Angiotensin II type 1 receptor polymorphisms and susceptibility to hypertension: A HuGE review

The angiotensin II type 1 receptor (AGTR1) plays an integral role in blood pressure control, and is implicated in the pathogenesis of hypertension. Polymorphisms within this gene have been extensively studied in association with hypertension; however, findings are conflicting. To clarify these data, we conducted a systematic review of association studies of AGTR1 polymorphisms and hypertension, and performed a meta-analysis of the rs5186 variant. Results show that the currently available literature is too heterogeneous to draw meaningful conclusions. The definition of hypertension and gender composition of individual studies helps to explain this heterogeneity. Although the structure and splicing pattern of AGTR1 would suggest a likely effect of polymorphisms within the promoter region on gene function, few studies have been conducted thus far. In conclusion, there is insufficient evidence that polymorphisms in the AGTR1 gene are risk factors for hypertension. However, most studies are inadequately powered, and larger well-designed studies of haplotypes are warranted.     

CD14 C-260T gene polymorphism and ischemic heart disease susceptibility: A HuGE review and meta-analysis

The CD14 gene C-260T polymorphism has been reported to be associated with ischemic heart disease, but results were conflicting. To evaluate the role of the CD14 C-260T polymorphism in ischemic heart disease, we performed meta-analyses of all available data. Comprehensive searches for studies on the association between the genotypes (CC, CT, TT) distributions and ischemic heart disease risk were performed. Patients with acute coronary syndrome, prior myocardial infarction, stable angina pectoris, or angiographic coronary artery stenosis were included. Potential sources of heterogeneity were explored by meta-regression. Analyses were performed under European, East Asian, and Indian studies, respectively. Data were available for 19 studies involving 11,813 cases and 6,196 controls. The summary odds ratio under the recessive model was 1.53 (95% confidence interval: 1.20–1.96) for East Asian studies published in English language journals on overall ischemic heart disease. Pooled odds ratios under the codominant model were about 1.81 (95% confidence interval: 1.36–2.40) and 1.70 (95% confidence interval: 1.26–2.29) for Chinese studies on overall ischemic heart disease and other ischemic heart disease (angina pectoris and angiographic coronary artery stenosis), respectively. No significant association was found in a European population, an Indian population, or the vulnerable plaque ischemic heart disease (acute coronary syndrome and prior myocardial infarction) subgroup of an East Asian population. It is probable that T allele and TT genotype are associated with ischemic heart disease in the East Asian population but not in the European or Indian populations. Further studies are warranted to assess these associations in greater details, especially in East Asian and Indian populations.     

RAS gene mutations in childhood acute myeloid leukemia: a Pediatric Oncology Group study

Mutations at codon 12, 13, and 61 of the HRAS, KRAS, and NRAS genes were evaluated in 99 cases of pediatric acute myeloid leukemia (AML) using oligonucleotide hybridization to polymerase chain reacted derived products. Twenty-four mutations were identified in the NRAS gene, 13 in the KRAS gene, and none in the HRAS gene. The mutations occurred in a broad spectrum of cases, and there was no specific association of RAS gene mutations with patient subsets defined on the basis of clinical or hematologic features. These data demonstrate that RAS gene mutations are at least as common in childhood AML as in adult AML and suggest that RAS gene mutations play a role in myeloid neoplasia in both age groups.     

Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria.

Mutation analysis was performed on DNA samples of 965 individuals from four different ethnic groups in South Africa, in an attempt to determine the spectrum of sequence variants in the haemochromatosis ( HFE ) gene. This population screening approach, utilizing a combined heteroduplex and single-strand conformation polymorphism (HEX-SSCP) method, revealed three previously described and four novel missense mutations. Novel variants V53M and V59M were identified in exon 2, Q127H in exon 3 and R330M in exon 5. The exon 5 variant was identified in one of 13 patients referred for a molecular diagnosis of hereditary haemochromatosis (HH), who tested negative for the known C282Y and H63D mutations. Mutation Q127H was detected in exon 3 of the HFE gene together with mutation H63D in an apparently severely affected patient previously shown to carry the protoporphyrinogen oxidase ( PPOX ) gene mutation R59W, which accounts for dominantly inherited variegate porphyria (VP) in >80% of affected South Africans. The mutant allele frequency of the C282Y mutation was found to be significantly lower in 73 apparently unrelated VP patients with the R59W mutation than in 102 controls drawn from the same population ( P = 0.005). The population screening approach used in this study revealed considerable genotypic variation in the HFE gene and supports previous data on the involvement of this gene in the porphyria phenotype.     

Genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common form of pediatric cancer. Although exposure to environmental agents appears to predispose individuals to this disease, little attention has been paid to the role of genetic susceptibility to environmental exposures in the etiology of childhood ALL. The enzymes GSTM1, GSTT1, GSTP1, CYP1A1, and CYP2E1 are involved in the bioactivation and detoxification of a variety of xenobiotics present in food, organic solvents, tobacco smoke, drugs, alcoholic drinks, pesticides, and environmental pollutants. Polymorphisms in the genes coding for these enzymes have been associated with increased susceptibility to different cancers, including hematologic malignancies. To investigate whether these polymorphisms represent risk-modifying factors for childhood ALL, a study was conducted involving 113 Brazilian patients of childhood ALL and 221 controls with similar ethnic backgrounds. The data revealed that carriers of the rare GSTP1 Val allele were at higher risk of ALL (odds ratio [OR] = 2.7; 95% confidence interval [CI] = 1.1-6.8; P = 0.04). No difference was found in the prevalence of the GSTM1 and GSTT1 null genotypes between ALL patients and the controls, and no association was found between CYP1A1*2 and CYP2E1*3 variants and ALL. However, when the mutant CYP1A1 and CYP2E1 alleles were considered together with the GSTM1 and GSTP1 risk-elevating genotypes, the risk of ALL was increased further (OR = 10.3; 95% CI = 1.0-111.8; P = 0.05), suggesting a combined effect. These results imply that genetic variants of xenobiotic metabolizing genes influence the risk of developing childhood ALL.     

NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review.

Nephrotic syndrome, characterized by edema, proteinuria, hyperlipidemia and low serum albumin, is a manifestation of kidney disease involving the glomeruli. Nephrotic syndrome may be caused by primary kidney disease such as focal segmental glomerulosclerosis. Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis. Podocin is an integral membrane protein located at the slit diaphragm of the glomerular permeability barrier. Complete information is lacking for the population frequency of some NPHS2 variants for all racial and ethnic groups. The most frequently reported variant, R229Q, is more common among European-derived populations than African-derived populations. We calculated crude odds ratios and 95% confidence intervals of childhood nephrotic syndrome and focal segmental glomerulosclerosis associated with R229Q heterozygosity using data from five studies. The R229Q variant is not associated with focal segmental glomerulosclerosis in the US population of African descent. In contrast, the R229Q variant is associated with a trend toward increased focal segmental glomerulosclerosis risk in European-derived populations, with an estimated increased risk of 20-40%. Our insight into the association between NPHS2 variants and nephrotic disease is hampered by the limitations of the existing studies, including small numbers of affected individuals and suboptimal control groups. Nevertheless, the available data suggest that large epidemiological case-control studies to examine the association between NPHS2 variants and nephrotic syndrome are warranted.     

Evidence for HLA-linked susceptibility factors in childhood leukemia

To test the hypothesis that susceptibility to leukemia can be governed by (a) recessive gene(s) associated with the major histocompatibility complex (MHC) in man, we performed an analysis of the inheritance of HLA antigens in 55 families in which one of the children developed ALL. We found among the parents of affected children a highly significant increased compatibility at the DR locus (p = 0.003). A similar increase was observed in sharing HLA antigens of the B locus (p = 0.02). The observed number of homozygotes among the patients was twice the expected value in families where the parents shared a B and a DR antigen. In segregation analysis, heterozygotes for the shared parental HLA antigen were significantly more prevalent among the healthy siblings. Our genetical analysis indicates that mating of certain shared alleles of the HLA system (especially of the DR locus) is associated with the risk for the offspring to develop ALL in childhood. This situation favors the expression of recessive genes associated with the MHC, and presumably those involved in the susceptibility to acute leukemia. Because familial leukemia is a rare event, the susceptibility to childhood ALL must also implicate genes outside the MHC and important environmental factors.     

HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls

C282Y/C282Y genotype is the prevalent genotype in Hereditary Haemochromatosis (HH), however, other genotypes have been associated with the disease. The objective of our study was to analyse the frequency of the three main mutations of HFE gene in HH patients and controls from the Basque population with differential genetic characteristics. Thirty five HH patients and 116 controls were screened for C282Y, H63D and S65C mutations using a PCR-RFLP technique. The association of HLA-A and-B alleles and HFE mutations was also studied in Basque controls. The frequency of C282Y homozygotes in the group of patients was only 57%. The rest of the patients presented heterogeneous genotypes, including compound heterozygotes: 11% of them were C282Y/H63D; and 2.85% were H63D/S65C. H63D or S65C heterozygotes had a frequency of 11% and 2.85 respectively and 5.71% patients lacked any mutation The high frequency of H63D in the healthy Basque population is confirmed in this study. A considerable incidence of S65C is observed either in controls and in HH (3%) or in iron overloaded patients. The peculiar genetic characteristics of Basques could explain the heterogeneity of genotypes in HH patients of this group. Further studies should be carried out to confirm these findings although the implication of other genetic or external factors in the development of HH is suggested.     

Genetic variation associated with preterm birth: a HuGE review.

Preterm birth (PTB) is a major public health concern because of its high prevalence, associated mortality and morbidity, and expense from both short-term hospitalization and long-term disability. In 2002, 11.9% of U.S. births occurred before 37 weeks gestation. Epidemiologic studies have identified many demographic, behavioral, and medical characteristics associated with PTB risk. In addition, recent evidence indicates a role for genetic susceptibility. We reviewed 18 studies published before June 1, 2004, that examined associations between polymorphisms in the maternal or fetal genome and PTB risk. Studies of a polymorphism in tumor necrosis factor-alpha, a proinflammatory cytokine, showed the most consistent increase in the risk of PTB. Environmental factors such as infection, stress, and obesity, which activate inflammatory pathways, have been associated with PTB, suggesting that environmental and genetic risk factors might operate and interact through related pathways. This review highlights maternal and fetal genetic susceptibilities to PTB, the potential relationships with environmental risk factors, and the need for additional well-designed studies of this critical public health problem.     

Casitas B lymphoma mutations in childhood acute lymphoblastic leukemia

Casitas B-lineage lymphoma (CBL) proteins are RING finger ubiquitin E3 ligases that attenuate the signaling of receptor tyrosine kinases and are mutated in a number of myeloid disorders. In this study, mutational screening of the linker-RING domains of CBL and CBLB was performed by denaturing high performance liquid chromatography in a cohort of diagnostic (n = 180) or relapse (n = 46) samples from children with acute lymphoblastic leukemia. Somatic mutations were identified in three children, giving an overall incidence of 1.7% and involved small deletions affecting the intron/exon boundaries of exon 8, leading to skipping of exon 8 and abolishing E3 ligase function. Mutated primary samples were associated with constitutive activation of the RAS pathway and sensitivity to MEK inhibitors was shown. Thus, mutation of CBL is an alternative route to activate the RAS pathway and may identify children who are candidates for MEK inhibitor clinical trials.     

Association between cystic fibrosis transmembrane conductance regulator gene mutations and susceptibility for childhood asthma in Korea

Purpose

Classic cystic fibrosis is now known part of cystic fibrosis transmembrane conductance regulator (CFTR)-related disorders. These include a wide spectrum, from multi-system disorders, such as cystic fibrosis, to mono-symptomatic conditions, such as chronic pancreatitis or congenital bilateral absence of the vas deferens. However, respiratory disease is considered typical for the multi system disorder, cystic fibrosis, and is the major cause of morbidity and mortality. The purpose of this study was to evaluate the potential effects of CFTR gene mutations in Korean children with asthma.

Materials and Methods

We selected 14 mutations identified in Korea and each of the 48 children with and without asthma were genotyped for the case-control study.

Results

No significant differences were found in genotype and allele frequencies of the 9 polymorphisms observed between the non-asthma and asthma groups. In a haplotype determination based on a Bayesian algorithm, 8 haplotypes were assembled in the 98 individuals tested. However, we also did not find any significant differences in haplotype frequencies between the non-asthma and asthma groups.

Conclusion

We have concluded that this study did not show any evidence in support of providing that CFTR genetic variations significantly contribute to the susceptibility of asthma in Korean children.     

HFE gene mutations in Polish patients with disturbances of iron metabolism: an initial assessment

Hereditary hemochromatosis is one of the most frequent genetic disorders in Europeans, but its prevalence in Poland is still unknown. The aim of the study was an initial assessment of the prevalence of C282Y and H62D HFE gene mutations and their influence on the course of chronic hepatitis C. Forty-one patients were admitted to the Department of Infectious Diseases, Medical University of Gdansk in 2000-2004 because of chronic liver diseases with accompanying disturbances in iron metabolism. Genetic tests for the C282Y and H63D mutations were performed by PCR and restriction fragment length polymorphism (PCR-RFLP) analysis. The HFE gene mutations were confirmed in 24 of 41 (59%) cases with symptoms of chronic liver disease and iron overload, significantly more frequently in HCV-negative patients (12/14 vs. 12/27; chi2=8.28; p=0.05). The C282Y and H63D HFE gene mutations were detected in 16 of 41 (39%) and 9 of 41 (22%) cases, respectively. HCV-negative patients were C282Y carriers significantly more frequently than HCV-positive patients [9/14 vs. 2/27 C282Y homozygotes; 2/14 vs. 3/27 C282Y heterozygotes (p<0.0001)]. The carrier state of the H63D HFE gene mutation was not significantly more frequent in HCV-positive than HCV-negative patients. HCV infection seems to be a negative predictive marker of HFE gene mutations in patients with iron overload. The relationship of H63D HFE gene mutations with chronic hepatitis C and the possible influence of HCV infection on iron metabolism needs further analysis.     

Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: A HuGE review and meta-analysis

Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy.     

Iron overload and HFE gene mutations in Czech patients with chronic liver diseases

The aim of the study was to identify the prevalence of HFE gene mutations in Czech patients with chronic liver diseases and the influence of the mutations on iron status. The presence of HFE gene mutations (C282Y, H63D, and S65C) analyzed by the PCR-RFLP method, presence of cirrhosis, and serum iron indices were compared among 454 patients with different chronic liver diseases (51 with chronic hepatitis B, 122 with chronic hepatitis C, 218 with alcoholic liver disease, and 63 patients with hemochromatosis). Chronic liver diseases patients other than hemochromatics did not have an increased frequency of HFE gene mutations compared to controls. Although 33.3% of patients with hepatitis B, 43% of patients with hepatitis C, and 73.2% of patients with alcoholic liver disease had elevated transferrin saturation or serum ferritin levels, the presence of HFE gene mutations was not significantly associated with iron overload in these patients. Additionally, patients with cirrhosis did not have frequencies of HFE mutations different from those without cirrhosis. This study emphasizes the importance, not only of C282Y, but also of the H63D homozygous genetic constellation in Czech hemochromatosis patients. Our findings show that increased iron indices are common in chronic liver diseases but {\it HFE} mutations do not play an important role in the pathogenesis of chronic hepatitis B, chronic hepatitis C, and alcoholic liver disease.     

Development of a multiplex ARMS test for mutations in the HFE gene associated with hereditary haemochromatosis.

Genetic testing for hereditary haemochromatosis is likely to be a significant workload for diagnostic laboratories. The C282Y and H63D mutations in the HFE gene associated with hereditary haemochromatosis have previously been detected using a number of methods including alterations in the restriction digest pattern of polymerase chain reaction (PCR) amplified products. An amplification refractory mutation system (ARMS) has been developed that will simultaneously detect both hereditary haemochromatosis mutations. Comparison of the results obtained from the analysis of 46 samples referred for hereditary haemochromatosis testing showed no discrepancies between ARMS and restriction enzyme digestion. Furthermore, consistent results were obtained by ARMS from both blood and buccal mouthwash samples. The ARMS test is quicker and less expensive in terms of consumables and scientist time than restriction enzyme analysis, and is therefore suited to the routine diagnostic analysis of hereditary haemochromatosis.     

Myeloperoxidase G-463A polymorphism and lung cancer: a HuGE genetic susceptibility to environmental carcinogens pooled analysis.

Myeloperoxidase is a phase I metabolic enzyme that converts the metabolites of benzo[a]pyrene from tobacco smoke into highly reactive epoxides. A polymorphism in the promoter region of myeloperoxidase (463G-->A) has been found to be inversely associated with lung cancer; differences in the association with age and gender have been suggested. We conducted a pooled analysis of individual data from 10 studies (3688 cases and 3874 controls) from the Genetic Susceptibility to Environmental Carcinogens database. The odds ratio for lung cancer was 0.88 (95% confidence interval: 0.80-0.97) for the AG variant of myeloperoxidase G-463A polymorphism, and 0.71 (95% confidence interval: 0.57-0.88) for the AA variant after adjusting for smoking, age, gender, and ethnicity. The inverse association between lung cancer and myeloperoxidase G-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders. The myeloperoxidase G-463A polymorphism was significantly protective in "ever" smokers but not in "never" smokers. Myeloperoxidase is a key enzyme in tobacco-induced carcinogenesis.