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FCGR3A gene polymorphisms may correlate with response to frontline R-CHOP therapy for diffuse large B-cell lymphoma.

The precise mechanism of rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy in diffuse large B-cell lymphoma (DLBCL) is not fully elucidated. Besides overcoming bcl-2-mediated chemoresistance, antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was also proposed as a mechanism of rituximab. The current study evaluated the impact of FcR polymorphism on the response to R-CHOP therapy for DLBCL with the basis that FcR polymorphism can affect rituximab's affinity for ADCC effector cells. The FCGR3A and FCGR2A gene polymorphisms were determined in DLBCL patients receiving R-CHOP (n = 113) compared with CHOP therapy (n = 85). The FCGR3A valine (V) allele was significantly correlated with a higher complete response rate to R-CHOP compared with the phenylalanine (F) allele (88% in V/V vs 79% in V/F vs 50% in F/F; P = .002), while no difference was found between FCGR2A polymorphisms. In addition, V/V allele was associated with faster achievement of response than other alleles. The impact of the FCGR3A gene polymorphism on response rate was not noted in the CHOP group. In terms of overall or event-free survival, no difference was found according to FCGR3A or FCGR2A alleles. The FCGR3A single nucleotide polymorphism (SNP) is predictive of response to R-CHOP, but does not correlate with survival in patients with DLBCL.

Adolescent↗

Integrin alpha-2 and beta-3 gene polymorphisms and breast cancer risk.

Integrins are cell surface receptors, which mediate cell-to-cell and cell-to-extracellular matrix adhesion. Some of them, e.g. alpha(V)beta(3), alpha(IIb)beta(3) and alpha(2)beta(1), have been suggested as key players for cancer development and tumor metastasis. Two polymorphisms in the gene for the alpha(2) component, ITGA2 807C>T and 1648G>A, have been associated with the cell-surface density of integrin alpha(2)beta(1). The 176T>C polymorphism in the ITGB3 gene, encoding the beta(3) subunit of integrins alpha(IIb)beta(3) and alpha(V)beta(3), modifies a variety of traits of beta(3) expressing cells. To analyze the role of ITGA2 and ITGB3 polymorphisms for breast cancer risk and prognosis, we performed a case-control study including 500 female breast cancer patients and 500 healthy female age-matched control subjects. All study participants were of Caucasian origin (Austria, Middle-Europe). The ITGA2 1648_AA genotype was significantly associated with breast cancer (odds ratio 3.12; 95% confidence interval 1.11-8.77). Carriers of the most common ITGA2 haplotype (807C_1648G, 'wildtype') were at decreased risk for breast cancer (odds ratio 0.72; 95% confidence interval 0.53-0.98). A histological grade of 3 or 4 was found more often in ITGA2 807TT subjects (p=0.039 compared to CC+CT genotypes) and carriers of an ITGA2 1648A allele (p=0.017 compared to GG genotype). Carriers of the ITGA2 807C_1648G haplotype were less likely to have a histological grade 3 or 4 compared to non-carriers (p=0.003). The ITGB3 176T>C polymorphisms was not associated with breast cancer susceptibility. In a Cox-regression analysis, carriers of the homozygous ITGB3 176-CC genotype had a higher risk for metastasis (relative risk 2.3; 95% CI 1.3-4.2; p=0.005). We conclude that functional polymorphisms in integrin genes ITGA2 and ITGB3 influence the development and progression of breast cancer, respectively. The precise mechanism remains to be determined, but likely involves dysregulated signaling pathways.

Breast↗

[Association between aldosterone synthase gene polymorphism and hypertrophic cardiomyopathy].

OBJECTIVE: To investigate the relationship between aldosterone synthase (CYP11B2) gene polymorphism and hypertrophic cardiomyopathy (HCM). METHODS: Fifteen HCM patients and 18 healthy subjects were enrolled in this study. Peripheral blood samples were collected from these subjects to exact genome DNA. PCR and Hae III restriction endonuclease digestion were employed to study -344C/T polymorphism of CYP11B2 gene. RESULTS: CYP11B2 gene showed a significant difference in CT genotype distribution in HCM groups as compared with that in the control groups (P<0.05). CONCLUSION: CT genotype of CYP11B2 gene may be one of factors responsible for the pathogenesis of HCM in a proportion of patients.

Cardiomyopathy, Hypertrophic↗

Association of serum lipids and apolipoprotein E gene polymorphism with the risk of colorectal adenomas.

OBJECTIVE: To investigate the relationship of serum lipids and apolipoprotein (apoE) gene polymorphism to colorectal adenomas. METHODS: This study took place in the Department of Gastroenterology, Renmin Hospital of Wuhan University, PR China from June 2003 to March 2005. Ninety-eight patients with colorectal adenomas and 40 healthy subjects were enrolled, and their serum levels of triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), and low density lipoprotein cholesterol (LDL-C) were determined. The apoE gene polymorphism was identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Serum TC levels of colorectal adenomas group (5.32 +/- 0.85 mmol/L), distal colorectal adenomas group (5.58 +/- 0.63 mmol/L), and villous adenoma group (5.49 +/- 0.69 mmol/L) were higher than the control group (4.28 +/- 0.62 mmol/L, p=0.016), proximal colorectal adenomas group (4.82 +/- 0.58 mmol/L, p=0.038) and non-villous adenoma group (4.76 +/- 0.58 mmol/L, p=0.03). Serum HDL-C levels of colorectal adenomas group (1.39 +/- 0.25 mmol/L) were lower than the control group (1.51 +/- 0.29 mmol/L) (p=0.035). Serum lipids levels of each genotype in colorectal adenomas group were not statistically significant. Apolipoprotein E3/E4 genotypic frequency in colorectal adenomas group (7.1%) was lower than the control group (17.5%) (p=0.012). CONCLUSION: The findings suggest that altered lipid metabolism may be differentially associated with colorectal adenomas and the persons with apoE E3/E4 genotype have lower risk suffering from colorectal adenomas than those with other genotypes.

Adenoma↗

Cytochrome P450 1A1 and manganese superoxide dismutase gene polymorphisms in Behçet's disease.

OBJECTIVE: To investigate the association of cytochrome p450 1A1 (CYP1A1) and manganese superoxide dismutase (MnSOD) gene polymorphisms with susceptibility to Behçet's disease (BD) in Taiwan. METHODS: The polymorphisms of CYP1A1 and MnSOD genes were determined in 51 patients with BD and 91 healthy controls by polymerase chain reaction/restriction fragment length polymorphism methods. RESULTS: The frequencies of CYP1A1 4889G and 4887A were significantly increased in patients with BD. In contrast, there was no significant difference in the frequencies of MnSOD gene polymorphisms between patients with BD and controls. Linkage disequilibrium was found between CYP1A1 4889G and CYP1A1 6235C in controls and patients with BD. However, a similar finding could not be found between CYP1A1 4889G and 4887A. We also found that the association of CYP1A1 4889G with BD was dependent on the presence of CYP1A1 4887A. On the other hand, the association of CYP1A1 4887A with BD was dependent on the presence of CYP1A1 4889G. An additive effect of CYP1A1 4889G and 4887A on the susceptibility to BD could be found. CONCLUSION: Simultaneous presence of CYP1A1 4889G and 4887A is associated with development of BD in Taiwan.

Adult↗

Association study of 90 candidate gene polymorphisms in panic disorder.

OBJECTIVE: In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD). METHODS: The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42). RESULTS: From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.

Cholecystokinin↗

Association between hepatocyte growth factor gene polymorphism and essential hypertension.

Hepatocyte growth factor (HGF) is a growth factor which contributes to protection and/or repair of vascular endothelial cells. Serum HGF level is elevated in response to hypertensive organ damage, which suggests that blood pressure regulation may be affected by HGF gene polymorphisms via serum HGF. To examine the interaction between a HGF gene polymorphism and hypertension, we carried out a case-control study. The present study was conducted in outpatients of Osaka University Hospital. Subjects (n=654) who gave informed consent to the study protocol and genetic analysis were recruited. A C to A nucleotide substitution in intron 13 of the HGF gene was determined by the TaqMan polymerase chain reaction (PCR) method using an MGB (Minor Groove Binder) probe. The genotype distribution of the C/A polymorphism of the HGF gene in total subjects was as follows: CC, 83%; CA, 16%; and AA 1%. This distribution was not significantly different from the predicted by Hardy-Weinberg's equilibrium. The prevalence of hypertension was significantly higher in subjects with the CC genotype than in those with an A allele, and the positive association remained after adjustment for confounding factors, with the estimated odds ratio for hypertension (CC vs. CA+AA) being 1.71 (95% confidence interval: 1.02-2.93). A significant association with hypertension was observed in lean or female subjects but not in obese or male subjects. In conclusion, our data suggested that C/A polymorphism in intron 13 of the HGF gene is associated with susceptibility to essential hypertension in lean or female subjects.

Aged↗

Case-control study of estrogen receptor gene polymorphisms in Parkinson's disease.

We investigated the association of Parkinson's disease (PD) with two estrogen receptor gene polymorphisms. In a sample of 319 unrelated PD cases and 196 control subjects including both men and women, we observed no association of PD with the estrogen receptor genotypes derived from XbaI and PvuII digests. Analyses restricted to women or to cases and controls of European origin yielded similar findings. Further analyses stratified by age at examination or by family history did not show associations. While exogenous and endogenous estrogen may modify the risk of PD in women, the two estrogen receptor gene polymorphisms considered here do not seem to contribute to PD susceptibility.

Adult↗

Angiotensin II type 2 receptor gene polymorphisms and essential hypertension.

AIM: To identify the genetic variants of angiotensin II type 2 receptor (AT2R) gene in a Chinese population and to determine whether the AT2R gene polymorphisms are associated with essential hypertension (EH). METHODS: The detection of single nucleotide polymorphisms (SNPs) was performed in 19 subjects by a direct DNA sequencing. Two hundred fifty patients with EH and 250 nomortensive controls were included in the study to assess the contribution of polymorphism of AT2R gene to hypertension. RESULTS: We identified 9 SNPs in the promoter, intron, exons and 3' untranslated region (3'UTR) of AT2R gene; among them 5 SNPs were novel molecular variants. A case-control study using a most frequent SNP (1334T/C) in the promoter region, showed a significant increase in allele frequency of C1334 in male hypertensive subjects (17.5 % vs 10.3 % for normotensive subjects, P<0.05). CONCLUSION: The catalogue of SNPs of AT2R gene in Chinese population showed ethnic difference in DNA sequence variation. A polymorphism in the promoter region (1334T/C) of AT2R gene might be involved in the development of hypertension in Chinese population.

Aged↗

[Relationship between human leukocyte antigen-DRB1 allele gene polymorphism and intrahepatic cholestasis of pregnancy].

OBJECTIVE: To study the relationship between human leukocyte antigen-DRB1 (HLA-DRB1) allele genes polymorphism and intrahepatic cholestasis of pregnancy (ICP). METHODS: Forty-two patients with ICP were tested for HLA-DRB1 allele genes polymorphism with the polymerase chain reaction technique and sequence specific oligonucleotide (PCR-SSO) probes hybridization, 56 normal pregnant women as control group were also tested. In addition, the phenotype frequencies of HLA-DRB1 alleles were compared with it's clinical character in patients with ICP. RESULTS: The higher frequencies were observed for alleles DR9, DR12 and DR4 in both groups. DR6 alleles were detected in 14 cases out of 42 patients. Patients with ICP had a significantly higher frequency of the allele DR6 when compared to control group (16.7% vs 3.6%), with a relative risk (RR) as 6.5 (P < 0.01). No significant differences were observed between the frequencies of other detected HLA-DRB1 alleles in both groups. There was no association between HLA-DR6 allele and the level of liver function and cholylglycine in ICP. CONCLUSION: The study showed that HLA-DR6 gene might be one of the susceptibility genes to ICP.

Adult↗

Gene polymorphism for microsomal epoxide hydrolase and susceptibility to emphysema in a Japanese population.

Recently, it was reported that gene polymorphism for microsomal epoxide hydrolase (mEPHX), an enzyme involved in the first-pass metabolism of epoxide intermediates, was associated with susceptibility to emphysema. This association was examined in a Japanese population, performing polymerase chain reaction (PCR)-based direct sequencing and restriction fragment length polymorphism assays for variant forms of mEPHX. The subjects consisted of 79 smokers with moderate to severe emphysema diagnosed by lung computed tomography scans, 58 smokers without emphysema, with a comparable smoking history, and 114 consecutive subjects who undertook annual health checkups. The allele frequency of exon 3 Tyr113 to His113, which was reported to confer slow mEPHX activity, was substantially higher in the population control group compared with that of the Caucasian control subjects in a previous study. However, neither the genotype distribution of exon 3, nor that of exon 4 His139 to Arg139, was significantly different between the two groups of smokers. These data indicate that the gene polymorphism for mEPHX is not associated with susceptibility to emphysema in the Japanese population. The discrepancy between the two studies may be explained either by racial difference or by the selection bias of subjects in the previous study, which examined those who had only mild to moderate emphysema with lung cancer or those who were clinically diagnosed as having chronic obstructive pulmonary disease.

Disease Susceptibility↗

Lack of involvement of nucleotide excision repair gene polymorphisms in colorectal cancer.

DNA repair has an essential role in protecting the genome from damage by endogenous and environmental agents. Polymorphisms in DNA repair genes and differences in repair capacity between individuals have been widely documented. For colorectal cancer, the loss of mismatch repair gene activity is a key genetic determinant. Nucleotide excision repair (NER), recombination repair (RR) and base excision repair (BER) pathways have critical roles in protection against other cancers, and we wished to investigate their role in colorectal cancer. We have compared the frequency of polymorphisms in the NER genes, XPD, XPF, XPG, ERCC1; in the BER gene, XRCC1; and in the RR gene, XRCC3; in colorectal cancer patients and in a control group. No significant associations were found for any of the NER gene polymorphisms or for the XRCC1 polymorphism. The C allele (position 18067) of the XRCC3 gene was weakly but significantly associated with colorectal cancer (odds ratio 1.52, 95% confidence interval 1.04-2.22, P=0.03). For all patients who were heterozygous for any of the repair genes studied, tumour tissue was investigated for loss of heterozygosity (LOH). Only one example of LOH was found for all the genes examined. From the association and LOH data, we conclude that these genes do not have an important role in protection against colorectal carcinogenesis.

Cell Transformation, Neoplastic↗

[The relationship of apolipoprotein H gene polymorphism with stroke].

OBJECTIVE: To study the association between apolipoprotein H (apoH) gene polymorphism and cerebral apoplexy among the Hans in Changsha, Hunan Province. METHODS: Polymorphisms in exon 3 of apoH gene was determined by PCR-single strand conformation polymorphism (PCR-SSCP) analysis and DNA sequencing among 260 patients with stroke of Han nationality in Changsha, including 130 cerebral hemorrhage (CH) patients, of which 50 were with a family history of CH, and 79 with hypertension and 51 without hypertension, and 130 cerebral infarction (CI) patients, of which 50 were with a family history of CI, and 66 with hypertension and 64 without hypertension; 20 members of stroke pedigrees, and 100 healthy controls. RESULTS: G341A (Ser88Asn) polymorphism in exon 3 of apoH gene was found in Changsha Hans. The frequency of A allele was 0.127 in the CH group, especially in CH patients with a family history of stroke or hypertension, significantly higher than that in control group (0.055, P < 0.05). The frequency of A allele was also significantly higher in members of CH pedigrees than in controls. No association between G341A (Ser88Asn) polymorphism and CI was found. CONCLUSION: A allele in G341A (Ser88Asn) polymorphism may be a genetic risk factor of CH among Changsha Hans, especially the CH patients with hypertension and those with a family history of hypertension.

Adult↗

Paraoxonase gene polymorphisms and haplotype analysis in a stroke population.

BACKGROUND: Paraoxonase (PON) has anti-atherogenic activity due to its protective function against low density lipoprotein (LDL) oxidation. Alteration of enzyme activity due to polymorphisms in the PON genes may influence the development of atheroma and thus affect stroke risk. Three PON genes (PON1, PON2 and PON3) have been identifiedand mapped to chromosome 7. METHODS: We looked at the distribution of paraoxonase polymorphisms and haplotype arrangement in 397 Caucasian ischaemic stroke patients and 405 controls. We investigated 6 different common single nucleotide polymorphisms (SNP) in PON genes; two substitutions in PON1 ["A/G": Gln (Q)/Arg (R)] at codon 192 and ["T/A": Leu (L)/Met (M)] at codon 55, two in PON2 at codon 311 ["G/A": Cys (C)/Ser (S)] and codon 148 ["C/G": Ala (A)/Gly (G)] and two SNPs, both "A" to "G" substitutions, in PON3--intronic rs2074353, which we designated PON3-1 and [Ala (A)/Ala (A)] at codon 99, designated as PON3-3. Dynamic Allele Specific Hybridisation (DASH) was used as the genotyping assay. Haplotype analysis was performed using both PHASE and EHPLUS programs. RESULTS: Genotype and allele frequencies were similar in cases and controls. Lipid profiles were not influenced by PON genotype. Haplotype frequencies for the six loci (PON2-148, PON2-311, PON3-3, PON3-1, PON1-55 and PON1-192) were estimated. Comparison of the two programs showed a significant difference in haplotype arrangements with EHPLUS (p-value = 0.005) but not with PHASE Ver.2 (p-value = 0.12). The 112211 (1 = frequent allele, 2 = rare allele) haplotype arrangement was commoner in cases than controls (p = 0.015), and the 111121 haplotype was commoner in controls (p = 0.006). CONCLUSION: Our study did not identify a role for individual paraoxonase gene polymorphisms in the pathogenesis of ischaemic stroke. Findings of haplotype differences should be confirmed in large scale studies. The importance of using a well-validated haplotype analysis program is also underlined.

Aged↗

Gene polymorphism and coronary risk factors in Indian population.

Asian Indians who have settled overseas and those in urban India have increased risk of coronary events. Reasons for this increased risk are thought to be genetic but are yet unclear. Advances in molecular cardiology have revealed a number of single nucleotide polymorphisms associated with atherosclerosis. In this review, gene polymorphisms that have been associated with coronary diseases among Indians are discussed. Topics include the genes involved in hyperlipidemia, hypertension, and homocysteine. Mutations in the low-density lipoprotein receptor (LDLR) gene resulting in familial hypercholesterolemia have strong association with premature atherosclerosis. Common polymorphism of the apolipoproteins (apo) B-100 and E genes have been associated with variation in lipid and lipoprotein levels. Recently identified polymorphisms in the apoC3 (T-455C, C-482T), and cholesteryl ester transfer protein (CETP) (B1/B2 allele) genes are associated with increased triglycerides and reduced high-density lipoprotein (HDL)-levels, a feature now also common among Asian Indians. Angiotensin-converting enzyme-deletion (DD) polymorphism has been shown to influence beta-blocker therapy in heart failure. Mutations in methylenetetrahydrofolate reductase (C667T), cystathionine beta-synthase (T833C), and methionine synthase (A2756G) genes cause hyperhomocysteinemia, an independent risk factor for atherothrombosis. As the genetics of atherosclerosis continues to evolve, these factors along with the newer emerging factors may become a part of the routine assessment, aiding prediction of future coronary events.

Coronary Disease↗

[Relationship between heat shock protein 70-hom gene polymorphism and ankylosing spondylitis].

OBJECTIVE: To investigate the association between heat shock protein 70-hom (HSP70-hom) gene polymorphism and ankylosing spondylitis(AS) in Chinese Han patients. METHODS: Genomic DNA from 98 Chinese AS patients and 70 ethnically matched controls were typed for HSP70-hom polymorphism by polymerase chain reaction-restriction fragment length polymorphism. RESULTS: The HSP70-hom genotypes in the AS patients consisted of homozygote AA (60.2%) and BB(4.1%), and heterozygote(35.7%), while the HSP70-hom genotypes in the controls were composed of AA(58.6%), BB(2.9%) and heterozygote(38.6%). No significant difference was found in the distribution of HSP70-hom genotype between these two groups(chi(2) test=0.280, P>0.05). The frequencies of HSP70-hom alleles in AS patients were 77.9%(AA) and 22.1%(BB), while they were 78.1% and 21.9% in the controls. The frequency of HSP70-hom allele in AS patients was not significantly increased, compared with that in controls (chi(2) test=0.002, P>0.05). CONCLUSION: There may be no association between the HSP70-hom gene polymorphism and ankylosing spondylitis in Chinese Han population.

Adolescent↗

Association between migraine and endothelin type A receptor (ETA -231 A/G) gene polymorphism.

BACKGROUND: Previous studies have described an association between migraine and endothelin, a potent vasoconstrictor. OBJECTIVE: To test the association between migraine and gene polymorphisms of the endothelin system. METHODS: A population-based study of elderly individuals (n = 1,188) in Nantes (western France) was conducted. Lifetime migraine was defined according to the International Headache Society criteria, after an interview with a headache specialist. Five polymorphisms in genes encoding endothelin 1, endothelin type A (ET(A)), and type B receptors were determined in more than 90% of the sample. RESULTS Migraine was diagnosed in 140 participants (11.9%). The ETA (-231 A/G) polymorphism was the only polymorphism significantly associated with migraine. There was a trend of decreasing prevalence of migraine with number of copies of the G allele (AA genotype: 15.7% of participants with migraine, AG: 9.7%, GG: 2.9%; p < 0.001). Carrying the G allele was associated with a sex- and age-adjusted odds ratio of 0.50 (95% CI, 0.34 to 0.74). The association was observed in both sexes and was stronger in participants with a family history of severe headaches than in those without. CONCLUSIONS: A variant of the ET(A) receptor gene modulates the risk for migraine. These results offer new insights into the pathophysiology of the vascular component of migraine.

Age Factors↗

Biomechanical muscle properties and angiotensin-converting enzyme gene polymorphism: a model-based study.

Previous studies reported an association of angiotensin-converting enzyme (ACE) I/D gene polymorphism with physical performance. The study was based on the hypothesis that certain individual biomechanical muscle properties could be associated with ACE genotype and that they could influence athletes' physical performance. Movement-independent individual biomechanical muscle properties of 62 sports students were determined by applying a mathematical model to experimental data. Subjects exerted concentric and isometric contractions at a leg-press. The model was based on a Hill-type muscle model, a function describing the geometrical arrangement of human leg extensor muscles, and an exponential function describing muscle activation. Mouthwash samples were taken to determine the ACE genotypes. Several combinations of experimentally determined biomechanical properties served as input variables for a discriminant analysis. We were able to show that individual biomechanical muscle properties correlated with ACE I/D gene polymorphism. With a combination of certain individual muscle parameters based on a Hill-type muscle model, we were able to separate three individual ACE genotypes (II, ID, DD) in a significant way (P<0.03) and correctly classify 89% of the cases using a discriminant analysis. We conclude that local biomechanical muscle properties are influenced by ACE genotype.

Adult↗