Peroxisome proliferator-activated receptor-gamma gene polymorphisms are not associated with osteonecrosis of the femoral head in the Korean population

Osteonecrosis of the femoral head (ONFH) is a multifactorial disease to which certain individuals are more at risk. Altered lipid metabolism is one of the major risk factors for osteonecrosis, especially corticosteroid therapy and alcoholism. Peroxisome Proliferator-Activated Receptor-gamma (PPARgamma) plays a crucial role in differentiation of mesenchymal cells to adipocytes, lipid homeostasis, and bone metabolism. To investigate the possible association between PPARgamma gene variants and susceptibility to ONFH, we genotyped three common polymorphisms (-796A > G, +34C > G[Pro12Ala], and +82466C > T[His477His]) in 448 ONFH patients and 336 control subjects. Genotypes, allele frequencies, and haplotypes of the polymorphisms in the complete set of patients as well as in subgroups by sex or etiology were not significantly different from those in the control group. This suggests that the examined polymorphisms and haplotypes of the PPARgamma gene are unlikely to be associated with susceptibility to ONFH.     

Lack of association of MTHFR gene polymorphisms with the risk of osteonecrosis of the femoral head in a Korean population

Some studies have suggested that coagulation disorders may be implicated in osteonecrosis of the femoral head (ONFH). The C677T polymorphism of the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene has been postulated to be a genetic risk factor for venous thromboembolism and osteonecrosis in Caucasians, but this relationship has not been established in other populations. In this study, we conducted case-control analysis of whether MTHFR polymorphisms are associated with ONFH in Korean patients. Fifteen single nucleotide polymorphisms (SNPs) were selected and genotyped in 443 ONFH patients and 273 control subjects using the TaqMan 5′ allelic discrimination assay. Comparison of ONFH and control subjects using logistic regression models revealed no statistically significant differences in the frequencies of the MTHFR polymorphisms and haplotypes. Further analysis stratified by etiology also showed no association. These results suggest that MTHFR polymorphisms play no significant role in susceptibility to ONFH in the Korean population.     

SLC11A1 Polymorphisms Are Associated with the Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

The solute carrier family 11 member 1 (SLC11A1) protein plays important roles in macrophage activation and displays pleiotropic effects on various macrophage functions, including the regulation of tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and oxidative burst. Considering the important roles of macrophage in the pathogenesis of chronic obstructive pulmonary disease (COPD), we hypothesized that the SLC11A1 gene may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, we first examined the frequencies of 12 candidate polymorphisms in the SLC11A1 gene in 27 healthy Korean individuals, and then genotyped 3 haplotype-tagging polymorphisms [IVS4 + 14G > C (rs3731865), D543 N (rs17235409), and (*)86A > G (rs1059823)] in 83 COPD patients and 203 healthy controls. Individuals with at least one variant allele of the D543 N and (*)86A > G polymorphisms were at a significantly increased risk for COPD compared with carriers with each homozygous wild-type allele [adjusted odds ratio (OR) = 2.23, 95% confidence interval (CI) = 1.24-4.02, P = 0.007; and adjusted OR = 1.92, 95% CI = 1.10-3.35, P = 0.022, respectively]. Consistent with the findings of the genotyping analysis, the 122 haplotype carrying both the 543 N and (*)86G alleles was associated with a significantly increased risk for COPD compared with the 111 haplotype with the 542D and (*)86A alleles (adjusted OR = 2.05, 95% CI = 1.19-3.51, P = 0.009 and Bonferroni corrected P = 0.027). These findings suggest that the SLC11A1 polymorphisms could be used as markers for genetic susceptibility to COPD. However, further studies with large numbers of subjects are needed to confirm our findings.     

混合家系中NOTCH4基因多态与精神分裂症、心境障碍关联研究

文章旨在探讨NOTCH4基因多态性与精神分裂症（SP）、心境障碍（MD）的关系,搜寻中国汉族人群SP与MD的共同易患基因。在中国汉族人群中收集61个SP与MD的混合家系,应用PCR-RFLP方法对NOTCH4基因多态性-1725T/G、-25T/C分型,进行传递不平衡检验（TDT）和基于单体型的单体型相对风险分析（HHRR）。结果显示-1725T/G 与SP或MD无明显关联（P>0.05）;-25T/C与SP无明显关联（P>0.05）,与女性或发病年龄≤25岁的MD相关联（P<0.05）;单体型-1725G/-25T与SP相关联（P<0.05）,与MD无明显关联（P>0.05）。本研究结果提示,在我们研究的家系中NOTCH4或邻近基因可能是精神分裂症与心境障碍的共同易患基因之一。     

Analysis of selected promoter polymorphisms and haplotypes of the CYBA gene encoding the p22phox,subunit of NADPH oxidases,in patients with coronary artery disease

Abstract

The p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA gene. It was shown that functionally relevant polymorphisms of the CYBA gene ?930A?>?G, ?852C?>?G, ?675A?>?T, ?536C?>?T, 214C?>?T (previously described as 242C?>?T), *24A?>?G (previously described as 640A?>?G), and *49A?>?G modulate generation of reactive oxygen species (ROS). To analyse whether the CYBA gene polymorphisms ?852C?>?G, ?675A?>?T, and ?536C?>?T were associated with coronary artery disease (CAD), and to designate haplotype blocks. Four hundred and ninety subjects: 245 patients with CAD and 245 age and sex-matched controls. The polymorphisms were genotyped using the PCR-RFLP method and the TagMan^® Pre-designed SNP Genotyping Assay. The analysed polymorphisms do not form haplotype blocks. Case–control study revealed that the ?930?G/-675T and ?930G/*49G diplotypes were a CAD risk factor. The 675T/*49G diplotype can modulate CAD risk in women. The protective effect reducing CAD risk in women was related to the ?930A/?675T and ?930A/*49A diplotypes. Carrier state of the ?852C allele (?852C?>?G) was associated with multivessel stenosis while the CC genotype of the ?536C?>?T polymorphism was more frequent in patients with peripheral artery disease. Hypercholesterolemic, cigarette smokers had an increased risk of CAD, especially C???852 allele (?852C?>?G) carriers (SIM?=?3.54; odds ratios (OR)?=?10.01, p?<?0.000). The CYBA gene polymorphisms modulate the risk of CAD but do not form a haplotype blocks.     

Association of CTLA4 gene polymorphisms with susceptibility and pathology correlation to pulmonary tuberculosis in Southern Han Chinese

The cytotoxic T lymphocyte antigen-4 (CTLA4) gene is a key negative regulator of the T lymphocyte immune response. It has been found that CTLA4 +49A>G (rs231775), +6230G>A (rs3087243), and 11430G>A (rs11571319) polymorphisms are associated with susceptibility to many autoimmune diseases, and can down-regulate the inhibition of cellular immune response of CTLA4. Three SNPs in CTLA4 were genotyped by using the PCR and DNA sequencing methods in order to reveal the susceptibility and pathology correlation to pulmonary tuberculosis in Southern Han Chinese. We found that the frequency of CTLA4 +49AG genotype in the pulmonary tuberculosis patients (38.42%) was significantly lower than that of the healthy controls (49.77%), (P(cor)=0.038, OR 0.653, 95% CI 0.436-0.978). But, no associations were found between the other 2 SNPs (+6230G>A, 11430G>A) and tuberculosis (P>0.05). Haplotype analysis showed that the frequency of haplotype AGG in the healthy controls group (6.9%) was significantly higher than the pulmonary tuberculosis patients group (1.4%), (global P=0.005, P(cor)=0.0002, OR 0.183, 95% CI 0.072-0.468). In addition, haplotype GGA was found to be significantly related to tuberculosis with double lung lesion rather than single lung lesion (P(cor)=0.042). This study is the first to report that genetic variants in the CTLA4 gene can be associated with pulmonary tuberculosis in Southern Han Chinese, and CTLA4 +49AG genotype as well as haplotype AGG may reduce the risk of being infected with pulmonary tuberculosis. The GGA haplotype was related to tuberculosis with double lung lesion, which provides a new experimental basis to clarify the pathogenesis of pulmonary tuberculosis.     

Association of interleukin (IL)-12 and IL-27 gene polymorphisms with chronic obstructive pulmonary disease in a Chinese population

The pathogenesis of chronic obstructive pulmonary disease (COPD) is not fully understood, and environment and genetic factors have been investigated. Moreover, cytokine genes play an important role in COPD pathogenesis. However, the molecular mechanism of COPD induced by the factors is still unknown. The present study was undertaken to clarify a role of interleukin (IL)-12 16974A/C and IL-27 4730T/C, -964A/G, and 2905T/G polymorphisms in Chinese subjects with COPD. Polymerase chain reaction/restriction fragment length polymorphism (PCR/RFLP) and sequence analyses were used to type IL-12 and IL-27 polymorphisms in 120 patients with COPD and 100 healthy controls. There were significant differences in the genotype and allele distribution of -964A/G and 2905T/G polymorphisms of the IL-27 gene among cases and controls in a Chinese population. When compared with the control group, subjects with AG genotype of the IL-27 -964A/G had a 2.22-fold decreased risk of COPD (odds ratio [OR] = 0.450, 95% confidence interval [CI]: 0.245-0.826; p = 0.009), and subjects with TG genotype of the IL-27 2905T/G had a 2.85-fold decreased risk of COPD (OR = 0.351, 95% CI: 0.137-0.899; p = 0.024). Compared with the TAT haplotype, the TGG haplotype was associated with a significantly decreased risk of COPD (OR = 0.29, 95% CI: 0.108-0.784; p = 0.010). Even after Bonferroni corrections, significant associations with COPD were observed for the AG genotype of the IL-27 -964A/G and the TGG haplotype of the IL-27 gene. Our data suggest that polymorphisms in the IL-27 gene may play a role in the development of COPD in Chinese population.     

Association of eNOS polymorphisms (-786T>C, 4a4b, 894G>T) with colorectal cancer susceptibility in the Korean population

Background

Polymorphisms of endothelial nitric oxide synthases (eNOS) have been shown to be associated with cancer susceptibility. However, the results of such studies are conflicting to date. We investigated whether polymorphisms of the eNOS gene correlated with patients with colorectal cancer (CRC), relative to healthy individuals.

Patients and methods

In the present study, we analyzed three polymorphisms of eNOS (-786T>C, 4a4b, and 894G>T) in 509 healthy controls and 528 patients with CRC. The genotyping of eNOS polymorphisms was performed using polymerase chain reaction or polymerase chain reaction–restriction fragment length polymorphism assays.

Results

We found that the TC+CC genotype of the -786T>C polymorphism was significantly associated with an increased risk of CRC compared with the TT genotype. Similarly, the GT+TT genotype of the 894G>T polymorphism was associated with an increased susceptibility to CRC. However, no evidence was found for any association between the 4a4b polymorphism and CRC risk. In addition, the C/4b/G (-786T>C/4a4b/894G>T) haplotype was significantly associated with increased risk of CRC and C/4b/T (-786T>C/4a4b/894G>T) haplotype was only detected in CRC patients.

Conclusions

Our study suggests that the eNOS -786T>C and 894G>T polymorphisms may be associated with the development of CRC in the Korean population.     

Haplotypes in the promoter region of the ADIPOQ gene are associated with increased diabetes risk in a German Caucasian population.

Adiponectin, which is encoded by the ADIPOQ gene, has been shown to modulate insulin sensitivity and glucose homeostasis. Plasma adiponectin levels are decreased in type 2 diabetes and obesity. Genetic variations within the ADIPOQ gene are associated with decreased adiponectin hormone levels. To analyze specific single-nucleotide polymorphisms (SNPs) and their association with T2D, 365 German subjects with T2D and 323 control subjects were screened. Three common SNPs - +45T>G in exon 2, and 2 promoter variants SNPs -11391G>A and -11377C>G - were analyzed. We found that the variant allele of SNP -11391G>A was significantly more frequent in the diabetic patient group than in the control group (p=0.003). Carrying the haplotype of SNP -11391A and SNP -11377C was associated with a 1.50-fold (p=0.03) increase in diabetes risk. The combination of the A-C haplotype and the G-C haplotype was associated with significantly elevated diabetes risk (OR=2.82 (95% CI: 1.35-5.91), p=0.006) after correction for BMI and age. Our observations suggest that diploid combinations of haplotype in the adiponectin gene promoter region contribute to the genetic risk of T2D in individuals from a German Caucasian population.     

Polymorphisms of the TIM-1 gene are associated with rheumatoid arthritis in the Chinese Hui minority ethnic population

The T-cell immunoglobulin and mucin domain 1 (TIM-1) is known to be associated with susceptibility to rheumatoid arthritis (RA). We investigated the association of four single-nucleotide polymorphisms (SNPs) in the promoter region of the TIM-1 gene with susceptibility to RA in a Chinese Hui ethnic minority group. Using RFLP or sequence specific primer-PCR, 118 RA patients and 118 non-arthritis control individuals were analyzed for the -1637A>G, -1454G>A, -416G>C, and -232A>G SNPs in the TIM-1 gene. The polymorphisms -232A>G and -1637A>G in the promoter region of TIM-1 were found to be associated with susceptibility to the RA gene in the Hui population, while -416G>C and -1454G>A SNPs were not. Of these, the polymorphism of -232A>G is inconsistent with that found in a Korean population, suggesting that genetic variations of the TIM-1 gene contribute to RA susceptibility in different ways among different populations. Based on haplotype analysis, individuals with haplotypes AGCA (Χ(2) = 22.0, P < 0.01, OR (95%CI) >1), AGCG (Χ(2) = 18.16, P < 0.01, OR (95%CI) >1) and AGGA (Χ(2) = 5.58, P < 0.05, OR (95%CI) >1) are at risk to develop RA in the Chinese Hui population; those with the GAGA (Χ(2) = 7.44, P < 0.01, OR (95%CI) <1) haplotype may have a decreased likelihood of RA. GGCA and GGCG are more common in both RA and non-RA subjects. We conclude that -1637A>G and -232A>G polymorphisms of TIM-1 are associated with susceptibility to RA in the Chinese Hui population.     

Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.     

The relationship between genetic polymorphisms in apolipoprotein E (ApoE) gene and osteonecrosis of the femoral head induced by steroid in Chinese Han population

Previous studies suggested that apolipoprotein E (ApoE) genetic polymorphisms (SNPs) may result in abnormal lipid metabolism. Therefore, genetic polymorphisms in ApoE may be associated with the occurrence of osteonecrosis of the femoral head (ONFH). A case control study was designed to include 580 patients with steroid-induced ONFH and 560 age- and sex-matched non steroid-induced ONFH control subjects to analyze the association between ApoE polymorphisms and susceptibility of steroid-induced ONFH. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was utilized to differentiate two genotypes SNPs (rs7412 C/T and rs429358 T/C) in ApoE gene. Both rs7412 C/T and rs429358 T/C were found to be associated with the risk of steroid-induced ONFH. However, no significant association was observed between the haplotypes T-T, T-C and C-C in ONFH. Furthermore, T allele of rs7412 and C allele of rs429358 carriers were associated with higher levels of TG in steroid-induced ONFH patients (P?<?0.05). The study suggested that ApoE genetic polymorphisms conferred susceptibility to steroid-induced ONFH in Chinese Han population. However, the results need further investigation with large sample size and various populations.     

Cytotoxic T-lymphocyte antigen 4 gene and recovery from hepatitis B virus infection

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an inhibitory T-cell receptor expressed by activated and regulatory T cells. We hypothesized that single-nucleotide polymorphisms (SNPs) in the gene encoding CTLA-4 may affect the vigor of the T-cell response to hepatitis B virus (HBV) infection, thus influencing viral persistence. To test this hypothesis, we genotyped six CTLA4 SNPs, from which all frequent haplotypes can be determined, using a large, matched panel of subjects with known HBV outcomes. Haplotypes with these SNPs were constructed for each subject using PHASE software. The haplotype distribution differed between those with viral persistence and those with clearance. Two haplotypes were associated with clearance of HBV infection, which was most likely due to associations with the SNPs -1722C (odds ratio [OR] = 0.60, P = 0.06) and +49G (OR = 0.73, P = 0.02). The wild-type haplotype, which contains an SNP leading to a decreased T-cell response (+6230A), was associated with viral persistence (OR = 1.32, P = 0.04). These data suggest that CTLA4 influences recovery from HBV infection, which is consistent with the emerging role of T regulatory cells in the pathogenesis of disease.     

Nine polymorphisms of angiotensinogen gene in the susceptibility to essential hypertension

Even if the importance of angiotensinogen (AGT) gene has been known in gene targeting animals and humans genetic studies, its precise mechanism and the interaction among AGT gene variants, plasma AGT concentration and risk for hypertension remain uncertain. We examined whether AGT gene variants predispose to hypertension via an increase of plasma AGT concentration. Plasma AGT concentration was estimated from plasma angiotensin I which was cleaved by an excess amount of human renin and measured by RIA. Using 9 AGT gene variants which included new polymorphisms (G-152A and T+31C), we examined the association with hypertension and with plasma concentration by a case-control study. Haplotype analysis revealed that G-6A, T+31C and M235T polymorphisms were in absolute linkage disequilibrium and were associated with hypertension but not with plasma AGT level. On the other hand, -1074t;T235 haplotype was associated with an increase of AGT level but not with hypertension. In the haplotype analysis, only H3 haplotype frequency, which contained G-6, T+31 and M235 alleles, was significantly increased in normotensive subjects, suggesting that this haplotype is associated with a hypotensive effect. According to combined haplotype analysis of diallele and microsatellite markers, it remains a possibility that M235T, T+31C, G-6A, A-20C and G-1074T polymorphisms may play an important role in increased risk for essential hypertension. Our results suggest that the positive association between AGT polymorphism and hypertension is not simply explained by an increase of plasma AGT concentration.     

延边朝鲜族和汉族脂联素启动子SNPs与原发性高血压的相关性

为了探讨延边朝鲜族和汉族脂联素基因启动子单核苷酸多态性(SNPs)与原发性高血压(EH)的关系, 文章采用PCR产物直接测序方法检测了220例EH患者和268例对照个体的脂联素启动子5个SNPs位点: -11426A>G(rs16861194)、-11391G>A(rs17300539)、-11377C>G(rs62620185)、-11156insCA(rs60806105)、-11043C>T(rs76786086), 氧化酶法测定空腹血糖、甘油三酯、总胆固醇、低密度脂蛋白、高密度脂蛋白, 酶联免疫吸附法(ELISA)测定血浆脂联素和胰岛素。结果显示: (1) -11426A>G、-11377C>G 和-11156insCA 3个位点具有多态性, 且它们的基因型频率分布符合Hardy-Weinberg平衡定律(P>0.05), -11391G>A和-11043C>T位点无多态性; (2) -11426A>G和-11156insCA呈完全连锁不平衡(D’=1; r2=1); (3) -11426G基因频率比较, 朝鲜族(21.10%)高于汉族(12.05%), 汉族EH组高于对照组; -11377C>G的基因型和基因频率在朝鲜族和汉族间及同一民族内EH组和对照组间比较均无统计学意义(P>0.05); (4)单倍型?11426G -11377C的频率, 汉族EH组高于对照组(P<0.05), 朝鲜族EH组和对照组比较无统计学意义(P>0.05); (5)EH组的血浆脂联素水平明显低于对照组(P<0.001)。据此得出结论: (1)首次发现?11426A>G和?11156insCA呈完全连锁不平衡, -11426 A>G的多态性在朝鲜族和汉族中存在民族差异; (2) -11426 G和-11426G -11377C是延边汉族EH的危险因子和危险单倍型, 但不是朝鲜族的; (3)低血浆脂联素是延边朝鲜族和汉族EH的重要危险因素; (4)血浆脂联素水平与-11426A>G基因型无关。     

Association of the MMP3, MMP9, ADAM33 and TIMP3 genes polymorphic markers with development and progression of chronic obstructive pulmonary disease

The contribution of the polymorphic markers of the matrix metalloproteinases MMP1 (-1607G > GG, rs1799750; -519A > G, rs494379), MMP2 (-735C > T, rs2285053), MMP3 (-1171 5A > 6A, rs35068180), MMP9 (-1562C > T, rs3918242; 2660A > G, rs17576), MMP12 (-82A > G, rs2276109), the disintegrin and metalloprotease 33 ADAM33 (12418A > G, rs2280091; 13491C > G, rs2787094), the tissue inhibitors of metalloproteinases TIMP2 (-418G > C, rs8179090), TIMP3 (-1296T > C, rs9619311) genes to chronic obstructive pulmonary disease has been assessed. For this purpose, PCR-RFLP analysis of the gene polymorphisms in case (N = 391) and control (N = 514) groups has been performed. The 6A6A genotype of the MMP3--1171 5A > 6A polymorphism was associated with significantly high risk of chronic obstructive pulmonary disease (OR = 2.490, Padj = 0.003979, Pcor = 0.0358 adjusted for age, sex, smoke pack-years, ethnos). Analysis showed an association of the G-G haplotype of 13491C > G and 12418A > G ADAM33 gene polymorphisms (OR = 0.39, Padj = 0.0012, Pcor = 0.006)with chronic obstructive pulmonary disease. We found a significant interaction of the smoking status and ADAM33 12418A > G (Pinteraction = 0.026) and TIMP3--1296T > C (Pinteraction = 0.044). The relationship between the GG genotype of the ADAM33 13491C > G and emphysema risk was found (OR = 1.74, Padj = 0.013, Pcor = 0.117). Severity of chronic obstructive pulmonary disease was modified by MMP9 -1562C > T in additive model (OR = 1.883, Padj = 0.028, Pcor = 0.252). The MMP3, MMP9, ADAM33, TIMP3 genes polymorphism may be an important risk factor for the development and progression of chronic obstructive pulmonary disease, important gene and environmental interactions were determined.