Haptoglobin polymorphism: a novel genetic risk factor for celiac disease development and its clinical manifestations

BACKGROUND: Haptoglobin (Hp) alpha-chain alleles 1 and 2 account for 3 phenotypes that may influence the course of inflammatory diseases via biologically important differences in their antioxidant, scavenging, and immunomodulatory properties. Hp1-1 genotype results in the production of small dimeric, Hp2-1 linear, and Hp2-2 cyclic polymeric haptoglobin molecules. We investigated the haptoglobin polymorphism in patients with celiac disease and its possible association to the presenting symptoms. METHODS: We studied 712 unrelated, biopsy-proven Hungarian celiac patients (357 children, 355 adults; severe malabsorption 32.9%, minor gastrointestinal symptoms 22.8%, iron deficiency anemia 9.4%, dermatitis herpetiformis 15.6%, silent disease 7.2%, other 12.1%) and 384 healthy subjects. We determined haptoglobin phenotypes by gel electrophoresis and assigned corresponding genotypes. RESULTS: Hp2-1 was associated with a significant risk for celiac disease (P = 0.0006, odds ratio [OR] 1.54, 95% CI 1.20-1.98; prevalence 56.9% in patients vs 46.1% in controls). It was also overrepresented among patients with mild symptoms (69.2%) or silent disease (72.5%). Hp2-2 was less frequent in patients than in controls (P = 0.0023), but patients having this phenotype were at an increased risk for severe malabsorption (OR 2.21, 95% CI 1.60-3.07) and accounted for 45.3% of all malabsorption cases. Celiac and dermatitis herpetiformis patients showed similar haptoglobin phenotype distributions. CONCLUSIONS: The haptoglobin polymorphism is associated with susceptibility to celiac disease and its clinical presentations. The predominant genotype in the celiac population was Hp2-1, but Hp2-2 predisposed to a more severe clinical course. The phenotype-dependent effect of haptoglobin may result from the molecule's structural and functional properties.     

Haptoglobin phenotype and gestational diabetes

OBJECTIVE: Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence of angiopathies. Gestational diabetes mellitus (GDM) is an early manifestation of type 2 diabetes in pregnant women. It is usually confined to the time of gestation, but carries an increased risk to develop type 2 diabetes later in life. RESEARCH DESIGN AND METHODS: From consecutive Caucasian pregnant women (n = 250) referred for oral glucose tolerance testing, the Hp phenotype was determined. Significance of distribution and odds ratios (ORs) associated with Hp phenotype were calculated for women with GDM (n = 110) and women with normal glucose tolerance (n = 140). RESULTS: -Frequency of GDM in Hp phenotype classes increased with the number of Hp2 alleles (P < 0.001). ORs for GDM in women heterozygous and homozygous for Hp2 were 2.7 (95% CI 1.06-6.84) and 4.2 (1.67-10.55), respectively. CONCLUSIONS: Hp phenotype is an apparent risk factor for the development of GDM in our study population. This might be due to the low antioxidative potential of Hp2 compared with Hp1.     

Serum vitamin C concentration is influenced by haptoglobin polymorphism and iron status in Chinese

BACKGROUND: Vitamin C is a powerful antioxidant (free radical scavenger). Apart from the diet, other factors regulating its catabolism may affect its serum concentration. Haptoglobin (Hp) is a plasma protein participating in iron metabolism. It shows a genetic polymorphism which shows marked geographical differences. We investigated the relationship between vitamin C, iron status and haptoglobin polymorphism in Chinese men and women. METHODS: Iron status markers were compared according to Hp phenotypes determined by chemiluminescence detection in 110 healthy Chinese subjects. The concentration of haptoglobin was determined using an immunoturbidimetric method. Serum vitamin C was tested by a 2,4-dinitrophenylhydrazine based method. RESULTS: In Chinese, the haptoglobin phenotype distribution was 10.0% Hp 1-1, 33.6% Hp 2-1, and 56.4% Hp 2-2. In the study group, serum vitamin C concentration was associated with haptoglobin type, showing lowest values in serum from Hp 2-2 subjects in males (p=0.028, ANOVA). In contrast to Hp phenotype, Hp concentration did not affect vitamin C concentration. Hp 2-2 shows higher haptoglobin (p=0.002 (ANOVA)) than individuals with the other types. Furthermore, vitamin C was influenced by (log)ferritin levels. In Chinese, vitamin C is influenced by haptoglobin polymorphism and iron status. CONCLUSION: The present findings support the role of non-nutritional factors in vitamin C status.     

The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women

OBJECTIVE: Antioxidant trials have not demonstrated efficacy in slowing cardiovascular disease but could not rule out benefit for specific patient subgroups. Antioxidant therapy reduces LDL oxidizability in haptoglobin 1 allele homozygotes (Hp 1-1), but not in individuals with the haptoglobin 2 allele (Hp 2-1 or Hp 2-2). We therefore hypothesized that haptoglobin type would be predictive of the effect of vitamin therapy on coronary atherosclerosis as assessed by angiography. RESEARCH DESIGN AND METHODS: We tested this hypothesis in the Women's Angiographic Vitamin and Estrogen (WAVE) trial, a prospective angiographic study of vitamins C and E with or without hormone replacement therapy (HRT) in postmenopausal women. Haptoglobin type was determined in 299 women who underwent baseline and follow-up angiography. The annualized change in the minimum luminal diameter (MLD) was examined in analyses stratified by vitamin use, haptoglobin type, and diabetes status. RESULTS: We found a significant benefit on the change in MLD with vitamin therapy as compared with placebo in Hp 1-1 subjects (0.079 +/- 0.040 mm, P = 0.049). This benefit was more marked in diabetic subjects (0.149 +/- 0.064 mm, P = 0.021). On the other hand, there was a trend toward a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (0.128 +/- 0.057 mm, P = 0.027). HRT had no effect on these outcomes. CONCLUSIONS: The relative benefit or harm of vitamin therapy on the progression of coronary artery stenoses in women in the WAVE study was dependent on haptoglobin type. This influence of haptoglobin type seemed to be stronger in women with diabetes.     

Haptoglobin polymorphism in patients with preeclampsia.

BACKGROUND: Haptoglobin (Hp) polymorphism has been associated with blood pressure regulation and essential hypertension. We investigated Hp polymorphism in patients with preeclampsia. METHODS: A total of 60 Caucasian women with preeclampsia were prospectively followed from hospital admission until delivery. Serum Hp phenotypes 1-1, 2-1, and 2-2 were determined by starch gel electrophoresis and compared with those in 200 normotensive controls of the same geographic and ethnic origin. Blood pressure and laboratory markers (serum uric acid, alanine aminotransferase, aspartate aminotransferase, platelet count, and 24-h proteinuria) were compared according to Hp phenotypes of preeclamptic women. RESULTS: We found a higher Hp1 allele frequency in the preeclamptic group than in normotensive controls (0.517 vs. 0.400, p<0.05). The Hp 1-1 phenotype was present in 28% of preeclamptic patients vs. 16% of the controls, with an odds ratio (95% CI) of 2.08 (1.05-4.08) for Hp 1-1 vs. the other Hp phenotypes. Diastolic (p<0.005) and systolic (p<0.05) blood pressure and proteinuria (p<0.05) were highest in Hp 1-1 patients. Other laboratory markers were not significantly different between Hp phenotype subgroups. CONCLUSIONS: The Hp1 allele frequency was higher among preeclamptic patients and the Hp 1-1 phenotype was associated with more severe hypertension and proteinuria.     

Haptoglobin polymorphism in breast cancer patients form Jordan

BACKGROUND: Previous reports regarding the occurrence of breast cancer and its association with Hp polymorphism are conflicting. The possible role of family history as a factor in determining the degree of association between the disease and Hp polymorphism has not been reported before. In this study, the distribution of haptoglobin phenotype among patients with familial and nonfamilial breast cancer was investigated. METHODS: Haptoglobin phenotypes were determined in serum of 128 breast cancer patients (familial, n=42; nonfamilial, n=86) and in controls (n=200) by vertical polyacrylamide gel electrophoresis. RESULTS: No significant difference of Hp phenotype distribution was observed between patients as a combined group when compared with the control group. In the familial group, the frequency of Hp1-1 and Hp2-1 phenotype distribution was higher and Hp2-2 was lower than that in the nonfamilial and the control groups. Similar but inversed Hp distribution pattern was observed in the nonfamilial group when compared with that in the other groups. An appreciable finding is the observation that Hp2-2 phenotype frequency in the nonfamilial group was significantly higher than that in the familial group (p=0.0365). CONCLUSIONS: Results of this study demonstrate that the pattern of Hp phenotype distribution in breast cancer patients is family history-dependent. Hp1 and Hp2 allele frequencies were over-represented in patients with familial and nonfamilial breast cancer, respectively. The pattern is probably attributed to genetic and oxidative stress mechanisms.     

Detection of Hpdel among Thais, a deleted allele of the haptoglobin gene that causes congenital haptoglobin deficiency

BACKGROUND: Congenital haptoglobin deficiency is a risk factor for anaphylactic nonhemolytic transfusion reactions in Japan. The deleted allele of the haptoglobin gene, Hp(del), which causes congenital haptoglobin deficiency, has also been observed in other Northeast Asian populations, such as Korean and Chinese persons. It has not been reported in several African and European-African populations, however, or investigated in other countries. STUDY DESIGN AND METHODS: To investigate the distribution of congenital haptoglobin deficiency in Southeast Asian countries, blood samples collected from 200 randomly selected healthy Thai volunteers were analyzed for serum haptoglobin and the haptoglobin gene. Plasma haptoglobin concentration was measured to identify haptoglobin deficiency. Haptoglobin phenotyping was performed with sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by Western blotting. The presence of the Hp(del) allele was determined with genomic DNA by an Hp(del)-specific polymerase chain reaction (PCR) method. RESULTS: There were no haptoglobin-deficient subjects detected among the 200 Thais. Their haptoglobin phenotypes were as follows: Hp 1-1 in 10, Hp 2-1 in 81, and Hp 2-2 in 109. Six individuals heterozygous for Hp(del) were detected. The frequency of the Hp(del) allele was calculated to be 0.015. The prevalence of haptoglobin deficiency caused by Hp(del) homozygosity was estimated to be approximately 1 in 4000. CONCLUSION: Congenital haptoglobin deficiency caused by Hp(del) homozygosity is presumed to be present in Thailand as a risk factor for anaphylactic transfusion reactions with a frequency similar to that in Japan. The causative deleted allele of the haptoglobin gene, Hp(del), is distributed among Southeast Asian populations as well as among Northeast Asian populations.     

结合珠蛋白基因多态性与急性冠脉综合征的相关性研究

目的 探讨结合珠蛋白(Hp)基因多态性与急性冠脉综合征(ACS)易感性的关系.方法 采用病例对照研究,选择2005年3月至2006年12月浙江大学医学院附属第二医院心内科住院并行冠脉造影检查证实的ACS患者112例(包括急性心肌梗死57例、不稳定性心绞痛55例)和同期年龄、性别匹配的健康体检者124例.采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)技术检测所有受试者Hp基因型,探讨Hp基因多态性与ACS发生的关系.用Hardy-Weinberg平衡检验样本群体代表性;各组基因型和等位基因频率差异比较采用x2检验,并以比值比(OR)及其95%可信区间(95%CI)表示相对的风险度;综合评价ACS危险性采用多因素Logistic回归分析;以P＜0.05为差异具有统计学意义.结果 ACS组Hp基因型分布与对照组相比差异具有统计学意义(P=0.003),表现为ACS组的Hp2-2基因型频率明显高于对照组(0.571 vs.0.355,P=0.001;OR=2.419,95%CI1.427～4.100),Hp2等位基因的频率也明显高于对照组(0.759 vs.0.616,P=0.001;OR=1.965,95%CI1.316～2.934).同时,多因素Logistic回归分析表明Hp2-2基因型是ACS的独立危险因素(P=0.002;OR=2.557,95%CI:1.410～4.639).结论 Hp2-2基因型与ACS的发生密切相关,可能是ACS发病的独立危险因子;Hp2等位基因可能是ACS的遗传易感基因.

Abstract：

Objective To assess the association of Haptoglobin(Hp) polymorphism with acute coronary syndrome(ACS) in Chinese. Method A total of 112 patients with ACS including 57 patients with acute myocardial infarction and 55 patients with unstable angina pectoris confirmed with angiography and 121healthy controls were recruited in this study. Polymerase chain reaction (PCR) method was utilized to genotype Hpl and Hp2 alleles and genotype frequencies in cases and controls were compared. All polymorphisms were test of Hardy-Weinberg equilibrium in both groups separately. The differences of genotypes and alleles between two groups were analyzed with x2 test. The association between Hp polymorphism and the risk of ACS was estimated by odds ratio (OR) and their 95% confidence intervals (95% CI), and the comprehensive evaluation of the factors associated with ACS were determined by using multivariate logistic regression analysis. P ＜0.05 was considered to be statistically significant. Results The frequency of Hp2-2 genotype was significantly higher in ACSs than in controls (0. 571 vs. 0. 355, P = 0. 001; OR = 2. 419, 95% CI:1. 427 ～4. 100), multivariate Logistic regression analysis indicates that Hp2-2 genotype is an independent risk factor to ACS (P = 0.002; OR = 2.557,95% CI: 1. 392 - 4.637). Similarly, the Hp2 allele frequency in ACS groups was significantly higher than that in the control subjects (0. 759 vs. 0. 616, P =0.001; OR = 1. 965,95% CI 1. 316 ～2. 934). Conclusion The Hp2-2 genotype is associated with ACS in Chinese. Hp2-2 genotype may be an independent risk factor to ACS, and Hp2 allele may be a genetic susceptibility factor to ACS in Chinese.     

Haptoglobin: function and polymorphism

Haptoglobin is an acute phase protein capable of binding haemoglobin, thus preventing iron loss and renal damage. Haptoglobin also acts as an antioxidant, has antibacterial activity and plays a role in modulating many aspects of the acute phase response. There are 3 major haptoglobin phenotypes--Hp(1-1), Hp(2-1) and Hp(2-2). Possession of a particular phenotype has been associated with a variety of common disorders (e.g. cardiovascular disease, autoimmune disorders, malignancy), a fact which can only be explained by the idea that possession of a particular phenotype offers some protection against the development of these disorders. Knowledge of phenotype could therefore aid in the prognosis of disease and allow treatment to be better tailored to suit an individuals' needs.     

Late diagnosis of Kawasaki disease is associated with haptoglobin phenotype

BACKGROUND: Kawasaki disease (KD) is an acute febrile illness characterized by multiple clinical and biochemical features of inflammation and the most common complications of coronary artery abnormality (CAA). Haptoglobin (Hp) is an acute-phase protein whose phenotype is known to be involved in coronary artery diseases. In this paper, we report the investigation of the association of Hp phenotype with the formation of CAA in KD. PATIENTS AND METHODS: Forty-seven consecutive patients with clinically diagnosed KD were admitted. Sera were taken before therapy of intravenous immunoglobulins (IVIG) plus aspirin, and levels of serum proteins were measured by a rate immunonephelometer. The echocardiographic criteria for coronary artery abnormality were evaluated during acute or subacute stages. Hp phenotyping was performed by Western immunoblotting. RESULTS: Duration of fever at diagnosis of KD was significantly different between patients with Hp 2-2 (6.4 +/- 1.2 days, n = 25) and with Hp1 allele (Hp 2-1 plus Hp 1-1; 8.8 +/- 3.5 days, n = 22). In contrast, serum levels of Hp between KD patients with Hp2-2 and with Hp1 allele (297 +/- 121 mg dL-1 vs. 330 +/- 101 mg dL-1, respectively) was not significantly different. On the other hand, no patients with Hp 2-2 (0/25) were recognized as having KD in subacute stage. However, 5 out of 20 patients with Hp 2-1 were recognized in subacute stage, and their incidence of CAA was 80.0% (4/5). CONCLUSIONS: Patients with Hp 2-1 have patterns of delayed or incomplete presentation of clinical symptoms. Therefore, the late diagnosis of KD is associated with haptoglobin phenotype.     

Iron status in black persons is not influenced by haptoglobin polymorphism.

Iron status in man is influenced by environmental and genetic factors. The molecular variation of haptoglobin is one of the genetic factors influencing iron status in Caucasians. Differences in iron metabolism between blacks and whites have been reported. We wanted to investigate the effect of haptoglobin polymorphism on iron status in blacks. We studied 300 African subjects who were apparently healthy with normal erythrocyte sedimentation rate and with no increase in dietary iron because of traditional beer consumption. We determined haptoglobin (Hp) phenotypes using starch gel electrophoresis and measured indirect iron status indices using standard methods. We compared iron status indices according to haptoglobin type. Ninety two individuals (31%) had Hp 1-1, 114 persons (38%) had Hp 2-1, 20 subjects (7%) had Hp 2-1(Modified) and 54 individuals (18%) had Hp 2-2 type. Haptoglobin was not detectable in 19 subjects and Hp 2-1(Johnson) was found in one subject. In both males and females, serum iron concentration, total iron binding capacity, transferrin saturation and ferritin concentration were not different with regard to Hp phenotype. These results suggest that haptoglobin phenotypic variation may not be a factor which influences iron status in black persons.     

Re-evaluation of the haptoglobin reference values with the radial immunodiffusion technique

The reference values of the three main types of serum haptoglobin Hp 1-1, Hp 2-1, and Hp 2-2, as determined by radial immunodiffusion and with phenotype determination on polyacrylamide gel electrophoresis have been re-evaluated for both sexes. For that purpose about 500 serum samples were collected from normal, healthy Dutch volunteers. The relative occurrence of the three main types of serum haptoglobin in Dutch men and women was found to be comparable to that reported for other whites, with the Hp 2-1 phenotype predominating in the Dutch population and phenotype Hp 0-0 being absent. The observed overall reference range of haptoglobin for the Dutch population, irrespective of the phenotype, was 0.50-3.30 g/L serum. As reported by other investigators we found that the reference values for the three main types of haptoglobin significantly differed (Hp 1-1: 1.40 +/- 0.51; Hp 2-1: 2.10 +/- 0.76; and Hp 2-2: 1.65 +/- 0.73 g/L serum, mean +/- SD). However, in contrast to the data available in the literature, the reference values of haptoglobin for men and for women, as determined by the radial immunodiffusion technique, were not significantly different.     

The haptoglobin 2-2 genotype is associated with carotid atherosclerosis in 64-year old women with established diabetes

BackgroundHaptoglobin polymorphism generates three common human genotypes: Hp1-1, Hp2-1 and Hp2-2. Among subjects with diabetes, Hp2-2 is associated with an elevated risk to develop cardiovascular disease. The impact of haptoglobin genotype on subclinical carotid atherosclerosis is not known. We hypothesized that Hp2-2 was associated with increased occurrence of carotid atherosclerosis in subjects with diabetes.MethodsWe studied a population-based sample of 64-year old women with diabetes (n = 226), either established diabetes known before study entry (n = 116) or new diabetes detected at study screening (n = 110). Haptoglobin genotype was determined by PCR. Carotid atherosclerosis was assessed by ultrasound imaging.ResultsIn the entire diabetes cohort, no differences were observed in carotid intima-media thickness (IMT) or plaque prevalence between the genotype groups. However, among those with established diabetes, Hp2-2 was associated with higher plaque prevalence and larger carotid IMT compared with the Hp2-1 and Hp1-1 genotypes. Common cardiovascular risk factors did not differ between the genotype groups.ConclusionsThe Hp2-2 genotype was associated with increased occurrence of subclinical carotid atherosclerosis in 64-year old women with established diabetes. This association was not explained by traditional risk factors for cardiovascular disease. These results extend previous observations that Hp2-2 is associated with clinical cardiovascular disease in diabetes.     

Fast determination of haptoglobin phenotype and calculation of hemoglobin binding capacity using high pressure gel permeation chromatography

A new and fast method for haptoglobin (Hp) phenotyping was developed based on high pressure gel permeation chromatography of hemoglobin-supplemented serum. Haptoglobin phenotypes 1-1, 2-1, and 2-2 are resolved on the difference in size of their hemoglobin-haptoglobin complexes. Results are available in less than 15 min. Results of the chromatographic typing correspond to those obtained by conventional starch gel electrophoresis. Next to the phenotyping of haptoglobin, the method allows reproducible calculation of the hemoglobin binding capacity (HBC) of human serum. Using this methodology, reference values for HBC were found to be 0. 75+/-0.25 g/l, with the lowest HBC in Hp 2-2 subjects and the highest in Hp 1-1 subjects (P<0.05). In contrast to earlier findings, the ratio HBC:Hp concentration was found to be comparable for the three Hp types. In conclusion, this method allows a rapid phenotyping in critical clinical conditions where Hp phenotyping can be useful, e.g. determining the donor's phenotype in liver transplantation.     

Haptoglobin phenotypes, which one is better and when?

Haptoglobin (Hp) phenotype 2-2 presents characteristics of being an independent risk factor for cardiovascular disease (CVD) and more significant in diabetic CVD. In chronic kidney disease (CKD), due to various processes that take place simultaneously, the combined effect is different in the elderly and the young. In older patients (> 60 years), Hp 2-2 is associated with a greater risk for cardiovascular and renal morbidity and mortality. In younger (< 60 years) hemodialysis patients, infections and high hemoglobin turnover are predominant, and patients with Hp 2-2 have a longer survivorship than those with Hp 1-1. The functional differences between the Hp phenotypes are most probably due to their antioxidative property and to macrophage activation with differential release of cytokines.     

Haptoglobin phenotype in patients with spondyloarthritis and healthy individuals

Haptoglobin (Hp) phenotype distribution was evaluated in 95 patients with seronegative spondylarthritis and 100 normal controls. The incidence of three Hp types was virtually the same in acute patients and controls. Reactive arthritis was associated with Hp2-1 type, psoriatic arthritis with Hp1-1 type, ankylosing spondylarthritis with Hp2-2 type. The authors suggest that the presence of Hp2-2 type is one of genetic factors of seronegative spondylarthritis.     

Is the turbidimetric immunoassay of haptoglobin phenotype-dependent?

Comparison of the turbidimetric immunoassay of haptoglobin with a reference method (the RID technique with appropriate correction for phenotype) clearly showed the turbidimetric assay to be phenotype-dependent. Correction factors for the three main phenotypes were calculated and reference values determined. The observed overall reference range of haptoglobin, irrespective of the phenotype, was 0.56-3.76 g/L. After correction for phenotype, reference values for the three types were: Hp 1-1: 0.77-2.49; Hp 2-1: 0.86-4.76; and Hp 2-2: 0.48-3.15 g Hp/L. From our reference values for the several phenotypes of haptoglobin it may be argued that phenotyping is desirable only when the uncorrected haptoglobin value, determined by turbidimetry, is within the range 0.38-0.98 g/L. Limited to hemolytic diseases, phenotype determination can be omitted beyond this range.     

Reference range of serum haptoglobin is haptoglobin phenotype-dependent in blacks

Reference values for serum haptoglobin (Hp), were established in a Black Zimbabwean population. The upper limit (2.15 g/l) is comparable to the one in Caucasians, but the lower limit (0.12 g/l) is much lower than the proposed interim international reference limit (0.3 g/l). Subjects that typed as Hp 0-0 by starch gel electrophoresis technique were retyped using high performance gel permeation chromatography. This resulted in a 32% decrease in the frequency of Hp 0-0, but an increase in Hp 2-2 and Hp 2-1M phenotype frequencies. In the Zimbabwean Blacks, the Hp 0-0 frequency was estimated to be 2.9%. Haptoglobin reference values were found to be Hp phenotype-dependent; highest values were found in Hp 1-1 (median 0.88 g/l; range 0.31-1.69 g/l) and in Hp 2-1 (median 0.90 g/l; range 0.31-2.22 g/l) and lower values (median 0.66 g/l; range 0.13-1.79 g/l) in Hp 2-2 subjects. The Hp 2-1M phenotype was characterized by low reference values (0.18-1.25 g/l) (P<0.05). In three cases of the rare variant Hp Johnson, high Hp concentrations were found (median 1. 57 g/l; range 0.98-1.57 g/l).     

Haptoglobin phenotypes and serum enzyme activity]

Haptoglobin (Hp) phenotypes were determined by thin-layer polyacrylamide gel electrophoresis in 2071 normal Russians, Tatars, and Bashkirs. Hp phenotype distribution was found similar in these populations, making up 13.4% for Hp 1-1, 48% for Hp 1-2, 38.6% for Hp 2-2. Hp1 gene incidence (0.37) was characteristic of the European populations. Serum alkaline phosphatase and gamma-glutamyl transpeptidase activities were similar in all the three Hp phenotypes. Alanine and aspartate aminotransferases and acid phosphatase activities were higher in Hp 1-1 phenotype by 25, 15, and 15 percent, respectively.     

环氧化酶-2启动子变异与幽门螺杆菌感染交互和食管癌发病风险的关系

目的 探讨环氧化酶-2(COX-2)启动子区遗传变异与食管癌发病风险的关系,并评价幽门螺杆菌(Hp)感染对其相互作用的影响.方法 以PCR-限制性片断长度多态性方法 在119例食管癌患者和238例健康对照中进行基因分型.以Logistic回归计算比值比(OR)和95%可信区间(CI).结果 COX-2启动子区-1195 G>A遗传变异和食管癌发病风险相关.与1195GG基因型携带者相比,1195GA基因型和1195AA基因型罹患食管癌的发病风险增高,其OR(95%CI)值分别为2.69(1.46～5.14)和2.30(1.23～4.89).而且这种相关关系仅存在于Hp感染阳性的个体中,其OR(95%CI)值为2.74(1.35～5.96).结论 COX-2启动子区遗传变异对食管癌发病风险的影响和Hp感染的状态有关.

Abstract：

Objective To evaluate the association of COX2 genetic variants with the risk of esophageal cancer and the interaction of COX2 genetic variants with Hp infection. Methods A total of 119 patients with esophageal cancer and 238 frequency-matched controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism method. Odds ratios (OR) and 95% confidence intervals ( CI) were estimated by logistic regression. Results Case-control analysis showed an increased risk of developing esophageal cancer for 1195 GA(OR =2.69,95% CI= 1. 46-5. 14) and 1195AA ( OR = 2. 30,95% CI = 1.23-4. 89) genotype carriers,respectively, compared with non 1195 GG carriers. When stratified by Hp status, the significantly increased risk of esophageal cancer was found among Hp carrier with OR (95%CI) =2.74 (1.35-5.96) ,but not among Hp non-carriers. Conclusion Genetic polymorphism in COX2 promoter region may play an important role in esophageal cancer by Hp infection.