Differential effects of paraoxonase 1 (PON1) polymorphisms on cancer risk: evidence from 25 published studies

Paraoxonase is an HDL-associated enzyme that plays a preventive role against oxidative stress, which is thought to contribute to cancer development. PON1 activity varies widely among individuals, which is in part related to two common nonsynonymous polymorphisms in the PON1 gene (Q192R and L55M). The polymorphisms in PON1 have been implicated in cancer risk. However, results from the studies to date have been conflicting. To clarify the association, a meta-analysis was performed for 7,073 cases and 9,520 controls from 25 published case–control studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association. Significant associations between PON1-L55M but not Q192R polymorphism and total cancer were observed from all the comparisons. In stratified analyses, PON1-55M allele was a risk factor for breast cancer. Similarly, increased risk was observed for prostate cancer (OR = 1.18, 95% CI: 1.01–1.36, P _{heterogeneity} = 0.260) and Caucasian population (OR = 1.18, 95% CI: 1.02–1.38, P _{heterogeneity} = 0.1) of the LM genotype, compared with the LL genotype. For PON1-Q192R polymorphism, PON1-192R allele was a decreased risk factor for cancer in the Asian group (RR vs QQ: OR = 0.61, 95% CI: 0.38–0.98, P _{heterogeneity} = 0.268; QR vs QQ: OR = 0.71, 95% CI: 0.52–0.96, P _{heterogeneity} = 0.130; RR + QR vs QQ: OR = 0.71, 95% CI: 0.53–0.95, P _{heterogeneity} = 0.135). Although some modest bias could not be eliminated, this meta-analysis suggests that the PON1-55M allele is a risk factor for the development of cancer, in particular for breast cancer. Future studies with larger sample sizes are warranted to further evaluate these associations.     

Synergism between paraoxonase Arg 192 and the angiotensin converting enzyme D allele is associated with severity of coronary artery disease

We have previously shown that angiotensin-converting enzyme (ACE) gene D allele is an independent risk factor for early onset coronary artery disease (CAD). Little is known about the concomitant presence of the ACE gene D allele and paraoxonase (PON1) codon 192 arginine (Arg) on the severity of CAD. Regarding the high rate of CAD among Iranians the aim of present study was to examine the hypothesis of synergistic effects between ACE-D and PON1-Arg alleles on predisposition and the severity of CAD in our population. The PON1 192 and ACE insertion/deletion (I/D) genotypes were detected by PCR-RFLP and PCR, respectively in 414 individuals undergoing their first coronary angiography. Patients were placed into one of two groups: CAD and control without CAD or diabetes. We mentioned the synergistic effects of both genes and not ACE gene alone is a risk factor for CAD. We found that PON1 Arg 192 and ACE D allele act synergistically to increase the risk of CAD (OR 1.3, P = 0.044). Our results showed a significant correlation between the possession of both PON1 192 Arg and the ACE D allele and the extent of CAD in CAD patients and CAD subjects without diabetes, represented by the increased frequency of three-vessel disease with OR 2.7, P = 0.046; χ² = 4, P = 0.046 and OR 2.4, P = 0.051; χ² = 3.8, P = 0.051, respectively. We found that PON1 Arg 192 and ACE D alleles act synergistically to increase the risk of CAD in CAD patients and CAD subjects without diabetes from west of Iran, who have high frequency of three-vessel disease. Our data suggest that PON1 192 Arg and the ACE D allele in combination with each other can be important independent risk factor for severity of CAD in patients carrying both PON1 192 Arg and the ACE D allele in a west population of Iran.     

Paraoxonase (PON)1 Q192R functional genotypes and PON1 Q192R genotype by smoking interactions are risk factors for the metabolic syndrome,but not overweight or obesity

Abstract

Background

The metabolic syndrome (MetS) is a complex of multiple risk factors that contribute to the onset of cardiovascular disorder, including lowered levels of high-density lipoprotein (HDL) and abdominal obesity. Smoking, mood disorders, and oxidative stress are associated with the MetS. Paraoxonase (PON)1 is an antioxidant bound to HDL, that is under genetic control by functional polymorphisms in the PON1 Q192R coding sequence.

Aims and methods

This study aimed to delineate the associations of the MetS with plasma PON1 activity, PON1 Q192R genotypes, smoking, and mood disorders (major depression and bipolar disorder), while adjusting for HDL cholesterol, body mass index, age, gender, and sociodemographic data. We measured plasma PON1 activity and serum HDL cholesterol and determined PON1 Q192R genotypes through functional analysis in 335 subjects, consisting of 97 with and 238 without MetS. The severity of nicotine dependence was measured using the Fagerström Nicotine Dependence Scale.

Results

PON1 Q192R functional genotypes and PON1 Q192R genotypes by smoking interactions were associated with the MetS. The QQ and QR genotypes were protective against MetS while smoking increased metabolic risk in QQ carriers only. There were no significant associations between PON1 Q192R genotypes and smoking by genotype interactions and obesity or overweight, while body mass index significantly increased MetS risk. Smoking and especially severe nicotine dependence are significantly associated with the MetS although these effects were no longer significant after considering the effects of the smoking by PON1 Q192R genotype interaction. The MetS was not associated with mood disorders, major depression or bipolar disorder.

Discussion

PON1 Q192R genotypes and genotypes by smoking interactions are risk factors for the MetS that together with lowered HDL and increased body mass and age contribute to the MetS.     

R-carrying genotypes of serum paraoxonase (PON1) 192 polymorphism and higher activity ratio are related to susceptibility against ischemic stroke

The polymorphic gene of serum paraoxonase (PON1) and its activity involved in atherosclerosis. The purpose of the study was to analyze PON1 192 Q/R polymorphism and the enzyme activities in ischemic stroke. The polymorphism as the most common polymorphism in PON1 gene coding sequence is associated with variation in the enzyme activity and vascular disease. The study included 85 stroke patients and 71 control subjects. PON1 192 polymorphism was genotyped using PCR protocol. Paraoxonase activity (Para) and arylesterase activity (Aryl) were determined spectrophotometrically using paraoxon and phenylacetate as the substrates. The QR and RR genotypes were more frequent in stroke population compared to controls, resulting in a higher frequency of the R allele in patients (0.24 vs 0.18, OR?=?1.41). Patients had significantly higher Para/Aryl ratio than that of controls (P?=?0.016). In stroke patients, Para/Aryl and Para/HDL ratios increased with this order: QQ?<?QR?<?RR. Hypertension significantly increased the risk of ischemic stroke by 15-fold among R-containing people, while this was significantly increased 4-fold for QQ homozygotes. Smoking increased the risk of having ischemic stroke in both QQ homozygote and QR?+?RR group (OR?=?2.84 and OR?=?2.33, respectively). In conclusion, these data highlight the importance of PON1 192 R allele and high Para/Aryl ratio in susceptibility to ischemic stroke in the population. The presence of the 192 R allele potentiates the risk of stroke especially in hypertensive people. Decreased Aryl and increased Para/Aryl, Para/HDL and Aryl/HDL ratios may be markers indicated the increased susceptibility to ischemic stroke in the population.     

HMGb1 promotes scratch wound closure of HaCaT keratinocytes via ERK1/2 activation

Background The aim of the present study was to investigate the association between genetic variants in metylenetetrahydrofolate reductase (MTHFR) and Paraoxonase-1 (PON1) 55/192 genes and total homocysteine (tHcy), folate, B12 vitamin, and PON1 levels in patients with coronary artery disease (CAD). Methods The study included 235 patients with CAD and 268 healthy control subjects. Results LL and LM genotypes and L allele of PON1 55 were over-represented in patients. In contrast, MM genotype and M allele were more frequent in controls. QQ genotype and Q allele of PON1 192 and CT genotype of MTHFR were significantly diminished and QR genotype and R allele were significantly elevated in CAD patients compared with controls. The plasma tHcy were elevated but B12 levels were diminished in patients. PON1 55 and 192 genetic variants were significantly associated with PON1 activity, triglyceride, total cholesterol, tHcy and, high-density lipoprotein-cholesterol and low-density lipoprotein-cholesterol in patients, respectively. Conclusion Genetic variants of PON1 55/192 and MTHFR were associated with CAD.     

Association between paraoxonase-1 gene polymorphisms and risk of metabolic syndrome

Paraoxonase-1 (PON1), a high-density lipoprotein (HDL) associated enzyme, is involved in the metabolism and detoxification of insecticides and pesticides. Three polymorphisms within the PON1 gene affect the enzyme activity. Two of these (L55M and Q192R) are located at the coding region and the third (–107C/T) is in promoter region. We performed a case–control study in order to elucidate the possible contribution of variability within PON1 at three mentioned positions to the risk of MS in a South-East Iranian population. DNA was isolated from peripheral blood of patients (N = 119) with MS and healthy controls (N = 201). Allelic polymorphisms at positions Q192R, L55M and –107C/T in the PON1 gene were studied by Amplification Refractory Mutation System (ARMS)-PCR. It was observed that genotypes RR and QR + RR of Q192R locus significantly increased the risk of MS (OR = 2; 95% CI: 1.17–3.40, P = 0.0001 and OR = 1.62; 95% CI: 1.0–2.63; P = 0.05, respectively). The risk in patients with MM and LM + MM genotypes at the L55M locus was marginal (OR = 1.33; 95% CI: 0.68–1.85; P = 0.34 and OR = 1.12; 95% CI: 0.68–1.85; P = 0.73 respectively). The CC genotype at –107C/T locus also increased the risk of metabolic syndrome, but was not significant. This association was somewhat stronger when combined genotypes at Q192R and L55M loci were analyzed (OR = 3.30; 95% CI: 1.34–8.24; P = 0.007). Our results, in this first study, provide evidence for association of PON1 gene polymorphisms with the risk for metabolic syndrome.     

Paraoxonase 1 Polymorphisms Within a Mississippi USA Population as Possible Biomarkers of Enzyme Activities Associated With Disease Susceptibility

Paraoxonase (PON1) hydrolyzes paraoxon (PO) and diazoxon (DZO), active metabolites of insecticides parathion and diazinon. The PON1 gene has single nucleotide polymorphisms (SNPs) including a codon 192 arginine (R) to glutamine (Q) and methionine (M) to leucine (L) at codon 55. Hydrolysis of PO (POase), DZO (DZOase), dihydrocoumarin (lactonase), and phenyl acetate (arylesterase) were evaluated for associations with race, gender, age, and PON1 55/192 SNP genotypes. Variables were analyzed both individually and in combination. QQ individuals had higher lactonase (p < 0.001) than RR individuals. This might partially explain why predominantly RR African Americans have higher rates of coronary disease than predominantly QQ Caucasians. Significant (p < 0.001) differences in arylesterase were seen among genotypes with QQ and MM lowest whereas RR and LL were highest. This opposes the prevailing belief that arylesterase is unaffected by genotype and suggests that this activity cannot be used to quantify PON1 protein.     

Q192R polymorphism in the PON1 gene and nasal polyp in a Turkish population

The pathogenesis of nasal polyps is not completely understood. Oxidative damage contributes to polyp formation in the nasal mucosa. The paraoxonase 1 (PON1) enzyme is an important liver enzyme with high antioxidant activity. In this study, we investigated the correlation between Q192R genotypic polymorphism of the PON1 enzyme and nasal‐polyp disease. The study examined 62 nasal‐polyp patients and 88 controls. PON1 Q192R polymorphism was determined using polymerase chain reaction‐restriction fragment length polymorphism. The genotype distribution of the PON1 gene was significantly different between nasal‐polyp patients (QQ = 69.35%, QR = 25.81%, RR = 4.83%) and healthy controls (QQ = 52.27%, QR = 44.31%, RR = 3.40%). Our results suggest that the PON1 QQ genotype (odds ratio [OR] = 2.066, P = .036) is associated with a higher risk of developing the nasal‐polyp disease while QR genotype (OR = 0.437, P = .021) showed a lower risk.     

A preliminary study of human paraoxonase and PON 1 L/M55–PON 1 Q/R 192 polymorphisms in Turkish patients with coronary artery disease

Paraoxonase 1 (PON 1) is a high‐density lipoprotein (HDL)‐associated enzyme with antioxidant function protecting low‐density lipoprotein (LDL) from oxidation. PON 1 has two amino acid polymorphisms in coding region; L/M 55 and Q/R 192. These polymorphisms modulate paraoxonase activity of the enzyme. PON 1 activity decreases in coronary artery disease (CAD). In the present study, distribution of PON 1 L/M 55 and Q/R 192 polymorphisms and the effect of these polymorphisms on the activities of PON 1, and on the severity of CAD in 277 CAD (+) patient and 92 CAD (?) subjects were examined. PON 1 L/M 55 and Q/R 192 genotypes were determined by PCR, RFLP and agarose gel electrophoresis techniques. Genotype distributions and allele frequencies for PON 1 Q/R 192 polymorphism were not significantly different between controls and CAD (+) patient group (p > 0.05), but in genotype and allele distribution of PON 1 L/M55 polymorphism, there was significantly difference among groups (p < 0.05). Genotype distributions for both polymorphisms were not significantly different between subgroups of single‐vessel disease (SVD), double‐vessel disease (DVD) and triple‐vessel disease (TVD). Serum PON 1 activity was lower in CAD (+) group than in controls and this was also statistically significant (p < 0.001). In both groups, the highest PON activities were detected in LL and RR genotypes. In summary, our results suggest that there is an association between the PON 1 L/M 55 polymorphism of paraoxonase and CAD in Turkish patients but not with PON 1 Q/R 192 polymorphism. However, it is hard to correlate these polymorphisms and severity of CAD. Copyright © 2009 John Wiley & Sons, Ltd.     

PON1 55/192 polymorphism, oxidative stress, type, prognosis and severity of stroke

We investigated the association of PON1 55/192 polymorphisms with type, severity and prognosis of stroke and oxidative markers. Paraoxonase1 (PON1), Glutathione Reductase (GSH-Rd) and Malondialdehyde (MDA) levels were measured at day 1 and at day 5 following the onset of stroke. Genotypes were determined by polymerase chain reaction and restriction digestion. The frequencies of QQ and MM genotypes of PON1 192 and PON1 55, respectively, were significantly higher in controls than in patients. However, the allele frequencies of PON1 192 R and PON1 55 L were significantly more frequent in patients compared to controls. The frequency of combined genotype of RR/LL was significantly higher in cardioembolic group than in atherothrombotic group. PON1 activities were significantly diminished in stroke patients compared to controls. In contrast, serum MDA levels were significantly greater in patients than the values in controls. GSH-Rd activity was higher in patients with small lesion and good prognosis than those with large and poor prognosis. Low density lipoprotein (LDL) levels in patients with large lesions were higher than those with small lesions. PON1 55/192 polymorphisms influence activity of the enzyme. PON1 55/192 genotypes have been associated with MDA levels. In conclusion, PON1 genetic variations are associated with risk factors, severity, type and prognosis of stroke and oxidative stress.     

Association between Paraoxonase 1 (PON1) Polymorphisms and the Risk of Acute Coronary Syndrome in a North African Population

The purpose of the present study was to investigate the distribution of PON1 Q192R and L55M polymorphisms and activities in a North African population and to determine their association with cardiovascular complications. The prevalence of the QQ, QR, RR, LL, LM, and MM genotypes in the study population was 55.4%, 34.09%, 9.83%, 41.97%, 48.20%, and 9.83% respectively. The Q, R, L, and M alleles had a gene frequency of 0.755, 0.245, 0.67, and 0.33, respectively. The PON1 192 RR genotype was significantly more prevalent among ACS patients than among healthy subjects. There was a 4.33-fold increase in the risk of ACS in subjects presenting the PON1 192 RR genotype compared to those with the QQ genotype (OR=4.33; 95% CI=1.27–17.7). There was a significantly different distribution of PON1 L55M in the ACS patient groups (UA, STEMI, NSTEMI). Moreover, individuals presenting the PON1 55MM genotype present a higher risk for ACS than those with LL genotype (OR=3.69; 95% CI=1.61–11.80). Paraoxonase activities were significantly lower in coronary patients than in healthy subjects. The decrease in PON1 activity was inversely correlated with the number of concomitant risk factors for CVD (r=0.57, p<0.0001). The results of the present study suggested that the PON1 R and M alleles may play a role in the pathogenesis of cardiac ischemia in our North African population and that a decrease in PON1 activity may be a valuable marker for monitoring the development of the atherosclerosis process and the associated cardiovascular complications.     

Paraoxonase 1 gene polymorphisms and enzyme activities in diabetes mellitus

Paraoxonase 1 (PON1), an antioxidant enzyme closely associated with HDL (high-density lipoproteins), preserves LDL (low-density lipoproteins) against oxidation. Less protection may be therefore supposed by decreased PON1 activity. This study was undertaken to investigate the association of PON1 gene polymorphisms with diabetic angiopathy and to evaluate the relationship of these polymorphisms with PON1 activity. Total of 86 Type 1 (T1DM) and 246 Type 2 (T2DM) diabetic patients together with 110 healthy subjects were examined. DNA isolated from leukocytes was amplified with polymerase chain reaction (PCR) followed by restriction enzyme digestion. The products were analyzed for L55M and Q192R polymorphisms in coding region and for -107 C/T and -907 G/C in promotor sequence of PON1. Serum enzyme activity was measured spectrophotometrically. Significant differences were found between T1DM or T2DM and control persons in L55M polymorphism (allele M more frequent in T1DM and T2DM vs. controls, p<0.05) and Q192R polymorphism (R allele less frequent in T1DM and T2DM vs. controls, p<0.01) of the PON1 gene. Serum PON1 activity was significantly decreased in T1DM (110+/-68 nmol/ml/min) and T2DM patients (118+/-69 nmol/ml/min) compared to the control persons (203+/-58 nmol/ml/min), both p<0.01. The presence of MM and QQ genotypes was accompanied by lower PON1 activity than of LL and RR genotypes (p<0.05), respectively. Better diabetes control was found in patients with LL than with MM genotypes and similarly in RR genotype than QQ genotype with p<0.05. Significantly different allele frequencies were found in diabetic patients with macroangiopathy than in those without it (M: 0.59 vs. 0.44. R: 0.12 vs. 0.19, p<0.01). The association of PON1 polymorphisms, lower PON1 activity and poorer diabetes control found in patients with macroangiopathy further support the idea of genetic factors contributing to the development of vascular disorders in diabetes.     

PON1 55 and 192 Gene Polymorphisms in Type 2 Diabetes Mellitus Patients in a Turkish Population

Diabetes mellitus is a multifactorial metabolic disease, caused by the complete or relative absence of insulin hormone, which results in the deterioration of carbohydrate, protein, and lipid metabolism. The PON1 55 and 192 polymorphisms have been reported to be associated with type 2 diabetes and its complications. In this study, the involvement of the PON1 55 and 192 polymorphisms and paraoxonase enzyme activity in diabetic complications was assessed. The MM and QQ genotypes were the most frequent in complications of type 2 diabetes in both of the polymorphisms. PON enzyme activity was lower in the type 2 diabetes group with respect to the control group. Regarding both genotypes and enzyme activity, correlations were found between the PON1 55 and 192 genotypes and diabetic complications. This study thus helps to outline a genotype?Cphenotype relation for the PON1 gene in a Turkish population.     

The Q192R polymorphism of the paraoxonase 1 gene is a risk factor for coronary artery disease in Saudi subjects

Paraoxonase-1 (PON1) is a HDL-bound antioxidant enzyme that protects LDL from oxidative modification. Discovery of the antioxidant properties of PON1 led to extensive research on its role in the initiation and progression of atherosclerosis. The Q192R (rs662; A/G) polymorphism, which results in the glutamine to arginine substitution at position 192, of the PON1 gene has been linked to increased atherosclerosis risk in several but not all population studies. Besides genetic factors, environmental variables and ethnicity have been implicated as factors responsible for the ambiguity in relating the PON1 gene with atherosclerotic risk. Here, we tested the association of the Q192R polymorphism with coronary artery disease (CAD) in Saudi ethnic subjects taking environmental factors into consideration. The genomic DNA samples from 121 angiographically confirmed CAD cases and 108 normal healthy control subjects were genotyped by PCR–RFLP analysis. The distribution of QQ, QR, and RR genotypes was significantly different between cases and controls (p < 0.005). The RR genotype was associated with CAD risk independently of several established risk factors including age, gender, smoking, obesity, and diabetes (OR 2.2, 1.4–7.4, p < 0.01). Genotype-based stratification of demographic and biochemical data revealed that the RR genotype has proatherogenic properties. This study, thus, identifies the Q192R polymorphism as an additional risk factor for CAD in the Saudi population and suggests that it may have prognostic value. The negative effect of this genetic variant is presumably due to the diminished ability of the RR variant genotype of PON1 to blunt LDL oxidation.     

MCP-1 −2518 A/G functional polymorphism is associated with increased susceptibility to active pulmonary tuberculosis in Tunisian patients

Monocyte chemoattractant protein-1 (MCP-1) plays crucial role in protective immunity against Mycobacterium tuberculosis (MT). In this study, we examined whether single nucleotide polymorphism (SNP) −2518 A/G (rs 1024611) of MCP-1 affect the susceptibility to active tuberculosis (TB) in Tunisian populations. Genomic DNA from patients with active TB (168 cases of pulmonary TB and 55 cases of extrapulmonary TB) and ethnically controls (150 cases) was genotyped for the MCP-1 −2518 A/G SNP by polymerase chain reaction fragment length polymorphism (PCR-RFLP). We observed that −2518 G allele and GG genotype (high MCP-1 producer) frequencies were significantly more elevated in active pulmonary TB group in comparison to control group [34 vs. 22%; P = 0.0007; 15 vs. 5%, P corrected for the number of genotypes (Pc) = 0.015; respectively]. Additionally, they were associated with increased risk development of this clinical form of TB [odds ratio (OR) = 1.83, 95% confidence intervals (CI) = 1.26–2.66; OR = 3.1, 95% CI = 1.28–7.76; respectively]. However, wild type allele −2518 A and AA genotype were over-represented in control group (78 and 62%) and seem to be protective factors against TB. Moreover, −2518 AA genotype was more frequent in control group and was associated with resistance against development of active pulmonary TB (OR = 0.56, 95% CI = 0.35–0.89, Pc = 0.03). Our findings confirm the key role of −2518 A/G SNP of MCP-1 and support its association with resistance/susceptibility to the development of active pulmonary TB in the Tunisian population.     

Association of PON1 and PON2 Polymorphisms with PON1 Activity and Significant Coronary Stenosis in a Tunisian Population

PON1 and PON2 have attracted considerable attention as candidate genes for coronary heart disease because their enzymes function as key factors in lipoprotein catabolism pathways. We studied the distribution of PON1 and PON2 polymorphisms, including genotyping, lipid profile, and PON1 activity, and their association with PON1 activity and significant coronary stenosis (SCS) in a Tunisian population. PON1 activity was lower in patients with SCS than in controls. It increased with the R allele (QQ < QR < RR) in PON1-192 genotypes and with the L allele (MM < ML < LL) in PON1-55 genotypes. In the presence of metabolic syndrome and diabetes, PON1-192RR and PON2-311CC were associated with an increased risk of SCS and PON1-55MM seems to have lower risk. This association was evident among nonsmokers for PON1-55MM and among smokers for PON1-192RR and PON2-311CC. The GTGC haplotype seemed to increase the risk of SCS compared with the wild haplotype in a Tunisian population.     

Paraoxonase 1 gene polymorphisms, paraoxonase/arylesterase activities and oxidized low-density lipoprotein levels in patients with migraine

The vascular endothelial dysfunction has been implicated in the pathogenesis of migraine. Oxidized low‐density lipoprotein (ox‐LDL) may impair endothelial function. Paraoxonase‐1 (PON‐1) prevents oxidative modification of LDL cholesterol (LDL‐C). So we investigated serum PON‐1 and arylesterase (ARE) activities, PON‐1 55 L/M and 192Q/R polymorphisms and the serum lipid profile in patients with migraine. Biochemical parameters and PON‐1 polymorphism analyses were assessed in 104 patients with migraine and 86 healthy subjects. Ox‐LDL was detected by ELISA, and polymorphisms were determined using PCR–restriction fragment length polymorphism analysis. Patients with migraine had lower PON‐1 and ARE activities (p < 0·001, for both) and higher ox‐LDL and LDL‐C levels (p < 0·001, for both) and ox‐LDL: LDL‐C ratio (p < 0·005) than the controls. The genotype distribution and the allele frequencies for PON‐1 55 L/M and 192Q/R polymorphisms were not different among the study populations. The results of our current study indicate that migrainous patients have decreased serum PON‐1 and ARE activities and increased serum ox‐LDL levels, which may have a clinical importance in the treatment of migraine. Copyright © 2011 John Wiley & Sons, Ltd.     

An <Emphasis Type="Italic">Msp</Emphasis>I polymorphism in the inhibin alpha gene and its associations with superovulation traits in Chinese Holstein cows

To identify a predictor to forecast superovulation response on the basis of associations between superovulation performance and gene polymorphism, the PCR–RFLP method was applied to detect an A>G transition determining an MspI polymorphism at position 192 in the exon I of the bovine inhibin alpha (INHA) gene and evaluate its associations with superovulatory response in 118 Chinese Holstein cows treated for superovulation. Association analysis showed that cows with the GG genotype resulted in a significant increase in the number of ova (TNO) than AG and AA genotypes in the first (P = 0.023), second (P = 0.004) and third (P = 0.002) superovulation treatments and produced more transferable embryos (NTE) than that of AG and AA genotypes in the third (P = 0.045) superovulation treatment. Moreover, individuals with GG genotype produced more transferable embryos than AA (P < 0.05) genotype in the second superovulation treatment and all cows without superovulation response were mutations with genotypes of AA and AG. These results indicate that INHA gene can be used as a predictor for superovulation in Chinese Holstein cows, and imply that cows with AA genotype should be excluded for superovulation practices.     

Association of ARHGEF11 R1467H polymorphism with risk for type 2 diabetes mellitus and insulin resistance in Chinese population

The human Rho guanine nucleotide exchange factor 11 (ARHGEF11), located on chromosome 1q21, is an activator of Rho GTPases involved in G protein signaling pathway known to regulate insulin secretion and action. The aim of our study was to evaluate the relationship between the previously reported R1467H G/A variant in ARHGEF11 and risk of type 2 diabetes mellitus (T2DM) and insulin resistance as well as metabolic traits in a Chinese population. We genotyped R1467H G/A polymorphism in 311 patients with T2DM and 328 control subjects in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) protocol and DNA sequencing methods. The genotype and allele distributions of the R1467H G/A polymorphism were significantly different between the T2DM group and the normal control group (P = 0.024, 0.018, respectively) and we also found that the A allele carriers (GA + AA genotype) had markedly higher risk of T2DM as compared with the wild-type GG genotype after adjustment for gender, age, and BMI (OR = 1.578, 95% CI 1.126–2.212, P = 0.008). Moreover, in the T2DM group the A allele carriers had higher FPG, FINS, and HOMA-IR than that of the GG homozygote (P = 0.015, 0.029, and 0.007, respectively). FPG and HOMA-IR levels were also significantly increased from A allele carriers to GG homozygote in the control group (P = 0.017, 0.012, respectively). Our investigation suggests that the R1467H polymorphism of ARHGEF11 gene may contribute to susceptibility to T2DM and insulin resistance in a Chinese population.     

Paraoxonase 1 genetic polymorphisms and susceptibility to breast cancer: a meta-analysis

AimThe paraoxonase 1 gene (PON1, MIN: 168820) is a member of the multifactorial antioxidant enzyme paraoxonase family (EC 3.1.1.2). Two common functional single-nucleotide polymorphisms L55M (dbSNP: rs854560) and Q192R (dbSNP: rs662) have been identified in the coding region of PON1. Several studies have investigated the associations between polymorphisms of PON1 and susceptibility to breast cancer, but have yielded apparently conflicting results. We therefore carried out a meta-analysis of published studies to clarify this inconsistency and to establish a comprehensive picture of the relationship between PON1 gene variants and breast cancer risk. Method: Overall six eligible studies were identified. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were obtained using fixed and random-effect models. Results: In our meta-analysis, the presence of the R allele was associated with decreased risk of breast cancer (QR + RR compared to QQ genotype, summary OR = 0.57, 95% CI: 0.49–0.67, P < 0.001). Both heterozygosity (OR = 1.32, 95% CI: 1.10–1.58, P = 0.002) and homozygosity (OR = 2.16, 95% CI: 1.75–2.68, P < 0.001) for the 55M allele were associated with increased risk of breast cancer. Also there was a significant linear trend in risk associated with zero, one, and two 55M alleles (χ² = 54.2, P < 0.001).ConclusionThe present study showed that PON1 M and Q alleles are associated with a higher risk of breast cancer. Individuals having MM and QQ genotypes have a lower level and lower detoxification activity of the PON1 enzyme, which may increase the vulnerability of the breast to genetic damage by reducing the ability to detoxify inflammatory oxidants, as well as dietary carcinogens.