Arg Allele Research Articles

Effect of TP53 codon 72 and MDM2 SNP309 polymorphisms on survival of gastric cancer among patients who receiving 5-fluorouracil-based postoperative adjuvant chemotherapy

Several studies have examined the prognostic value of the TP53 Arg72Pro polymorphism (rs1042522) and/or MDM2 SNP309 (rs2279744) in multiple tumors. Our aim was to determine whether these two genetic variants were correlated with clinical outcome of gastric cancer. We genotyped the two SNPs, TP53 codon 72 polymorphism and MDM2 SNP309, in 940 gastric cancer patients with complete follow-up information and analyzed the correlation between the SNPs and gastric cancer survival. The two SNPs were not significantly associated with gastric cancer survival. However, the TP53 codon 72 polymorphism had a prominent correlation with clinical outcome of patients receiving 5-fluorouracil (5-Fu)-based postoperative chemotherapy [Arg/Arg + Arg/Pro vs. Pro/Pro, adjusted hazard ratio (HR) = 1.63, 95 % confidence interval (CI) = 1.08-2.44]. Moreover, the unfavorable effect of Arg allele on survival outcome was more predominant for subgroups of older (age >60 years), male, intestinal histology type, advanced stage (T3/T4), and none metastasis of lymph node (N0) or distant (M0) (adjusted HR = 2.34, 95 % CI = 1.24-4.44 for age >60 years; 1.72, 1.10-2.69 for male; 2.30, 1.10-4.80 for intestinal; 1.62, 1.01-2.59 for T3/T4; 3.42, 1.26-9.24 for N0; and 1.62, 1.06-2.47 for M0). Among multiple chemotherapy regimens, the association was only significant in the subgroup of 5-Fu/calcium folinate plus oxaliplatin (FOLFOX) chemotherapy regimen (adjusted HR = 4.47, 95 % CI = 1.21-16.55). Our findings showed that TP53 codon 72 polymorphism was associated with survival of gastric cancer patients treated with 5-Fu-based postoperative chemotherapy. The codon 72 polymorphism may be a potential prognostic factor.

Beta-3-adrenergic receptor Trp64Arg polymorphism: does it modulate the relationship between exercise and percentage of body fat in young adult Japanese males?

The Trp64Arg polymorphism of the beta-3-adrenergic receptor gene has been studied as a potential genetic factor contributing to the development of obesity. Several studies have investigated whether or not this polymorphism affects weight reduction due to exercise, but the results of these studies have not been consistent. Moreover, information on a population characterized by a wide ranges of physical activities is scarce. Thus, to further understand the impact of this polymorphism, we examined whether the polymorphism modulates the relationship between physical activity due to exercise (PAE) and percentage of body fat (%BF). The study population was 70 Japanese male young adults with a high prevalence of habitual exercise. PAE was estimated by a questionnaire, and %BF was measured by bioelectrical impedance analysis. Genotyping was done by PCR-restriction fragment length polymorphism analysis. The median PAE value of the subjects was 6.9 MET-h/day with an interquartile range of 1.5-10.3 MET-h/day. PAE correlated significantly with %BF in the entire population and within the two subpopulations, namely, carriers or non-carriers of the Arg allele. Multiple regression analysis of PAE, Trp64Arg polymorphism, and the interaction term revealed that while the PAE-derived independent variable was statistically significant, the interaction term was insignificant. When the two regression lines of subjects with and without the Arg allele were considered, the difference between the two slopes did not deviate from zero, nor did the vertical distance of the two regression lines. These findings suggest that the impact of this polymorphism is limited. In our study population of young adult Japanese males, the impact of the Trp64Arg polymorphism on the association between exercise and body composition was weak, if it existed at all.

Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients

To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival. Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ(2) test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ(2) test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC. In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ(2) = 3.589, P = 0.166) and alleles (χ(2) = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ(2) = 5.449, P = 0.020), well differentiated (log rank χ(2) = 12.798, P = 0.000), T1 or T2 stage (log rank χ(2) = 4.745, P = 0.029), without lymph node involvement (log rank χ(2) = 6.647, P= 0.010), and at an early clinical stage (log rank χ(2) = 4.615, P = 0.032). Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.

No evidence of correlation between p53 codon 72 polymorphism and risk of bladder cancer in Moroccan patients

Background: The p53 codon 72 polymorphism has been investigated extensively for its association with various cancers around the world. Several studies have investigated the association between p53 polymorphism at codon 72 and risk of developing bladder cancer, but the results are still controversial. Aim: The aim of our study was to evaluate the association between the p53 polymorphism and the bladder cancer risk among Moroccan patients. Materials and Methods: This study was carried out on fresh biopsies from 41 patients with bladder cancer confirmed and 38 blood samples from control donors. Deoxyribonucleic acid was genotyped by Allele-specific polymerase chain reaction using specific primers to each polymorphic variant. Results: Frequencies of Arg/Arg, Arg/Pro and Pro/Pro genotypes among cases were 17%, 66%, and 17%, while in controls the frequencies of Arg/Arg, Arg/Pro and Pro/Pro were 15.8%, 63.2%, and 21%, respectively. The difference between cases and controls was not statistically significant. An increased risk of bladder cancer development was not clearly related to any polymorphic variant of the p53 Arg72Pro in our study group from Moroccan population. Moreover, the frequency of the Arg allele was higher (71.45%) than the Pro allele (28.55%) in high stage of bladder tumors, but this difference was statistically not significant. Conclusion: This study suggests that Arg allele could be more involved in developing bladder tumor in Moroccan population than the Pro allele. Therefore, enlarging the sampling will be necessary to confirm this association in Moroccan population.

Predictive Value of Xrcc1 Gene Polymorphisms for Side Effects in Patients undergoing Whole Breast Radiotherapy: a Meta-analysis

Radiation-induced side effects on normal tissue are determined largely by the capacity of cells to repair radiation-induced DNA damage. X-ray repair cross-complementing group 1 (XRCC1) plays an important role in the repair of DNA single-strand breaks. Studies have shown conflicting results regarding the association between XRCC1 gene polymorphisms (Arg399Gln, Arg194Trp, -77T>C and Arg280His) and radiation-induced side effects in patients undergoing whole breast radiotherapy. Therefore, we conducted a meta-analysis to determine the predictive value of XRCC1 gene polymorphisms in this regard. Analysis of the 11 eligible studies comprising 2,199 cases showed that carriers of the XRCC1 399 Gln allele had a higher risk of radiation-induced toxicity than those with the 399 ArgArg genotype in studies based on high-quality genotyping methods [Gln vs. ArgArg: OR, 1.85; 95% CI, 1.20-2.86] or in studies with mixed treatment regimens of radiotherapy alone and in combination with chemotherapy [Gln vs. ArgArg: OR, 1.60; 95% CI, 1.09-2.23]. The XRCC1 Arg399Gln variant allele was associated with mixed acute and late adverse reactions when studies on late toxicity only were excluded [Gln allele vs. Arg allele: OR, 1.22; 95% CI, 1.00-1.49]. In contrast, the XRCC1 Arg280His variant allele was protective against radiation-induced toxicity in studies including patients treated by radiotherapy alone [His allele vs. Arg allele: OR, 0.58; 95% CI, 0.35-0.96]. Our results suggest that XRCC1 399Gln and XRCC1 280Arg may be independent predictors of radiation-induced toxicity in post-surgical breast cancer patients, and the selection of genotyping method is an important factor in determining risk factors. No evidence for any predictive value of XRCC1 Arg194Trp and XRCC1 -77T>C was found. So, larger and well-designed studies might be required to further evaluate the predictive value of XRCC1 gene variation on radiation-induced side effects in patients undergoing whole breast radiotherapy.

P53 Arg72Pro Polymorphism, HPV Status and Initiation, Progression, and Development of Cervical Cancer: A Systematic Review and Meta-Analysis

Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15-1.62; P < 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407-15.

Association of common WRAP 53 variant with ovarian cancer risk in the Polish population

Among many alterations within the TP53 gene the rs1042522 (C72G, p.Pro72Arg) has been associated with numerous cancers , however the results differ between populations for opposite Pro or Arg alleles. Similar thus inconclusive results are observed in ovarian cancer, which may suggest that the rs1042522 does not influence ovarian carcinogensis directly, but might be linked to another pathogenic alteration. WRAP53 which overlaps the TP53 is required to maintain normal levels of p53 upon DNA damage, but also when altered may independently increase the risk of cancer. To evaluate the association between three SNPs located in WRAP53–TP53 region: rs1042522, rs2287497, rs2287498 and ovarian cancer risk in Polish population we genotyped 626 cases and 1,045 healthy controls. Our results provide the evidence for an association between studied SNPs and a risk of invasive ovarian cancer in Poland. We found that CC homozygotes in rs1042522 were more frequent in cancers when compared to controls (OR = 1.46, p = 0.03). Similarly in WRAP53 both TT homozygotes in rs2287497 (OR = 1.95, p = 0.03) and AA homozygotes in rs2287498 (OR = 2.65, p = 0,01) were more frequent among cases than healthy individuals. There is also a suggestive evidence that specific homozygosity of studied SNPs in TP53–WRAP53 region is significantly overrepresented in ovarian cancer patients. In conclusion SNPs in WRAP53 (rs2287497 and rs2287498) have stronger association with an ovarian cancer risk than rs1042522 in TP53.

β-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: Implication of ethnicity

Common functional polymorphisms in β-adrenergic receptor (βAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with βAR blockers. This study evaluated the association between βAR polymorphisms and carvedilol drug response and prognosis in patients with HF. In this prospective cohort controlled study, 326 volunteers were enrolled [146 HF patients (ejection fraction (EF)<50% by Simpson) and 180 healthy controls]. Drug response was evaluated by echocardiography and outcomes were mortality and hospitalization. DNA was extracted from peripheral blood leukocytes, fragments were amplified by the polymerase reaction and genotyped by restriction fragment length polymorphism (RFLP) for Ser49Gly and Arg389Gly βAR-1 polymorphisms and Gln27Glu and Arg16Gly βAR-2 polymorphisms. The study population was in Hardy‑Weinberg equilibrium. The survival rate was adjusted using the Kaplan-Meier method. HF patients showed the following characteristics: EF 35±9%, 69.9% male, age 59±13 years, 50.7% self-identified as black, 46% had ischemic etiology. The mean follow-up of 23 months showed 18 mortalities and 46 hospitalizations. The genotypes Glu27Glu (24.7 vs. 6.1%, p=0.0004) and Arg16Arg (72.6 vs. 22.8, p<0.0001) of βAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the βAR1 polymorphism were higher in HF patients compared with controls. Patients with hospital admission showed a significantly higher Gly389 allelic frequency (54.9 vs. 42.1%, p=0.039), and the trend prevailed among patients who succumbed to the disease (61.1%, p=0.047). Black patients with the Ser49Ser genotype showed a reduced survival compared with the Gly49Gly or Ser49Gly genotypes (p=0.028). There was no association between improved LVEF >20% and βAR polymorphisms. HF patients with β-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing β-blocker therapy, self‑identified as black and homozygous for Ser49Ser may have reduced event-free survival, while Glu27Glu, Arg16Arg and Gly49Gly genotypes may be associated with risk for HF.

Impact of UCP1 and β3AR gene polymorphisms on age-related changes in brown adipose tissue and adiposity in humans

Brown adipose tissue (BAT) is involved in the regulation of whole-body energy expenditure and adiposity. The activity and prevalence of BAT decrease with age in humans. To examine the effects of single nucleotide polymorphisms of the genes for uncoupling protein 1 (UCP1) and β3-adrenergic receptor (β3AR), key molecules of BAT thermogenesis, on age-related decline of BAT activity and accumulation of body fat in humans. One hundred ninety-nine healthy volunteers (20-72 years old (y.o.)) underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) after 2-h cold exposure to assess BAT activity. The visceral and subcutaneous fat areas at the abdominal level were estimated from the CT images. They were genotyped for -3826 A/G polymorphism of the UCP1 gene and 64 Trp/Arg mutation of the β3AR gene. BAT was detected in 88 subjects out of 199 (44%), more in younger (30 y.o., 55%) than older subjects (>40 y.o., 15%). BAT prevalence of older subjects tended to be lower in the UCP1 G/G group than the A allele group (A/A and A/G), and also in the β3AR Arg allele group (Trp/Arg and Arg/Arg) than the Trp/Trp group. When compared subjects who had two or more base substitutions on the two genes (the 2-4 allele group) with those who had less than two base substitutions (the 0-1 allele group), BAT prevalence was comparable in younger subjects (62% vs 50%) but lower in older subjects (0% vs 24%, P<0.05). Visceral fat area of the 2-4 allele group was higher than that of the 0-1 allele group (P<0.05) in older subjects, but not in younger subjects. UCP1 -3826 A/G and β3AR 64 Trp/Arg substitutions accelerate age-related decrease in BAT activity, and thereby may associate with visceral fat accumulation with age.

Are polymorphisms of the β3‐adrenoceptor gene associated with an altered bladder function?

As the presence of a Trp64Arg polymorphism of the gene encoding the β(3)-adrenoceptor (B3AR) has been linked to the presence of overactive bladder, we investigated whether additional polymorphisms are detectable in this gene and explore their relationships parameters related to lower urinary tract function. The coding region and adjacent stretches of the B3AR gene was sequenced in 91 patients. In total, 1015 patients from a single academic hospital were genotyped for the presence of two single nucleotide polymorphisms. Symptom scores and parameters from pressure-flow studies were analyzed relative to genotype in the B3AR gene. No frequent novel polymorphisms were detected in the coding region. Five polymorphisms were found in the non-coding region of the gene but were in complete linkage with the 64Arg allele. Out of 32 parameters including bladder compliance, only prostate size was weakly (44 vs. 39 mL) but significantly associated with the 64Arg allele, but was not mirrored by an association with prostate-specific antigen levels. Our data do not support the hypothesis that polymorphisms in the B3AR gene are associated with alterations of bladder function.

Human-specific SNP in obesity genes, adrenergic receptor beta2 (ADRB2), Beta3 (ADRB3), and PPAR γ2 (PPARG), during primate evolution.

Adrenergic-receptor beta2 (ADRB2) and beta3 (ADRB3) are obesity genes that play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. The Glu27 allele in ADRB2 and the Arg64 allele in ADRB3 are associated with abdominal obesity and early onset of non-insulin-dependent diabetes mellitus (NIDDM) in many ethnic groups. Peroxisome proliferator-activated receptor γ (PPARG) is required for adipocyte differentiation. Pro12Ala mutation decreases PPARG activity and resistance to NIDDM. In humans, energy-expense alleles, Gln27 in ADRB2 and Trp64 in ADRB3, are at higher frequencies than Glu27 and Arg64, respectively, but Ala12 in PPARG is at lower frequency than Pro12. Adaptation of humans for lipolysis, thermogenesis, and reduction of fat accumulation could be considered by examining which alleles in these genes are dominant in non-human primates (NHP). All NHP (P. troglodytes, G. gorilla, P. pygmaeus, H. agilis and macaques) had energy-thrifty alleles, Gly16 and Glu27 in ADRB2, and Arg64 in ADRB3, but did not have energy-expense alleles, Arg16, Gln27 and Trp64 alleles. In PPARG gene, all NHP had large adipocyte accumulating type, the Pro12 allele.ConclusionsThese results indicate that a tendency to produce much more heat through the energy-expense alleles developed only in humans, who left tropical rainforests for savanna and developed new features in their heat-regulation systems, such as reduction of body hair and increased evaporation of water, and might have helped the protection of entrails from cold at night, especially in glacial periods.

The p53 Codon 72 Polymorphism and the Risk of Oral Cancer in a Chinese Han Population

The p53 codon 72 polymorphism has been investigated extensively for its association with various cancers around the world. It is still unclear whether the p53 codon 72 polymorphism is associated with oral cancer risk. The aim of our study was to evaluate the association between the p53 codon 72 polymorphism and the oral cancer risk in Chinese Han patients. A hospital-based case-control study with 200 patients with oral cancer and 200 matched controls was conducted. Genomic DNA was isolated from peripheral blood, and gene polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. The arginine (Arg)/Arg genotype conferred 0.57 times reduced risk to oral cancer (95% confidence interval [CI]=0.36, 0.89; p=0.01). The Arg allele frequency was significantly lower (odds ratios [OR]=0.74, 95% CI=0.56, 0.98; p=0.03) in comparison with controls in patients with oral cancer. The proline allele frequency was significantly higher (OR=1.35, 95% CI=1.02, 1.79; p=0.03) in comparison with controls in patients with oral cancer. When stratified by the clinical stage, lymph node metastasis, and histological differentiation of oral cancer, no statistically significant results were observed. Our results thus suggest that the p53 codon 72 polymorphism modulates susceptibility to oral cancer in Chinese Han patients.

Response to Catecholamine Stimulation of Polymorphisms of the Beta-1 and Beta-2 Adrenergic Receptors

Previous studies have demonstrated that β-adrenergic receptor polymorphisms affect outcomes in patients with heart failure or after an acute coronary syndrome. Whether β-adrenergic polymorphisms influence catecholamine responses in patients with cardiovascular disease is not known. Cardiovascular responses to the β1-receptor agonist dobutamine and the β2-receptor agonist terbutaline were studied using gated blood pool scintigraphy in 21 patients on long-term β-blocker therapy. Heart rate (HR), stroke volume (SV), and cardiac output (CO) increased, and end-systolic volume decreased with dobutamine and terbutaline. Changes in HR and CO with dobutamine were higher for those with ≥1 β1 Arg389 allele than those homozygous for the Gly389 allele (change in HR 15 vs 1 beat/min, p = 0.02; change in CO 2.4 vs 1.0 L/min, p = 0.02). Increases in HR, CO, and SV with terbutaline were greater for those homozygous for the β2 Glu27 allele than those with ≥1 Gln27 allele (change in HR 13.7 vs 4.8 beats/min, p = 0.048; change in CO 3.1 vs 1.6 L/min, p = 0.034; change in SV 28.3 vs 14.8 ml, p = 0.045). Changes in CO and volume with terbutaline were greater in those with an ejection fraction <40% than in those with an ejection fraction ≥40%. In conclusion, β-receptor gene variants significantly influence inotropic and chronotropic responses to β-agonist exposure in patients on β-blocker therapy.

XRCC1 Gene Polymorphisms and Risk of Lung Cancer in Turkish Patients

Polymorphisms in the X-ray repair cross complementing 1 (XRCC1) gene have been found to be associated with susceptibility to various types of cancers. We investigated the association between the XRCC1 gene Arg399Gln polymorphism and the susceptibility to lung cancer in Turkish patients. To determine the association of this polymorphism with the risk of lung cancer in Turkish patients, a hospital-based case-control study was designed, involving 67 patients with lung cancer and 60 control subjects with no cancer history who were matched for age and gender. XRCC1 genotypes (Arg/Arg, Arg/Gln, and Gln/Gln) were determined using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis on genomic DNA. No statistically significant relationship was determined between the lung cancer and control groups (p>0.05). Among the patients, 61% were Arg/Arg, 28% were Arg/Gln, and 11% were Gln/Gln. Among the controls, 50% were Arg/Arg, 38% were Arg/Gln, and 12% were Gln/Gln. There was no difference in the distribution of XRCC1 genotypes or the frequencies of the Arg (75% versus 69%) and Gln (25% versus 31%) alleles between the lung cancer patients and controls. Our results suggest that the XRCC1 gene Arg399Gln polymorphism is not associated with an increased risk for the development of lung cancer in Turkish patients.

Possible impact of ADRB3 Trp64Arg polymorphism on BMI in patients with schizophrenia

The β3-adrenoceptor (ADRB3) gene Trp64Arg polymorphism has been shown to be associated with obesity as well as type 2 diabetes and cardiovascular disease. The incidence of overweight and the risks of type 2 diabetes and cardiovascular disease are also increased in major depression and schizophrenia. We hypothesized that the Trp64Arg polymorphism may be associated with increased risk of schizophrenia and depression. The Trp64Arg was genotyped in 504 patients with schizophrenia, 650 with major depressive disorder (MDD), and 1170 healthy controls. Of these participants, body mass index (BMI) data were available for 125 patients with schizophrenia, 219 with MDD, and 261 controls. No significant difference in genotype or allele distribution was found across the diagnostic groups. No significant difference in BMI was observed between the Arg allele carriers and the non-carriers in the MDD and the control groups. However, patients with schizophrenia carrying the Arg allele had significantly higher BMI (Mean (SD): Arg carriers: 26.5 (6.9), Arg non-carriers: 23.8 (4.3); P=0.019) and a higher rate of being overweight (BMI of 25 or more) compared to their counterparts (Trp/Trp group) (% overweight (SE): Arg carriers: 52.3 (7.5), Arg non-carriers: 32.1 (5.2); P=0.027). We obtained no evidence for the association of ADRB3 Trp64Arg with the development of MDD or schizophrenia. However, the Arg allele was found to be associated with higher BMI and being overweight in patients with schizophrenia. This may imply that genotyping ADRB3 is of clinical use to detect schizophrenic individuals at risk for developing obesity.

Abstract 1183: Monoallelic expression in codon 72 of TP53 in heterozygote individuals

Abstract Background &amp; Aim: Correlations between DNA variation and human phenotypic differences, such as susceptibility to certain diseases, are not well understood. Polymorphisms can contribute to the observed variation in complex human traits, but their relative contributions remain to be determined. Expression differences between alleles of the same gene have been observed, contributing to phenotypic variation between individuals. Studies showed that variations exist in the relative allelic expression levels in certain genes of heterozygote individuals. Polymorphism at codon 72 of TP53 results in either Arginine or Proline, whose functional significance in carcinogenesis is controversial. Studies showed that the Pro72 is less efficient than Arg72 allele in suppressing cell transformation and inducing apoptosis. We have investigated if the expression of these p53 polymorphs is selectively regulated, using mRNA and DNA from colorectal cancer (CRC). Methods: 89 non-related patients treated at ACCamargo Hospital/Brazil were evaluated. DNA/RNA were isolated from frozen tumor tissue using phenol/chloroform protocol and evaluated by sequencing. Associations were analyzed by Pearson Chi-Square or Fisher Exact tests and Multiple Logistic Regression. Results: We found 24 (27%) heterozygotes tumors and 10 (41.7%) of these showed monoallelic expression: 70% (7/10) of them preferentially expressed the Pro allele. Thus, the allele frequencies showed a discrete decrease, from 0.26 for Pro allele of expression analysis to 0.25 for Pro allele of tumor genomic analysis. Previous results revealed that the p53 codon 72 expression was significantly associated with gender (P= .037), recurrence (P= .005), dirty tumor necrosis (P= .025), border pattern of tumor growth (P= .05), post chemoradiotherapy use (P= .002), p53 immunohistochemistry expression (P= .041) and TP53 mutation (P= .004), suggesting that the presence of at least one Arg72 allele is associated with better prognosis. According to multiple logistic regression the variable independently associated with the presence of the Arginine allele is the absence of tumor necrosis factor (OD= 8.64/P= .047). This is the first report describing the monoallelic expression of the p53 codon 72 in CRC and revealed that heterozygotes preferentially express the Pro allele, suggesting that the Pro allele is selectively activated during CRC development. Conclusions: The expression of the different p53 polymorphs is selectively regulated in Pro72Arg heterozygotes individuals. The silent Arg allele seems to have a negative relation with cancer susceptibility, since it is better in inducing apoptosis. The differences in the expression of heterozygotes resulted in an increase in the total numbers of Pro expressers in this cancer population. Thus, the expression status of the p53 polymorphs, rather than the genotypic status, might be a useful indicator for cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1183. doi:1538-7445.AM2012-1183

Abstract 727: Homozygosity for Arg of p53 codon 72 correlates with poor prognosis in Puerto Rican patients with head and neck squamous cell carcinoma

Abstract Objective: Genetic variations at codon 72 of p53 gene results in altered activities for p53 and are suggested as a potential cancer risk. However, epidemiologic findings have been inconsistent. The p53 gene has a polymorphic site at exon 4 codon 72, which, in an occurrence of a base substitution, can produce Proline or Arginine (Arg72Pro). This polymorphism is differentially dispersed among different ethnic populations. The objective of this study is to evaluate the association between p53 polymorphism and head and neck squamous cell carcinoma (HNSCC) in the Puerto Rican population. Methods: Genotyping of the p53 polymorphism at exon 4 codon 72 was performed using PCR-based restriction fragment polymorphism (PCR-RFLP) in a study with 72 HNSCC patients. Correlations between clinicopathological parameters and p53 polymorphism were analyzed by Fisher's exact test and chi-square when suitable. Survival analysis of HNSCC patients, with each type of p53 genotype, was performed using Mantel-Cox test. Results: The frequencies for homozygote Arg allele were 34.7% in HNSCC cases and 31.1% in controls. The Pro allele carriers (Arg/Pro or Pro/Pro) had a frequency of 65.3% in HNSCC cases and 68.9% in healthy controls. The OR of HNSCC cancer-associated with the Arg-Arg genotypes of codon 72 was 1.18 [95% confidence interval (CI): 0.53-2.61]. Survival analysis showed that HNSCC patients with the Arg/Arg allele had a poorer survival rate compared to patients with the Pro allele (Hazard Ratio = 2.40, 95% CI: 1.27-4.56, P=0.0074). Also, there were differences in survival based on patient's genotype and response to treatment. However, no statistically significant association was found between p53 polymorphic variants and gender, age, risk factors and staging. Conclusion: Our results suggest that homozygosity for Arg of p53 Arg72Pro may have a role in the progression of HNSCC in the Puerto Rican population. Detection of the p53 polymorphic variants may be used as an indicator of prognosis in HNSCC patients. Accurate prognosis in HNSCC will help clinicians to establish proper treatment and increase the survival of HNSCC patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 727. doi:1538-7445.AM2012-727

Paraoxonase 1 gene (Gln192–Arg) polymorphism and the risk of coronary artery disease in type 2 diabetes mellitus

Paraoxonase 1 (PON1) is reported to have antioxidant and cardioprotective properties. Recently, an association of glutamine (Gln) or type A/arginine (Arg) or type B polymorphism at position 192 of PON1 gene has been suggested with coronary artery disease (CAD) among patients with diabetes mellitus (DM). However, conflicting results have also been reported. To investigate the relationship between PON1 gene (Gln 192 –Arg) polymorphism and the presence, extent and severity of CAD in type 2 DM. The study comprised 180 patients recruited from those undergoing coronary angiography for suspected CAD, who were divided according to the presence or absence of CAD and DM into four groups: Group I ( n = 40 patients) nondiabetic subjects without CAD, Group II ( n = 45 patients) diabetic patients without CAD, Group III ( n = 47 patients) nondiabetic patients with CAD and Group IV ( n = 48 patients) diabetic patients with CAD. PON1(Gln 192 –Arg) genotype was assessed using polymerase chain reaction (PCR) followed by AlwI digestion. The frequency of Gln allele (type A) was significantly higher in Group I and Group II compared to Group III and Group IV (62.5%, 60% vs. 38.3%, 31.25%, respectively, p < 0.001) while the frequency of Arg allele (type B + type AB) was significantly higher in ischemic groups (III and IV) compared to nonischemic groups (I and II) (61.7%, 68.75% vs. 37.5%, 40%, respectively, p < 0.001). Patients with CAD and DM (Group IV) have significantly higher severity score and vessel score than those with CAD only (Group III) (9.7 ± 2.97, 2.44 ± 0.56 vs. 6.99 ± 3.71, 1.67 ± 0.89, respectively, p < 0.001) Patients with vessel score 3 had significantly higher severity score and higher Arg allele frequency than patients with vessel score 2, the latter group had also significantly higher severity score and Arg allele frequency than patients with vessel score 1 (8.9 ± 2.79 vs. 5.21 ± 2.13 and 80.49% vs. 67.86%), (5.21 ± 2.13 vs. 3.11 ± 0.89 and 67.86% vs. 53.85%), p < 0.001 for all. In multivariate logistic regression analysis of different variables for prediction of CAD, age [OR 2.99, CI (1.11–10.5), p < 0.01], smoking [OR 4.13, CI (1.37–11.7), p < 0.001], low-density lipoprotein (LDL) cholesterol > 100 mg/dL [OR 4.31, CI (1.25–12.5), p < 0.001], high-density lipoprotein (HDL) cholesterol < 40 mg/dL [OR 5.11, CI (1.79–16.33), p < 0.001] and PON1 192 Arg allele [OR 4.62, CI (1.67–13.57), p < 0.001] were significantly independent predictors of CAD. Arg allele of PON1 192 gene polymorphism is an independent risk factor for CAD and is associated not only with the presence of CAD but also with its extent and severity and its impact is clearly more pronounced in diabetic patients.

TP53 codon 72 polymorphism in pigmentary phenotypes

The p53 protein exerts different cellular functions, and recent findings have demonstrated its influence on the cascade of skin pigmentation during UV exposure. Among TP53 gene polymorphisms, the most studied is the G to C transversion in exon 4 at codon 72, which results in three distinct genotypes, Arg/Arg, Pro/Pro and Arg/Pro, each one encoding different p53 isoforms. Therefore, this study aimed to determine the relationship between TP53 codon 72 polymorphism and skin protection against sunburn. Genomic DNA was extracted from peripheral blood samples and genotyping was performed by PCR and confirmed by restriction enzyme digestion. The genotype frequency was 50% for Arg/Arg and 14.6% for Pro/Pro genotype. The frequency of heterozygous subjects was 35.4%. In our population, p53 genotypes were in Hardy-Weinberg (HW) equilibrium (X2 HM less than 3.84), showing a predominance of arginine allele (total Arg allele frequency of 68%). No significant association between p53 genotype and skin colour, hair or eye colour and susceptibility to sun exposure was found. However, further analysis demonstrated a significant association between the genotype Pro/Pro and blue/green eyes among participants who presented redness (P=0.016). Our findings indicate susceptibility to sun exposure when this phenotype (eye colour) occurs simultaneously with Pro/Pro genotype.

Lack of an association between TSC gene Arg904Gln polymorphisms and essential hypertension risk based on a meta-analysis

Although there have been several studies investigating a possible association between essential hypertension and TSC gene Arg904Gln polymorphisms, the results have been inconsistent. We conducted a meta-analysis of four case-control studies (one study in Europe and three studies in Asia), including 1811 essential hypertension cases and 1381 controls. The pooled results showed no significant associations between any of these polymorphisms and essential hypertension (allele Arg vs allele Gln: odds ratio (OR) = 0.94, 95% confidence interval (95%CI) = 0.70-1.27), additive genetic model (Arg/Arg vs Gln/Gln: OR = 0.98, 95%CI = 0.43-2.23), dominant genetic model (Arg/Arg + Arg/Gln vs Gln/ Gln: OR = 0.97, 95%CI = 0.43-2.21), and recessive genetic model (Arg/ Arg vs Arg/Gln + Gln/Gln: OR = 1.03, 95%CI = 0.45-2.35). Based on the results of our meta-analysis, we conclude that the TSC gene Arg904Gln polymorphism is not associated with essential hypertension risk.