype association with CRC.No evidence of an association between ABCB1 alleles and CRC occurrence as a whole was found. However, ABCB1 showed either association with carcinoma of the sigmoid colon, and appeared able to influence the sex ratio among CRC patients. These two effects seemed to act independently based on multivariate analysis. We showed that ABCB1 polymorphisms were able to influence CRC susceptibility related to tumor localization and patient gender.

Conclusions

We suggest that sensitivity to undetermined risk factors could depend on the genetic background of ABCB1 locus, with a mechanism that also depends on patient gender.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-014-0089-8) contains supplementary material, which is available to authorized users.     

The long-run effect of education on obesity in the US

The proportion of obese population has been gradually increasing in the US over the past few decades. In this study I investigate how education is associated with Body Mass Index (BMI) in later stages of life. BMI, weight(kg)/height(m)², is the principle measure used for classifying people as obese. Using sibling data and methods that take account of unobserved endowments and environment shared by siblings, I find that there is large variation in BMI between siblings and that education is negatively associated with BMI. One more year of schooling is associated with an estimated reduction of 0.15 in BMI. When considering different education levels, completing college education is associated with 0.7 reduction in BMI relative to high school graduation only. The significant effect of education on obesity that remains in the long-run has policy implications.     

Euphorbia factor L1 reverses ABCB1-mediated multidrug resistance involving interaction with ABCB1 independent of ABCB1 downregualtion

Euphorbia factor L1 (EFL1) belongs to diterpenoids of genus Euphorbia. In this article, its reversal activity against ABCB1-mediated MDR in KBv200 and MCF-7/adr cells was reported. However, EFL1 did not alter the sensitivity of KB and MCF-7 cells to chemotherapeutic agents. Meanwhile, EFL1 significantly increased accumulation of doxorubicin and rhodamine 123 in KBv200 and MCF-7/adr cells, showing no significant influence on that of KB and MCF-7 cells. Furthermore, EFL1 could enhance the ATP hydrolysis activity of ABCB1 stimulated by verapamil. At the same time, EFL1 inhibited the efflux of ABCB1 in KBv200 and MCF-7/adr cells. In addition, EFL1 did not downregulate expression of ABCB1 in KBv200 and MCF-7/adr cells either in mRNA or protein level.     

ABCB1 与氯吡格雷抵抗的研究进展

氯吡格雷和阿司匹林双联抗血小板已是急性冠状动脉综合征和经皮冠脉介入术后的标准治疗,因此氯吡格雷抵抗越来越受到人们的关注,但焦点更多的集中在氯吡格雷氧化代谢基因(P2Y12、CYP3A4等)多态性方面,而对氯吡格雷吸收方面基因多态性的关注相对较少,本文就调控氯吡格雷在肠道吸收的基因(ABCB1)进行综述,并探讨其多态性与氯吡格雷抵抗的关系。     

NRAMP1 polymorphism in a hybrid population between Japanese and Taiwanese macaques in Wakayama, Japan

A macaque population produced by the hybridization of native Japanese macaques (Macaca fuscata) and introduced Taiwanese macaques (M. cyclopis) in Wakayama Prefecture was shown to possess three DNA haplotypes of the natural resistance-associated macrophage protein 1 (NRAMP1). Based on genotyping and comparison with M. fuscata populations, it was revealed that the introduced M. cyclopis population was polymorphic for the NRAMP1 locus. Extensive crossbreeding of the introduced species with the native species was confirmed using this genetic marker and the proportion of M. cyclopis genes was 57.4%. Results of statistical tests suggested non-random mating in the hybrid population.     

Financial hardship and obesity

There is a substantial correlation between household debt and health. Individuals with less healthy lifestyles are more likely to hold debt, yet there is little evidence as to whether this is merely a correlation or if financial hardship actually causes obesity. In this paper, we use data from the National Longitudinal Survey of Adolescent Health to test whether financial hardship affects body weight. We divide our sample into two groups: men and women, explore two different types of financial hardship: holding credit card debt and having trouble paying bills, and three outcomes: overweight, obese and body mass index (BMI). We use a variety of econometric techniques: Ordinary Least Squares, Propensity Score Matching, Sibling Fixed Effects, and Instrumental Variables to investigate the relationship that exists between financial hardship and body weight. In addition, we conduct several robustness checks. Although our OLS and PSM results indicate a correlation between financial hardship and body weight these results appear to be largely driven by unobservables. Our IV results suggest that there is no causal relationship between credit card debt and overweight or obesity for either men or women. However, we find suggestive evidence that having trouble paying bills may be a cause of obesity for women.     

Analysis of caprine pituitary specific transcription factor-1 gene polymorphism in indigenous Chinese goats

Since mutations on POU1F1 gene possibly resulted in deficiency of GH, PRL, TSH and POU1F1, this study revealed the polymorphism of goat POU1F1-AluI locus and analyzed the distribution of alleles on 13 indigenous Chinese goat breeds. The PCR-RFLP analysis showed the predominance of TT genotype and the frequencies of allele T varied from 0.757 to 0.976 in the analyzed populations (SBWC, Bo, XH and HM). Further study, distributions of genotypic and allelic frequencies at this locus were found to be significantly different among populations based on a χ²-test (P < 0.001), suggesting that the breed factor significantly affected the molecular genetic character of POU1F1 gene. The genetic diversity analysis revealed that Chinese indigenous populations had a wide spectrum of genetic diversity in goat POU1F1-AluI locus. However, the ANOVA analysis revealed no significant differences for gene homozygosty, gene heterozygosty, effective allele numbers and PIC (polymorphism information content) among meat, dairy and cashmere utility types (P > 0.05), suggesting that goat utility types had no significant effect on the spectrum of genetic diversity. X. Y. Lan and M. J. Li equally contributed to this work.     

Absence of a general association between ABCB1 genetic variants and response to antiepileptic drugs in epilepsy patients

Over-expression of efflux transporter P-glycoprotein (PgP) encoded by ABCB1 gene has been implicated in poor responsive epilepsy. Several genetic variants have been shown to influence the expression levels of P-glycoprotein. The aim of the present study was to investigate the role of ABCB1 polymorphisms: C1236T, G2677T/A and C3435T in determining drug response to first line antiepileptic drugs (AEDs) namely phenobarbitone, phenytoin, carbamazepine and valproate in North Indian cohort of epilepsy patients. DNA samples were obtained from 392 consecutive epilepsy patients, out of which 228 had completed follow-up evaluation at 12 months. After attaining steady state of the AEDs in the first two months of study, 133 patients showed complete freedom from seizures (no-seizure group) and 95 patients continued to have seizures (recurrent-seizures group) in the remaining period of study. Comparison of “no-seizure” and “recurrent-seizures” groups revealed no significant differences in allelic, genotypic and haplotypic frequencies for all the studied variants. In conclusion, our finding disproves a general association between ABCB1 polymorphisms and drug response in epilepsy patients.     

生化指标与2型糖尿病患者实验诊断及预后相关性研究

目的：研究BMI、HbA1c、病程、相关代谢指标与2型糖尿病（T2DM）诊断及预后的关系。方法：收集379例T2DM患者与383例健康体检者,采用生化分析仪分析二组人群的生化指标,采用高效液相色谱法检测T2DM组HbA1c水平,胰岛素及C肽采用电化学发光法检测。计量资料采用t检验、单因素方差及相关性分析,计数资料采用卡方检验分析。结果：对各组结果进行比较显示（1）T2DM患者的BMI、FBG、TG、LDL-C、BUN、uA、HbA1c水平明显高于正常对照组（P均〈0．01）,HDL-C、CREA水平明显低于对照组（P均〈0．01）;（2）TC、LDL—C、BUN、CREA及2hINS与年龄相关。（3）肥胖组的TG、CREA、UA、FCP、2hCP高于非肥胖组（P均〈0．05）;（4）初诊T2DM患者的FBG、TG、HbA1c、LDL-C水平明显高于5年以上患者（P均〈0．05）,而HDL-c低于5年以上患者（P〈0．05）;（5）HbA1c≥11％组的FBG水平明显高于HbA1c≤8％及HbA1c=8-11％组（P〈0．01）,而UA、FINS、FCP、2hINS、2hCP水平明显低于HbA1c〈8％组（P均〈0．01）;FBG、TG与HbA1c水平呈正相关（P〈0．05）;FINS、FCP、2hINS、2hCP、UA与HbA1c水平呈负相关（P〈0．01）;结论：BMI、FBG、TG、LDL-C、BUN、UA、HDL-C、CREA均可作为T2DM诊断的参考指标。其中LDL—C、BUN、CREA、2hINs指受年龄影响。TG、CREA、uA、FCP（空腹C-肽）、2hCP与肥胖相关。FBG、TG、HbA1c、LDL-C、HDL-C与病程相关;FBG、TG、HbA1c、FINS、FCP、2hINS、2hCP、UA与HbA1c相关。     

生化指标与2 型糖尿病患者实验诊断及预后相关性研究

目的：研究BMI、HbA1c、病程、相关代谢指标与2 型糖尿病（T2DM）诊断及预后的关系。方法：收集379 例T2DM 患者与 383 例健康体检者,采用生化分析仪分析二组人群的生化指标,采用高效液相色谱法检测T2DM 组HbA1c 水平,胰岛素及C 肽 采用电化学发光法检测。计量资料采用t 检验、单因素方差及相关性分析,计数资料采用卡方检验分析。结果：对各组结果进行比 较显示（1）T2DM 患者的BMI、FBG、TG、LDL-C、BUN、UA、HbA1c 水平明显高于正常对照组（P均<0.01),HDL-C、CREA 水平明 显低于对照组（P均<0.01);（2 ）TC、LDL-C、BUN、CREA及2hINS 与年龄相关。（3）肥胖组的TG、CREA、UA、FCP、2hCP 高于非肥 胖组（P 均<0.05);（4 ）初诊T2DM 患者的FBG、TG、HbAlc、LDL-C 水平明显高于5 年以上患者（P均<0.05),而HDL-C 低于5 年 以上患者（P<0.05);（5 ）HbA1c≥ 11%组的FBG水平明显高于HbA1c≤ 8%及HbA1c＝8～11%组（P<0.01）,而UA、FINS、FCP、 2hINS、2hCP 水平明显低于HbA1c<8%组（P 均<0.01);FBG、TG 与HbA1c 水平呈正相关（P<0.05）;FINS、FCP、2hINS、2hCP、UA 与HbA1c 水平呈负相关（P<0.01);结论：BMI、FBG、TG、LDL-C、BUN、UA、HDL-C、CREA均可作为T2DM诊断的参考指标。其中 LDL-C、BUN、CREA、2hINS 指受年龄影响。TG、CREA、UA、FCP(空腹C-肽）、2hCP与肥胖相关。FBG、TG、HbAlc、LDL-C、HDL-C 与病程相关;FBG、TG、HbA1c、FINS、FCP、2hINS、2hCP、UA与HbA1c 相关。     

Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes

Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P = 0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.     

ABCB1 identifies a subpopulation of uveal melanoma cells with high metastatic propensity

Metastasis of tumor cells to distant organs is the leading cause of death in melanoma. Yet, the mechanisms of metastasis remain poorly understood. One key question is whether all cells in a primary tumor are equally likely to metastasize or whether subpopulations of cells preferentially give rise to metastases. Here, we identified a subpopulation of uveal melanoma cells expressing the multidrug resistance transporter ABCB1 that are highly metastatic compared to ABCB1(-) bulk tumor cells. ABCB1(+) cells also exhibited enhanced clonogenicity, anchorage-independent growth, tumorigenicity and mitochondrial activity compared to ABCB1(-) cells. A375 cutaneous melanoma cells contained a similar subpopulation of highly metastatic ABCB1(+) cells. These findings suggest that some uveal melanoma cells have greater potential for metastasis than others and that a better understanding of such cells may be necessary for more successful therapies for metastatic melanoma.     

Increased ABCB1 Expression in TP-110-Resistant RPMI-8226 Cells

TP-110, a novel proteasome inhibitor, has been found to possess potent growth inhibition in human multiple myeloma cells. To enhance its therapeutic effects, we established TP-110-resistant RPMI-8226 (RPMI-8226/TP-110) cells and elucidated their resistance mechanisms. The IC₅₀ value for TP-110 cytotoxicity in the RPMI-8226/TP-110 cells was about 10-fold higher than that of the parental sensitive cells. The RPMI-8226/TP-110 cells exhibited distinct drug resistance to other proteasome inhibitors. Furthermore, they showed high cross-resistance to the cytotoxic effects of doxorubicin, etoposide, taxol, and vincristine. P-glycoprotein (MDR1), encoded by ABCB1, was elevated in the RPMI-8226/TP-110 cells, and the MDR1 inhibitor verapamil overcame their resistance to TP-110. The results of DNA microarray and RT-PCR suggested that the expression of ABCB1 is significantly elevated in RPMI-8226/TP-110 cells. This indicates that resistance in RPMI-8226/TP-110 cells is involved in the expression of P-glycoprotein, a drug-efflux pump.     

Association of a CXCL9 polymorphism with pediatric Crohn's disease

Genetic and environmental factors contribute to the etiopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). To identify new susceptibility genes, we determined the mRNA expression level of 88 genes from different biological contexts on colonic biopsies of CD and UC patients. We show that CXCL9 was overexpressed in colonic tissue of 3/5 CD and 3/3 UC patients compared to healthy controls. SNP genotyping for the 77147452G-->A polymorphism of the CXCL9 gene on 114 pediatric IBD patients and 120 ethnically matched unaffected adults detected a minor allele frequency of 20.3% in CD patients compared to 31.3% in controls (p=0.016). Strikingly, children with homozygosity for the wild-type allele had a significant earlier onset of CD than heterozygous individuals (11.1 versus 13.8 years). This is the first report of inverse association of the CXCL9 77147452G-->A polymorphism with pediatric CD. Our data may contribute to a better understanding of the pathophysiology underlying CD.     

Association of apolipoprotein B XbaI gene polymorphism and lipid profile in northern Indian obese

BACKGROUND:

Over the last few decades, obesity, diabetes, and hypertension have become main health evils. The health problems of obesity are well-recognized. However, the fact that all obese individuals are not at the same risk of developing a disease is also recognized. The apolipoprotein B (APOB) plays a central role in lipid metabolism. So we compare the association of APOB XbaI gene polymorphism and lipid profile total in obese north Indian population.

MATERIALS AND METHODS:

A total of 132 obese (body mass index [BMI] >25 kg/m²) and 132 age matched non-obese (BMI ≤ 25 kg/m²) subjects were studied after taking detailed clinical profile. Lipid profile in serum/plasma was done using commercial kits. Genetic analysis of APOB XbaI was done using Polymerase Chain Reaction-Restriction Fragment Leanth polymorphism (PCR-RFLP).

STATISTICAL ANALYSIS:

Statistical analysis was performed by Statistical Package for the Social Sciences (SPSS) (version 11.5) software (IBM Corporation). All continuous variables were expressed as mean ± SD and tested by analysis of variance test. Comparisons of categorical variables were assessed using χ² tests or Fisher''s exact test. P < 0.05 was considered as significant.

RESULTS:

Analysis showed that obese subjects had significantly higher value of the waist-to-hip ratio, blood pressure (systolic and diastolic), and lipid profile. In APOB XbaI gene polymorphism, we did not find significant differences in genotype or allele frequencies. Moreover, none of the studied metabolic parameters (lipid profile) showed any association with the gene polymorphism.

CONCLUSIONS:

Study reveals no considerable association of APOB XbaI gene polymorphism with obesity and lipid profile in north Indians.     

Genetic polymorphism of <Emphasis Type="Italic">GSTT1</Emphasis> may be under natural selection in a population chronically exposed to natural sour gas

Objective In order to examine whether chronic exposure to natural sour gas containing sulfur compounds act as natural selection force on genetic polymorphisms of glutathione S-transferase M1 (GSTM1) and T1 (GSTT1), the present study was done. Methods The study was performed on two groups of healthy individuals of Masjid-i-Sulaiman (Khozestan province, southwest of Iran) citizens with the mean ages of 47.5 ± 12.4 (36 male and 58 female) and 16.3 ± 2.4 (47 male and 140 female) that were considered as first and second generation, respectively. The GSTT1 and GSTM1 genotypes were determined using a PCR-based method. Results The genotypic frequencies of GSTM1 did not change significantly (χ² = 0.085, df = 1, P = 0.770). The frequency of the GSTT1 null genotype was 52.1% in the first generation and reached to 36.4% in the second generation. There was significant difference between two generations for the GSTT1 polymorphism (χ² = 6.397, df = 1, P = 0.011). Conclusion It was suggested that the GSTT1 polymorphism may be under natural selection because of probably favored ability of GSTT1-active genotype to survival and reproduction.