Linkage disequilibrium analyses of natriuretic peptide precursor B locus reveal risk haplotype conferring high plasma BNP levels

BACKGROUND: Brain natriuretic peptide (BNP) has been widely used for the diagnosis and prognostic evaluation of chronic heart failure (CHF). In the present study, we performed association study of single nucleotide polymorphisms (SNPs) surrounding the natriuretic peptide precursor B (NPPB) gene with plasma BNP levels in 2970 adult Japanese. METHODS AND RESULTS: Association analysis between SNPs of the NPPB gene and plasma BNP revealed significant associations of the 8 SNPs surrounding the entire NPPB gene with plasma BNP levels. For instance, as to SNP rs198389 (T-381C), plasma BNP levels among the three genotypic categories, i.e., 2189 homozygous T-allele carriers (BNP 26.4+/-0.6pg/ml), 697 heterozygous carriers (35.0+/-1.1pg/ml), and 52 homozygous C-allele carriers (46.0+/-4.1pg/ml) indicated a co-dominant effect of the minor C-allele on elevating plasma BNP levels (P<0.0001). Linkage disequilibrium (LD) analysis among the 8 SNPs revealed that the region consisted of two, 5' major and 3' minor, LD blocks. Haplotype-based association analysis demonstrated that plasma BNP levels were associated closely with the haplotypes-1 and -2 of the major LD block. CONCLUSION: These results suggest that genetic variation at the primary locus NPPB gene, represented by definition of risk haplotypes, may be an important determinant of plasma BNP levels.     

Plasma brain natriuretic peptide as a surrogate marker for cardioembolic stroke

Background

Cardioembolic stroke generally results in more severe disability, since it typically has a larger ischemic area than the other types of ischemic stroke. However, it is difficult to differentiate cardioembolic stroke from non-cardioembolic stroke (atherothrombotic stroke and lacunar stroke). In this study, we evaluated the levels of plasma brain natriuretic peptide in acute ischemic stroke patients with cardioembolic stroke or non-cardioembolic stroke, and assessed the prediction factors of plasma brain natriuretic peptide and whether we could differentiate between stroke subtypes on the basis of plasma brain natriuretic peptide concentrations in addition to patient's clinical variables.

Methods

Our patient cohort consisted of 131 consecutive patients with acute cerebral infarction who were admitted to Kagawa University School of Medicine Hospital from January 1, 2005 to December 31, 2007. The mean age of patients (43 females, 88 males) was 69.6 ± 10.1 years. Sixty-two patients had cardioembolic stroke; the remaining 69 patients had non-cardioembolic stroke (including atherothrombotic stroke, lacunar stroke, or the other). Clinical variables and the plasma brain natriuretic peptide were evaluated in all patients.

Results

Plasma brain natriuretic peptide was linearly associated with atrial fibrillation, heart failure, chronic renal failure, and left atrial diameter, independently (F_4,126 = 27.6, p < 0.0001; adjusted R² = 0.45). Furthermore, atrial fibrillation, mitral regurgitation, plasma brain natriuretic peptide (> 77 pg/ml), and left atrial diameter (> 36 mm) were statistically significant independent predictors of cardioembolic stroke in the multivariable setting (Χ² = 127.5, p < 0.001).

Conclusion

It was suggested that cardioembolic stroke was strongly predicted with atrial fibrillation and plasma brain natriuretic peptide. Plasma brain natriuretic peptide can be a surrogate marker for cardioembolic stroke.     

Dysregulation of MicroRNAs in cancer

Background

The association between ischemic stroke and 2 single nucleotide polymorphisms (SNPs) on chromosome 12p13, rs12425791 and rs11833579 appears inconsistent across different samples. These SNPs are close to the ninjurin2 gene which may alter the risk of stroke by affecting brain response to ischemic injury. The purpose of this study was to investigate the association between these two SNPs and ischemic stroke risk, as well as prognostic outcomes in a Taiwanese sample.

Methods

We examined the relations of these two SNPs to the odds of new-onset ischemic stroke, ischemic stroke subtypes, and to the one year risk of stroke-related death or recurrent stroke following initial stroke in a case-control study. A total of 765 consecutive patients who had first-ever ischemic stroke were compared to 977 stroke-free, age-matched controls. SNPs were genotyped by Taqman fluorescent allelic discrimination assay. The association between ischemic stroke and SNPs were analyzed by multivariate logistic regression. Cox proportional hazard model was used to assess the effect of individual SNPs on stroke-related mortality or recurrent stroke.

Results

There was no significant association between SNP rs12425791 and rs11833579 and ischemic stroke after multiple testing corrections. However, the marginal significant association was observed between SNP rs12425791 and large artery atherosclerosis under recessive model (OR, 2.30; 95%CI, 1.22-4.34; q-value = 0.062). Among the 765 ischemic stroke patients, 59 died or developed a recurrent stroke. After adjustment for age, sex, vascular risk factors and baseline stroke severity, Cox proportional hazard analysis indicated that the hazard ratios were 2.76 (95%CI, 1.34-5.68; q-value, 0.02) and 2.15 (95%CI, 1.15-4.02; q-value, 0.03) for individuals with homozygous variant allele of rs12425791 and rs11833579, respectively.

Conclusions

This is a precedent study that found genetic variants of rs12425791 and rs11833579 on chromosome 12p13 are independent predictors of stroke-related mortality or stroke recurrence in patients with incident ischemic stroke in Taiwan. Further study is needed to explore the details of the physiological function and the molecular mechanisms underlying the association of this genetic locus with ischemic stroke.     

A Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population

To investigate whether single nucleotide polymorphisms (SNPs) of eicosanoid biosynthesis genes are associated with intracerebral hemorrhage (ICH) and ischemic stroke (IS), seven SNPs in the coding or promoter regions were selected: ALOX12 (rs434473, Asn322Ser), ALOX5 (rs2228064, Thr90Thr), ALOX5AP (rs17222919, -1316T/G), PTGES (rs7872802, -404A/G), PTGIS (rs5628, Leu256Leu), PTGS1 (rs3842788, Gln41Gln) and PTGS2 (rs5275, 3'UTR). A total of 398 control subjects and 196 stroke patients (79 ICH and 117 IS) were genotyped by direct sequencing. The rs17222919 SNP was associated with ICH in codominant 1 (P=0.008), dominant (P=0.003) and log-additive (P=0.004) models. Allele frequencies of rs17222919 were different between ICH and controls (P=0.007). However, the seven tested SNPs were not associated with clinical phenotypes (NIHSS, MBI and CRPS) in ICH and IS. These results suggest that the promoter SNP rs17222919 of ALOX5AP may be associated with the development of ICH in Korean population.     

Association of ALOX5AP with ischemic stroke: a population-based case-control study

Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P = 0.019 and P < 10⁻⁴, respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.     

Association of SNP41, SNP56 and a novel SNP in PDE4D gene with stroke and its subtypes

An association between phosphodiesterase 4D (PDE4D) gene and risk of stroke has been suggested by deCODE group in an Icelandic population. In the present case–control study we investigated the association of SNP41 (rs12153798) and SNP56 (rs702553) with ischemic stroke and stroke subtypes. Five hundred and sixteen ischemic stroke patients and 513 healthy age and sex matched controls were included in the study. The genotypes were determined by subjecting the PCR products to sequencing. Both the SNPs 56 and 41 associated significantly with stroke [adjusted OR = 1.97; 95% CI (1.262–3.082); p = 0.003: adjusted OR = 5.42; 95% CI (3.45–8.5); p < 0.001 respectively]. In addition to this, a novel SNP at position 59736747 T > G was found while sequencing the PCR products including SNP56. This novel SNP was found in patients as well as controls but did not show a significant association with the disease. We found significant association of SNPs 56 and 41 with large artery atherosclerosis, lacunar and cardioembolic stroke. In conclusion PDE4D gene plays a key part in the pathogenesis of ischemic stroke in the South Indian population from Andhra Pradesh.     

Association of adiponectin gene polymorphisms with the risk of ischemic stroke in a Chinese Han population

Adiponectin is inversely associated with the risk of ischemic stroke through its anti-inflammatory and anti-atherogenic effects. Genetic variations in the adiponectin gene (ADIPOQ) have been shown to be associated with the risk of ischemic stroke in Caucasians and Japanese populations. However, it was unknown whether variations in the ADIPOQ gene were associated with the risk of ischemic stroke in Chinese population. A case-control study was performed among 302 patients with ischemic stroke and 338 unrelated controls in a Chinese Han population. The single-nucleotide polymorphisms (SNPs) rs266729 (−11377C/G), rs2241766 (+45T/G), rs1501299 (+276G/T) in the ADIPOQ gene were genotyped by the polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method. The frequencies of GG genotype and G allele of rs266729 in the patients with ischemic stroke were significantly higher than those in the controls (P = 0.034, P = 0.010, respectively). In univariate logistic analysis, compared with CC genotype, GG genotype of rs266729 increased the risk of ischemic stroke (odds ratio (OR) = 2.062, 95% confidence interval (CI) = 1.145–3.715, P = 0.016). After adjustment for potential risk factors by the multivariate logistic analysis, rs266729 remained positive correlation with ischemic stroke (OR = 2.165; 95% CI = 1.116–4.197, P = 0.022). However, no significant association was observed among rs2241766, rs1501299 and ischemic stroke. In addition, no significant difference was found in haplotype frequencies between the patients with ischemic stroke and control subjects. The present study demonstrated that the promoter polymorphism rs266729 of the ADIPOQ gene was associated with an increased risk of ischemic stroke in the Chinese Han population.     

Neuroserpin polymorphisms and stroke risk in a biracial population: the stroke prevention in young women study

Background

Neuroserpin, primarily localized to CNS neurons, inhibits the adverse effects of tissue-type plasminogen activator (tPA) on the neurovascular unit and has neuroprotective effects in animal models of ischemic stroke. We sought to evaluate the association of neuroserpin polymorphisms with risk for ischemic stroke among young women.

Methods

A population-based case-control study of stroke among women aged 15–49 identified 224 cases of first ischemic stroke (47.3% African-American) and 211 age-matched control subjects (43.1% African-American). Neuroserpin single nucleotide polymorphisms (SNPs) chosen through HapMap were genotyped in the study population and assessed for association with stroke.

Results

Of the five SNPs analyzed, the A allele (frequency; Caucasian = 0.56, African-American = 0.42) of SNP rs6797312 located in intron 1 was associated with stroke in an age-adjusted dominant model (AA and AT vs. TT) among Caucasians (OR = 2.05, p = 0.023) but not African-Americans (OR = 0.71, p = 0.387). Models adjusting for other risk factors strengthened the association. Race-specific haplotype analyses, inclusive of SNP rs6797312, again demonstrated significant associations with stroke among Caucasians only.

Conclusion

This study provides the first evidence that neuroserpin is associated with early-onset ischemic stroke among Caucasian women.     

Association between IL10, IL10RA, and IL10RB SNPs and ischemic stroke with hypertension in Korean population

The pathogenesis of stroke is associated with the immune and inflammatory responses. Cytokines, such as interleukin 10 (IL10), play an important role in the process of inflammation. To investigate whether IL10, IL10RA, and IL10RB polymorphisms are associated with the risk of ischemic stroke (IS), selected two IL10 SNPs (rs1518111 and rs1554286), three IL10RA SNPs (rs2256111, rs4252243, and rs2228054), and two IL10RB SNPs (rs999788 and rs2834167) were analyzed in 120 patients with IS and 285 control subjects. All IS patients were classified into the clinical subgroups, according to the levels of blood pressure (hypertension, present and absent), fasting plasma glucose (diabetes mellitus, present and absent), and lipids (dyslipidemia, present and absent). SNPStats and SPSS 18.0 program were used to obtain the odds ratios, 95 % confidence intervals, and P values. Multiple logistic regression models (codominant1, codominant2, dominant, recessive, and log-additive models) were performed to analyze the genetic data. Seven polymorphisms were not associated with the IS, but showed significant associations with hypertension, in the risk of IS. These results suggest that the IL10, IL10RA, and IL10RB genes may be contributed to the hypertension in the risk of IS in the Korean population.     

Lysyl oxidase polymorphisms and ischemic stroke—a case control study

Ischemic stroke is a common neurological disease and causes severe disability and death worldwide. Lysyl oxidase (LOX) plays a crucial role in the maintenance of extracellular matrix stability and may participate in vascular remodeling in the development of ischemic stroke. The objective of this study is to identify polymorphisms in LOX genes and investigate the association between LOX polymorphisms and the susceptibility to ischemic stroke in the Chinese population. Genomic DNA sequencing analysis was performed on all 7 exons and all exon/intron splice sites of lysyl oxidase and 850?bp upstream, including the predicted promoter region in 25 control subjects. The identified polymorphisms were then detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 702 ischemic stroke cases and 733 age-matched controls. Data were analyzed using the Chi-square test. Two polymorphisms in the LOX gene, 473G/A (rs1800449) and rs2278226, were observed in the Chinese population. Frequencies of LOX 473AA genotype and A allele were significantly higher in ischemic stroke patients than in controls (odds ration (OR)?=?1.76, 95?% confidence interval (CI) 1.16-2.67, P?=?0.007; and OR?=?1.33, 95?% CI 1.10-1.60, P?=?0.003). Also, the prevalence of AC haplotype was significantly increased in ischemic stroke cases (OR?=?1.32, 95?% CI 1.10-1.60, P?=?0.004). Our data suggest that the G473A polymorphism of LOX gene could be a new risk factor for ischemic stroke.     

Contribution of the OBSCN nonsynonymous variants to aspirin exacerbated respiratory disease susceptibility in Korean population

Airway remodeling and exacerbated airway narrowing in asthma have been attributed to the regulation of intracellular Ca(2+) by sarcoplasmic reticulum (SR) of the airway smooth muscle cells. The protein encoded by obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF (OBSCN) is a crucial factor in determining the SR architecture in Obscn(-/-) mice. This study genotyped a total of 55 common single-nucleotide polymorphisms (SNPs) in 592 Korean asthmatics including 163 aspirin exacerbated respiratory disease (AERD) cases and 429 aspirin-tolerant asthma (ATA) controls. Eight SNPs, including two nonsynonymous polymorphisms rs1188722C>T (Leu2116Phe) and rs1188729G>C (Cys4642Ser), and one haplotype BL2_ht1 showed statistically significant associations with AERD development (p=0.003-0.03). Two variants, rs1188722C>T (Leu2116Phe) and rs369252C>A, also revealed nominal association with FEV1 decline by aspirin provocation in asthmatics (p=0.03-0.04). Intriguingly, rs1188722C>T (Leu2116Phe) is a highly conserved amino acid residue among species, suggesting its functional relevance to AERD. In addition, the A allele of rs369252C>A, which was more prevalent in AERD than in ATA, was predicted as a potential branch point (BP) site for alternative splicing (BP score=4.29). Although further functional evaluation is required, our findings suggest that OBSCN polymorphisms, in particular, highly conserved nonsynonymous Leu2116Phe variant, might contribute to aspirin hypersensitivity in asthmatics.     

Association of <Emphasis Type="Italic">ACYP2</Emphasis> and <Emphasis Type="Italic">TSPYL6</Emphasis> Genetic Polymorphisms with Risk of Ischemic Stroke in Han Chinese Population

The development of ischemic stroke is associated with advanced age. Telomere length, as a marker of biological aging, has been reported to influence the risk of several age-related diseases, including ischemic stroke. Recent studies have identified the genetic variant within ACYP2 and TSPYL6 associated with shorter telomere length. The objective of this study is to investigate the putative association of ischemic stroke with common polymorphisms in ACYP2 and TSPYL6 genes in a Chinese Han population. We found that the risk alleles of six single nucleotide polymorphisms (SNPs), including rs11125529, rs12615793, rs843711, rs11896604, and rs843706 within both ACYP2 and TSPYL6, and rs17045754 in ACYP2 gene, were related with increased risk of ischemic stroke according to both allelic and genotype association analyses. The significant correlations between ACYP2 and TSPYL6 SNPs and ischemic stroke risk were also observed in dominant, recessive, and additive models, respectively. Two blocks in high linkage disequilibrium were identified in this study, and two haplotypes were associated with higher ischemic stroke susceptibility. In conclusion, the genetic polymorphisms of ACYP2 and TSPYL6 are associated with increased risk of developing ischemic stroke. Further studies with larger sample sizes are required to validate our findings.     

Association of the Genetic Polymorphisms in Pre-MicroRNAs with Risk of Ischemic Stroke in a Chinese Population

microRNA (miRNA) plays a role in the pathogenesis of ischemic stroke, and single nucleotide polymorphisms in miRNA genes may contribute to disease susceptibility. However, the effect of miR-146a, miR-196a2, and miR-499 polymorphisms on ischemic stroke susceptibility has been rarely reported. Using the TaqMan assay, we evaluated the association of hsa-miR-146a/rs2910164, hsa-miR-196a2/rs11614913, and hsa-miR-499/rs3746444 polymorphisms with the risk of ischemic stroke in a Chinese population with 531 ischemic stroke patients and 531 control subjects. Rs2910164 C/G genotypes were significantly associated with increased risk of ischemic stroke in different genetic model (homozygote comparison: OR = 2.00, 95% CI, 1.29–3.12, P = 0.002; additive model: OR = 1.35, 95% CI, 1.10–1.65, P = 0.004;dominant model: OR = 1.33, 95% CI, 1.00–1.75, P = 0.049; recessive model: OR = 1.82, 95% CI, 1.20–2.74, P = 0.004). Subjects with allele G of hsa-miR-146a/ rs2910164 also showed increased risk of ischemic stroke (OR = 1.33, 95% CI, 1.09–1.62, P = 0.005). Stratification analysis showed that the association between rs2910164 and the risk of ischemic stroke was more pronounced in subjects over 60 years old, females, non-drinkers, subjects without hypertension or diabetes mellitus. There were significant combined effects between miR-146a/rs2910164 and fasting glucose/low-density lipoprotein cholesterol levels on ischemic stroke susceptibility. However, we failed to find any association between the alleles/genotypes of rs11614913 T/C and ischemic stroke, respectively (P> 0.05). In summary, this study provides evidence that miR-146a/rs2910164 might be associated with a significantly increased risk of ischemic stroke in a Chinese population, and the combined effects between miRNA polymorphism and fasting glucose /blood lipid levels may contribute to stroke pathogenesis.     

miR-146a and miR-196a2 Polymorphisms in Patients with Ischemic Stroke in the Northern Chinese Han Population

MicroRNAs are endogenous non-coding RNAs about 22 nucleotides in length that can repress the expression of proteins by binding to the 3′-untranslated regions of target messenger RNAs. We hypothesized that polymorphisms in miR-146a and miR-196a2 are associated with risk of ischemic stroke in the northern Chinese Han population. In a case–control study of 368 ischemic stroke patients and 381 control subjects that were frequency matched by age and gender, we genotyped two single nucleotide polymorphisms (rs11614913 in miR-196a2 and rs2910164 in miR-146a) using polymerase chain reaction-ligation detection reaction. The frequencies of the rs2910164 CC genotype and C allele within miR-146a were not significantly different in patients with ischemic stroke compared with those in the healthy control group. In subgroup meta-analysis, rs2910164 in miR-146a and large-artery atherosclerosis, rather than small-vessel disease, showed the significant association under the dominant model (CC vs CG+GG, OR 1.694; 95 % CI 1.199–2.395 p = 0.003). After adjusting for confounding risk factors of ischemic stroke by logistic regression analysis, this significant correlation remained. In addition, the distributions of the miR-196a2 genotypes and alleles were not statistically different between ischemic stroke and healthy groups. We also did not find any significant association from stroke subtypes. The CC genotype and C allele of rs2910164 within miR-146a are associated with an increased incidence of large-artery athersclerotic stroke in the northern Chinese Han population. This study indicates that miR-146a (rs2910164) might contribute to ischemic stroke susceptibility in the northern Chinese Han population.     

Association study of single nucleotide polymorphisms in pre-miRNA and rheumatoid arthritis in a Han Chinese population

The aim of this study was to perform an association study between two single nucleotide polymorphisms (SNPs) rs2910164 G>C and rs3746444 T>C in pre-miRNA (hsa-mir-146a and hsa-mir-499) and rheumatoid arthritis (RA) in the Han Chinese population. 208 Han Chinese patients with RA and 240 healthy controls were recruited in this study. The SNPs was genotyped by polymerase chain reaction-restriction fragment length polymorphism. Anti-cyclic citrullinated peptide (anti-CCP) antibody was measured by enzyme linked immunosorbent assay and rheumatoid factor (RF) was measured by rate nephelometry. The genotype frequencies between cases and controls were compared by χ(2) analysis. No significant association between the SNPs (rs2910164 and rs3746444) and RA was observed (P = 0.631 and 0.775, respectively), and the SNPs did not show any association with the RF-positive (P = 0.631 and 0.775, respectively). However, there was a significant difference on the level of anti-CCP antibody between different genotypes in rs3746444 (P = 0.007). The heterozygote CT had significantly higher level of anti-CCP antibody compared with homozygote CC and TT (P = 0.054 and 0.003, respectively). We first investigated the association between the SNPs (rs2910164 G>C and rs3746444 T>C) in the pre-miRNA (hsa-mir-146a and hsa-mir-499) and RA in a Han Chinese population. We did not find a significant association between the SNPs and the susceptibility to RA, while the SNP rs3746444 may affect anti-CCP antibody production.     

Association of rs10912745 and rs4916375 polymorphisms located in the cluster of flavin-containing monooxygenase genes, with ischaemic cardioembolic stroke

Twenty-one SNPs located in the cluster of genes FMO1-FMO2-FMO3-FMO4 and adjacent areas were analyzed in the patients with ischaemic cardioembolic stroke and in the control group. Significant differences between these samples were found in the distribution of genotype and allele differences in two polymorphic loci, rs10912745 and rs4916375. It was shown that these polymorphic loci are associated with the risk of ischaemic cardioembolic stroke development.     

Pathway analysis of genome-wide association study on serum prostate-specific antigen levels

The wide application of prostate-specific antigen (PSA) has contributed to the early diagnosis and improved management of prostate cancer (PCa). Accumulating evidence has suggested the involvement of genetic components in regulating serum PSA levels, and several single nucleotide polymorphisms (SNPs) have been identified by genome-wide association studies (GWASs). However, the GWASs' results have the limited power to identify the causal variants and pathways. After the quality control filters, a total of 330,540 genotyped SNPs from one GWAS with 657 PCa-free Caucasian males were included for the identify candidate causal SNPs and pathways (ICSNPathway) analysis. In addition, the genotype–phenotype association analysis has been conducted with the data from HapMap database. Overall, a total of four SNPs in three genes and six pathways were identified by ICSNPathway analysis, which in total provided three hypothetical mechanisms. First, CYP26B1 rs2241057 polymorphism (nonsynonymous coding) which leads to a Leu-to-Ser amino acid shift at position 264, was implicated in the pathways including meiosis, proximal/distal pattern formation, and M phase of meiotic cell cycle. Second, CLIC5 rs3734207 and rs11752816 polymorphisms (regulatory region) to the 2 iron, 2 sulfur cluster binding pathway through regulating expression levels of CLIC5 mRNA. Third, rs4819522 polymorphism (nonsynonymous coding) leads to a Thr-to-Met transition at position 350 of TBX1 and involves in the pathways about gland and endocrine system development. In summary, our results demonstrated four candidate SNPs in three genes (CYP26B1 rs2241057, CISD1 rs2251039, rs2590370, and TBX1 rs4819522 polymorphisms), which were involved in six potential pathways to influence serum PSA levels.     

Genome-wide and follow-up studies identify CEP68 gene variants associated with risk of aspirin-intolerant asthma

Aspirin-intolerant asthma (AIA) is a rare condition that is characterized by the development of bronchoconstriction in asthmatic patients after ingestion of non-steroidal anti-inflammatory drugs including aspirin. However, the underlying mechanisms of AIA occurrence are still not fully understood. To identify the genetic variations associated with aspirin intolerance in asthmatics, the first stage of genome-wide association study with 109,365 single nucleotide polymorphisms (SNPs) was undertaken in a Korean AIA (n = 80) cohort and aspirin-tolerant asthma (ATA, n = 100) subjects as controls. For the second stage of follow-up study, 150 common SNPs from 11 candidate genes were genotyped in 163 AIA patients including intermediate AIA (AIA-I) subjects and 429 ATA controls. Among 11 candidate genes, multivariate logistic analyses showed that SNPs of CEP68 gene showed the most significant association with aspirin intolerance (P values of co-dominant for CEP68, 6.0×10⁻⁵ to 4.0×10⁻⁵). All seven SNPs of the CEP68 gene showed linkage disequilibrium (LD), and the haplotype of CEP68_ht4 (T-G-A-A-A-C-G) showed a highly significant association with aspirin intolerance (OR  = 2.63; 95% CI  = 1.64–4.21; P = 6.0×10⁻⁵). Moreover, the nonsynonymous CEP68 rs7572857G>A variant that replaces glycine with serine showed a higher decline of forced expiratory volume in 1s (FEV₁) by aspirin provocation than other variants (P = 3.0×10⁻⁵). Our findings imply that CEP68 could be a susceptible gene for aspirin intolerance in asthmatics, suggesting that the nonsynonymous Gly74Ser could affect the polarity of the protein structure.     

Analysis of the polymorphic variants of the PDE4D gene in patients with acute stroke in the Moldavian population

The risk of the ischemic stroke is mediated by both environmental and genetic factors. Recent studies of DeCode group identified the risk of polymorphisms for ischemic stroke in the phosphodiesterase 4D gene (PDE4D). The goal of this study was to explore the role of two variants of the gene encoding PDE4D [SNP41 (rs152312) and SNP87 (rs2910829)] in the Moldavian patients with ischemic stroke and in control. No significant association with ischemic stroke was observed with SNP41 and 87.     

Replication of genetic effects of FTO polymorphisms on BMI in a Korean population

It has been newly reported in recent studies that single-nucleotide polymorphisms (SNPs) in the first intron of the FTO gene have been associated with BMI in whites. To determine whether the gene is associated with BMI in Asians also, we performed a replication study of the association of the gene with BMI in a Korean population. Two SNPs in the FTO gene (rs1421085 and rs17817449) were genotyped using the TaqMan method in a Korean population (n = 1,733). The two SNPs were then used for an association study with BMI through statistical analyses. The rs1421085 C allele (P = 0.0015, effect size = 0.0056) and rs17817449 G allele (P = 0.0019, effect size = 0.0053) were found to be significantly associated with increased BMI. Our results suggest that FTO may be one of the worldwide obesity-risk genes.