No evidence of association of the KLF12 gene with rheumatoid arthritis in Spanish and Dutch cohorts and a meta-analysis of published data

The aim of the present study was to replicate the previously reported association of KLF12 gene polymorphisms with rheumatoid arthritis (RA). Two independent cohorts from Spain (1,360 RA patients and 1,520 controls) and the Netherlands (1,018 RA patients and 1,150 controls) were genotyped for KLF12 rs1887346 and rs9565072 single-nucleotide polymorphisms using a TaqMan 5'-allele discrimination assay. No evidence of association of RA with the minor T allele of rs9565072 (31.82% vs 33.73%; p = 0.14, odds ratios [OR] 0.92 [95% confidence interval (CI) 0.82-1.03]) or the minor A allele of rs1887346 polymorphism (21.60% vs 21.77%; p = 0.88, OR 0.99 [95% CI 0.87-1.13]) was observed in Spanish patients compared with healthy controls. This lack of association was also confirmed in the Dutch cohort: the minor T allele frequency of rs9565072 in Dutch RA patients was 35.34% versus 35.57% in controls; p = 0.87, OR 0.99 (95% CI 0.87-1.12); and the minor A allele frequency of rs1887346 in Dutch RA patients was 27.64% versus 28.17% in controls; p = 0.70, OR 0.97 (95% CI 0.85-1.12). A meta-analysis of published KLF12 gene association with RA revealed a pooled OR of 0.99 (95% CI 0.93-1.04) for rs1887346 and a pooled OR of 0.99 (95% CI 0.95-1.04) for rs9565072. In conclusion, our findings indicate that the KLF12 rs1887346 and rs9565072 polymorphisms do not play a relevant role in RA.     

Impact of MICA-TM, MICB-C1_2_A and C1_4_1 microsatellite polymorphisms on the susceptibility to chronic periodontitis in Germany

The major histocompatibility complex class I chain-related gene A (MICA)-TM exon 5 trinucleotide polymorphism, the MICB-C1_2_A intron 1 dinucleotide polymorphism and the tetranucleotide polymorphism C1_4_1 located in the major histocompatibility complex class I region on chromosome 6 were shown to influence various chronic inflammatory conditions. We investigated the association of these microsatellite polymorphisms with chronic periodontitis, a highly prevalent oral inflammatory disease in 389 periodontitis patients and 771 healthy controls with South German genetic background. Genotyping of the MICA-TM, MICB-C1_2_A and C1_4_1 microsatellite polymorphisms was performed by PCR amplification and fragment analysis. Global frequency distribution of MICB-C1_2_A (P = 0.006) and C1_4_1 (P = 0.028) alleles was significantly different between both study groups. Allele-specific analysis revealed that the MICA-TM allele A5 was more prevalent among male periodontitis patients [P = 0.0001; odds ratio (OR) 2.17, 95% confidence interval (CI) 1.55-3.03]. In C1_4_1 allele, three was significantly higher in healthy controls (P = 0.006; OR 0.74, 95% CI 0.60-0.91). Two haplotypes (MICA:A5-C1_4_1:5; P = 0.002; OR 2.63, 95% CI 1.46-4.74 and MICB:CA16-C1_4_1:3; P = 0.014; OR 0.68, 95% CI 0.50-0.92) showed significant differences between periodontitis patients and controls. The MICA-TM, MICB-C1_2_A and C1_4_1 microsatellite polymorphism seem to influence the individual susceptibility to chronic periodontitis in patients with German genetic background.     

Association between VEGF polymorphisms (936c/t, -460t/c and -634g/c) with haplotypes and coronary heart disease susceptibility

Aim: Our aim was to investigate the association between single nucleotide polymorphisms (SNPs) of vascular endothelial growth factor (VEGF) and coronary heart disease (CHD) susceptibility in Chinese Han population. Methods: 144 CHD patients and 150 healthy individuals were enrolled in the study. Three SNPs (936C/T, -460T/C and -634G/C) of VEGF were chose and then were genotyped with Sequenom time-of-flight mass spectrometry (TOFMS). Odds ratio (OR) with 95% confidence interval (CI) were used to evaluate the association of genotypes and haplotypes and CHD susceptibility. Results: The frequencies of -460T/C CC genotype (13.6%) was found higher in the case group than that of control group (6.7%), which indicated that CC genotype was a risk factor for CHD (OR=2.50, 95% CI=1.10-5.68). Correspondently, the C allele appeared to increase the risk of CHD (OR=1.54, 95% CI=1.07-2.22). For -634G/C polymorphism, the risk of the CC genotype carrier for CHD increased 2.24 fold compared to the wild genotype. Moreover, -634G/CC allele was significantly associated with CHD susceptibility (OR=1.65, 95% CI=1.15-2.36). In addition, +936C/T CT genotype and C allele appeared to be a genetic-susceptibility factors for CHD (OR=2.43, 95% CI=1.44-4.10; OR=1.95, 95% CI=1.26-3.02). The haplotype analysis showed that T-C-T, C-C-C and C-G-C haplotypes all could increase the risk for CHD (OR: 2.43, 2.77 and 2.33). Conclusion: we concluded VEGF polymorphisms were associated with CHD susceptibility. Moreover, the haplotypes of T-C-T, C-C-C and C-G-C all could increase the risk for CHD.     

Outcome of testicular sperm recovery and ICSI in patients with non-obstructive azoospermia with a history of orchidopexy

BACKGROUND: Little is known about sperm recovery and ICSI using testicular sperm from men with non-obstructive azoospermia who had a previous orchidopexy. We therefore studied the sperm recovery in this subgroup and evaluated clinical parameters predicting successful sperm retrieval and the outcome of ICSI. METHODS: A total of 79 non-obstructive azoospermic men with a history of orchidopexy underwent a sperm recovery procedure. The predictive value of clinical parameters such as age at sperm retrieval, age at orchidopexy, testicular volume, FSH, FSH/LH ratio, testosterone and androgen sensitivity index (LH x testosterone) for successful testicular sperm retrieval was evaluated using receiver operating characteristics (ROC) curve analysis. A comparison between 64 ICSI cycles performed in these couples and 92 cycles performed in couples in which the men had an unexplained non-obstructive azoospermia was carried out. RESULTS: Testicular spermatozoa were recovered in 41 patients (52%). The mean age at orchidopexy of the patients with a positive sperm recovery was 10.6 years [95% confidence interval (CI) 7.3-13.8] versus 15.5 years (95% CI 11.3-19.8) for those where no spermatozoa were found. The mean testicular volume of the largest testis of patients with spermatozoa found was 10 ml (95% CI 8.3-11.9) versus 8.5 ml (95% CI 5.8-11.1) in patients with no spermatozoa found. The mean FSH and testosterone value for patients with successful and unsuccessful sperm recovery, respectively, was 24.1 IU/l (95% CI 17.9-30.3) and 4.4 ng/ml (95% CI 3.7-5.1) versus 28.8 IU/l (95% CI 19.4-38.2) and 3.4 ng/ml (95% CI 2.2-4.5). All clinical and biological parameters examined failed to predict the outcome of the testicular sperm extraction. No differences were observed between the orchidopexy and unexplained group for the number of oocytes retrieved, fertilization rate, embryo quality, pregnancy rate and implantation rate. CONCLUSIONS: As in the population of men with non-obstructive azoospermia, the sperm recovery rate for patients with a history of orchidopexy is approximately 50% and there are currently no clinical parameters predicting successful sperm retrieval in this subpopulation of patients. The outcome of the ICSI cycles is comparable with that in the population of men with non-obstructive azoospermia.     

The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy

BACKGROUND: CD14, the receptor for LPS, plays an important role in innate immunity. A polymorphism in the promotor for CD14, -159 C-->T, has been implicated in atopy. OBJECTIVE: We explored the relationship of this polymorphism with both atopic and nonatopic asthma, as well as with food allergy. METHODS: Patients with asthma and food allergy were recruited along with nonatopic, nonasthmatic control subjects. The -159 C-->T polymorphism was genotyped by using the PCR-based RFLP assay. RESULTS: The -159 T allele was more common among patients with nonatopic asthma and food allergy than among control subjects (chi(2) = 6.03, P =.01 and chi(2) = 4.94; P =.03, respectively). Patients with food allergy had a 4-fold increased odds of having the TT genotype versus carriers of the C allele compared with control subjects (odds ratio [OR] = 3.9, 95% CI = 1.5-10.3), whereas patients with nonatopic asthma had a 3-fold increased odds of having the TT genotype (OR = 3.1 [95% CI = 1.1-9.1]). Controlling for sex differences between groups did not alter this relationship, which remained significant for patients with food allergy (OR = 3.7 [95% CI = 1.4-10.1]) or nonatopic asthma (OR = 2.7 [95% CI = 0.9-8.0]). We performed a stratified analysis, limited to white patients, to reduce population stratification. The relationship with the TT genotype was stronger in white patients with nonatopic asthma (OR = 4.4 [95% CI = 1.3-14.8]) and patients with food allergy (OR = 5.1 [95% CI = 1.6-16.2]), even adjusting for sex differences (OR = 3.9 [95% CI = 1.1-13.5] and OR = 4.6 [95% CI = 1.4-14.8], respectively). CONCLUSIONS: The TT genotype of -159 C-->T CD14 is associated with nonatopic asthma and food allergy, particularly in white subjects. Thus CD14 is a candidate gene specifically for nonatopic asthma and not for asthma in general. This indicates that atopic and nonatopic asthma might be distinct conditions in their genetic predisposition, despite the fact that they are very similar once they have been established.     

Association of RIP2 gene polymorphisms and systemic lupus erythematosus in a Chinese population

The aim of this study was to investigate the association of receptor interacting protein 2 (RIP2) single-nucleotide polymorphisms (SNPs) with susceptibility to systemic lupus erythematosus (SLE) in a Chinese population. A case-control study was performed on the SNPs rs16900617 and rs16900627 in 590 Chinese SLE patients and 660 healthy controls. These SNPs were typed by TaqMan allele discrimination assays. We found a significant association of rs16900617 G allele [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.41-0.72] and rs16900627 G allele (OR = 1.28, 95% CI 1.04-1.58) with SLE. Significant differences in genotype frequency distribution were also found in SLE and control individuals (rs16900617: AG versus AA, OR = 0.59, 95% CI 0.44-0.81; GG versus AA, OR = 0.08, 95% CI 0.01-0.65; AG + GG versus AA, OR = 0.55, 95% CI 0.41-0.75; rs16900627: AG versus AA, OR = 1.51, 95% CI 1.17-1.93; AG + GG versus AA, OR = 1.43, 95% CI 1.13-1.82). Analysis of the haplotypes revealed that two haplotypes of AG and GA were also significantly associated with SLE (OR = 1.37, 95% CI 1.11-1.70; OR = 0.60, 95% CI 0.45-0.79). Our findings suggest that the RIP2 gene polymorphisms may be associated with susceptibility to SLE in the Chinese population.     

Hyperhomocysteinemia, methylenetetrahydrofolate reductase 677TT genotype, and the risk for schizophrenia: a Dutch population based case-control study.

Evidence for an involvement of aberrant homocysteine metabolism in the aetiology of schizophrenia is limited and controversial. A case-control study was performed to quantify the risk of schizophrenia in the presence of elevated homocysteine concentrations or homozygosity for the 677C --> T polymorphism (677TT) in the methylenetetrahydrofolate reductase (MTHFR) gene in subjects of Dutch ancestry. We determined the 677C --> T MTHFR genotype distribution in 254 well-defined patients and 414 healthy controls. Plasma homocysteine concentrations were measured in 62 patients with schizophrenia and 432 control subjects. When homocysteine concentrations were stratified into quartiles of the control distribution, we calculated an increased risk for schizophrenia in the fourth and third quartile versus the lowest quartile [odds ratio (OR) = 3.3; 95% confidence interval (CI): 1.2-9.2, and OR = 3.1; 95% CI: 1.2-8.0, respectively]. A significant dose-response relation of increasing homocysteine levels and increasing risk for schizophrenia was observed (P = 0.036). The 677TT genotype was associated with an OR of 1.6 [95% CI: 0.96-2.8] of having schizophrenia. Heterozygosity for the T allele compared to 677CC subjects accounted for an OR of 1.3 [95% CI: 0.91-1.8]. Elevated homocysteine levels and the MTHFR 677TT genotype are associated with an increased risk for schizophrenia. These observations support a causal relation between disturbed homocysteine metabolism and schizophrenia.     

Analysis of the SREBF2 gene as a genetic risk factor for vascular dementia.

A case-control study was performed to examine the association between vascular dementia and the polymorphisms of the human gene encoding sterol regulatory element binding protein-2 (SREBF2) that regulates cholesterol metabolism. The 16 genetic variants of SREBF2 were identified in 24 Koreans, and 5 out of 16 variants were genotyped in 207 vascular dementia patients and 207 control subjects. Significant association with vascular dementia was shown in 34995G/T with the GT genotype (odds ratio [OR] = 1.57; 95% CI = 1.04-2.37; P < 0.05) and the GG genotype (OR = 0.65; 95% CI = 0.44-0.96; P < 0.05). The CGC, the most common haplotype combined with three SNPs, 24489C/T, 34995G/T, and 68891C/T, was associated with the disease (OR = 0.72; 95% CI = 0.53-0.97; P < 0.05), and the individuals with the CGC might be less susceptible to vascular dementia than those carrying any haplotype including at least one minor allele. This study implied that the variants of SREBF2 might be genetic factors involved in the pathogenesis of vascular dementia.     

Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry

The ATM gene variants segregating in ataxia-telangiectasia families are associated with increased breast cancer risk, but the contribution of specific variants has been difficult to estimate. Previous small studies suggested two functional variants, c.7271T>G and c.1066-6T>G (IVS10-6T>G), are associated with increased risk. Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T>G allele (P=0.1). In cases, this allele was more prevalent in women with an affected mother (odds ratio [OR]=5.5, 95% confidence interval [CI]=1.2-25.5; P=0.04) and delayed child-bearing (OR=5.1; 95% CI=1.0-25.6; P=0.05). The estimated cumulative breast cancer risk to age 70 years (penetrance) was 52% (95% CI=28-80%; hazard ratio [HR]=8.6; 95% CI=3.9-18.9; P<0.0001). In contrast, 13 of 3,757 breast cancer cases (0.3%) and 10 of 1,268 controls (0.8%) were heterozygous for the c.1066-6T>G allele (OR=0.4; 95% CI=0.2-1.0; P=0.05), and the penetrance was not increased (P=0.5). These findings suggest that although the more common c.1066-6T>G variant is not associated with breast cancer, the rare ATM c.7271T>G variant is associated with a substantially elevated risk. Since c.7271T>G is only one of many rare ATM variants predicted to have deleterious consequences on protein function, an effective means of identifying and grouping these variants is essential to assess the contribution of ATM variants to individual risk and to the incidence of breast cancer in the population.     

Interaction between Polymorphisms of DNA Repair Genes Significantly Modulated Bladder Cancer Risk

DNA repair is a primary defense mechanism against damage caused by exogenous and endogenous sources. We examined the associations between bladder cancer and 7 polymorphisms from 5 genes involved in the maintenance of genetic stability (MMR: MLH1-93G>A; BER: XRCC1--77T>C and Arg399Gln; NER:XPC Lys939Gln and PAT +/-; DSBR:ATM G5557A and XRCC7 G6721T) in 302 incident bladder cancer cases and 311 hospital controls. Genotyping was done using a polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) technique. The homozygous variant of XRCC7 G6721T (Odds Ratio [OR]: 2.36; 95% Confidence Interval [CI]: 1.13-4.92) was associated with increased bladder cancer risk. In an analysis of combined genotypes, the combination of XRCC1Arg399Gln (Gln allele) with XRCC1-77 T/T led to an increase in risk (OR: 1.61; 95% CI: 1.10-2.36). Moreover, when the XPCLys939Gln (Gln allele) (nucleotide excision repair [NER]) was present together with XRCC7 (T allele) (double strand break repair [DSBR]), the bladder cancer risk dramatically increased (OR: 4.42; 95% CI: 1.23-15.87). Our results suggest that there are multigenic variations in the DNA repair pathway involved in bladder cancer susceptibility, despite the existence of ethnic group differences.     

CASP8 -652 6N del polymorphism and cancer risk: a meta-analysis of 30 case-control studies in 50 112 subjects

Disruptions of normal apoptotic pathways, which are mainly mediated by caspases, play an essential role in cancer development. Caspase-8 (CASP8) is encoded by the CASP8 gene and is centrally involved in the apoptosis of T lymphocytes. The association between a six-nucleotide deletion polymorphism (-652 6N del) of the CASP8 gene and the risk of cancer is widely reported; however, study results have been inconsistent and contradictory. To evaluate the association between the CASP8 -652 6N del polymorphism and the risk of cancer and to overcome the limitations of any individual study, a meta-analysis based on a total of 23?700 cases and 26?412 controls from 30 case-control studies was conducted. The results of the overall analysis suggested that the CASP8 -652 6N del polymorphism is associated with decreased risk of cancer for the allele contrast [del versus ins: odd ratio (OR) = 0.86, 95% confidence interval (CI) = 0.80-0.92], the additive genetic model (del/del versus ins/ins: OR = 0.78, 95% CI = 0.69-0.88), the dominant genetic model (del/del+del/ins versus ins/ins: OR = 0.83, 95% CI = 0.78-0.89) and the recessive genetic model (del/del versus ins/ins+del/ins: OR = 0.84, 95% CI = 0.75-0.93). In addition, after stratification for ethnicity and cancer type, significantly reduced risk was found for Asians and Caucasians as well as for individuals in the colorectal cancer group and the 'other cancers' group. Accordingly, there is an association between the CASP8 -652 6N del polymorphism and reduced cancer risk, especially among Asians, Caucasians and those with colorectal cancer. However, further research, such as studies focusing on additional ethnic groups and cancer types, is needed to provide a more exact and comprehensive synthesis conclusion.     

Risk factors for human herpesvirus 8 seropositivity in the AIDS Cancer Cohort Study.

BACKGROUND: Cigarette smoking has been associated with a decreased risk for AIDS-related and classical KS, but whether it is associated with decreased risk of human herpesvirus 8 (HHV-8) infection is unknown. STUDY DESIGN: We evaluated factors associated with HHV-8 seropositivity in 2795 participants (132 with KS) in the National Cancer Institute AIDS Cancer Cohort, including 1621 men who have sex with men (MSM), 660 heterosexual men and 514 women. Odds ratios (OR) and 95% confidence intervals were estimated using logistic regression models. RESULTS: Among non-KS subjects, HHV-8 seropositivity was 6%, 13% and 29% among women, heterosexual men and MSM, respectively. HHV-8 seropositivity was decreased in heavier (> or =1/2 pack/day) compared to lighter smokers among women (5% versus 8%; adjusted OR (aOR) 0.4; 95% CI 0.2-0.8) and MSM (27% versus 32%; aOR 0.7; 95% CI 0.6-1.0), but not among heterosexual men (12% versus 16%; aOR 0.7; 95% CI 0.4-1.2). HHV-8 seroprevalence was increased in heavier (> or =1 drink/day) compared to lighter consumers of alcohol among women (16% versus 4%; adjusted OR 5.2; 95% CI 2.3-12), but not among MSM (33% versus 28%; aOR 1.2; 95% CI 0.9-1.6) or heterosexual men (13% versus 13%; aOR 1.1; 95% CI 0.6-2.0). In analyses adjusted for smoking and drinking, HHV-8 seropositivity was positively associated with chlamydia infection (OR=4.3; 95% CI 1.2-13) and with marital status among women p(heterogeneity)=0.03, and with hepatitis (OR=1.6; 95% CI 1.2-2.1), gonorrhea (OR=1.5; 95% CI 1.1-1.9), genital warts (OR=1.5; 95% CI 1.1-2.0) and nitrate inhalant use (OR=1.7; 95% CI 1.3-2.3) among MSM. CONCLUSIONS: Inverse association of HHV-8 seropositivity with cigarette smoking may indicate protective effect of tobacco smoke on HHV-8 infection, whereas positive associations with alcohol may reflect either behavioral factors or biological effects modulating susceptibility. Smoking and drinking may influence KS risk, at least in part, by altering the natural history of HHV-8 infection.     

Interdependent effect of angiotensin-converting enzyme and platelet-activating factor acetylhydrolase gene polymorphisms on the progression of immunoglobulin A nephropathy

In order to investigate the interdependent action of the insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene and polymorphism in exon 11 (C1136-->T; Ala379Val) of the platelet-activating factor acetylhydrolase (PAF-AH) gene, which encodes a functional antagonist of PAF, on the progression of immunoglobulin A (IgA) nephropathy, we analysed both polymorphisms in patients with primary IgA nephropathy, who were followed-up for longer than 3 years. During the follow-up (87.3 +/- 50.0 months), the disease progressed in 38 of the 191 patients (19.9%). The D allele of the ACE gene in the absence of the T allele of the PAF-AH gene did not affect the prognosis [odds ratio (OR), 3.6; 95% confidence interval (CI), 0.8-16.4] and neither did the T allele in the absence of the D allele (OR, 3.0; 95% CI, 0.4-24.2). However, the presence of both was a significant prognostic factor (OR, 6.6; 95% CI, 1.4-31.3). After adjusting for other risk factors, the presence of both proved to be an independent risk factor (OR, 4.5; 95% CI, 1.6-12.7). These results suggest that the interdependent effects of ACE and PAF-AH polymorphisms on the progression of IgA nephropathy might be more important than the effect of the individual polymorphisms.     

Apolipoprotein gene E4 allele promoter polymorphisms as risk factors for Alzheimer's disease

Alzheimer's disease is a complex neurodegenerative disorder, characterized by progressive cognitive decline and distinct neuropathology. The apolipoprotein gene E4 allele (APOE 4) is a major risk factor for the disease. Promoter polymorphisms at -491 and -427 may also contribute to the risk. We examined the two polymorphisms in 178 Alzheimer's patients and 141 controls. The -491AA genotype was overrepresented among the patients (68 versus 54%, P=0.01). However, in patients who were APOE4 carriers, the -491AA genotype more than doubled the risk [odds ratio (OR)=2.5; 95% confidence interval (CI)=1.2-5.4], especially in combination with -427TT [odds ratio (OR)=3.3; 95% confidence interval (CI)=1.5-7.7]. Moreover, the -491A/-427T/APOE4/APOC1A haplotype was threefold higher for patients. These results contribute to the evidence that regulation of APOE4 expression modulates risk for Alzheimer's disease.     

The +874T/A polymorphism in the interferon-γ gene and tuberculosis risk: an update by meta-analysis

The +874T/A polymorphism in the interferon-γ (IFN-γ) gene has been extensively examined for association to tuberculosis (TB); however, results of different studies have been inconsistent. The aim of this study was to comprehensively analyze the genetic risk of the +874T/A polymorphism in IFN-γ gene for TB by meta-analysis. A total of 4553 cases and 4631 controls in 21 case-control studies were included in this meta-analysis. The results indicated that the variant T allele carriers had a 27% decreased risk of TB, when compared with the homozygote AA (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.61-0.87 for TT + TA versus AA). In the subgroup analysis by ethnicity, significant decreased risks were associated with T allele carriers in Asians (OR= 0.71, 95% CI = 0.52-0.97, p = 0.03) but not in Caucasians (OR = 0.87, 95% CI = 0.65-1.17, p = 0.37). Our results suggest that the IFN-γ +874T/A polymorphism contributes to susceptibility to TB.     

Interleukin 12B gene polymorphism and apparent resistance to hepatitis C virus infection

Cellular immunity with interferon gamma production could have a role in protection from hepatitis C virus (HCV). Interleukin (IL)-12 is a key cytokine in promoting such anti-viral T helper 1 (Th1) responses. We hypothesized that a genetic background able to promote cellular responses may be associated with apparent protection from infection and have investigated the distribution of the functional 1188A/C polymorphism of IL-12B in HCV exposed but uninfected cases. The frequency of the high IL-12-producing C allele was determined by restriction enzyme genotyping in 76 exposed-uninfected individuals and 105 healthy controls. Overall, the C allele was found in 27.6% of exposed-uninfected cases compared with 16.7% of healthy controls [chi(2) = 6.3, P = 0.02, odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.2]. CC genotype was found in 10.5% of exposed-uninfected cases compared with 0.9% controls (chi(2) = 9.3, P = 0.01, OR = 12, 95% CI = 1.5-100). Individuals at high risk of HCV infection yet who remain uninfected may be resistant in some way to infection. In our cohort of exposed-uninfected cases a genetic background of enhanced IL-12 production was associated with apparent resistance to HCV infection. This lends support to a central role for cellular immune responses in protecting from infection.     

PPARγ2 Pro12Ala基因多态性与我国胃癌关系的研究

目的：研究PPARγ2 Pro12Ala基因多态性在我国普通人群和胃癌患者中的分布，探讨我国汉人PPARγ2 Pro12Ala基因多态性、幽门螺杆菌 (Hp)感染与胃癌的关系。方法:胃癌患者、健康志愿者各104例，两组人群在性别以及年龄均匹配。采用限制性片段长度多态性（PCR-RFLP）分析PPARγ2 Pro12Ala基因多态性，采用酶联免疫吸附法（ELISA）检测血清抗Hp-IgG抗体。结果:胃癌人群Hp感染率明显高于对照人群 (81.7% vs 59.6%，2=12.27，P<0.01；OR=3.0，95%CI=1.6-5.7)。我国汉人普通人群PPARγ2 CC、CG和GG基因型频率分别为91.3%、8.7%、0，G等位基因频率为4.3%。胃癌患者中携带有PPARγ2 G等位基因者比率明显高于对照人群 (19.2% vs 8.7%, P<0.05；OR＝2.5，95%CI=1.1-5.8)，并使Hp感染后胃癌发生的危险性增加 (P<0.01, OR=8.9, 95% CI=2.2-35.7)。结论:PPARγ2 G等位基因与我国汉族人群胃癌的发生有关，增加Hp感染后胃癌发生的危险性。     

CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland

We examined the association between single-nucleotide polymorphisms (SNPs) previously associated with chronic obstructive pulmonary disease (COPD) and/or lung function with COPD and COPD-related phenotypes in a novel cohort of patients with severe to very severe COPD. We examined 315 cases of COPD and 330 Caucasian control smokers from Poland. We included three SNPs previously associated with COPD: rs7671167 (FAM13A), rs13180 (IREB2), and rs8034191 (CHRNA 3/5), and four SNPs associated with lung function in a genome-wide association study of general population samples: rs2070600 (AGER), rs11134242 (ADCY2), rs4316710 (THSD4), and rs17096090 (INTS12). We tested for associations with severe COPD and COPD-related phenotypes, including lung function, smoking behavior, and body mass index. Subjects with COPD were older (average age 62 versus 58 years, P < 0.01), with more pack-years of smoking (45 versus 33 pack-years, P < 0.01). CHRNA3/5 (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.5-2.4; P = 7.4 × 10(-7)), IREB2 (OR, 0.69; 95% CI, 0.5-0.9; P = 3.4 × 10(-3)), and ADCY2 (OR, 1.35; 95% CI, 1.1-1.7; P = 0.01) demonstrated significant associations with COPD. FAM13A (OR, 0.8; 95% CI, 0.7-1.0; P = 0.11) approached statistical significance. FAM13A and ADCY2 also demonstrated a significant association with lung function. Thus, in severe to very severe COPD, we demonstrate a replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2).     

Gender-specific association of the PTPN22 C1858T polymorphism with achalasia

The protein tyrosine phosphatase N22 (PTPN22) gene encodes a lymphoid-specific phosphatase (LYP), a downregulator of T-cell activation. Because a functional PTPN22 polymorphism, C1858T, has been found to be associated with different autoimmune diseases, we aimed to elucidate the role of this variant in predisposition to achalasia. We performed a case-control study with 231 nonrelated Spanish patients of white ethnicity diagnosed with achalasia and in 554 healthy control subjects, all genotyped for PTPN22 C1858T using TaqMan chemistry. The frequency of the 1858T allele was higher in the achalasia patients than in the healthy controls (carriers of allele T vs CC: OR = 1.38, 95% confidence interval [95% CI] 0.88-2.16, p = 0.13). Moreover a different genotype distribution was found between female and male patients (carriers of allele T vs CC: OR = 2.06, 95% CI 0.96-4.42, p = 0.04) and also between female patients and controls (OR = 1.94, 95% CI 1.12-3.36, p = 0.01), but not between male patients and controls (OR = 0.94, 95% CI 0.50-1.77, p = 0.85). We conclude that the PTPN22 1858T allele is a susceptibility factor for Spanish women with achalasia.     

Serotonin receptor 3A polymorphism c.-42C &gt; T is associated with severe dyspepsia

Background

The association between anxiety and depression related traits and dyspepsia may reflect a common genetic predisposition. Furthermore, genetic factors may contribute to the risk of having increased visceral sensitivity, which has been implicated in dyspeptic symptom generation. Serotonin (5-HT) modulates visceral sensitivity by its action on 5-HT₃ receptors. Interestingly, a functional polymorphism in HTR3A, encoding the 5-HT₃ receptor A subunit, has been reported to be associated with depression and anxiety related traits. A functional polymorphism in the serotonin transporter (5-HTT), which terminates serotonergic signalling, was also found associated with these psychiatric comorbidities and increased visceral sensitivity in irritable bowel syndrome, which coexistence is associated with higher dyspeptic symptom severity. We investigated the association between these functional polymorphisms and dyspeptic symptom severity.

Methods

Data from 592 unrelated, Caucasian, primary care patients with dyspepsia participating in a randomised clinical trial comparing step-up and step-down antacid drug treatment (The DIAMOND trial) were analysed. Patients were genotyped for HTR3A c.-42C > T SNP and the 44 bp insertion/deletion polymorphism in the 5-HTT promoter (5-HTTLPR). Intensity of 8 dyspeptic symptoms at baseline was assessed using a validated questionnaire (0 = none; 6 = very severe). Sum score ≥20 was defined severe dyspepsia.

Results

HTR3A c.-42T allele carriers were more prevalent in patients with severe dyspepsia (OR 1.50, 95% CI 1.06-2.20). This association appeared to be stronger in females (OR 2.05, 95% CI 1.25-3.39) and patients homozygous for the long (L) variant of the 5-HTTLPR genotype (OR 2.00, 95% CI 1.01-3.94). Females with 5-HTTLPR LL genotype showed the strongest association (OR = 3.50, 95% CI = 1.37-8.90).

Conclusions

The HTR3A c.-42T allele is associated with severe dyspeptic symptoms. The stronger association among patients carrying the 5-HTTLPR L allele suggests an additive effect of the two polymorphisms. These results support the hypothesis that diminished 5-HT₃ mediated antinociception predisposes to increased visceral sensitivity of the gastrointestinal tract. Moreover, the HTR3A c.-42C > T and 5-HTTLPR polymorphisms likely represent predisposing genetic variants in common to psychiatric morbidity and dyspepsia.