Genetic variation in tumour necrosis factor and lymphotoxin is not associated with endometriosis in an Australian sample

BACKGROUND: Tumour necrosis factor (TNF) is a pleiotropic cytokine with a wide range of immunoregulatory effects. Variation in the promoter region of TNF and the neighbouring lymphotoxin alpha (LTA) gene might be associated with endometriosis. METHODS: We examined the association between endometriosis and common single-nucleotide polymorphisms (SNPs) or haplotypes in the TNF/LTA region in an Australian sample by analysing 26 SNPs in 958 endometriosis cases and 959 unrelated controls. We selected functional SNPs in the coding and the promoter region of the TNF gene and HapMap tagging SNPs and typed them on a Sequenom MassARRAY platform. A key SNP (rs1800630) in the promoter region typed in previous studies did not give reliable results. Therefore, we also examined a statistically identical (r(2) = 1) SNP (siSNP) (rs2844482), identified using the web based program ssSNPer. RESULTS: Genotype completion rate was 99.5% for SNPs spanning a region of 15.5 kb across the TNF/LTA locus. There was no evidence for association between endometriosis and TNF/LTA SNPs or SNP haplotypes in our case-control study. CONCLUSIONS: Our data suggest both TNF and LTA genes are not major susceptibility genes for endometriosis.     

Polymorphism in the insulin-like growth factor 1 gene is associated with age at menarche in caucasian females

BACKGROUND: The insulin-like growth factor 1 (IGF1) gene, which plays a crucial role in hypothalamic-pituitary-ovarian hormone-controlled metabolic processes, may influence the onset of menarche. Our study aimed to test association between IGF1 polymorphisms with the variation of age at menarche (AAM) in Caucasian females. METHODS: We recruited a sample of 1048 females from 354 Caucasian nuclear families and genotyped 19 single-nucleotide polymorphisms (SNPs) spanning the entire IGF1 gene. Pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both single SNP markers and haplotypes were tested for association with AAM using the quantitative transmission disequilibrium test. RESULTS: Significant association (P = 0.0153) between AAM and SNP3 (rs6214) in block1 was detected. CONCLUSIONS: Our results suggested a potential effect of SNP3 in the IGF1 gene on AAM variation in Caucasian women for the first time. However, further independent studies are needed to confirm our findings.     

Determination of cytokine regulatory haplotypes by induced heteroduplex analysis of DNA

Multiple single nucleotide polymorphisms (SNP) in the promoter region of the human interleukin-10 (IL-10) gene and in the signal/leader sequence of the human transforming growth factor beta 1 (TGF-beta1) gene, have been associated with susceptibility, severity and clinical outcome for a number of diseases. One common explanation for this, is that different haplotypes of these SNPs regulate the expression of the respective cytokines. Therefore, accurate determination of haplotypes by physical linkage analysis represents an important tool in investigating the pathogenesis of such diseases. Here, we demonstrate that the use of induced heteroduplex generators (IHGs) may be used to identify haplotypes within target sequences in the IL-10 and TGF-beta1 genes. Four haplotypes were observed within the IL-10 promoter region, consisting of -1082, -851, -819 and -592 SNPs. For the TGF-beta1 signal/leader sequence, we observed three haplotypes of the T869C (Leu10Pro) and G915C (Arg25Pro) SNPs. In both cases, all combinations of these haplotypes could be resolved unequivocally with a single IHG reagent.     

Gender-related association between the TGFB1+869 polymorphism and multiple sclerosis.

Our objective was to investigate whether polymorphisms and haplotypes in the TGFB1 gene are associated with susceptibility or disease characteristics of multiple sclerosis (MS). In 247 MS patients and 194 controls, single nucleotide polymorphisms (SNPs) at position +869 (Leu10Pro) and position +915 (Arg25Pro) in the signaling sequence of the TGFB1 gene were determined, and the distribution of alleles, genotypes, and haplotypes was related to clinical data. In addition, magnetic resonance imaging (MRI) data were studied in a subgroup of patients (n = 96). The allele distribution of the two polymorphisms studied was in Hardy-Weinberg equilibrium in patients and in controls. No association was found with any of the three haplotypes found in the Dutch population, denoted as haplotype 1 (TGFB1+869T-TGFB1+915G), haplotype 2 (TGFB1+869C-TGFB1+915G), and haplotype 3 (TGFB1+869C-TGFB1+915C). However, the TGFB1+869 genotype CC was significantly more frequent in patients (p = 0.031, chi2 test). The highest frequency of the TGFB1+869 genotype CC was observed in male patients (25.2% vs. 10.0% in controls, p = 0.004, chi2 test), and carriership of TGFB1+869 allele C was correspondingly increased in male patients (74.8% vs. 56.7%, p = 0.008, chi2 test, OR 2.27, 95% CI 1.23-4.17). Although there was no association with clinical markers of disease progression, patients homozygous for TGFB1+869 allele C showed a significantly higher annual increase in two MRI parameters: ventricular fraction (central atrophy) and T1-hypointense lesion load (matrix destruction). The TGFB1 T+869C (Leu10Pro) gene polymorphism is associated with MS susceptibility, especially in males, and with a more destructive course of the disease as illustrated by MRI.     

Family-based association analysis of beta2-adrenergic receptor polymorphisms in the childhood asthma management program

BACKGROUND: Beta2-adrenergic receptor (B2AR) polymorphisms have been associated with a variety of asthma-related phenotypes, but association results have been inconsistent across different studies. OBJECTIVE: We sought to apply family-based association methods to individual single nucleotide polymorphisms (SNPs) and haplotypes of SNPs in B2AR to define the relationship of these genetic variants to asthma-related phenotypes. METHODS: DNA samples were obtained from 707 Childhood Asthma Management Program participants, representing 650 sibships, as well as their parents. Genotyping was performed at 8 B2AR SNPs. Qualitative asthma-related phenotypes were analyzed with single SNPs and haplotypes by using TRANSMIT; quantitative asthma-related phenotypes were analyzed with the Family-Based Association Test. RESULTS: Several SNPs, including SNP -654 and SNP +46, demonstrated significant associations (P <.05) to postbronchodilator FEV1 as both a qualitative (<80% of predicted value) and quantitative phenotype. Quantitative phenotypic association analysis demonstrated significant evidence for association of SNP +523 with bronchodilator responsiveness expressed as a percentage of baseline FEV1 (P =.012) or a percentage of predicted FEV1 (P =.008). Similar evidence for association between the +523 SNP and qualitative bronchodilator responsiveness phenotypes was also found. Analysis of haplotypes supported an association of B2AR variants with spirometric values and bronchodilator responsiveness. CONCLUSION: B2AR variants are associated with spirometric values and bronchodilator responsiveness, but different regions of the gene provide evidence for association with these phenotypes.     

Association between the candidate susceptibility gene ACVR2A on chromosome 2q22 and pre-eclampsia in a large Norwegian population-based study (the HUNT study)

Genome-wide scans in Icelandic, Australian/New Zealand and Finnish pedigrees have provided evidence for maternal susceptibility loci for pre-eclampsia on chromosome 2, although at different positions (Iceland: 2p13 and 2q23, Australia/New Zealand: 2p11-12 and 2q22, Finland: 2p25). In this project, a large population-based (n=65 000) nested case-control study was performed in Norway to further explore the association between positional candidate genes on chromosome 2q and pre-eclampsia, using single-nucleotide polymorphisms (SNPs). DNA samples from 1139 cases (women with one or more pre-eclamptic pregnancies) and 2269 controls (women with normal pregnancies) were genotyped using the Applied Biosystems SNPlex high-throughput genotyping assay. In total, 71 SNPs within positional candidate genes at 2q22-23 locus on chromosome 2 were genotyped in each individual. Genotype data were statistically analysed with the sequential oligogenic linkage analysis routines (SOLAR) computer package. Nominal evidence of association was found for six SNPs (rs1014064, rs17742134, rs1424941, rs2161983, rs3768687 and rs3764955) within the activin receptor type 2 gene (ACVR2A) (all P-values <0.05). The non-independence of statistical tests due to linkage disequilibrium between SNPs at a false discovery rate of 5% identifies our four best SNPs (rs1424941, rs1014064, rs2161983 and rs3768687) to remain statistically significant. The fact that populations with different ancestors (Iceland/Norway-Australia/New Zealand) demonstrate a common maternal pre-eclampsia susceptibility locus on chromosome 2q22-23, may suggest a general role of this locus, and possibly the ACVR2A gene, in pre-eclampsia pathogenesis.     

IL-4 receptor alpha chain genetic polymorphism and total IgE levels in the English population: two-locus haplotypes are more informative than individual SNPs

The IL-4RA locus encodes for the alpha chain of the IL-4 receptor, and is both a functional and positional candidate gene for atopy and allergic disease. Recently Ober et al. have shown that the study of haplotypes at multiple loci in the IL-4RA gene could be more informative than the separate study of single nucleotide polymorphisms (SNPs). One hundred and fifty subjects affected by atopic asthma and 150 healthy control subjects were studied in the English population (Oxford district). Subjects and controls were genotyped for the Ile50Val, Ser478Pro and Gln551Arg polymorphism of the IL-4 receptor alpha chain. The distribution of haplotypes 50-478 shows a highly significant association with IgE levels. In particular, the haplotype Val50/Pro478 is much less frequent in subjects with IgE levels > 100 U mL-1 than in those with IgE levels < 100 U mL-1. Furthermore, the distribution of haplotype 50-551 shows a weak association with IgE levels that is lacking for 478-551 haplotypes. A lower frequency of the Val50/Pro478 haplotype is also observed among asthmatic subjects as compared to healthy controls. With regard to individual SNPs (50 478 and 551), no significant association has been observed with IgE levels or with asthma, thus confirming the higher informative value of the haplotype analysis as compared to separate study on SNPs.     

抗原加工相关转运体基因多态性及夫妻共享率与妊娠期高血压疾病的相关性

目的基于妊娠期高血压疾病的免疫病因学，通过测定重度子瘸前期患者和正常孕妇抗原加工相关转运体（transporter associated with antigen processing，TAP）基因（TAP）多态性及夫妻共享率来探讨该基因与妊娠期高血压疾病发病的相关性。方法取102例重度子痫前期患者及其配偶为研究对象，随机选择200名正常孕妇及其配偶作为对照。所选孕妇均为初孕，无输血史，孕35～40周。各取2mL外周静脉血抽提DNA，应用PCR-扩增阻碍突变系统方法检测TAP333、637、379、565、665五个基因位点，分别对TAP基因的单倍体型进行统计分析。结果在所有标本中，检出4种TAP1单倍体型及7种TAP2单倍体型，其中TAP2H未能检出。TAP2B（x^2=9．19，P〈0．01，RR=4．18），TAP2F（x^2=5．34，P〈0．05，RR=4．63）在子痫前期组中的分布频率显著高于对照组。余单倍体型在两组中的分布差异无统计学意义。TAP1B（X^2=4．87，P〈0．05，RR=3．14），TAP1C（x^2=5．42，P〈0．05，RR=4．90），TAP2B（x^2=9．65，P〈0．01，RR=5．39）在子痫前期组与正常孕妇组的夫妻共享率比较，子瘸前期组的夫妻共享率显著增高，有统计学意义。结论TAP2B和TAP2F可能使妊娠期高血压疾病的易感性增高。TAPIB，TAPIC，TAP2B基因共享率升高时，母胎相容性增大，妊娠期高血压疾病发生的可能性增加。     

Lack of association between leukocyte telomere length and genetic variants in two ageing-related candidate genes

BACKGROUND: Leukocyte telomere length, a putative marker of ageing, is a highly variable and heritable complex trait. In order to determine the possible underlying genetic variants for leukocyte telomere length variation, we conducted an association study of leukocyte telomere length and two candidate genes for ageing-related traits, TGFB1 and KLOTHO, in a female Caucasian dizygotic twin population. METHODS AND MATERIALS: Terminal restriction fragment (TRF) length, an index of telomere length, was measured using Southern Blotting. Six and four single nucleotide polymorphisms (SNP) were genotyped in TGFB1 and KLOTHO gene, respectively, and tested for association. When there is strong LD between SNPs (r(2) > 0.5), haplotypic association was investigated using haplotype trend regression approach. RESULTS: All SNPs were in Hardy-Weinberg equilibrium (p > 0.05). No significant association was detected for individual SNPs (p > 0.101), or two-locus haplotypes (p = 0.7497) with TRF variation. CONCLUSION: We failed to find any significant association between leukocyte telomere length and 10 SNPs in two ageing-related candidate genes, TGFB1 and KLOTHO. This result suggests that while we could not exclude minor effects, none of 10 SNPs in these two candidate genes showed significant association with the variation of leukocyte telomere length in our cohort. But as it is unclear whether telomere length dynamics is the cause or the effect of the ageing process, it is still possible the genes are associated with ageing via alternate mechanisms.     

Lymphotoxin-α and galectin-2 SNPs are not associated with myocardial infarction in two different German populations

Recent data provided strong evidence for the association of single nucleotide polymorphisms (SNPs) in the lymphotoxin-alpha (LTA) and galectin-2 (LGALS2) genes with myocardial infarction (MI) in a Japanese population. For populations of other genetic background, the relevance of these polymorphisms in the pathogenesis of MI remains controversial. We aimed to define the role of LTA and LGALS2 SNPs in two German MI populations with markedly different ascertainment strategies. Two different MI populations were studied. In the first population, MI patients were ascertained by a strong family history of MI (n = 1214). Controls were unrelated disease-free participants of the study (n = 1080). The second population included patients suffering from sporadic (nonfamilial) MI from the German KORA register (n = 607). The control group consisted of participants of the WHO MONICA survey in Germany (n = 1492). TaqMan assays were used to determine the genotypes of 4 SNPs in the LTA genomic region and 1 SNP in the LGALS2 gene. Single SNPs in both genomic regions as well as haplotypes in the LTA genomic region were tested for association in various models of inheritance. No association with MI could be found for any of the examined SNPs in the LTA genomic region and LGALS2 gene, or for haplotypes spanning the LTA genomic region. In two MI populations of European descent with markedly different ascertainment strategies, we were not able to identify a significant association of SNPs in the LTA genomic region or the LGALS2 gene with MI. These variants are unlikely to play a significant role in populations of European origin.     

Linkage disequilibrium fine mapping and haplotype association analysis of the tau gene in progressive supranuclear palsy and corticobasal degeneration

Background: The haplotype H1 of the tau gene, MAPT, is highly associated with progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Objective: To investigate the pathogenic basis of this association. Methods: Detailed linkage disequilibrium and common haplotype structure of MAPT were examined in 27 CEPH trios using validated HapMap genotype data for 24 single nucleotide polymorphisms (SNPs) spanning MAPT. Results: Multiple variants of the H1 haplotype were resolved, reflecting a far greater diversity of MAPT than can be explained by the H1 and H2 clades alone. Based on this, six haplotype tagging SNPs (htSNPs) that capture 95% of the common haplotype diversity were used to genotype well characterised PSP and CBD case–control cohorts. In addition to strong association with PSP and CBD of individual SNPs, two common haplotypes derived from these htSNPs were identified that are highly associated with PSP: the sole H2 derived haplotype was underrepresented and one of the common H1 derived haplotypes was highly associated, with a similar trend observed in CBD. There were powerful and highly significant associations with PSP and CBD of haplotypes formed by three H1 specific SNPs. This made it possible to define a candidate region of at least ∼56 kb, spanning sequences from upstream of MAPT exon 1 to intron 9. On the H1 haplotype background, these could harbour the pathogenic variants. Conclusions: The findings support the pathological evidence that underlying variations in MAPT could contribute to disease pathogenesis by subtle effects on gene expression and/or splicing. They also form the basis for the investigation of the possible genetic role of MAPT in Parkinson''s disease and other tauopathies, including Alzheimer''s disease.     

Serum paraoxonase activity is associated with variants in the PON gene cluster and risk of Alzheimer disease

Previous studies have shown association of single nucleotide polymorphisms (SNPs) in 3 contiguous genes (PON1, PON2, and PON3) encoding paraoxonase with risk of Alzheimer disease (AD). We evaluated the association of serum paraoxonase activity measured by phenyl acetate (PA) and thiobutyl butyrolactone (TBBL) with risk of AD and with 26 SNPs spanning the PON gene cluster in 266 AD cases and 306 sibling controls from the MIRAGE study. The odds of AD (adjusted for age, gender, and ethnicity) increased 20% for each standard deviation decrease in PA or TBBL activity. There were association signals with activity in all 3 genes. Haplotypes including SNPs spanning the PON genes were generally more significant than haplotypes comprising SNPs from 1 gene. Significant interactions were observed between SNP pairs located across the PON cluster with either serum activity measure as the outcome, and between several PON SNPs and PA activity with AD status as the outcome. Our results suggest that low serum paraoxonase activity is a risk factor for AD. Furthermore, multiple variants in PON influence serum paraoxonase activity and their effects may be synergistic.     

Matrix Metalloproteinases 2 and 3 Gene Polymorphisms and the Risk of Target Vessel Revascularization after Percutaneous Coronary Intervention: Is There Still Room for Determining Genetic Variation of MMPs for Assessment of an Increased Risk of Restenosis?

Objective: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. Methods and results: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. Conclusion: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI.     

Association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes

OBJECTIVE: To study the association of the Pro12Ala and C1431T polymorphism of the PPAR gamma2 gene and their haplotypes with obesity and type 2 diabetes in Chinese population. METHODS: PCR-restriction fragment length polymorphism was used to determine the Pro12Ala and C1431T polymorphisms in 207 patients with type 2 diabetes and 101 non-diabetic control subjects. RESULTS: (1) In non-diabetic control population, the Ala allele frequency was 0.064, the T1431 allele frequency was 0.252. Haplotype analysis showed that the Pro12Ala and C1431T polymorphisms were in linkage disequilibrium (Do=0.63, r(2)=0.074), which constituted three major haplotypes Pro-C, Pro-T and Ala-T. (2) There were no significant differences of the distribution frequencies of the Pro12Ala and C1431T polymorphism and their haplotypes between the type 2 diabetes mellitus group and non-diabetic control group (P > 0.05). (3) The Pro12Ala polymorphism was associated with blood pressure and lipidemia in diabetic patients. The Ala allele significantly decreased the diastolic blood pressure of non-obese diabetic patients (P < 0.05), but it did not benefit to the obese diabetic patients for the lipidemia (P < 0.05). The C1431T polymorphism was associated with overweight and obesity in diabetic patients. The T1431 allele frequency in the body mass index >/= 25 layer was significantly higher than that in the body mass index < 25 layer (P < 0.05). CONCLUSION: The Pro12Ala and C1431T polymorphisms of the PPAR gamma2 gene might not be a major etiological factor for type 2 diabetes; the C1431T polymorphism was associated with overweight or obesity in diabetic patients.     

Genetic association of the activin A receptor gene (ACVR2A) and pre-eclampsia

Pre-eclampsia is a common serious disorder of human pregnancy,which is associated with significant maternal and perinatalmorbidity and mortality. The suspected aetiology of pre-eclampsiais complex, with susceptibility being attributable to multipleenvironmental factors and a large genetic component. Recently,we reported significant linkage to chromosome 2q22 in 34 Australian/NewZealand (Aust/NZ) pre-eclampsia/eclampsia families, and activinA receptor type IIA (ACVR2A) was identified as a strong positionalcandidate gene at this locus. In an attempt to identify theputative risk variants, we have now comprehensively re-sequencedthe entire coding region of the ACVR2A gene and the conservednon-coding sequences in a subset of 16 individuals from thesefamilies. We identified 45 single nucleotide polymorphisms (SNPs),with 9 being novel. These SNPs were genotyped in our total familysample of 480 individuals from 74 Aust/NZ pre-eclampsia families(including the original 34 genome-scanned families). Our bestassociations between ACVR2A polymorphisms and pre-eclampsiawere for rs10497025 (P = 0.025), rs13430086 (P = 0.010) andthree novel SNPs: LF004, LF013 and LF020 (all with P = 0.018).After correction for multiple hypothesis testing, none of theseassociations reached significance (P > 0.05). Based on thesedata, it remains unclear what role, if any, ACVR2A polymorphismsplay in pre-eclampsia risk, at least in these Australian families.However, it would be premature to rule out this gene as significantassociations between ACVR2A SNPs and pre-eclampsia have recentlybeen reported in a large Norwegian (HUNT) population sample.     

Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease

Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case-control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3-CCR2-CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Delta32 was observed with an allele frequency of 10.7% in the control population compared to 6.5% in the KD patients (P = 0.04). Two haplotypes of the CCR3-CCR2-CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 was observed.     

Interaction between variants in the interleukin-4 receptor α and interleukin-9 receptor genes in childhood wheezing: evidence from a birth cohort study

BACKGROUND: Several polymorphisms in the IL-4 receptor alpha (IL4RA) gene have been associated with asthma and atopy, but with variable success in different populations. Immunologic studies suggest that IL4RA may interact with other cytokines and receptors, and gene-gene interactions have also been observed with respect to asthma. Such interactions have been proposed to explain partly the difficulties in replicating association studies. METHODS: Using the prospective birth cohort BAMSE, we examined eight single nucleotide polymorphisms (SNPs) and corresponding haplotypes in the IL4RA gene in relation to wheezing and sensitization up to age 4. We also evaluated potential interaction effects (departure from a multiplicative interaction model) between the IL4RA SNPs and four SNPs in the IL-9 receptor (IL9R) gene previously associated with childhood wheezing. RESULTS: We found no main effect of the IL4RA SNPs alone and only weak associations to wheezing and sensitization when haplotypes were considered. Gene-gene interactions between several IL4RA and IL9R SNPs with regard to wheezing were observed (P=0.009), especially between IL4RA Q576R (rs1801275) and IL9R rs731476 (P=0.005). An interaction was also seen between IL4RA and IL9R haplotypes. CONCLUSION: Variants in the IL4RA gene alone may not exert any major influence on susceptibility to asthma-related diseases in childhood, but in combination with other genes, such as IL9R, IL4RA may be an important gene for disease susceptibility.     

DNA polymorphisms and haplotypes of apolipoprotein A5's attribution to the plasma triglyceride levels in Koreans

PURPOSE: Recent studies using human and mice reported that apolipoprotein A-V (APOA5) gene plays an important role in controlling triglyceride (TG) concentrations. The purpose of the present study was to investigate the correlation between single nucleotide polymorphisms (SNPs) and haplotypes in the APOA5 gene and TG in subjects and to search for possible associations of the APOA5 gene variants and common haplotypes with hypertriglyceridemia (HTG). MATERIALS AND METHODS: We examined the case-control subjects including 100 HTG patients and 243 unrelated healthy control. The genes were screened for SNPs by direct sequencing in 48 genetically unrelated individuals. Six SNPs (-1390C>T, -1020G>A, -3A>G, V150M, G182C and 1259T>C) were genotyped in case and control populations. RESULTS: In this study, our results indicated a strong association between APOA5 SNP -3A>G and G182C and elevated TG levels (p<0.001). Analysis of the SNPs from APOA5 gene has identified major haplotype showing very strong association with HTG, CGGGTT (p<0.001). Likelihood ratio test (LRT) of these six SNPs revealed that haplotypes were strong independent predictors of HTG (p<0.001). Haplotype-trend logistic regression (HTR) analysis revealed a significant association between the CGGGGC (haplotype 2) and CGGGTT (haplotype 4) and HTG (OR=2.48, 95% CI=1.06-5.76 and OR=8.54, 95% CI=2.66-27.42, respectively). CONCLUSION: We confirm that the APOA5 variants are associated with triglyceride levels and the haplotype may be strong independent predictors of HTG among Koreans.     

Association of the neuropilin-2 (NRP2) gene polymorphisms with autism in Chinese Han population.

Autism is a pervasive neurodevelopmental disorder, with a significant role of genetic factors in its development. The neuropilin-2 (NRP2) gene is localized to 2q34, an autism susceptibility locus. NRP2 has been demonstrated to both guide axons and to control neuronal migration in the central nervous system. It has been reported that NRP2 may be required in vivo for sorting migrating cortical and striatal interneurons to their correct destination. We examine the association between the NRP2 gene and autism using a cohort of 169 Chinese Han family trios. Four single nucleotide polymorphisms (SNPs) were genotyped by the polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) analyses. The transmission disequilibrium tests (TDT) of SNPs and haplotype association were carried out using the TDTPHASE program. We found significant genetic association between autism and two of the SNPs of the NRP2 gene (rs849578: P = 0.017, rs849563: P = 0.027), as well as specific haplotypes, especially those formed by rs849563. Furthermore, haplotypes constructed with all markers showed significant excess transmission in both global and individual haplotype analyses (P = 0.004 and 0.017, respectively). The polymorphisms in the NRP2 gene are associated with autism, implying that the NRP2 gene may render individuals to be predisposed to autism.