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Background and Aim: Recent genome-wide association studies of colorectal cancer (CRC) have identified rs6983267 and trs10505477 polymorphisms as key loci in the 8q24 region to be associated with CRC. In the present study, we performed a meta-analysis to determine whether these loci are risk factors for susceptibility to CRC. Methods: We meta-analyzed the 22 included studies (47 003 cases and 45 754 controls) that evaluated the association of rs6983267 and trs10505477 with CRC under alternative genetic models. Results: A meta-analysis of the pooled data showed allelic and genotypic association of the rs6983267 polymorphism with CRC risk in Asians, Europeans, and European-Americans. A subanalysis of the US studies showed negative results in the studies with non-identified ethnicity of the patients. A meta-analysis of included studies of rs10505477 polymorphisms identified allelic and genotypic associations with CRC risk in the US patients. A further meta-analysis of the US studies demonstrated positive results in the studies with non-identified ethnicity of the samples. Conclusion: Our data suggested that the rs6983267 G > T polymorphism is a risk factor for CRC in Asians, Europeans, and Americans with European ancestry. [ABSTRACT FROM AUTHOR]

The association between a specific polymorphism ( 3435C> T) in the ABCB1 gene, coding for the membrane drug transporter P-glycoprotein (PgP), and pharmacoresistance to seizure control is controversial. Studies have been limited by multiple drug use, chronic cohorts with varying definitions, and retrospective clinical data. Herein we examine the relationship of this polymorphism with seizure recurrence in three independent international cohorts of patients newly treated for epilepsy. Data were collected on demographics, medication details, and seizure control after 12 months of treatment. The distribution of ABCB1 3435C>T genotypes was compared between patients with and without recurrent unprovoked seizures. Five hundred forty-two newly treated patients were enrolled (212 from Australia, 285 from Scotland, and 45 from Hong Kong). A total of 38.4% had recurrent unprovoked seizures after starting antiepileptic drug (AED) treatment. Genotype frequencies and ethnicity did not differ between the Scottish and Australian cohorts, but both were significantly different in the Hong Kong cohort. There was no significant relationship between the ABCB1 3435C> T genotype and the rate of recurrence of unprovoked seizures in the three cohorts individually or combined; however the epilepsy syndrome and a greater number of seizures pretreatment was associated with an increased risk of seizure recurrence. The ABCB1 3435C> T genotype does not have a major role in determining the efficacy of seizure control with initial AED therapy. The study highlights issues that arise in combining pharmacogenetic datasets from different ethnic regions and health systems, an approach that is essential to advance this field. [ABSTRACT FROM AUTHOR]

Aims: It remains controversial whether polymorphisms of the multidrug resistance gene ABCB1 are associated with pharmacoresistance in epilepsy. To further study the potential association, we genotyped a broad set of tagging SNPs, and explored whether any associations were affected by other host factors. We correlated any association with cerebral mRNA expression of ABCB1. Materials & methods: A total of 12 tagging and candidate SNPs of ABCB1 were genotyped in 464 Chinese epilepsy patients (270 drug responsive, 194 drug resistant). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. ABCB1 mRNA was quantified by real-time PCR in brain samples resected from 20 patients with drug-resistant epilepsy. Its level was compared between patients with different genotypes of ABCB1 SNPs found to be associated with drug resistance. Results: The intronic polymorphism rs3789243 (p = 0.009 for allele analysis) and the coding polymorphism 2677G/T/A (p = 0.02), and haplotypes containing them, were associated with drug resistance. The 2677G/T/A genotypes remained significantly associated with drug resistance after multiple logistic regression and correction for multiple comparisons. The associations with drug resistance were found in males (p = 0.004 for rs3789243 and p = 0.0007 for 2677T/A>G) but not females, and in patients with localization-related (p = 0.006 for rs3789243 and p = 0.01 for 2677T/A>G) but not idiopathic-generalized epilepsy. ABCB1 mRNA levels did not correlate with genotypes. Conclusion: In Chinese epilepsy patients, the ABCB1 intronic polymorphism rs3789243 and the coding polymorphism 2677, and haplotypes containing them, may be associated with drug resistance, without an effect on mRNA expression. There was preliminary evidence of interactions between these polymorphisms and gender and epilepsy syndrome. [ABSTRACT FROM AUTHOR]

Abstract: There is accumulating evidence to suggest that overexpression of efflux drug transporters at the blood–brain barrier, by reducing antiepileptic drug (AED) accumulation in the seizure foci, contributes to drug resistance in epilepsy. P-glycoprotein, encoded by the ABCB1 gene, is the most studied drug transporter. There are conflicting data as to whether the CC genotype of the ABCB1 3435C>T polymorphism is associated with drug resistance in Caucasian patients with epilepsy. We investigated this association in ethnic Chinese. ABCB1 3435C>T was genotyped in 746 Han Chinese patients with epilepsy and 179 controls. Patients with drug-resistant epilepsy were more likely to have the TT genotype compared with those with drug-responsive epilepsy (16.7% vs 7.4%, odds ratio=2.5, 95% confidence interval=1.4–4.6, P =0.0009). Our results contrast with those of studies of Caucasians, and highlight the complexity of the possible role of this polymorphism in AED response in different ethnic populations. [Copyright &y& Elsevier]

A previous study conducted in Taiwan found a 100% association between HLA-B*1502 allele and carbamazepine-induced Steven s-Johnson syndrome (SJS) in Han Chinese subjects, with an extremely high odds ratio compared with carbamazepine-tolerant subjects (odds ratio = 2,504). We examined this association in 24 Hong Kong Han Chinese subjects who had cutaneous adverse reactions induced by different antiepileptic drugs (AEDs). They were matched with 48 AED-tolerant controls. HLA-B*1502 was associated with severe cutaneous reactions (SCR) induced by AEDs, which included carbamazepine, phenytoin, and lamotrigine (p = 0.001, odds ratio = 17.6), but was not associated with maculopapular exanthema (MPE) (p = 0.32). Further studies in larger samples of ethnically matched subjects should be conducted to confirm the findings. Identification of genetic polymorphisms predisposing to development of AED-induced SCR offers the possibility of avoiding these high-risk drugs in genetically susceptible individuals. [ABSTRACT FROM AUTHOR]

Background/Aims: The apolipoprotein E (ApoE) exon 4 polymorphism has been associated with vascular dementia (VaD) risk. Since not all studies confirm this finding, we explored this association in a case-control study. Methods: We genotyped ApoE in 144 VaD patients and 251 controls. Results: VaD patients were more likely than controls to have ApoE ε3/ε4 or ε4/ε4 genotypes: 23.6% versus 15.1%, odds ratio (OR) = 1.7, p = 0.036. This association remained significant after adjustment for age, sex, hypertension and diabetes by multiple logistic regression: OR = 1.9, p = 0.030. The association of ε3/ε4 or ε4/ε4 genotypes with VaD was strong among people with hypertension (OR = 2.9, p = 0.007) or diabetes (OR = 6.5, p = 0.011). The association was absent among people without hypertension (OR = 1.1, p = 0.79) or diabetes (OR = 1.3, p = 0.43). Conclusion: This interaction with hypertension and diabetes should be examined in other studies to confirm or refute this observation. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Objectives: : Paraoxonase (PON1), an enzyme associated with high-density lipoprotein (HDL) particles, inhibits oxidation and atherogenesis. We sought to investigate the association of the PON1 Q192R polymorphism with stroke and heart disease. Design and methods: : In a case control study, we genotyped 242 ischemic stroke, 231 myocardial infarction (MI), and 310 healthy control subjects, all Chinese. Results: : R-containing genotypes (R+) were associated with vascular disease, OR = 1.5, P = 0.03. RR was increased in MI patients who were either smokers (OR = 3.1, P = 0.01), male, or younger than 60. R+ but not RR genotypes were increased in stroke patients, particularly large artery type (OR = 2.6 and P = 0.02 for R+, OR = 1.0 for RR) or among smokers. The relative dearth of RR in stroke might be due to earlier MI or death in at-risk people, such as smokers. R+ genotypes were increased with stroke in hypertensive (OR = 2.1, P = 0.02) but not normotensive (OR = 1.0) subjects. Conclusions: : PON1 192R+ genotypes were associated with stroke and MI, particularly in subsets of patients, in patterns suggesting a possible survivor effect. [Copyright &y& Elsevier]

Background: Because apolipoprotein E (apoE) and lipopoprotein lipase (LPL) polymorphisms interact with each other and with other factors to affect lipid metabolism, we sought to determine their separate and combined effects in association with ischemic vascular disease. Methods: We performed a case-control study of 816 subjects: 246 acute ischemic stroke patients, 234 acute myocardial infarction patients, and 336 controls. APOE exon 4 and LPL S447X genotypes were determined. Results: APOE ɛ2 and ɛ4 homozygotes were increased in stroke (4.5% vs. 1.0%, p=0.008), while in myocardial infarction the ɛ4 allele was increased (12.6% vs. 9.5%, p=0.006) but ɛ2 was decreased (3.7% vs. 12.1%, p=0.000006). For subjects with either APOE ɛ2 or ɛ4 alleles, LPL X alleles were increased in vascular disease (OR=2.2, p=0.01). LPL X alleles displayed opposite tendencies toward association with disease when subjects were divided by sex, smoking, or APOE genotype. Meta-analysis and regression analysis of previous studies supported the sex and smoking dichotomies. Conclusion: This is the first report of an association of vascular disease with an interaction of APOE exon 4 and LPL S447X genotypes. Therefore, APOE genotypes and LPL S447X interactions with apoE, sex, and smoking may affect the risk of myocardial infarction and ischemic stroke. [ABSTRACT FROM AUTHOR]

Objective: Triglyceride-rich lipoprotein particles may promote the progression of diabetic nephropathy. Patients with diabetic nephropathy have increased plasma triglycerides and reduced activity of hepatic lipase (HL), which hydrolyzes triglycerides. We hypothesized that the HL -514C-->T polymorphism, which reduces HL expression, and its interactions with polymorphisms in apolipoprotein (apo) E and apoC3 increase the risk of diabetic nephropathy.Research Design and Methods: In a case-control study involving 374 Chinese type 2 diabetic patients with and 392 without diabetic nephropathy, we genotyped the HL -514C-->T, apoE exon 4, and apoC3 -482C-->T polymorphisms.Results: HL -514T-containing genotypes (T+) were associated with diabetic nephropathy (OR = 1.7, P = 0.0009). Adjustment by multiple logistic regression for hypertension, triglycerides, sex, non-HDL cholesterol, BMI, smoking, and alcohol intake did not diminish the association (OR = 1.8, P = 0.003). The association between HL T+ genotypes and diabetic nephropathy appeared stronger in diabetic patients with apoC3 -482 non-TT genotypes (OR = 1.9, P = 0.003) or apoE epsilon2 or epsilon4 alleles (OR = 2.2, P = 0.005). Subjects with HL TT exhibited trends toward increased triglyceride and non-HDL cholesterol levels compared with CC carriers.Conclusions: HL T+ genotypes might increase the risk of developing diabetic nephropathy by slowing clearance of triglyceride-rich remnant lipoproteins. In concert with other risk factors (e.g., hyperglycemia), lipid abnormalities may damage the kidneys and endothelium, where reduced binding sites for lipases may precipitate a vicious cycle of dyslipidemia, proteinuria, and nephropathy. [ABSTRACT FROM AUTHOR]

The 5,10-methylenetetrahydrofolate reductase (MTHFR) gene 677C→T polymorphism causes an A222V amino acid change which affects MTHFR enzyme activity and can increase homocysteine, a vascular disease risk factor. This polymorphism was examined for association with stroke. In a case-control study of 241 ischemic stroke patients and 304 controls in Hong Kong, the V allele increased in stroke [28% vs. 20%, odds ratio (OR) 1.5, p =0.003]. A lack of significance for the increase in the Wgenotype (7.5% vs. 4.6%, OR 1.7, p =0.16) may be due to its rarity in this region. V-allele carriers had more severe strokes (according to the NIH stroke scale). The association of the V allele with stroke occurred mostly in women or older subjects and was due to decreasing V allele frequency with age, as seen in other studies. This V frequency decline with age might be due to a loss of V-carrying controls from a higher risk of cancer, vascular disease, bone fracture, and kidney failure when folate is sparse. Examination of previous studies revealed that the association of VV genotype with stroke appeared stronger in Japan than elsewhere, possibly due to dietary differences. Perhaps folate supplementation for stroke prevention would particularly benefit VV individuals in such high-risk regions. [ABSTRACT FROM AUTHOR]

Background. Diabetic nephropathy represents a heterogeneous group of renal pathologies that may be associated with genetic susceptibility. There have been clinical reports on the risk association of diabetic nephropathy with an apolipoprotein E (ApoE) exon 4 polymorphism although its correlations with renal histopathological changes have not been explored. Methods. A total of 213 adult autopsies with type 2 diabetes and 111 non-diabetic control cases were analysed. Genomic DNA samples were obtained from spleen tissues. The ApoE genotype was determined by PCR-LDR analysis. Histopathological examination of kidney sections was performed in a subset of 51 diabetic and 111 control cases. ApoE protein expression in diabetic carriers with similar clinical status was examined by immunohistochemical staining. Results. In type 2 diabetes, ε2 carriers (P = 0.04; odds ratio = 5.42; 95% CI: 1.10–26.8) and ε3/ε4 (P = 0.04; odds ratio = 22.5; 95% CI: 1.11–454.90) genotype carriers were more likely to have glomerular hypertrophy than were ε3/ε3 carriers. The ε2 carriers showed an increase in glomerular ApoE protein expression. A correlation between ApoE genotype and nodular glomerulosclerosis was not found. Conclusions. Our findings confirm the risk association of the ApoE polymorphism with diabetic nephropathy in clinical studies and is the first study demonstrating the correlations between ApoE genotypes, protein expression and structural changes in diabetic nephropathy. [ABSTRACT FROM AUTHOR]

Abstract: Background: Familial combined hyperlipidaemia (FCH) is the most common genetic dyslipidaemia associated with coronary artery disease. Single nucleotide polymorphisms (SNPs) and haplotypes in the APOA1/C3/A4/A5 gene cluster are associated with FCH in Caucasians and with elevated triglycerides (TG) in various ethnic groups. We examined these associations with FCH in Hong Kong Chinese. Methods: Fifty-six Chinese FCH patients and 176 unrelated controls were studied. Thirteen SNPs in the APOA1/C3/A4/A5 cluster were genotyped. Results: Four alleles in APOA5 were associated with FCH (P <0.001). The −1131T>C (rs662799) and −3A>G (rs651821) SNPs in APOA5 were in almost complete linkage disequilibrium (LD, r 2 =0.99), and their minor alleles were more frequent (P <0.001) in FCH than controls (0.60 vs. 0.24). The odds ratio (OR) for FCH was 6.2 (95% CI, 2.6–14.8) and 6.1 (2.6–14.6) per copy of −1131C and −3G, respectively, and 24.6 (8.4–72.0) and 24.4 (8.4–70.9) in −1131C and −3G homozygotes, respectively, as compared to wild-type homozygotes. The 1891T>C (rs2266788) SNP was in LD (r 2 =0.68) with −1131T>C and −3A>G, and the minor allele was more frequent in FCH than controls (0.42 vs. 0.19, P <0.001). The 553G>T (rs2075291) nonsynonymous variant was also associated with FCH (0.15 vs. 0.04, P =0.001) and, along with −3A>G (or −1131T>C) and 1891T>C, contributed to haplotypes predicting FCH. The two tightly linked SNPs, −1131T>C and −3A>G polymorphism were significantly associated with lipid traits in all subjects combined, with variant homozygous subjects having higher TG and LDL-C and lower HDL-C levels. Conclusions: Some common polymorphisms and haplotypes in APOA5 are closely associated with FCH in Hong Kong Chinese, and these differ from those found in Caucasians. [Copyright &y& Elsevier]

Abstract: Objective: Ischemic stroke is prevalent in type 2 diabetes and may be due to metabolic, vascular and inflammatory factors. Genetic variants implicated in these pathways may have joint effects on stroke risk. In this proof-of-concept study, we examined gene–gene interactions on risk of incident ischemic stroke in an 8-year prospective cohort of Chinese type 2 diabetic patients. Methods: Seventy-seven single nucleotide polymorphisms (SNPs) of 53 candidate genes for cardiovascular disease and inflammation were genotyped in 1327 patients with no past history of ischemic stroke. The association of SNPs with stroke was tested using Cox proportional hazard regression analysis. Permutation procedure was performed to control for multiple statistical comparisons. Results: Genetic variants including A/A of IL5RA (interleukin-5 alpha subunit) -5091G>A, X/X of LPL (lipoprotein lipase) S447X, A/A of ITGA2 (integrin A2) G873A and T/T or G/T of NOS3 (endothelial nitric oxide synthase) G894T showed significant correlations with incident ischemic stroke. The hazard ratios (HR) increased with number of genetic risk factors reaching an adjusted HR (confidence interval) of 3.68 (1.78–7.62, P =4.4×10−4) in those with ≥2 genetic risk factors compared to those without. Conclusion: Polymorphisms in IL5RA, LPL, ITGA2 and NOS3 genes were independently associated with ischemic stroke in Chinese diabetic population. [Copyright &y& Elsevier]