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1.  Interrelationships between ALOX5AP Polymorphisms, Serum Leukotriene B4 Level and Risk of Acute Coronary Syndrome 
PLoS ONE  2014;9(9):e106596.
Background
We investigated the relationships between the ALOX5AP gene rs10507391 and rs4769874 polymorphisms, serum levels of leukotriene (LT) B4, and risk of acute coronary syndrome (ACS).
Methods
A total of 709 participants, comprising 508 ACS patients (ACS group) and 201 noncoronary artery disease patients with chest pain (control group) were recruited from the Han population of the Changwu region in China. Two polymorphic loci were genotyped using polymerase chain reaction and restriction fragment length polymorphism analysis. Serum LTB4 level was determined by enzyme-linked immunosorbent assay.
Results
Serum LTB4 levels were significantly higher (P<0.001) in the ACS group (median/interquartile range, 470.27/316.32 pg/ml) than in the control group (233.05/226.82 pg/ml). No statistical differences were observed between genotype, allele and haplotype frequencies for the tested loci in either the ACS group or the control group, even after adjustments were made for conventional risk factors by multivariate logistic regression. This suggests there is no association between the ALOX5AP rs10507391 and rs4769874 polymorphisms and ACS risk. Elevated serum LTB4 level was closely linked to ACS risk, and may be independent of traditional risk factors as a risk factor for ACS (P<0.001). There was no significant association between serum LTB4 levels and the two variants in either the ACS group or the control group.
Conclusions
Rs10507391, rs4769874 and its haplotypes in ALOX5AP are unrelated to ACS risk in the Chinese Han population of Changwu, but elevated serum LTB4 level is strongly associated with ACS risk. Serum LTB4 level is not subject to the influence of either the rs10507391, rs4769874 or the haplotype.
doi:10.1371/journal.pone.0106596
PMCID: PMC4161330  PMID: 25210744
2.  Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and risk of ischemic stroke in Han Chinese of eastern China☆ 
Journal of Biomedical Research  2011;25(5):319-327.
Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been suggested to play an important role in the pathogenesis of atherosclerosis and ischemic stroke. This study was aimed to explore the association of ALOX5AP variants with ischemic stroke risk in Han Chinese of eastern China. A total of 690 ischemic stroke cases and 767 controls were recruited. The subjects were further subtyped according to the Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. On the basis of that, two polymorphisms of the ALOX5AP gene (rs10507391 and rs12429692) were determined by TaqMan genotyping assay. In addition, plasma leukotriene B4 (LTB4) levels were analyzed in these subjects. There was no evidence of association between the two variants of ALOX5AP and the risk of ischemic stroke or its TOAST-subtypes. Haplotype analysis and stratification analysis according to sex, age, body mass index, hypertension, and diabetes also showed negative association. Analysis of LTB4 levels in a subset of cases and controls revealed that LTB4 levels were significantly higher in ischemic stroke cases than in the controls (70.06±14.75 ng/L vs 57.34±10.93 ng/L; P = 0.000) and carriers of the T allele of the rs10507391 variant were associated with higher plasma LTB4 levels (P = 0.000). The present study suggests there is no association of the two polymorphisms in the ALOX5AP gene with ischemic stroke risk in Han Chinese of eastern China.
doi:10.1016/S1674-8301(11)60043-2
PMCID: PMC3596728  PMID: 23554707
arachidonate 5-lipoxygenase-activating protein; ischemic stroke; variants; leukotriene B4; risk factors
3.  ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos 
Background
Understanding the effects of interactions between multiple genes and asthma medications may aid in the understanding of the heterogeneous response to asthma therapies.
Objective
To identify modulating effects of ALOX5AP and LTA4H gene polymorphisms on the drug-drug interaction between leukotriene modifiers and albuterol in Mexicans and Puerto Ricans.
Methods
In a cross-sectional study of 293 Mexicans and 356 Puerto Ricans with asthma, ALOX5AP and LTA4H genes were sequenced, and interactions between gene polymorphisms and bronchodilator responsiveness to albuterol was analyzed between leukotriene modifier users and non-users.
Results
In heterozygotes and homozygotes for the minor allele at LTA4H SNP rs2540491 and heterozygotes for the major allele at LTA4H SNP rs2540487, leukotriene modifier use was associated with a clinically significant increase in percent change in forced expiratory volume in 1 second (FEV1) after albuterol administration of 7.10% (p=0.002), 10.06% (p=0.001), and 10.03% (p<0.001), respectively. Presence of the major allele at ALOX5AP SNP rs10507391 or the minor allele at ALOX5AP SNP rs9551963 augmented this response. When stratified by ethnicity, these findings held true for Puerto Ricans, but not Mexicans.
Conclusions
LTA4H and ALOX5AP gene polymorphisms modify the augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans but not Mexicans with asthma.
doi:10.1016/j.jaci.2010.06.048
PMCID: PMC2950217  PMID: 20810156
asthma; leukotriene; leukotriene modifier; Latino; albuterol; drug responsiveness; association study; genetic polymorphism
4.  No association of ALOX5AP polymorphisms with risk of MRI-defined brain infarcts 
Neurobiology of Aging  2011;33(3):629.e1-629.e3.
The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene has been associated with stroke. The majority of the reported ALOX5AP associations have considered non-radiologically confirmed infarcts as the stroke phenotype. We assessed the association of genetic variants in ALOX5AP with stroke defined by the presence infarcts on brain Magnetic Resonance Imaging (MRI). We studied 202 persons with MRI-defined brain infarcts cases and 487 healthy individuals of Caribbean Hispanic ancestry. Another sample of European ancestry comprised of 1,823 persons with MRI-defined brain infarct and 7,578 controls. Subjects were genotyped for the four SNPs that define ALOX5AP HapA haplotype. No association was found between SNPs and MRI-defined brain infarcts. Our data do not support the hypothesis that variants in ALOX5AP are associated with risk of MRI-defined brain infarcts.
doi:10.1016/j.neurobiolaging.2011.10.010
PMCID: PMC3259245  PMID: 22074807
MRI-defined brain infarcts; ALOX5AP
5.  Correlation between the single nucleotide polymorphisms of the human phosphodiesterase 4D gene and the risk of cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China 
In this study, the correlation between the single nucleotide polymorphisms (SNPs) at rs2910829 and rs918592 in the phosphodiesterase 4D (PDE4D) gene and cerebral infarction in the Uygur and Han ethnic groups of Xinjiang, China were examined. The study population consisted of 373 Uygur and Han patients with cerebral infarction and 377 Uygur and Han control participants with no nervous system diseases. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and gene sequencing methods were used to assess the SNPs at the rs2910829 and rs918592 loci in the PDE4D gene. The differences in genotype and allele frequency distribution were compared between the two groups. The C allele frequency of the rs2910829 locus in the PDE4D gene of the cerebral infarction group (81.0%) was significantly higher than that of the control group (76.4%) (P<0.05). Furthermore, the A allele frequency of the rs918592 locus in the PDE4D gene in the Uygur cerebral infarction group was significantly higher than that of the Uygur control group (P<0.05). There were no significant differences in the genotype and allele frequency distributions between the Uygur and Han groups (P>0.05). The A allele of the rs918592 locus may be associated with the occurrence of cerebral infarction in the Uygur population. In addition, it was indicated that the C allele of the rs2910829 locus in the PDE4D gene confers susceptibility to cerebral infarction; however, no significant difference was identified between Uygur and Han patients with cerebral infarction.
doi:10.3892/etm.2013.1370
PMCID: PMC3861451  PMID: 24348782
phosphodiesterase 4D; single nucleotide polymorphism; cerebral infarction; Uygur
6.  Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma 
Rationale: Interpatient variability in montelukast response may be related to variation in leukotriene pathway candidate genes.
Objective: To determine associations between polymorphisms in leukotriene pathway candidate genes with outcomes in patients with asthma receiving montelukast for 6 mo who participated in a clinical trial.
Methods: Polymorphisms were typed using Sequenom matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass array spectrometry and published methods; haplotypes were imputed using single nucleotide polymorphism–expectation maximization (SNP-EM). Analysis of variance and logistic regression models were used to test for changes in outcomes by genotype. In addition, χ2 and likelihood ratio tests were used to test for differences between groups. Case-control comparisons were analyzed using the SNP-EM Omnibus likelihood ratio test.
Measurements: Outcomes were asthma exacerbation rate and changes in FEV1 compared with baseline.
Results: DNA was collected from 252 participants: 69% were white, 26% were African American. Twenty-eight SNPs in the ALOX5, LTA4H, LTC4S, MRP1, and cysLT1R genes, and an ALOX5 repeat polymorphism were successfully typed. There were racial disparities in allele frequencies in 17 SNPs and in the repeat polymorphism. Association analyses were performed in 61 whites. Associations were found between genotypes of SNPs in the ALOX5 (rs2115819) and MRP1 (rs119774) genes and changes in FEV1 (p < 0.05), and between two SNPs in LTC4S (rs730012) and in LTA4H (rs2660845) genes for exacerbation rates. Mutant ALOX5 repeat polymorphism was associated with decreased exacerbation rates. There was strong linkage disequilibrium between ALOX5 SNPs. Associations between ALOX5 haplotypes and risk of exacerbations were found.
Conclusions: Genetic variation in leukotriene pathway candidate genes contributes to variability in montelukast response.
doi:10.1164/rccm.200509-1412OC
PMCID: PMC2662939  PMID: 16293801
antiinflammatory; montelukast; pharmacodynamic; pharmacogenetic
7.  ALOX5 Is Associated with Tuberculosis in a Subset of the Pediatric Population of North China 
Background: Genetic factors are involved in the etiology of Mycobacterium tuberculosis infection. Recently, ALOX5 has been identified as a candidate gene for tuberculosis (TB) susceptibility. We investigated whether an association between ALOX5 and TB exists in a Chinese pediatric population from northern China. Methods: We conducted a case–control study comprising 488 individuals aged 2 months to 17 years by genotyping 18 tag-single-nucleotide polymorphisms (SNPs) from the ALOX5 gene. The tag-SNPs were selected from the international HapMap project. An Illumina BeadXpress Scanner was utilized for genotyping, supported by the high-density BeadArray technology in combination with an allele-specific extension, adapter ligation, and amplification assay. Statistical analyses were performed to determine correlations between genetic variation and disease. Results: Our study is the first to show that ALOX5 is associated with susceptibility to pediatric TB in a subset of children in northern China. The rs2115819 T allele of ALOX5 presents a risk factor for childhood TB disease.
doi:10.1089/gtmb.2012.0426
PMCID: PMC3609609  PMID: 23448388
8.  Association of LOX-1 gene polymorphisms with cerebral infarction in northern Chinese Han population 
Background
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays an important role in the pathophysiology of atherosclerosis and thrombosis. This study is aimed at evaluating the potential association of 3’-UTR-C188T and G501C in LOX-1 gene with cerebral infarction.
Methods
A total of 386 patients with cerebral infarction and 386 healthy controls were included in the study, which were unrelated Chinese Han population in the Liaoning Province of northern China. The single nucleotide polymorphisms, 3’-UTR-C188T and G501C, were analyzed by polymerase chain reaction–ligation detection reaction method.
Results
The frequencies of CC + GC genotype, GC genotype and C allele of G501C in the patients with cerebral infarction were significantly higher than those in the controls (P < 0.01, P < 0.01, P = 0.04, respectively). The correlation still remained after adjusting for confounding risk factors of cerebral infarction. In addition, no significant association was observed between 3’-UTR-C188T and cerebral infarction.
Conclusions
The study indicated that the G501C variant in LOX-1 gene may be associated with susceptibility to cerebral infarction, independent of other common risk factors, in northern Chinese Han population.
doi:10.1186/1476-511X-13-55
PMCID: PMC3994314  PMID: 24661313
LOX-1; Ox-LDL; Polymorphisms; Cerebral infarction; Atherosclerosis
9.  Correlation of PCSK9 Gene Polymorphism with Cerebral Ischemic Stroke in Xinjiang Han and Uygur Populations 
Background
Cerebral ischemic stroke (CIS) is a major cause of morbidity and mortality. Its main pathological basis is atherosclerosis (AS); in turn, the main risk factor in AS is dyslipidemia. Human proprotein convertase subtilisin/kexin9 (PCSK9) plays a key role in regulating plasma low-density lipoprotein (LDL) cholesterol levels. We sought to assess the association between PCSK9 and CIS in Chinese Han and Uygur populations.
Material/Methods
We selected 408 CIS patients and 348 control subjects and used a single-base terminal extension (SNaPshot) method to detect the genotypes of the 20 single-nucleotide polymorphisms (SNPs) in PCSK9.
Results
Distribution of SNP8 (rs529787) genotypes showed a significant difference between CIS and control participants (P=0.049). However, when analyzing Han and Uygur populations separately, we found that only Han subjects showed distribution of SNP1 (rs1711503), SNP2 (rs2479408), and SNP8 (rs529787) alleles that was significantly different between CIS and control participants (P=0.028, P=0.013, P=0.006, respectively), and distribution of SNP2 (rs2479408) in the dominant model (CC vs. CG + GG) was significantly different between CIS and control participants (P=0.013), even after adjustment for covariates (OR: 75.262, 95% confidence interval [CI]: 7.232–783.278, P<0.001). Distribution of the 2 haplotypes (A-C and G-C) (rs1711503 and rs2479408) was significantly different between CIS and control participants (both, P=0.011).
Conclusions
Both rs1711503 and rs2479408 of PCSK9 genes were associated with CIS in the Han population of China. A-C haplotype may be a genetic marker of CIS risk in this population.
doi:10.12659/MSM.892091
PMCID: PMC4189717  PMID: 25266949
Atherosclerosis; Ethnic Groups; Ischemic Attack; Transient; Proprotein Convertases
10.  Association of ALOX5AP with ischemic stroke in eastern Chinese 
BACKGROUND:
5-lipoxygenase protein (ALOX5AP) has been recognized as a susceptibility gene for stroke and coronary artery diseases. The present study was to explore the role of this gene in the eastern Chinese patients with ischemic stroke.
METHODS:
Using a case-control design, we studied 658 patients with ischemic stroke and 704 unrelated population-based controls who were age- and sex-matched. The 658 patients were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Two single-nucleotide polymorphisms (SNPs) covering ALOX5AP were genotyped.
RESULTS:
The genotype frequencies of TG of the SNPs rs17222919 located in the promoter of the ALOX5AP gene were significantly higher in patients with ischemic stroke than in controls (OR*=1.34, 95%CI*=1.02-1.75), especially in patients with ischemic stroke caused by small-artery occlusion (SAO) (OR*=1.40, 95%CI*=1.02-1.93). Meanwhile, the genotype frequencies of TG and TG/GG were higher in female patients than in the controls. After specification, the genotype frequencies of TG and TG/GG were higher in the patients than in controls with hypertension. The genotype frequencies of AG and AG/GG of the SNPs rs9579646 located in the intron of the ALOX5AP gene were higher in the controls than in the patients. After specification, the genotype frequencies of TG were higher in the controls than patients without hypertension.
CONCLUSION:
The present study suggests that sequence variants in the ALOX5AP gene are significantly associated with ischemic stroke.
doi:10.5847/wjem.j.issn.1920-8642.2012.02.005
PMCID: PMC4129791  PMID: 25215047
5-lipoxygenase activating protein (ALOX5AP); Leukotrienes (LTs); Trial of Org 10172 in Acute Stroke Treatment (TOAST); Single nucleotide polymorphisms (SNPs); Ischemic stroke
11.  Genetic Variation in the Lipoxygenase Pathway and Risk of Colorectal Neoplasia 
Genes, chromosomes & cancer  2013;52(5):437-449.
Arachidonate lipoxygenase (ALOX) enzymes metabolize arachidonic acid to generate potent inflammatory mediators and play an important role in inflammation-associated diseases. We investigated associations between colorectal cancer risk and polymorphisms in ALOX5, FLAP, ALOX12, and ALOX15, and their interactions with non-steroidal anti-inflammatory drug (NSAID) use. We genotyped fifty tagSNPs, one candidate SNP, and two functional promoter variable nucleotide tandem repeat (VNTR) polymorphisms in three US population-based case-control studies of colon cancer (1424 cases/1780 controls), rectal cancer (583 cases/775 controls), and colorectal adenomas (485 cases/578 controls). Individuals with variant genotypes of the ALOX5 VNTR had decreased risk of rectal cancer, with the strongest association seen for individuals with one or more alleles of >5 repeats (wildtype=5, OR>5/≥5=0.42, 95% CI 0.20-0.92; p=0.01). Four SNPs in FLAP (rs17239025), ALOX 12 (rs2073438), and ALOX15 (rs4796535 and rs2619112) were associated with rectal cancer risk at p≤0.05. One SNP in FLAP (rs12429692) was associated with adenoma risk. A false discovery rate (FDR) was applied to account for false positives due to multiple testing; the ALOX15 associations were noteworthy at 25% FDR. Colorectal neoplasia risk appeared to be modified by NSAID use in individuals with variant alleles in FLAP and ALOX15. One noteworthy interaction (25% FDR) was observed for rectal cancer. Genetic variability in arachidonate lipoxygenases may affect risk of colorectal neoplasia, particularly for rectal cancer. Additionally, genetic variability in FLAP and ALOX15 may modify the protective effect of NSAID use against colorectal neoplasia.
doi:10.1002/gcc.22042
PMCID: PMC3698944  PMID: 23404351
12.  Association between polymorphisms in the flanking region of the TAFI gene and atherosclerotic cerebral infarction in a Chinese population 
Background
Atherosclerosis is the leading etiologic factor of Atherosclerotic Cerebral Infarction (ACI). Previous studies have shown that thrombin activatable fibrinolysis inhibitor (TAFI) may play an important role in the occurrence of acute cerebral infarction, and the levels of TAFI are affected by several single nucleotide polymorphisms (SNPs) located in the regulatory and coding regions of the gene encoding TAFI. The present study aimed to determine whether polymorphisms (TAFI –2345 2G/1G, –1690 A/G, –438 A/G, +1583 A/T) of the TAFI gene were associated with ACI in a Han Chinese population.
Methods
The variant genotypes were identified by restriction fragment length polymorphism (RFLP) and allele-specific polymerase chain reactions (AS-PCR) in 225 patients with ACI and 184 age-matched healthy individuals.
Results
There was a significant difference in the genotype and allele frequencies of TAFI –2345 2G/1G and −1690 A/G polymorphisms between the ACI and control subjects. Further stratification analysis by gender revealed that the presence of the –438 AA genotype and the A allele conferred a higher risk of developing ACI in male patients (p < 0.05). Haplotype analysis demonstrated that four haplotypes of TAFI are significantly associated with ACI.
Conclusions
Our study provides preliminary evidence that the TAFI –2345 2G/1G and –1690 A/G polymorphisms are associated with ACI susceptibility in a Han Chinese population.
doi:10.1186/1476-511X-13-80
PMCID: PMC4026123  PMID: 24886076
Thrombin activatable fibrinolysis inhibitor (TAFI); Atherosclerotic Cerebral Infarction (ACI); Polymorphism
13.  MRAS Genetic Variation Is Associated with Atherothrombotic Stroke in the Han Chinese Population 
Background and Purpose
Atherothrombotic cerebral infarction [atherothrombotic stroke (ATS)] shares common risk factors and pathophysiological mechanisms with coronary artery disease (CAD), and both diseases appear to have common susceptibility loci. The muscle RAS oncogene homolog gene (MRAS) has been identified as a susceptibility locus for CAD and is implicated in atherosclerosis. The aim of this study was to elucidate whether the single-nucleotide polymorphisms (SNPs) and haplotypes of MRAS are associated with increased risk of ATS in a population of Han Chinese.
Methods
A case-controlled association study was conducted in which only patients with ATS (identified as a major subtype in the Korean modification of the Trial of Org 10172 in Acute Stroke Treatment classification) were enrolled. Subgroup analyses were carried out to determine whether the effect of the MRAS polymorphism was specific to age and gender among the subjects.
Results
In total, 194 ATS and 186 control subjects were included in the present study. Two tagging SNPs were identified in MRAS (rs40593 and rs3755751). A multivariate regression analysis revealed a positive association between rs40593 and ATS under dominant and additive models after adjustment for covariates. Subgroup analyses revealed that there were no gender differences with respect to allele or genotype frequencies between the groups. The AG genotype for rs40593 (p=0.028), the CT genotype for rs3755751 (p=0.036), and G-allele carriers (AG plus GG) for rs40593 (p=0.015) exhibited a significant protective effect among those aged ≥45 years. For the haplotype analysis, ATS subjects aged ≥45 years had a higher frequency of the ACAC haplotype (76.0%) than the controls (68.1%; p<0.05); that haplotype was associated with an increased risk of ATS.
Conclusions
The obtained data suggest a positive association between MRAS and ATS among the Han Chinese. Further studies should be performed with larger sample and among different ethnic populations, and gene-gene or gene-environment interactions should be considered.
doi:10.3988/jcn.2013.9.4.223
PMCID: PMC3840132  PMID: 24285963
ischemic stroke; atherothrombotic stroke; single-nucleotide polymorphism; haplotype; genetic variation
14.  Role of LTA4H and ALOX5AP genes in the risk for asthma in Latinos 
Background
Leukotrienes play an important role in allergic and inflammatory diseases, but reports on the involvement of ALOX5AP and LTA4H in asthma have been inconclusive.
Objective
To determine whether polymorphisms in ALOX5AP and LTA4H genes are risk factors for asthma in two different Latino groups: Mexicans and Puerto Ricans.
Methods
The LTA4H gene was sequenced in individuals from both groups to identify novel polymorphisms. Single-nucleotide polymorphisms (SNPs) in the ALOX5AP and LTA4H genes were analyzed for associations with asthma and asthma-related phenotypes in 687 parent-child trios of Mexican and Puerto Rican origin.
Results
In LTA4H, five previously unknown polymorphisms were identified. Two SNPs within LTA4H (rs17525488 and rs2540493) were protective for asthma in Latinos (P = 0.007 and 0.05, respectively). Among Mexican patients, LTA4H polymorphisms were associated with baseline lung function and IgE levels. For ALOX5AP, the minor allele at SNP rs10507391 was associated with protection from asthma (OR = 0.78, P = 0.02) and baseline lung function (P = 0.018) in Puerto Ricans. A gene-gene interaction was identified between LTA4H (rs17525488) and ALOX5AP (rs10507391), (P = 0.003, in the combined sample).
Conclusion
Our results support the role of LTA4H and ALOX5AP variants as risk factors for asthma in Latino populations.
doi:10.1111/j.1365-2222.2009.03438.x
PMCID: PMC2866051  PMID: 20067482
Asthma; Leukotriene; Latino populations; Association study
15.  Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease 
Human genetics  2008;123(4):399-408.
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
doi:10.1007/s00439-008-0489-5
PMCID: PMC4023692  PMID: 18369664
16.  The relationship between the polymorphism of SG13S114 A/T in ALOX5AP gene and the vulnerability of carotid atherosclerosis in Chinese Han population 
The purpose of this study was to determine the relationship between the polymorphism of SG13S114 A/T in ALOX5AP gene and the vulnerability of carotid atherosclerosis in Chinese Han population. Polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) of SG13S114 A/T in ALOX5AP gene was performed for 284 patients with atherothrombotic cerebral infarction, of which 152 cases were diagnosed with stable plaque and the other 132 cases had vulnerable plaques. We found that the frequency of SG13S114 AA genotype and A allele of ALOX5AP gene in the cases with vulnerable plaques was significantly higher than those in the cases with stable plaques. These results suggested that high expression of SG13S114 AA genotype was related to the vulnerability of carotid atherosclerosis. SG13S114 A allele may be a risk factor of vulnerable plaques.
PMCID: PMC2848303  PMID: 20369037
5-lipoxygenase activating protein; atherosclerosis; gene polymorphism; polymerase chain reaction
17.  ALOX12 polymorphisms are associated with fat mass but not peak bone mineral density in Chinese nuclear families 
Objective:
Arachidonate 12-lipoxygenase (ALOX12) is a member of the lipoxygenase superfamily, which catalyzes the incorporation of molecular oxygen into polyunsaturated fatty acids. The products of ALOX12 reactions serve as endogenous ligands for peroxisome proliferator-activated receptor γ (PPARG). The activation of the PPARG pathway in marrow-derived mesenchymal progenitors stimulates adipogenesis and inhibits osteoblastogenesis. Our objective was to determine whether polymorphisms in the ALOX12 gene were associated with variations in peak bone mineral density (BMD) and obesity phenotypes in young Chinese men.
Methods:
All six tagging single-nucleotide polymorphisms (SNPs) in the ALOX12 gene were genotyped in a total of 1215 subjects from 400 Chinese nuclear families by allele-specific polymerase chain reaction. The BMD at the lumbar spine and hip, total fat mass (TFM) and total lean mass (TLM) were measured using dual-energy X-ray absorptiometry. The pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both the individual SNP markers and the haplotypes were tested for an association with the peak BMD, body mass index, TFM, TLM and percentage fat mass (PFM) using the quantitative transmission disequilibrium test (QTDT).
Results:
Using the QTDT, significant within-family association was found between the rs2073438 polymorphism in the ALOX12 gene and the TFM and PFM (P=0.007 and 0.012, respectively). Haplotype analyses were combined with our individual SNP results and remained significant even after correction for multiple testing. However, we failed to find significant within-family associations between ALOX12 SNPs and the BMD at any bone site in young Chinese men.
Conclusions:
Our present results suggest that the rs2073438 polymorphism of ALOX12 contributes to the variation of obesity phenotypes in young Chinese men, although we failed to replicate the association with the peak BMD variation in this sample. Further independent studies are needed to confirm our findings.
doi:10.1038/ijo.2010.157
PMCID: PMC3061002  PMID: 20697415
ALOX12; fat mass; lean mass; peak bone mineral density; quantitative transmission disequilibrium test
18.  ALOX5AP gene variants show differential association with coronary artery disease in different populations 
Journal of community genetics  2010;1(3):107-115.
Coronary artery disease (CAD) is a complex disease with various components, genetic as well as environmental. Previous reports correlating ALOX5AP gene variants and CAD showed conflicting results depending on the population studied. In this study, we examined the contribution of ALOX5AP genetic predisposition to CAD in a group of CAD patients and controls carefully selected from the Lebanese population. We genotyped SNPs for ALOX5AP variants in 289 catheterized patients aged ≤52 years with >50% stenosis in at least one main coronary artery and 227 catheterized control subjects aged 60 years and above with 0% stenosis. Chi-square (χ2) tests and logistic regression showed no significant difference in the allele and genotype frequencies between the CAD or myocardial infarction (MI) cases and the healthy controls. Haplotype analysis using PHASE showed that the distribution of the risk haplotypes among cases and controls were not significantly different and had no attributable risk to CAD (P = 1.00 and P = 0.5, respectively) or MI (P = 0.2 and P = 0.5, respectively). Our data revealed that ALOX5AP gene variants are not predictors of CAD risk or MI risk among Lebanese patients.
doi:10.1007/s12687-010-0015-z
PMCID: PMC3185993  PMID: 22460243
CAD; Stenosis; ALOX5AP; SNP; Inflammation
19.  Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis 
Human genetics  2009;125(2):217-229.
Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility.
doi:10.1007/s00439-008-0619-0
PMCID: PMC2759090  PMID: 19130089
20.  The Association between Individual SNPs or Haplotypes of Matrix Metalloproteinase 1 and Gastric Cancer Susceptibility, Progression and Prognosis 
PLoS ONE  2012;7(5):e38002.
Background
The single nucleotide polymorphisms (SNPs) in matrix metalloproteinase 1(MMP-1)play important roles in some cancers. This study examined the associations between individual SNPs or haplotypes in MMP-1 and susceptibility, clinicopathological parameters and prognosis of gastric cancer in a large sample of the Han population in northern China.
Methods
In this case–controlled study, there were 404 patients with gastric cancer and 404 healthy controls. Seven SNPs were genotyped using the MALDI-TOF MS system. Then, SPSS software, Haploview 4.2 software, Haplo.states software and THEsias software were used to estimate the association between individual SNPs or haplotypes of MMP-1 and gastric cancer susceptibility, progression and prognosis.
Results
Among seven SNPs, there were no individual SNPs correlated to gastric cancer risk. Moreover, only the rs470206 genotype had a correlation with histologic grades, and the patients with GA/AA had well cell differentiation compared to the patients with genotype GG (OR=0.573; 95%CI: 0.353–0.929; P=0.023). Then, we constructed a four-marker haplotype block that contained 4 common haplotypes: TCCG, GCCG, TTCG and TTTA. However, all four common haplotypes had no correlation with gastric cancer risk and we did not find any relationship between these haplotypes and clinicopathological parameters in gastric cancer. Furthermore, neither individual SNPs nor haplotypes had an association with the survival of patients with gastric cancer.
Conclusions
This study evaluated polymorphisms of the MMP-1 gene in gastric cancer with a MALDI-TOF MS method in a large northern Chinese case-controlled cohort. Our results indicated that these seven SNPs of MMP-1 might not be useful as significant markers to predict gastric cancer susceptibility, progression or prognosis, at least in the Han population in northern China.
doi:10.1371/journal.pone.0038002
PMCID: PMC3360011  PMID: 22655095
21.  Human Lipoxygenase Pathway Gene Variation and Association with Markers of Subclinical Atherosclerosis in the Diabetes Heart Study 
Mediators of Inflammation  2010;2010:170153.
Aims. Genes of the 5-lipoxygenase pathway are compelling candidates for atherosclerosis. We hypothesize that polymorphisms in ALOX12, ALOX15, ALOX5, and ALOX5AP genes are associated with subclinical atherosclerosis in multiple vascular beds. Methods. Families with two or more siblings with type 2 diabetes and their nondiabetic siblings were studied as part of the Diabetes Heart Study (DHS). European American diabetic (n = 828) and nondiabetic (n = 170) siblings were genotyped for SNPs in the ALOX12, ALOX15, ALOX5, and ALOX5AP genes. Subclinical measures of atherosclerosis (IMT, coronary (CorCP), carotid (CarCP) and aortic (AorCP) calcified plaque) were obtained. Results. Associations were observed between ALOX12 with CorCP, ALOX5 with CorCP, AorCP, and IMT, and ALOX5AP with CorCP and CarCP, independent of known epidemiologic risk factors. Further, lipoxygenase pathway SNPs that were associated with measures of atherosclerosis were associated with markers of inflammation (CRP, ICAM-1) and calcification (MGP). Conclusions. Polymorphisms within ALOX12, ALOX5, and ALOX5AP are genetically associated with subclinical atherosclerosis and with biomarkers of disease in families with type 2 diabetes. These results suggest that variants in lipoxygenase pathway genes may have pleiotropic effects on multiple components that determine risk of cardiovascular disease.
doi:10.1155/2010/170153
PMCID: PMC2878676  PMID: 20592751
22.  A novel polymorphism of the GP78 gene is associated with coronary artery disease in Han population in China 
Background
GP78 is a membrane-anchored ubiquitin ligase mediating the degradation of 3-hydroxy-3-methyl-glutaryl-CoA coenzyme A reductase (HMGCR) and Insig-1, which was very essential for the synthesis of cholesterol process. Cholesterol levels have a causal role in the development of cardiovascular disease. The aim of the present study was to assess the association between the human gp78 gene polymorphism and coronary artery disease (CAD) in a Han and Uygur population of China.
Methods
We used two independent case–control studies: a Han population (602 CAD patients and 572control subjects) and a Uygur population (374 CAD patients and 376control subjects). All CAD patients and controls were genotyped for the same three single nucleotide polymorphisms (SNPs) (rs731119, rs2617849and rs2440472) of gp78 gene by a Real-time PCR instrument.
Results
In the Han population, for total and men, the distribution of SNP3 (rs2440472) alleles and the dominant model (AA vs AG + GG) and recessive model (GG vs AG + AA) showed a significant difference between CAD and control participants (for allele: P = 0.003 and P = 0.002, respectively; for dominant model: P = 0.041 and P = 0.026, respectively; for recessive model: p = 0.004 and p = 0.004, respectively).The significant difference in both the two models was retained after adjustment for covariates (for dominant model OR:0.760, 95% confidence interval [CI]:0.584-0.99, P = 0.042; OR:0.686, 95% CI: 0.498-0.946, P = 0.022, respectively; for recessive model OR: 1.451, 95% CI: 1.067-1.974, P = 0.018; OR: 1.789, 95% CI: 1.219-2.627, P = 0.000). Our data was also assessed via haplotype-based case–control studies. For the Han population, for total, The G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.02), and the G-C-A haplotype in CAD was significantly lower than that in the control group (P = 0.0443), And for man, the G-T-G haplotype in CAD was significantly higher than that in the control group (P = 0.0048).
Conclusions
The GG genotype and G allele of rs2440472 in gp78 gene could be a risk genetic marker of CAD in Han population in China.
doi:10.1186/1476-511X-13-147
PMCID: PMC4175632  PMID: 25200441
gp78; Single nucleotide polymorphism; Coronary artery disease; Case–control study; Haplotype
23.  Susceptibility gene for stroke or cerebral infarction in the Han population in Hunan Province of China★ 
Neural Regeneration Research  2013;8(16):1519-1527.
The scavenger receptor class B type I gene can protect against atherosclerosis; a mononucleotide polymorphism is associated with differences in blood lipid metabolism, postprandial serum lipid levels, insulin resistance, coronary artery disease and familial hyperlipidemia. In this study, the scavenger receptor class B type I gene exon 1 G4A gene polymorphism in atherosclerotic cerebral infarction patients, cerebral hemorrhage patients and normal controls was detected using the polymerase chain reaction-restriction fragment length polymorphism method. The results showed that the GA + AA genotype frequency of scavenger receptor class B type I gene G4A in atherosclerotic cerebral infarction patients was similar to that in cerebral hemorrhage patients and normal controls; however, the A allele frequency was significantly lower than that in normal controls. The serum level of high-density lipoprotein cholesterol in patients with the scavenger receptor class B type I gene G4A GA + AA genotype was significantly higher, while the serum level of low-density lipoprotein cholesterol was significantly lower than that in patients with the GG genotype, in both the atherosclerotic cerebral infarction and cerebral hemorrhage groups. The serum level of high-density lipoprotein cholesterol in patients with the scavenger receptor class B type I gene G4A GA + AA genotype was significantly higher, while the serum levels of low-density lipoprotein cholesterol and total cholesterol were significantly lower than those in normal controls with the GG genotype. Our experimental results suggest that the G4A polymorphism of the scavenger receptor class B type I gene is a possible predisposing risk factor for atherosclerotic cerebral infarction, and that it has no association with cerebral hemorrhage in the Han population in Hunan province of China. The A allele is possibly associated with the metabolism of high-density and low-density lipoprotein cholesterol.
doi:10.3969/j.issn.1673-5374.2013.16.009
PMCID: PMC4107805  PMID: 25206448
neural regeneration; scavenger receptor class B type I; stroke; atherosclerotic cerebral infarction; cerebral hemorrhage; genetic polymorphism; cholesterol; neuroregeneration
24.  Evaluation of LOXL1 polymorphisms in exfoliation syndrome in the Uygur population 
Molecular Vision  2011;17:1734-1744.
Purpose
In Uygur populations, exfoliation syndrome (XFS) and exfoliation glaucoma (XFG) occurred at a high frequency. In this study, we evaluate the association profiles of the lysyl oxidase-like 1 (LOXL1) gene polymorphisms with XFS in the Uygur population.
Methods
Sixty-four unrelated Uygur patients with XFS and 127 Uygur control subjects were included in this study. Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs2165241, and rs3825942) were analyzed by direct sequencing, and a case-control association study was performed.
Results
The three SNPs were significantly associated with XFS and XFG individually. The G allele of rs1048661 (OR [95%CI]: 1.92 [1.14–3.22]), G of rs3825942 (OR [95%CI]: 4.86 [2.02–11.68]), and T of rs2165241 (OR [95%CI]: 3.98 [2.54–6.25]) were risk alleles for the disorder. The genotypes GG for rs1048661 (OR [95%CI]: 2.13 [1.14–3.97]), GG for rs3825942 (OR [95%CI]: 5.68 [2.28–14.17]), and TT for rs2165241 (OR [95%CI]: 6.13 [2.68–14.01]) were risk genotypes for the disease. The haplotypes G-G for the SNPs rs1048661and rs3825942, G-T for the SNPs rs1048661 and rs2165241, and SNPs rs3825942 and rs2165241 were found to be significantly associated with XFS/G. The haplotypes G-G-T for the three SNPs were determined to be significantly associated with XFS/G. There were significant differences of the allelic and genotypic proportion in different gender/age patients and controls for all three SNPs. T allele of rs2165241 and G of rs3825942 were risk alleles for the disorder in both the male and female groups. G allele of rs1048661 was a risk allele for the disorder in the below 65-year-old group. T of rs2165241 was a risk allele for the disorder in both age groups. G of rs3825942 was a risk allele for the disorder in the over 65-year-old group. The genotypes also showed significant differences in the below 65-year-old group of rs1048661, both groups of rs2165241, and over 65-year-old group of rs3825942.
Conclusions
LOXL1 is a susceptibility gene of XFS/XFG in Uygur populations. The risk alleles of rs1048661, rs3825942 and rs2165241 in Uygur subjects were found to be similar to those of populations in Iceland and the United States and different from Han populations in China. The genotypic and allelic distributions of these SNPs are similar between XFS and XFG.
PMCID: PMC3130722  PMID: 21738402
25.  Association of MYLIP rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations 
Background
The association of rs3757354 single nucleotide polymorphism (SNP) in the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP, also known as IDOL) gene and serum lipid levels is not well known in the general population. The present study aimed to detect the association of rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.
Method
A total of 627 subjects of Bai Ku Yao minority and 614 participants of Han nationality were randomly selected from our stratified randomized cluster samples. Genotyping of the rs3757354 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.
Results
The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of G allele was 49.92% in Bai Ku Yao and 56.27% in Han (P < 0.05). The frequencies of AA, GA and GG genotypes were 25.52%, 49.12% and 25.36% in Bai Ku Yao, and 19.87%, 47.72% and 32.41% in Han (P < 0.05); respectively. There were no significant differences in the genotypic and allelic frequencies between males and females in both ethnic groups. The levels of HDL-C in Bai Ku Yao were different among the genotypes (P < 0.05), the G allele carriers had higher serum HDL-C levels than the G allele noncarriers. The levels TC, HDL-C and ApoAI in Han were different among the genotypes (P < 0.05 for all), the participants with GA genotype had lower serum TC, HDL-C and ApoAI levels than the participants with AA genotype. These findings were found only in females but not in males. The levels of TG and HDL-C in Bai Ku Yao were correlated with the genotypes, whereas the levels of TC in Han, and TC, LDL-C in Han females were associated with the genotypes (P < 0.05 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, and body mass index in both ethnic groups (P < 0.05-0.001).
Conclusions
The present study suggests that the MYLIP rs3757354 SNP is associated with serum TC, HDL-C and ApoAI levels in the Bai Ku Yao and Han populations. But the association is different between the two ethnic groups.
doi:10.1186/1476-511X-11-141
PMCID: PMC3496621  PMID: 23107276

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