Leptin and leptin receptor gene polymorphisms and their association with plasma leptin levels and obesity in a multi-ethnic Malaysian suburban population

Background

This study was to investigate the prevalence of single nucleotide polymorphisms (SNPs) in leptin gene LEP (A19G and G2548A) and leptin receptor gene LEPR (K109R and Q223R) and their association with fasting plasma leptin level (PLL) and obesity in a Malaysian suburban population in Kampar, Perak.

Methods

Convenience sampling was performed with informed consents, and the study sample was drawn from patients who were patrons of the Kampar Health Clinic. A total of 408 subjects (mean age, 52.4 ± 13.7 years; 169 men, 239 women; 190 obese, 218 non-obese; 148 Malays, 177 ethnic Chinese, 83 ethnic Indians) participated. Socio-demographic data and anthropometric measurements were taken, and genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).

Results

The LEP A19G, G2548A and LEPR K109R, Q223R variant allele frequencies were 0.74, 0.67 and 0.61, 0.79, respectively. The genotype and allele distributions of these gene variants were significantly different among ethnic groups, but not among body mass index (BMI) classes. Subjects with LEPR K109 and Q223 allele had significantly higher systolic blood pressure and adiposity indices after adjustment for ethnicity (higher BMI, total body and subcutaneous fat; lower skeletal muscle percentage). Subjects with LEPR 109R allele had lower PLL than their wild-type allele counterparts. The influence of LEP A19G and G2548A SNPs on blood pressures, anthropometrics, and PLL was not evident. Interestingly, synergistic effect of the LEP and LEPR SNPs was observed as subjects homozygous for all four SNPs studied exhibited significantly higher subcutaneous fat and PLL than those with other genotype combinations.

Conclusions

The LEP and LEPR SNPs in this study may not be an obesity marker among Malaysians in this population, but were associated with ethnicity. Our findings suggest that each of these SNPs contributes to minor but significant variation in obesity-related traits and in combination they display synergistic effects on subcutaneous fat and PLL.     

Leptin G-2548A and leptin receptor Q223R gene polymorphisms are not associated with obesity in Romanian subjects

We aimed to investigate whether polymorphisms LEP G-2548A and LEPR Q223R in the human leptin (LEP), and leptin receptor (LEPR) genes are associated with obesity and metabolic traits in a sample of Romanian population. Two hundred and two subjects divided in obese (body mass index, BMI ? 30 kg/m²), and non-obese were included in this study. The polymorphisms were genotyped using polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP) analysis. The results showed no significant differences in LEP and LEPR genotype and allele frequencies between obese and non-obese subjects. Logistic regression analysis showed that LEP -2548GG genotype presented an increased risk of obesity (p = 0.013, OR = 1.003, 95% CI = 1.000-1.007), after adjusting for age and gender. The association analysis with metabolic syndrome quantitative traits showed that homozygous for LEP -2548G allele had significantly higher leptin levels (17.2 ± 6.6 ng/ml vs. 13.2 ± 4.9 ng/ml, p = 0.011), and carriers of R allele had higher levels of triglycerides (p = 0.017) and glucose (p = 0.040), and enhanced systolic (p = 0.015) and diastolic blood pressure (p = 0.026), after adjustment for age, gender, and BMI. These results indicate that LEP G-2548A and LEPR Q223R SNPs may not be considered as genetic risk factors for obesity in a sample of Romanian population. However, LEP -2548GG genotype appear to be important in regulating leptin levels, whereas the LEPR 223R allele might predispose healthy subjects to develop metabolic disturbances.     

The Q223R polymorphism in LEPR is associated with obesity in Pacific Islanders

Various Pacific Island populations have experienced a marked increase in the prevalence of obesity in past decades. This study examined the association of a promoter polymorphism of the leptin gene (LEP), G-2548A (rs7799039), and two non-synonymous single nucleotide polymorphisms of the leptin receptor gene (LEPR), K109R (rs1137100) and Q223R (rs1137101), with body weight, body mass index (BMI) and obesity (BMI ≥ 30) in Pacific Islanders. A total of 745 Austronesian (AN)-speaking participants were analyzed after adjusting for age, gender, and population differences. The results revealed that carriers of the 223Q alleles of LEPR had significantly higher body weight (P = 0.0009) and BMI (P = 0.0022) than non-carriers (i.e., 223R homozygotes); furthermore, the 223Q carriers also had a significantly higher risk of obesity in comparison to non-carriers (P = 0.0222). The other two polymorphisms, G-2548A and K109R, were associated with neither body weight, BMI, nor obesity. The 223Q allele was widely found among the AN-speaking study subjects, thus suggesting that the LEPR Q223R polymorphism is one of the factors contributing to the high prevalence of obesity in the Pacific Island populations.     

Association between variants of the leptin receptor gene (LEPR) and overweight: a systematic review and an analysis of the CoLaus study

Background

Three non-synonymous single nucleotide polymorphisms (Q223R, K109R and K656N) of the leptin receptor gene (LEPR) have been tested for association with obesity-related outcomes in multiple studies, showing inconclusive results. We performed a systematic review and meta-analysis on the association of the three LEPR variants with BMI. In addition, we analysed 15 SNPs within the LEPR gene in the CoLaus study, assessing the interaction of the variants with sex.

Methodology/Principal Findings

We searched electronic databases, including population-based studies that investigated the association between LEPR variants Q223R, K109R and K656N and obesity- related phenotypes in healthy, unrelated subjects. We furthermore performed meta-analyses of the genotype and allele frequencies in case-control studies. Results were stratified by SNP and by potential effect modifiers. CoLaus data were analysed by logistic and linear regressions and tested for interaction with sex. The meta-analysis of published data did not show an overall association between any of the tested LEPR variants and overweight. However, the choice of a BMI cut-off value to distinguish cases from controls was crucial to explain heterogeneity in Q223R. Differences in allele frequencies across ethnic groups are compatible with natural selection of derived alleles in Q223R and K109R and of the ancient allele in K656N in Asians. In CoLaus, the rs10128072, rs3790438 and rs3790437 variants showed interaction with sex for their association with overweight, waist circumference and fat mass in linear regressions.

Conclusions

Our systematic review and analysis of primary data from the CoLaus study did not show an overall association between LEPR SNPs and overweight. Most studies were underpowered to detect small effect sizes. A potential effect modification by sex, population stratification, as well as the role of natural selection should be addressed in future genetic association studies.     

Association between Tumor Necrosis Factor-α 308G/A Gene Polymorphism and Silicosis Susceptibility: A Meta-Analysis

Background

Tumor necrosis factor-α (TNF-α) 308 G/A gene polymorphism has been reported to be associated with susceptibility to silicosis. However, the relevant study results are still inconsistent.

Objective and Methods

A meta-analysis was performed in order to drive a more precise estimation of the relationship between TNF-α-308 G/A gene polymorphism and susceptibility to silicosis. Electronic databases were searched and nine separate studies were included. The pooled odds ratios (ORs) and the corresponding 95% confidence internal (CI) were calculated by a fixed effect model.

Results

A total of 1267 cases and 1214 controls were included. In the overall analysis, significantly increased silicosis risk was found (for GA+AA vs. GG OR=1.45, 95%CI: 1.20-1.760, P=1.58E4; for GA vs. GG: OR=1.53, 95%CI=1.25-1.86, P=3.11E5; for A allele vs. G allele: OR=1.27, 95%CI=1.08-1.50, P= 0.004). In the subgroup analysis, significantly increased silicosis risk was also found among Asians (for GA+AA vs. GG: OR=1.63, 95%CI=1.27-2.08, P=1.01E4), for GA vs. GG: OR=1.71, 95%CI=1.33-2.20, P=3.44E5), for A allele vs. G allele: OR=1.45, 95%CI=1.17-1.80, P=0.001). However, no significantly increased risk was found among non-Asians for all genetic models.

Conclusions

TNF-α-308 G/A polymorphism might lead to an increased risk of silicosis susceptibility, especially for Asians. However, further studies with large sample sizes should be conducted to confirm the association.     

The Leptin Gene Family and Colorectal Cancer: Interaction with Smoking Behavior and Family History of Cancer

Background

Pathologic condition associated with metabolic syndrome traits seems to increase the risk of colorectal cancer. One mechanism underlying this relationship may involve the growth-promoting effects of the circulation hormones associated with obesity and insulin resistance, such as leptin.

Methodology/Principal Findings

A two-stage case-control study was used to explore the role of polymorphisms of Leptin (LEP) and Leptin receptor (LEPR), either alone or in combination with environmental factors in colorectal carcinogenesis. In stage 1, 20 single nucleotide polymorphisms (SNPs) that tag common SNPs in these two genes were genotyped among 470 cases and 458 controls. In stage 2, another population with 314 cases and 355 controls were genotyped for the two most promising SNPs from stage 1. LEPR rs12037879 only presented modestly increased colorectal cancer risk, with odds ratios of 1.41 (95% confidence interval [CI] 1.13–1.76) and 1.74 (95%CI 1.08–2.81) for GA and AA genotype when compared with GG genotype in combined population. Smokers carrying LEPR rs12037879 A allele presented 1.67-fold (95%CI 1.39-fold to 2.01-fold) increased colorectal cancer risk when compared with non-smokers carrying GG genotype in combined analysis. Individuals with family history of cancer harboring LEPR rs12037879 A allele showed 1.52-fold (95%CI: 1.24-fold to 1.86-fold) increased colorectal cancer risk, compared with individuals without family history of cancer harboring GG genotype. Multifactor gene-environment interaction analysis revealed significant interactions among LEPR rs12037879, LEPR rs6690625, smoking status and family history of cancer, exhibiting a gradient of increased colorectal cancer risk along with the increasing number of risk factors (P = 9.82×10⁻¹⁰).

Conclusions/Significance

Our research supports that polymorphisms in LEPR may be associated with marginal increase in the risk for colorectal cancer. Moreover, this association could be strengthened by cigarette smoking and family history of cancer.     

Persistent High IgG Phase I Antibody Levels against Coxiella burnetii among Veterinarians Compared to Patients Previously Diagnosed with Acute Q Fever after Three Years of Follow-Up

Background

Little is known about the development of chronic Q fever in occupational risk groups. The aim of this study was to perform long-term follow-up of Coxiella burnetii seropositive veterinarians and investigate the course of IgG phase I and phase II antibodies against C. burnetii antigens and to compare this course with that in patients previously diagnosed with acute Q fever.

Methods

Veterinarians with IgG phase I ≥1:256 (immunofluorescence assay) that participated in a previous seroprevalence study were asked to provide a second blood sample three years later. IgG antibody profiles were compared to a group of acute Q fever patients who had IgG phase I ≥1:256 twelve months after diagnosis.

Results

IgG phase I was detected in all veterinarians (n = 76) and in 85% of Q fever patients (n = 98) after three years (p<0.001). IgG phase I ≥1:1,024, indicating possible chronic Q fever, was found in 36% of veterinarians and 12% of patients (OR 3.95, 95% CI: 1.84–8.49).

Conclusions

IgG phase I persists among veterinarians presumably because of continuous exposure to C. burnetii during their work. Serological and clinical follow-up of occupationally exposed risk groups should be considered.     

HIF-1α 1772 C/T and 1790 G/A Polymorphisms Are Significantly Associated with Higher Cancer Risk: An Updated Meta-Analysis from 34 Case-Control Studies

Background

HIF-1 activates various genes in cancer progression and metastasis. HIF-1α 1772 C/T and 1790 G/A polymorphisms are reportedly associated with cancer risk; however, the results are inconclusive.

Methodology/Principal Findings

A meta-analysis of 34 studies that involved 7522 cases and 9847 controls for 1772 C/T and 24 studies that involved 4884 cases and 8154 controls for 1790 G/A was conducted to identify the association of C/T and G/A polymorphisms with cancer risk. Odds ratio (OR) and 95% confidence intervals (95% CI) were used to assess the strength of association.HIF-1α 1772 C/T and 1790 G/A polymorphisms were associated with higher cancer risk in homozygote comparison (1772C/T: TT vs. CC: OR = 2.45, 95% CI: 1.52, 3.96; P _{heterogeneity} = 0.028; 1790G/A: AA vs. GG: OR=4.74, 95% CI: 1.78, 12.6; P _{heterogeneity} < 0.01), dominant model (1772C/T: TT/CT vs. CC: OR = 1.27, 95% CI: 1.04, 1.55; P _{heterogeneity} < 0.01, 1790G/A: AA/GA vs. GG: OR = 1.65, 95% CI: 1.05, 2.60; P _{heterogeneity} < 0.01), T allele versus C allele (T vs. C: OR = 1.42, 95% CI: 1.18, 1.70; P _{heterogeneity} < 0.01), and A allele versus G allele (A vs. G: OR = 1.83, 95% CI: 1.13, 2.96; P _{heterogeneity} < 0.01). On a subgroup analysis, the 1772 C/T polymorphism was significantly linked to higher risks for breast cancer, lung cancer, prostate cancer, and cervical cancer, whereas the 1790 G/A polymorphism was significantly linked to higher risks for lung cancer and prostate cancer. A significantly increased cancer risk was found in both Asians and Caucasians for 1772C/T polymorphism, whereas a significantly increased cancer risk was found in Caucasians in the heterozygote comparison and recessive model for 1790G/A polymorphism.

Conclusions

HIF-1α 1772 C/T and 1790 G/A polymorphisms are significantly associated with higher cancer risk.     

Leptin −2548 G/A polymorphisms are associated to clinical progression of oral cancer and sensitive to oral tumorization in nonsmoking population

Oral cancer is causally associated with environmental carcinogens, and the susceptibility to carcinogen-mediated tumorigenesis is proposed to be genotype-dependent. Leptin (LEP) and leptin receptor (LEPR) both play a crucial role in the mediation of physiological reactions and carcinogenesis and may serve as a candidate biomarker of oral cancer. The current case-control study aimed to examine the effects of LEP −2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) single-nucleotide polymorphisms (SNPs) with or without interacting to environmental carcinogens on the risk for oral squamous cell carcinoma. The SNPs of three genetic allele, from 567 patients with oral cancer and 560 healthy controls in Taiwan were analyzed. The results shown that the patients with polymorphic allele of LEP −2548 have a significant low risk for the development of clinical stage (A/G: adjusted odds ratio [AOR] = 0.670, 95% confidence interval [CI] = 0.454-0.988, P < 0.05; A/G + G/G: AOR = 0.676, 95% CI = 0.467-0.978, P < 0.05) compared to patients with ancestral homozygous A/A genotype. In addition, an interesting result was found that the impact of LEP −2548 G/A SNP on oral carcinogenesis in subjects without tobacco consumption is higher than subjects with tobacco consumption. These results suggest that the genetic polymorphism of LEP −2548 G/A (rs7799039), LEPR K109R (rs1137100), and LEPR Q223R (rs1137101) were not associated to the susceptibility of oral cancer; SNP in LEP −2548 G/A showed a poor clinicopathological development of oral cancer; population without tobacco consumption and with polymorphic LEP −2548 G/A gene may significantly increase the risk to have oral cancer.     

High Postoperative Serum Cortisol Level Is Associated with Increased Risk of Cognitive Dysfunction Early after Coronary Artery Bypass Graft Surgery: A Prospective Cohort Study

Context

Stress response induced by surgery is proposed to play an important role in the pathogenesis of postoperative cognitive dysfunction.

Objective

To investigate the association between postoperative serum cortisol level and occurrence of cognitive dysfunction early after coronary artery bypass graft surgery.

Design

Prospective cohort study.

Setting

Two teaching hospitals.

Patients

One hundred and sixth-six adult patients who were referred to elective coronary artery bypass graft surgery from March 2008 to December 2009.

Intervention

None.

Main Outcome Measures

Neuropsychological tests were completed one day before and seven days after surgery. Cognitive dysfunction was defined using the same definition as used in the ISPOCD1-study. Blood samples were obtained in the first postoperative morning for measurement of serum cortisol concentration. Multivariate Logistic regression analyses were performed to assess the relationship between serum cortisol level and occurrence of postoperative cognitive dysfunction.

Results

Cognitive dysfunction occurred in 39.8% (66 of 166) of patients seven days after surgery. Multivariate Logistic regression analysis showed that high serum cortisol level was significantly associated with the occurrence of postoperative cognitive dysfunction (odds ratio [OR] 2.603, 95% confidence interval [CI] 1.371-4.944, P = 0.003). Other independent predictors of early postoperative cognitive dysfunction included high preoperative New York Heart Association functional class (OR 0.402, 95% CI 0.207-0.782, P = 0.007), poor preoperative Grooved Pegboard test score of nondominant hand (OR 1.022, 95% CI 1.003-1.040, P = 0.020), use of penehyclidine as premedication (OR 2.565, 95% CI 1.109-5.933, P = 0.028), and occurrence of complications within seven days after surgery (OR 2.677, 95% CI 1.201-5.963, P = 0.016).

Conclusions

High serum cortisol level in the first postoperative morning was associated with increased risk of cognitive dysfunction seven days after coronary artery bypass graft surgery.     

CYP2D6*4 Allele Polymorphism Increases the Risk of Parkinson’s Disease: Evidence from Meta-Analysis

Background

Many epidemiological studies have been conducted to explore the association between a single CYP2D6 gene polymorphism and Parkinson’s disease (PD) susceptibility. However, the results remain controversial.

Objectives

To clarify the effects of a single CYP2D6 gene polymorphism on the risk of PD, a meta-analysis of all available studies relating to CYP2D6*4 polymorphism and the risk of PD was conducted.

Methods

A comprehensive literature search of PubMed, EMBASE, and the China National Knowledge Infrastructure (CNKI) up to September 1, 2013 was conducted. Data were extracted by two independent authors and pooled odds ratio (OR) with 95% confidence interval (CI) were calculated. Meta-regression, Galbraith plots, subgroup analysis, sensitivity analysis, and publication bias analysis were also performed.

Results

Twenty-two separate comparisons consisting of 2,629 patients and 3,601 controls were included in our meta-analysis. The pooled analyses showed a significant association between CYP2D6*4G/A polymorphism and PD risk in all of the comparisons (A vs. G allele: OR = 1.28, 95% CI = 1.14–1.43, P = 0.001; AA vs. GG: OR = 1.43, 95% CI = 1.06–1.93, P = 0.018; AG vs. GG: OR = 1.22, 95% CI = 1.06–1.40, P = 0.006; AG+AA vs. GG: OR = 1.26, 95% CI = 1.10–1.44, P = 0.001; AA vs. AG+GG: OR = 1.37, 95% CI = 1.02–1.83, P = 0.036). In subgroup analysis stratified by ethnicity, significant associations were also demonstrated in Caucasians but not in Asians. No significant association was found in subgroup analysis stratified by age of onset or disease form.

Conclusions

We concluded that the CYP2D6*4G/A polymorphism denotes an increased genetic susceptibility to PD in the overall population, especially in Caucasians. Further large and well-designed studies are needed to confirm this association.     

Genetic Variation in DROSHA 3’UTR Regulated by hsa-miR-27b Is Associated with Bladder Cancer Risk

Purpose

miRNAs can regulate the biological processes, including differentiation, proliferation and apoptosis. DICER and DROSHA are two members of RNase III family, playing pivotal roles in the pathway of miRNAs biogenesis. In this study, we hypothesized that genetic variations of the DICER and DROSHA genes were associated with the bladder cancer risk.

Experimental Design

We performed a case-control study of 685 bladder cancer cases and 730 controls to investigate the association between the seven functional SNPs of DICER and DROSHA genes and bladder cancer risk. We then evaluated the functionality of the important SNPs.

Results

We found that rs10719T>C polymorphism located in 3’ untranslated region (UTR) of DROSHA gene was associated with the increased risk of bladder cancer. Stratified analysis suggested that rs10719TC/CC genotype can increase risk of bladder cancer among male patients (Adjusted OR = 1.34, 95% CI = 1.05-1.70, P = 0.018), and ever smokers (1.56, 1.14-2.14, 0.006), compared with TT genotype. Furthermore, DROSHA rs10719T>C polymorphism was predicted to regulate the binding activity of hsa-miR-27a/b. Luciferase reported gene assay confirmed that rs10719 T to G substitution disrupted the binding site for hsa-miR-27b, resulting the increased levels of DROSHA protein.

Conclusions

Taken together, these findings suggested that DROSHA rs10719T>C polymorphism may be associated with bladder cancer risk in a Chinese population, and hsa-miR-27b can influence the expression of DROSHA protein by binding with 3’UTR.     

The -607C/A Polymorphisms in Interleukin-18 Gene Promoter Contributes to Cancer Risk: Evidence from A Meta-Analysis of 22 Case-Control Studies

Background

Several observational studies have investigated the association between -607 C/A polymorphism of IL-18 gene and cancer risk; however, the results were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of the association to help us better understand the relationship between -607 C/A polymorphism of IL-18 gene promoter and risk of cancer.

Methods

A literature search was carried out using PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) database between January 1966 and February 2013. Fixed-effect and random-effect models were used to estimate the pooled odds ratio (OR) and the corresponding 95% confidence intervals (CIs).

Results

A total of 22 case-control studies including 4100 cancer cases and 4327 controls contributed to the analysis. Significant association between -607C/A polymorphism in IL-18 gene promoter and cancer risk was observed (CA vs CC:OR =1.221, 95% CI: 1.096, 1.360; P_{heterogeneity}=0.219; AA/CA vs. CC:OR =1.203, 95% CI: 1.057, 1.369; P_{heterogeneity}=0.064). In the subgroup analysis by ethnicity, -607C/A polymorphism significantly increased risk of cancer among Asian population (AA/CA vs. CC:OR =1.197, 95% CI: 1.023,1.401; P_{heterogeneity}=0.088); however, no significant association was found in Caucasian or African population. The -607C/A polymorphism was associated with a significantly increased risk of nasopharyngeal carcinoma (CA vs CC:OR =1.330, 95% CI: 1.029,1.719; P_{heterogeneity}=0.704; AA/CA vs. CC:OR =1.323, 95% CI: 1.037,1.687; P_{heterogeneity}=0.823) and esophageal cancer (AA/CA vs. CC:OR =1.289, 95% CI: 1.002,1.658; P_{heterogeneity}=0.700).

Conclusions

The present meta-analysis suggests that the -607C/A polymorphisms in IL-18 gene promoter is associated with a significantly increased risk of cancer, especially for nasopharyngeal carcinoma and esophageal cancer and in Asian population. More studies with larger sample size, well controlled confounding factors are warranted to validate this association.     

Novel Single Nucleotide Polymorphism Markers for Low Dose Aspirin-Associated Small Bowel Bleeding

Background

Aspirin-induced enteropathy is now increasingly being recognized although the pathogenesis of small intestinal damage induced by aspirin is not well understood and related risk factors have not been established.

Aim

To investigate pharmacogenomic profile of low dose aspirin (LDA)-induced small bowel bleeding.

Methods

Genome-wide analysis of single nucleotide polymorphisms (SNPs) was performed using the Affymetrix DMET™ Plus Premier Pack. Genotypes of candidate genes associated with small bowel bleeding were determined using TaqMan SNP Genotyping Assay kits and direct sequencing.

Results

In the validation study in overall 37 patients with small bowel bleeding and 400 controls, 4 of 27 identified SNPs: CYP4F11 (rs1060463) GG (p=0.003), CYP2D6 (rs28360521) GG (p=0.02), CYP24A1 (rs4809957) T allele (p=0.04), and GSTP1 (rs1695) G allele (p=0.04) were significantly more frequent in the small bowel bleeding group compared to the controls. After adjustment for significant factors, CYP2D6 (rs28360521) GG (OR 4.11, 95% CI. 1.62 -10.4) was associated with small bowel bleeding.

Conclusions

CYP4F11 and CYP2D6 SNPs may identify patients at increased risk for aspirin-induced small bowel bleeding.     

FTO Gene Variant and Risk of Overweight and Obesity among Children and Adolescents: a Systematic Review and Meta-Analysis

Objective

The fat mass and obesity associated gene (FTO) polymorphisms have been implicated in the susceptibility of overweight/obesity in children and adolescents. However, the results have been inconsistent. In this study, we performed a meta-analysis to clarify the association of FTO gene polymorphisms with overweight/obesity risk among children and adolescents.

Methods

PubMed and Embase were used to search for eligible published literatures. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random- or fixed-effect models.

Results

A total of 21 articles containing 23 studies (11208cases and 35015controls) were included in our analysis. The results indicated that variant in FTO gene was significantly associated with increased risk of overweight/obesity in children and adolescents (OR=1.35; 95%CI: 1.27-1.44; P<0.001). The overall pooled ORs for risk obesity and overweight were 1.34 (95%CI: 1.21-1.48) and 1.35 (95%CI: 1.25-1.47), respectively. Subgroup analyses also showed similar trends in most subgroups of adjustment for covariates and unadjustment, different ethnicities (Caucasians, Asians, and Amerindians), and each of three investigated polymorphisms (rs9939609, rs1421085, and rs1558902).

Conclusions

The present meta-analysis suggested a positive association between FTO gene polymorphism and overweight/obesity risk among children and adolescents. Further prospective studies should be recommended to confirm the observed association, and underlying mechanism should be investigated to clarify the association of FTO gene polymorphism with overweight/obesity.     

Association of leptin receptor gene Q223R polymorphism on lipid profiles in comparison study between obese and non-obese subjects

Objectives

Leptin is a hormone secreted from adipocytes. It regulates metabolism and energy homeostasis through the leptin receptor (LEPR) which is localized centrally in hypothalamus as well as in peripheral tissues. The aim of this study was to investigate the association of leptin receptor gene Q223R polymorphism on obesity in association with body mass index (BMI), lipid parameters, plasma leptin levels and homeostasis model assessment of insulin resistance (HOMA-IR).

Design and methods

The study included 110 obese and 90 non-obese subjects. The LEPR Q223R polymorphism was determined by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP). Plasma leptin levels, serum lipid and antropometric parameters were measured.

Results

No association was found between LEPR gene Q223R polymorphism and BMI in both study and control groups. Strikingly study group with non-obese subjects and with the RR genotype (homozygous mutant) had significantly higher serum total cholesterol (p < 0.001) and low density lipoprotein cholesterol (LDL-cholesterol) levels (p < 0.05) than QR (heterozygous) and QQ (wild type) genotypes. In obese group, subjects with the RR genotypes had significantly higher triglycerides (p < 0.05) levels, waist (p < 0.05) and hip circumferences (p < 0.001) than the QQ and QR genotypes.

Conclusions

Our results suggest that the LEPR gene Q223R polymorphism has an association with waist and hip circumferences in obese group but no direct association with obesity although there is a significant influence on lipid profile both in obese and non-obese subjects.     

The Association between Two MicroRNA Variants (miR-499, miR-149) and Gastrointestinal Cancer Risk: A Meta-Analysis

Background

MicroRNAs (miRNAs) are small RNA molecules that regulate the expression of corresponding messenger RNAs (mRNAs). Single nucleotide polymorphisms (SNPs) in miRNAs may contribute to cancer susceptibility due to changes in the microRNA’s properties and/or maturation. The present study aimed to investigate the association between two miRNA polymorphisms (miR-499 rs3746444 and miR-149 rs2292832) and gastrointestinal (GI) cancer risk.

Methodology/Principal Findings

We conducted a search of case-control studies in PubMed, Wiley Online Library, Web of Science and the CNKI database. Eleven rs3746444 studies and six rs2292832 studies were included in our meta-analysis. The only obvious association between the miR-499 polymorphism and colorectal cancer susceptibility was found in the homozygote comparison (GG vs. AA: OR = 1.66, 95% CI: 1.02–2.70, P _h = 0.10, P = 0.04). No significant association was found in the subgroup analysis for ethnicity and risk of hepatocellular and gastric cancer. A marginally elevated GI cancer risk was discovered in the recessive model for miR-149 (TT vs. TC+CC: OR = 1.15, 95% CI: 1.03–1.30, P _h = 0.68, P = 0.02). Stratifying the results by ethnicity revealed a slight association between the recessive model and the Asian population (TT vs. TC+CC: OR = 1.14, 95% CI: 1.01–1.29, P _h = 0.79, P = 0.03).

Conclusions/Significance

The present meta-analysis indicates that miR-499 may be associated with the risk to colorectal cancer. MiR-149 may confer a marginally increased risk of susceptibility to gastrointestinal cancer, especially for Asians.     

The Association between Hypoxia-Inducible Factor-1 α Gene C1772T Polymorphism and Cancer Risk: A Meta-Analysis of 37 Case-Control Studies

Background

The possible association between HIF-1α C1772T polymorphism and cancer risk has been studied extensively. However, the results were controversial. In order to get a more precise conclusion of this association, a meta-analysis was performed.

Methods

A total of 10186 cases and 10926 controls in 37 case-control studies were included in this meta-analysis. Allele and genotypic differences between cases and controls were evaluated. Subgroup analysis by cancer site, ethnicity, source of controls and gender was performed.

Results

The T allele of HIF-1α gene C1772T was significantly associated with increased cancer risk in three genetic models: TT+CT vs.CC (dominant model OR=1.23, 95%CI=1.03-1.47), TT vs. CT+CC (recessive model OR=2.51, 95%CI=1.54-4.09), TT vs. CC (homozygote comparison OR=2.02, 95%CI=1.21-3.39).In subgroup analysis, the frequency of the T variant was found to be significantly increased in cervical cancer, pancreatic cancer, head and neck cancer, renal cell carcinoma, Asian and female subgroups.

Conclusions

Our meta-analysis suggests that the substitution of C allele with T at HIF-1α gene C1772T polymorphism is a risk factor of cancer, especially for cervical, head and neck cancer, pancreatic cancer and renal cell carcinoma. It is also a risk factor of cancer in Asian group as well as in female group.     

Can K-ras Gene Mutation Be Utilized as Prognostic Biomarker for Colorectal Cancer Patients Receiving Chemotherapy? A Meta-Analysis and Systematic Review

Introduction

K-ras gene mutations were common in colorectal patients, but their relationship with prognosis was unclear.

Objective

Verify prognostic differences between patient with and without mutant K-ras genes by reviewing the published evidence.

Method

Systematic reviews and data bases were searched for cohort/case-control studies of prognosis of colorectal cancer patients with detected K-ras mutations versus those without mutant K-ras genes, both of whom received chemotherapy. Number of patients, regimens of chemotherapy, and short-term or long-term survival rate (disease-free or overall) were extracted. Quality of studies was also evaluated.

Principal Findings

7 studies of comparisons with a control group were identified. No association between K-ras gene status with neither short-term disease free-survival (OR=1.01, 95% CI, 0.73-1.38, P=0.97) nor overall survival (OR=1.06, 95% CI, 0.82-1.36, P=0.66) in CRC patients who received chemotherapy was indicated. Comparison of long-term survival between two groups also indicated no significant difference after heterogeneity was eliminated (OR=1.09, 95% CI, 0.85-1.40, P=0.49).

Conclusions

K-ras gene mutations may not be a prognostic index for colorectal cancer patients who received chemotherapy.     

Association of Trichomonas vaginalis and Cytological Abnormalities of the Cervix in Low Risk Women

Objective

Is Trichomonas vaginalis (TV) an inducing factor for the development of (pre-)cancerous lesions of the cervix?

Design

Cross sectional study.

Setting

Screening healthy Belgian women with low infection risk.

Sample

63,251 consecutive liquid based cervical samples.

Methods

Real time quantitative PCR for presence of TV, 18 HPV types and Pap smear analysis of cytologic abnormalities.

Main Outcome Measures

Association of TV and HPV with cervix dysplasia

Results

The overall prevalence of TV DNA was 0.37%, of low risk HPV 2%, of high risk HPV 13.2%, and 8.8 % had cytological abnormalities. Both LR-HPV and HR-HPV were significantly associated with all cytological abnormalities. Presence of TV was associated with LR- and HR-HPV, ASC-US and HSIL, but not with other abnormalities. All women with TV and HSIL also had HR-HPV, while the latter was present in only 59% of women with TV and ASC-US. Amongst HPV negative women, TV was found in 1.3% of women with ASC-US, but only in 0.03% of women with normal cytology (OR 4.2, CL95% 2.1-8.6). In HR-HPV positive women, presence of TV increased the likelihood of cytological abnormalities somewhat (P=0.05), mainly due to an increase in ASC-US and LSIL, but not HSIL.

Conclusions

We conclude that TV infection is associated with both LR and HR-HPV infection of the cervix, as well as with ASC-US and HSIL. TV is a concomitant STI, but is not thought to be a co-factor in the causation of HSIL and cervical cancer. However, TV may cause false positive diagnoses of ASC-US.