A meta-analysis of DNA repair gene <Emphasis Type="Italic">XPC</Emphasis> polymorphisms and cancer risk

Polymorphisms (A33512C, C21151T and PAT −/+) of the xeroderma pigmentosum group C (XPC) were shown to contribute to genetic susceptibility to cancer. However, association studies on these polymorphisms in cancer have shown conflicting results. Thus, we performed a meta-analysis. Overall, there was no significant association between 33512C (9,091 patients and 11,553 controls) and cancer risk. No significant association was found in stratification analysis by tumor sites and ethnicities except an elevated lung cancer risk under the recessive genetic model in all subjects [P = 0.04, odds ratio (OR) = 1.20, 95% confidence interval (CI) 1.00–1.45, P _{heterogeneity} = 0.88]. There was no significant association between 21151T (5,227 patients and 5,959 controls) and cancer risk in all subjects but an increased cancer risk in Caucasians under the recessive genetic model (P = 0.006, OR = 1.45, 95% CI 1.11–1.90, P _{heterogeneity} = 0.75) and homozygote comparison (P = 0.02, OR = 1.41, 95% CI 1.07–1.81, P _{heterogeneity} = 0.41). It might be that 21151T increases bladder cancer risk under the recessive genetic model (P = 0.02, OR = 1.49, 95% CI 1.06–2.09, P _{heterogeneity} = 0.47) and homozygote comparison (P = 0.02, OR = 1.49, 95% CI 1.05–2.11, P _{heterogeneity} = 0.23). There was no significant association between PAT + (4,600 patients and 4,866 controls) and cancer risk in all subjects. An increased cancer risk in Caucasians was found under the recessive genetic model (P = 0.02, OR = 1.20, 95% CI 1.03–1.40, P _{heterogeneity} = 0.37) and homozygote comparison (P = 0.008, OR = 1.26, 95% CI 1.06–1.50, P _{heterogeneity} = 0.13). The XPC PAT + allele might increase head and neck cancer risk (P = 0.02, OR = 1.29, 95% CI 1.04–1.59, P _{heterogeneity} = 0.15). More studies based on larger, stratified, case–control population, especially studies investigate the combined effect of XPC A33512C, C21151T, and PAT, are required to further evaluate the role of these polymorphisms in different cancers.     

Methylenetetrahydrofolate reductase gene polymorphisms and lung cancer: a meta-analysis

So far, case-control studies on the association between methylenetetrahydrofolate reductase (MTHFR) gene polymorphisms and lung cancer provide controversial or inconclusive results. To clarify the effect of MTHFR polymorphisms on the risk of lung cancer, a meta-analysis of all case-control observational studies was performed. The studies provided 5,111/6,415 cases/controls for C677T and 5,087/6,232 cases/controls for A1298C. The heterogeneity (P = 0.0001, I ² = 76.6%) for C677T among the eight studies was extreme. Cluster analyses based on the frequencies of the C677T genotype of the control group in each study revealed that the studies could not cluster together according to their ethnicity. The random effects (RE) model showed that the 677T allele was not associated with the risk of lung cancer compared with the C allele [OR = 1.12, 95% confidence interval (CI) (0.97–1.28), P = 0.12]. The contrast of homozygotes, recessive model, dominant model produced the same pattern of results as the allele contrast. In regard to the A1298C polymorphism, there was no heterogeneity among the seven studies comparing the C versus the A allele (P = 0.24, I ² = 24.4%), but no significant association was detected by the RE model or the fixed effects model [FE odds ratio (OR) = 0.99 (0.93–1.05) and RE OR = 1.00 (0.92–1.08)]. The effect of MTHFR polymorphisms (C677T, A1298C) on the risk of lung cancer was undetectable, even though analyzed on a relatively good number of subjects (totally 11,526 subjects) by meta-analysis (statistical power = 93.9%). Although MTHFR polymorphisms were associated with the risk of colorectal cancer, leukemia, and gastric cancer supported by other meta-analysis, our pooled data suggest no evidence for a major role of these two variants in carcinogenesis of lung cancer. The results implied that different tumors evolve by different pathological pathways and the roles of MTHFR in cancer is determined by its target genes.     

Interleukin-18 and its three gene polymorphisms relating to allergic rhinitis

The study aimed to examine an association of three different single nucleotide polymorphisms (SNPs) of the IL-18 gene (−607 C/A, −137 G/C and −133 C/G) on chromosome 11q22 with allergic rhinitis (AR). Genotyping for the SNPs was performed using 539 patients with AR and 312 healthy control volunteers. Positivity to the skin prick test for the fungus Alternaria sp. in patients with AR, and IgE levels according to particular genotypes of selected SNPs, were also determined. There were no significant differences in the distribution of single IL-18 alleles or genotypes between controls and AR patients. However, frequencies of combined IL-18 genotypes arising from combinations of the three common polymorphisms (−607, −137 and −133) were significantly different between both groups (P = 0.009, P _corr < 0.05, OR = 5.35, 95% CI: 1.9–15.2). There was a marginally significant association of the IL-18–607 variant with IgE levels (P = 0.05) in patients, but not in the case of the other SNPs. Patients allergic to Alternaria, but not those allergic to other antigens, showed a significant association with the IL-18–607 polymorphism (P = 0.0037, P _corr < 0.05). Results suggest that IL-18 gene variants may be one of the factors participating in the pathogenesis of AR or its intermediary phenotypes.     

Interleukin-10 and Tumor Necrosis Factor-α Gene Polymorphisms in Tuberculosis

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is an infectious disease in humans killing nearly three million people and eight million cases annually. The cytokines TNF-α and IL-10 have been implicated in the pathogenesis of TB. Certain single nucleotide polymorphisms within the promoter region of the IL10 and TNF genes have been associated with altered levels of circulating IL10 and TNF- α. We analyzed TNF-α (−308 G/A, −238 G/A, −376 G/A) and IL10 (−1,082 G/A, −819 C/T, −592 C/A) polymorphisms in 128 patients with TB and 80 healthy subjects using by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). A significant association was found between TB and −1,082 G allele (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41). Significant difference was observed in IL10 GCC and ACC haplotypes distribution between TB and control subjects (Pc: 0.000, O.R 2.22, 95% CI 1.45–3.41; Pc: 0.004, O.R 0.53, 95% CI 0.35–0.81). No statistically significant association was found between IL-10 −819 C/T, TNF-α 308 G/A, −238 G/A, −376 G/A polymorphisms, functional TNFα/IL-10 genotypes and TB. Our findings suggest that IL-10 108 2G/A alleles or haplotypes containing these alleles may influence the Th1/Th2 balance and hence may play a role in TB susceptibility and increase risk of developing disease. This polymorphism may be one of the many genetic factors affecting disease outcome.     

Polymorphisms of Genes for Programmed Cell Death 1 Ligands in Patients with Rheumatoid Arthritis

To investigate the role of ligands for programmed cell death 1 (PD-L) in the pathogenesis of rheumatoid arthritis (RA), 129 patients with RA and 125 unrelated healthy controls were enrolled in this study. The PD-L1 and PD-L2 polymorphisms were determined by the method of polymerase chain reaction (PCR)/direct sequencing or PCR/reaction fragment length polymorphisms. The genotype distributions of PD-L1 6777 C/G were not significantly different between the patients with RA and healthy controls. There was also no significant difference in the allele frequencies of PD-L1 6777 C/G polymorphisms between the patients with RA and controls. Similar findings could also be found in the phenotypes and alleles frequencies of PD-L2 47103 C/T and 47139 T/C polymorphisms between the patients with RA and controls. The patients with PD-L1 6777 G had higher prevalence of rheumatoid nodule in comparison with those without PD-L1 6777 G (p = 0.005, OR = 4.0, 95% CI = 1.5–10.9). In contrast, the PD-L2 47103 C/T and 47139 T/C polymorphisms were not related to the occurrence of rheumatoid nodule. This study demonstrated that the PD-L1 and PD-L2 polymorphisms were not associated with susceptibility to RA in Taiwan. PD-L1 6777 G was associated with the prevalence of rheumatoid nodule. Shu-Chen Wang and Chia-Hui Lin contributed equally to this work.     

The combination of <Emphasis Type="Italic">ApoCIII</Emphasis>, <Emphasis Type="Italic">hepatic lipase</Emphasis> and <Emphasis Type="Italic">hormono sensitive lipase</Emphasis> gene polymorphisms suggests an association with susceptibility to gestational hypertension

Dyslipidemia and insulin resistance contribute to the endothelial cell dysfunction in hypertensive disorders of pregnancy (HDP) and increase the long-term risk of cardiovascular disease (CVD). The genes linking susceptibility to gestational hypertension (GH) and/or preeclampsia (PE) to the long-term risk of CVD are still unknown. We evaluated the potential association between 14 polymorphisms from six genes involved in lipid metabolism and insulin action and the risk of HDP: namely the lipoprotein lipase (LPL), hepatic lipase (LIPC), hormone sensitive lipase (LIPE), cholesteryl ester transfer protein (CETP), ApoCIII and ApoE gene polymorphisms. Overall, 169 women with HDP [proteinuria (PE) and gestational hypertension without proteinuria (GH)] and 169 controls matched for age and year of delivery were genotyped. Homozygosity of the −514T allele of the −514C > T polymorphism (LIPC gene) decreased the risk of GH (OR = 0.17, CI₉₅: 0.02–0.76), while there were more −60G carriers of the −60C > G LIPE gene polymorphism (OR = 3.51, CI₉₅:1.02–12.10) among GH cases, but not in PE cases. The common ApoCIII two-locus −482CC/3238CC genotype was lower in women with GH compared with controls (OR = 0.53, CI₉₅: 0.3–0.9). The combined frequency of at-risk genotypes was higher in cases of GH compared with controls [one at-risk genotype: OR = 3.38 (95% CI: 0.48–41.8); two or more at-risk genotypes: OR = 7.14 (95% CI: 1.21–92.3, P = 0.01)], suggesting a gene-dose effect. We conclude that the combined effect of LIPC, LIPE and ApoCIII gene polymorphisms may increase the likelihood of GH, but seemingly not of PE.     

Analysis of associations of <Emphasis Type="Italic">NAT2</Emphasis> gene polymorphisms with the risk of lung cancer

The incidence of 5 polymorphisms of N-acetyltransferase-2 gene was evaluated in patients with lung cancer. A803G polymorphism is a factor of lung cancer resistance in tobacco smoking Caucasians in Novosibirsk. Opposite effects of NAT2 gene polymorphisms on the risk of lung cancer are possible. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 143, No. 1, pp. 89–92, January, 2007     

In vitro effects of folic acid on γ-glutamyltransferase and glutathione reductase activities in malignant lung and thymus tumors

In vitro effects of folic acid (10⁻⁵, 10⁻⁴, and 10⁻³ M) on activities of γ-glutamyltransferase and glutathione reductase, the enzymes involved in glutathione metabolism, were studied in tissue samples obtained after surgical treatment of the lungs and thymus. Folic acid did not change γ-glutamyltransferase activity in lung cancer tissue, but in thymoma tissue this substance in a concentration of 10⁻³ M inhibited it by 16%. Folic acid had no effects on glutathione reductase activity in benign tumors and normal lung and thymus tissues, but increased this activity in thymoma and lung cancer tissues. Activation of glutathione reductase was probably related to binding of folic acid in the allosteric center of the enzyme, which probably induced conformational changes in the catalytic center, acceleration of electron transport from NADPH₂ to oxidized glutathione via flavin adenine nucleotide, and intense production of reduced glutathione. Translated fromByulleten', Eksperimental'noi Biologii i Meditsiny, Vol. 130, No. 10, pp. 422–425, October, 2000     

Thermodynamic parameters of binding of mouse 2G3 antitheophylline monoclonal antibodies to theophylline

The binding of 2G3 mouse antitheophylline monoclonal antibodies (affinity constant K_aff=2×10¹⁰ liter/mol) to theophylline is studied using isothermal titration microcalorimetry. Thermodynamic parameters of the binding are: enthalpy change ΔH=−0.23 kcal/mol; Gibbs free energy change ΔG=−16.42 kcal/mol; entropy change ΔS=0.054 kcal/(mol×K). Regression analysis shows a two-site kinetic binding model. A great contribution of entropy component to the free energy change of 2G3 antibody binding to theophylline is indicative of an entropy-dependent process. The entropy-dependent nature of the binding presumably determines the binding kinetics. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 124, No. 11, pp. 570–573, November, 1997     

Correlation between survivin genetic polymorphisms and lung cancer susceptibility

Aims: The purpose of the study was to analyze the relationship of survivin polymorphisms including -31G/C, -625G/C, 9194A/G and 9809T/C with the susceptibility to lung cancer. Methods: Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to test the polymorphisms of -31G/C, -625G/C, 9194A/G and 9809T/C in 104 patients with lung cancer and 104 healthy controls. Then, linkage disequilibrium and haplotypes were analyzed by HaploView software. The differences of genotype, allele and haplotype frequencies in case and control group were assessed via chi-square test. Odds ratio (OR) with 95% CI were used to evaluate the correlation of survivin polymorphisms with lung cancer. Results: Genotype distribution of each polymorphism site in control group was in agreement with Hardy-Weinberg equilibrium (HWE) (P>0.05). The frequency of -31G/C CC genotype and C allele in case group were much higher than that of controls, respectively (CC: 33.6% vs. 22.1%; C: 57.2% vs. 46.6%) and CC genotype as well as C allele were appeared to be risk factors for lung cancer. Meanwhile, 9194A/G GG genotype could increase the risk for lung cancer (OR=2.86, 95% CI=1.14-7.20). The risk of G allele carriers for lung caner was higher than that of A allele (OR=1.63, 95% CI=1.08-2.47). The haplotypes analysis indicated that CGGC and GCAT were associated with the susceptibility to lung cancer (OR=2.79, 95% CI=1.58-4.92; OR=2.36, 95% CI=1.29-4.30). Conclusions: Survivin -31G/C and 9194A/G polymorphisms were associated with the risk of lung cancer. The CGGC and GCAT haplotypes carriers were more likely to develop lung cancer.     

Association between polymorphisms in the biometabolism genes CYP1A1, GSTM1, GSTT1 and GSTP1 in bladder cancer

Numerous enzymes, including Cytochrome P450s (phase I) and Glutathione-S-transferases (phase II), are involved in the metabolic activation and detoxification of carcinogens. Epidemiological studies have consistently demonstrated that bladder cancer is strongly associated with cigarette smoking, and the risk for the development of this neoplasia may be modified by individual differences in carcinogen-metabolizing genes. We investigated the relationship between polymorphisms in the CYP1A1, GSTM1, GSTT1, and GSTP1 genes in a case–control study with 100 bladder cancer patients and 100 controls matched for age, gender, race, and smoking status. The GSTM1, GSTT1, CYP1A1 (A2455→G), and GSTP1 (A313→G) genotypes were determined using a multiplex PCR, an allele specific PCR, and a restriction fragment length polymorphism-PCR method. The present case–controlled association study did not detect any positive or negative association for the GSTM1 and GSTP1 genes [odds ratios (OR) = 1.35; 95% confidence interval (CI) = 0.76–2.41 and OR = 0.75; 95% CI = 0.41–1.38, respectively]. Notably, the genes GSTT1 and CYP1A1 exhibited a statistically significant association with bladder cancer (OR = 1.77; 95% CI = 1.01–3.12 and OR = 1.99; 95% CI = 1.07–3.73). No differences for GSTM1 and GSTP1 genotype prevalence between the bladder cancer cases and the controls were observed, however, the null genotype for the GSTT1 gene and the A/G and G/G variants of the CYP1A1 gene may contribute to the development of bladder cancer.     

Genetic polymorphisms of ataxia telangiectasia mutated affect lung cancer risk

The ataxia telangiectasia mutated (ATM) gene is known to be activated by DNA damage and involved in cell cycle arrest, apoptosis and DNA repair. Therefore, ATM gene polymorphisms may act as important factors predicting individual susceptibility to lung cancer. To evaluate the role of ATM gene polymorphisms in lung cancer development, genotypes of the ATM polymorphisms, -4518A>G, IVS21-77C>T, IVS61-55T>C, and IVS62+60G>A, were determined in 616 lung cancer patients and 616 cancer-free controls. When the effects of selected ATM genotypes were evaluated separately, only one ATM genotype (IVS62+60G>A) showed an association with lung cancer risk. Subjects with the A allele at the site (IVS62+60G>A) have significantly higher risk of lung cancer than those with the G allele [odds ratio (OR)=1.6, 95% confidence interval (CI) 1.1-2.1]. When the haplotypes of four ATM single nucleotide polymorphism sites (-4518A>G, IVS21-77C>T, IVS61-55T>C and IVS62+60G>A) were studied, the ATTA haplotype showed significantly increased risk of lung cancer compared with the GCCA haplotype, the most common haplotype (OR=7.6, 95% CI 1.7-33.5). Furthermore, subjects with the (NN)TA haplotype showed highly significant and increased risk of lung cancer when compared with those without the (NN)TA haplotype (OR=13.2, 95% CI 3.1-56.1). Therefore, our results suggest that polymorphisms or haplotypes of the ATM gene play an important role in the development of lung cancer.     

Association of positional and functional candidate genes<Emphasis Type="Italic"> FGF1</Emphasis>,<Emphasis Type="Italic"> FBN2</Emphasis>, and<Emphasis Type="Italic"> LOX</Emphasis> on 5q31 with intracranial aneurysm

We previously performed a genome-wide linkage study of intracranial aneurysm (IA) and found positive evidence of linkage at chromosomes 5q22–31, 7q11, and 14q22. In the present study, we focus on 5q31, where three candidate genes, fibroblast growth factor 1 (FGF1), fibrillin 2 (FBN2), and lysyl oxidase gene (LOX) lie, and evaluate associations with IA. Genomic DNAs were obtained from 172 IA patients and 192 controls. Association analysis was performed with ten, five, and four single-nucleotide polymorphisms (SNPs) identified in FGF1, FBN2, and LOX, respectively. A difference in allelic frequency was observed for only the SNP at intron 4 in FGF1 (χ²=4.44, df=1, P=0.035). Although a haplotype association was observed with the combination of ten SNPs in FGF1 (χ²=16.04, df=1, P=0.00006), significant haplotype associations were not observed when haplotypes were constructed with the three, two, and four SNPs in FGF1 according to the linkage disequilibrium structure. No associations of FBN2 and LOX with IA were detected in the present study.     

Combinational effect of genes for the renin–angiotensin system in conferring susceptibility to diabetic nephropathy

To elucidate the role of the renin–angiotensin system (RAS) in diabetic nephropathy, we examined the association between diabetic nephropathy in a large cohort of Japanese type 2 diabetic patients and polymorphisms within the genes that encode angiotensin-converting enzyme (ACE), angiotensinogen (AGT) and angiotensin II receptor type 1 (AGTR1). Single nucleotide polymorphisms (SNPs) within these genes were genotyped using invader assay in 747 nephropathy cases and 557 control subjects. Eight SNPs within the ACE gene were significantly associated with diabetic nephropathy (P<0.05), including five SNPs in almost complete linkage disequilibrium to the insertion/deletion polymorphism in the 16th intron (P=0.01, odds ratio =1.34, 95% CI 1.07–1.69). Three SNPs within the AGT, including M235T and one SNP in the AGTR1, were also significantly associated with nephropathy (M235T P=0.01, odds ratio =0.74, 95% CI 0.59–0.94). In addition, we found that the allelic mRNA expression corresponding to the 235M allele was significantly higher than that for the 235T allele in normal kidney tissues. Furthermore, we found a significant additional effect of these three genes by a step-wise logistic regression analysis (final empirical P value =0.00005). We concluded that RAS gene polymorphisms may contribute to the susceptibility to diabetic nephropathy in type 2 diabetes. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Gene–gene interaction between IL-13 and IL-13Rα1 is associated with total IgE in Korean children with atopic asthma

Interleukin (IL)-13, which is essential for IgE synthesis, mediates its effects by binding with a receptor composed of IL-4Rα and IL-13Rα1. We investigated the effects of IL-13 and IL-13Rα1 polymorphisms in Korean children with asthma, and whether these have been associated with IgE production. We enrolled 358 atopic asthmatic, 111 non-atopic asthmatic, and 146 non-atopic healthy children. IL-13 and IL-13Rα1 genotypes were identified using the PCR-RFLP method. There was an association between the asthma susceptibility and homozygosity for risk allele of IL-13 G+2044A. In children with atopic asthma, risk alleles in IL-13 (A−1512C and C−1112T) and IL-13Rα1 (A+1398G) showed increased total IgE (P=0.012, 0.015 and 0.017, respectively). Three-loci haplotype analysis for IL-13 showed that the haplotype composed of −1512C, −1112T and +2044A was associated with higher total IgE than other tested haplotypes in children with atopic asthma (P=0.003). The gene–gene interaction between risk alleles of each IL-13 promoter polymorphism and IL-13Rα1 polymorphism was associated with higher total IgE in children with atopic asthma (P=0.002, 0.010). These findings indicate that the IL-13 G+2044A is associated with asthma development and the IL-13 and IL-13Rα1 polymorphisms may interact to enhance IgE production.Hyo-Bin Kim, and Yong-Chul Lee contributed equally to this work. This work was supported by grants from the Asan Institute for Life Science (2005-091) and the National Research Laboratory Program, Korea Science and Engineering Foundation and by Korea Research Foundation Grants funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2005-201-E00014), Republic of Korea.     

Association of interleukin-1B and interleukin-1RN polymorphisms with gastric cancer in a high-risk population of Costa Rica

Abstract Several risk factors have been associated with gastric cancer, among them Helicobacter pylori infection. This bacterium yields inflammation, the degree of which depends on the bacterial strain and the severity of the host response. The inflammatory response involves a complex cytokine network. Recently, polymorphisms of the genes coding for interleukin-1β (IL-1B), interleukin-1Ra (ILRN) and interleukin-10 have been associated with an increased risk of gastric cancer. In order to determine the association of the IL-1B, IL-1RN and IL-10 polymorphisms with gastric cancer in a high-risk Costa Rican population, we analysed purified DNA of 58 gastric cancer patients, 99 controls and 41 patients classified as group I or II, according to the Japanese classification. Genotyping was carried out by PCR, PCR-RFLP and pyrosequencing analysis. We did not find any association of the IL-1B-31, IL-1B-511 and IL-10 polymorphisms with the risk for developing gastric cancer in the studied population. Carriers of the IL-1B+3954T/– had an increased risk for developing gastric cancer (OR 3.7; 95%CI: 1.34–10.2). Also we found an increased risk for developing gastric cancer for allele 2 heterozygotes of the IL-1RN (OR 2.94; 95%CI: 1.09–7.93). This is the first time that IL-1B+3954 has been associated with gastric cancer. This is one of the first studies trying to describe the role played by IL-1B, IL-1RN and IL-10 genetic polymorphisms in gastric cancer in one of the highest risk American countries. Further investigation on American countries is needed.     

Low frequency of the CYP21A2 deletion in ethnic Chinese (Taiwanese) patients with 21-hydroxylase deficiency

Congenital adrenal hyperplasia (CAH) is a common autosomal recessive disorder which causes more than 90% of CAH cases due to defects in the steroid 21-hydroxylase gene (CYP21A2). The frequency of large mutations was determined in 200 ethnic Chinese (i.e., Taiwanese) CAH patients belonging to 200 families with different clinical forms of CYP21A2 deficiency over 10 years of molecular diagnoses. For a large-gene deletion (or conversion) and the CYP21A2 deletion identification, a PCR product covering the TNXB gene and the 5′-end of the CYP21A2 gene with TaqI endonuclease digestion was analyzed by electrophoresis on agarose gels. For CYP21A2 mutational analysis, secondary PCR amplification of the amplification-created restriction site method was applied. From the results of the analysis, we found that large-gene deletions (or conversions) occurred in 7.5% of the alleles including three different types of the chimeric CYP21A1P/CYP21A2 genes and the haplotype of IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation). The CYP21A2 deletion occurred in 2.0% of the alleles which contained three types of the chimeric TNXA/TNXB genes with two novel ones. We concluded that the CYP21A2 deletion in the ethnic Chinese (Taiwanese) patients exhibits a low occurrence, with the haplotype of the IVS2-12A/C>G in combination with the 707-714del mutation (without the P30L mutation) being prevalent among large gene deletions or conversions.     

VSX1 gene variants are associated with keratoconus in unrelated Korean patients

Keratoconus is a bilateral ectatic disorder characterized by the central thinning of corneal tissue leading to visual impairment. To investigate the possibility of visual system homeobox 1 (VSXI) as a candidate susceptibility gene for Korean patients with keratoconus, we performed a mutation screening of the VSXI gene in 249 unrelated patients with keratoconus and 208 control subjects without the ocular disorder. We found two heterozygous novel missense mutations in exon 2: N151S and G160V. The G160V mutation was identified in 13 keratoconus patients (5.3%), and the N151S mutation was found in only one keratoconus patient (0.4%). We also detected three synonymous polymorphisms and four intragenic polymorphisms. The IVS1-11*a allele was associated with a significantly increased risk of keratoconus in Korean patients [3.6 vs. 0.5%, p = 0.001, odds ratio (OR) = 7.76, 95% confidence interval (CI) 1.989–30.241). Other polymorphisms did not show an association with keratoconus risk. Our data is the first reported VSX1 mutation screening in Korean keratoconus patients. We detected two novel missense mutations and one intragenic polymorphism in the VSX1 gene, which show a strong statistical association with unrelated keratoconus patients. Consequently, our study suggests that VSX1 gene variants seem to be significant genetic variants for keratoconus predisposition in unrelated Korean patients.     

Myeloperoxidase gene sequence variations are associated with low-density-lipoprotein characteristics

The small, dense low-density-lipoprotein (LDL) phenotype is associated with an increased atherosclerosis risk. A genome-wide scan performed on 236 nuclear families of the Quebec Family Study (QFS) revealed a quantitative trait locus (QTL) for LDL peak-particle size (LDL-PPD) on the 17q21 region. This region encodes the myeloperoxidase (MPO) gene. MPO is able to oxidize LDL by its reactive intermediates. To test the associations between MPO gene polymorphisms and LDL-PPD as well as plasma lipid levels, we performed direct sequencing of the coding regions, exon-intron splicing boundaries, and the regulatory regions on 25 subjects to identify new genetic variants. Genotyping was performed either by TaqMan or direct sequencing on 680 subjects in the QFS. LDL-PPD was measured by gradient gel electrophoresis (GGE) on nondenaturing 2–16% polyacrylamide gradient gels. MPO gene sequencing revealed 16 polymorphisms. The c.-653G > A MPO polymorphism was associated with lower plasma total cholesterol, LDL cholesterol (LDL-C), and LDL apolipoprotein B (LDL-apoB) levels (P = 0.026, 0.042 and 0.014, respectively). No significant association with a gene-dosage effect were observed for LDL-PPD. The MPO gene variants are not associated with LDL-PPD and thus are unlikely to be responsible for the quantitative trait locus reported on 17q21. However, the c.-653G > A is associated with plasma LDL-C and LDL-apoB concentrations. Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

<Emphasis Type="Italic">IκBα</Emphasis> Promoter Polymorphisms in Patients with Systemic Lupus Erythematosus

To investigate the associations of IκBα gene polymorphisms with the development and clinical manifestations of systemic lupus erythematosus (SLE), 110 patients with SLE and 120 unrelated healthy controls were enrolled in this study. The IκBα −881 A/G, −826 C/T, −550 A/T, −519 C/T, and −297 C/T polymorphisms were determined by the polymerase chain reaction/reaction fragment length polymorphism method. The genotype frequency of IκBα −826 C/T in the patients with SLE was significantly higher than that of the controls (p = 0.003, OR = 2.2, 95% CI = 1.3–3.9). The SLE patients also have significantly higher carriage rate of IκBα −826 T than the controls (p = 0.01, OR = 2.0, 95% CI = 1.2–3.4). We also found that the estimated haplotype frequency of IκBα −881A −826T −550A −519C −297C was significantly increased in the patients with SLE in comparison with that of the controls. This study also demonstrated that the association of IκBα −826 T with SLE was independent of HLA-DR15, which is associated with susceptibility to SLE in Taiwan. Moreover, a synergistic effect could also be found between IκBα −826 T and HLA-DR15. IκBα −826 T is associated with the development of SLE in Taiwan. The IκBα −881A −826T −550A −519C −297C haplotype is also associated with susceptibility to SLE. This study also demonstrated that IκBα -881G was associated with the occurrence of vasculitis in SLE patients. IκBα −550T might be a protective factor for the development of malar rash. Chia-Hui Lin and Shu-Chen Wang contributed equally to this research work.