Candidate gene analysis of SPARCL1 gene in patients with multiple sclerosis

Recently, proteomic analysis in cerebrospinal fluid (CSF) from patients with MS identified four proteins which are present in MS but not in normal human CSF, including SPARCL1, an extracellular matrix-associated protein member of the SPARC family. One hundred eighty-six patients with MS and 185 age-matched controls were genotyped for A/G single nucleotide polymorphism (SNP) in exon 1 (rs1049539), C/G SNP in exon 4 (rs1049544), resulting in a substitution of an aspartate with an histidine, and A/G substitution in the exon 5 (rs1130643), leading to the substitution of alanine with threonine. No significant differences in either allelic or genotypic frequency of the three SNPs were found (P>0.05), even in stratifying MS patients according to the course of the disease. Stratifying according to gender, a trend towards a decreased frequency of the C/C genotype of the rs1049544 was observed in male patients as compared with male controls (30.2% versus 44.0%; P=0.217). Despite proteomic studies in CSF from MS patients suggested an important role for SPARCL1 in the development of the disease, SPARCL1 gene does not appear to act as susceptibility factor for MS in the population investigated here. However, the frequency of the C/C genotype of rs1049544 was decreased in male patients, possibly conferring a lower risk of developing MS in male population. Further studies are needed to clarify this issue.     

Association study between CYP24A1 gene polymorphisms and cancer risk

CYP24A1, an essential gene in regulation of vitamin D, has been reported to play an important role in enhancing immune activity and inhibiting tumorigenesis. Previous studies proposed that rs2585428, rs4809960, rs6022999 and rs6068816 in CYP24A1 gene might be greatly associated with cancer risk. To validate the findings, we here investigated the associations of these four polymorphisms and colorectal cancer (CRC) risk in a central Chinese population (426 colon cancer patients, 361 rectal cancer patients and 800 healthy controls). The genotyping was conducted by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by sequencing. Our results revealed that the rs4809960 and rs6022999 were strongly associated with the CRC risk, especially with the colon cancer risk. Moreover, the analysis of haplotypes consisting of rs2585428(G > A), rs4809960(T > C), rs6022999(A > G) and rs6068816(C > T) indicated that haplotype ATGC significantly decreased the CRC risk, especially the colon cancer risk. Haplotype GCAT significantly increased the CRC risk, especially the rectal cancer risk. However, haplotype ACAC was only found to be associated with increased risk of CRC. To improve the statistical strength, an updated meta-analysis was further performed. The results showed that rs2585428 was associated with cancer risk in Caucasian population, rs4809960 was associated with breast cancer risk in Caucasian population, and rs6022999 was associated with cancer risk in Asian population. Collectively, the rs4809960 and rs6022999 may be the genetic biomarkers for prediction of colon cancer risk in Chinese population, the rs2585428 and rs6022999 may link to cancer susceptibility in Caucasian population and in Asian population respectly.     

Single nucleotide polymorphism and haplotype association of the interleukin-8 gene with nasopharyngeal carcinoma

The cytokine interleukin-8 (IL-8) may play a role in the pathogenesis of nasopharyngeal carcinoma (NPC) through the modulation of tumor immune response or enhanced angiogenesis. Polymorphism of IL-8 gene, which may affect the production level of cytokine, has been inversely associated with a number of cancers. To test this hypothesis, we investigated the relationship of IL-8 gene polymorphisms and NPC in a Chinese population. We analyzed single nucleotide polymorphisms (SNPs) of IL-8 gene -845 T/C, -738 T/A, -353 A/T, -251 A/T and +678 T/C in 280 patients with NPC and 290 age and sex matched controls, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and polymerase chain reaction-sequence specific primers method (PCR-SSP). There were significant differences in the genotype and allele distribution of -251 A/T polymorphism of the IL-8 gene among cases and controls. The -251 AA and AT genotypes were associated with a significantly increased risk of NPC as compared with the -251 TT genotypes (OR=1.820, 95% CI, 1.120-2.959, P=0.015 and OR=1.590, 95% CI, 1.104-2.290, P=0.013, respectively). Haplotype analysis revealed that the homozygosity of the AAT haplotype (defined by SNPs at positions -353, -251 and +678) of IL-8 gene conveys the highest risk for NPC compared with the homozygosity for the TTC haplotype (OR=1.396; 95% CI, 1.064-1.831; P=0.016). The -251 A/T polymorphism of IL-8 and its haplotype are associated with NPC in a Chinese population. Our data suggests that IL-8 gene may play a role in the development of NPC.     

The association study between CYP24A1 gene polymorphisms and risk of liver,lung and gastric cancer in a Chinese population

Recently, four single nucleotide polymorphisms (rs2585428, rs4809960, rs6022999 and rs6068816) in CYP24A1 gene were extensively studied for their associations with cancer risk. However, these studies included only a few types of cancer, which calls for further investigations. In view of this, we here conducted a case-control study to explore the associations between these four CYP24A1 gene polymorphisms and risk of liver, lung and gastric cancer in a Chinese population. A total of 480 liver cancer patients, 550 lung cancer patients, 460 gastric cancer patients and 800 normal controls were recruited in this study. The genotyping of CYP24A1 gene polymorphisms was applied with Sanger sequencing assay. Single-locus analysis demonstrated that rs6022999 was significantly associated with risk of liver and lung cancer, while rs6068816 was significantly associated with the risk of gastric cancer. Haplotype analysis revealed that haplotype GTAT was associated with an increased risk of liver cancer and a decreased risk of lung cancer, and haplotype ATGC was associated with a decreased risk of lung cancer. The further meta-analysis of rs6068816 and lung cancer risk showed that rs6068816 was not associated with lung cancer risk in Chinese population, which confirmed our present finding. Conclusively, rs6022999 may be a genetic biomarker for liver and lung cancer susceptibility in Chinese population, and rs6068816 may be used to predict gastric cancer risk in Chinese population.     

Dandy-Walker综合征胎儿的遗传学分析

目的对1例B超提示为Dandy-Walker畸形的胎儿进行遗传学分析,探讨其染色体DNA拷贝数变异与表型的相关性。方法对1例产前诊断Dandy-Walker综合征胎儿行G显带染色体核型分析、单核苷酸多态性微阵列芯片(single nucleotide polymorphism array,SNP array)及荧光原位杂交(fluorescence in situ hybridization,FISH)检测。胎儿父母行外周血染色体核型分析及FISH检测。结果SNP array分析显示患儿染色体6p25.3p25.1存在4266 kb缺失,FISH验证了SNP array的结果。根据父母外周血FISH结果,确认胎儿父亲为隐匿性t(6;14)(p25.1;p13)携带者,而胎儿遗传了其中一条衍生的6号染色体der(6)t(6;14)(p25.1;p13)。结论成功诊断了Dandy-Walker综合征胎儿的遗传学病因,6p25.3p25.1片段缺失的染色体是由于父亲隐匿性平衡易位产生的不平衡配子所致。     

PRKCI基因单核苷酸多态性与神经管畸形的相关性研究

目的探讨PRKCI基因单核苷酸多态性（SNP）与中国山西省神经管畸形（NTDs）发生的相关性。方法采用病例对照研究,利用MassARRAY分子量阵列分析平台,检测133例NTDs标本和135例非病理性胎儿标本PRKCI基因中17个标签SNPs的基因分型,分析其与NTDs发生的相关性。结果 17个SNPs位点中,16个的微效等位基因频率（MAF）与HapMap或dbSNP数据库的结果基本一致。除rs9876082外,其余SNPs位点的基因型分布和等位基因频率在病例组和对照组均无明显差异。rs9876082位点为纯合的微效等位基因A时,NTDs的发病率增加（P=0.035,比值比=2.135,95%可信区间=1.846-2.471）,但是调整其它变量后进行logistic回归分析,这种相关性不再明显（P=0.057）。结论 PRKCI基因rs9876082位点与NTDs的发生有弱的相关性,这种相关性需进一步加大样本进行验证,PRKCI基因可能不是通过其SNPs影响NTDs的易感性。     

Genomic structure and multiple single-nucleotide polymorphisms (SNPs) of the thiopurine S-methyltransferase (TPMT) gene

Thiopurine S-methyltransferase (TPMT) catalyzes the S-methylation of drugs such as azathiopurine, 6-mercaptopurine, and 6-thioguanine, which are widely prescribed for immunosuppressive or cytotoxic applications. We report here the entire genomic structure of the TPMT gene and the presence of 30 single-nucleotide polymorphisms (SNPs) within that structure. The gene spans a genomic region about 27 kb long and consists of nine exons. By screening its entire genomic sequence for SNPs in 48 Japanese chromosomes by direct DNA sequencing, we detected 1 SNP in the 870-bp promoter region, 26 SNPs in introns, and 3 SNPs in the 3' untranslated region (3'UTR) for investigating correlations between TPMT genotypes and the side-effects caused by thiopurine drugs. Received: June 26, 2000 / Accepted: July 31, 2000     

RET基因调控区遗传变异与先天性巨结肠患病风险研究

目的先天性巨结肠（HSCR）是一种复杂的先天性疾病,RET是其主要的易感性基因。本研究对RET非编码区单核甘酸多态性（SNP）-5G〉A（rs10900296）,-1A〉C（rs10900297）和intron1 C〉T（rs2435357）进行分型分析,评估RET基因调控区SNPs及单倍型与先天性巨结肠之间的相关性。方法选取115名病例组病人和139名对照组正常人群,应用聚合酶链反应（PCR）技术和直接测序的方法进行基因分型。回归模型中使用OR值和95%置信区间（CI）作为基因型危险性的评价指标。结果 -5G〉A,-1A〉C,intron1C〉T各基因型频率在病例和对照人群的分布具有显著差异。-5 AA（OR=6.26,95%CI=3.62-10.83）,-1 CC（OR=7.54,95%CI=2.06-27.66）和intron1 TT（OR=19.22,95% CI=7.54-48.99）基因型均能显著增加HSCR发病的风险。单倍型A-C-T（OR=6.28,95% CI=3.77-10.46）和双体型A-C-T/A-C-T（OR=13.62,95% CI=3.48-53.30）分析同样表明与HSCR发病风险存在较强的相关性,并呈现出一定的累积效应。结论 RET基因调控区的基因多态性可能与HSCR的发病易感性有关,支持RET通路的常见变异在HSCR的发展过程中起着重要的作用的假设。     

An association study of asthma and related phenotypes with polymorphisms in negative regulator molecules of the TLR signaling pathway

Although associations between endotoxin exposure or respiratory infection and asthma have been recognized, the genetic effects in these conditions are unclear. Toll-like receptors (TLRs) play an essential role in innate host defense and in the control of adaptive immune responses. IL-1R-associated kinase-M (IRAK-M) and single immunoglobulin IL-1R-related molecule (SIGIRR) negatively regulate TLR-signaling pathways. To investigate whether polymorphisms in these genes were associated with asthma or asthma-related phenotypes, we screened these genes for polymorphisms by direct sequencing of 24 asthmatics and identified 19 variants in IRAK-M and 12 variants in SIGIRR. We next conducted linkage disequilibrium mapping of the genes, and examined the association of polymorphisms and haplotypes using 391 child patients with asthma, 462 adult patients with asthma, and 639 controls. None of the alleles or haplotypes of IRAK-M and SIGIRR were associated with asthma susceptibility or asthma-related phenotype. Our results indicate that polymorphisms in IRAK-M and SIGIRR are not likely to be associated with the development of asthma in the Japanese population.Electronic Supplementary Material Supplementary material is available for this article at and is accessible for authorized users.     

HLA-DQ遗传多态性与乙肝病毒感染结局相关

目的 探讨中国汉族人群人类白细胞抗原(HLA)-DQ基因单核苷酸多态性(rs9275572和rs9275319)与乙肝病毒感染结局的关系.方法 用TaqMan探针对纳入的921例样本进行HLA-DQrs9275572和rs9275319位点多态性的检测,921例血样本包括310例HBV相关慢性肝病者(CLD)、295例乙肝感染后自发清除者(SC)和316例健康对照者(HC).结果 1)Rs9275572 AG基因型有利于乙肝感染后病毒自发清除(OR 1.82,95％ CI 1.26～2.62;显性基因模型:OR 1.84,95％ CI 1.30～2.61).2)SNPrs9275319位点与乙肝易感性及感染后病毒的自发清除关系密切,携带rs9275319 C等位基因是一个保护因素(CLD vs HC:等位基因模型OR 0.49,95％ CI0.33 ～0.73,显性模型OR0.47,95％ CI0.31～0.72;CLD vs SC:等位基因模型OR 1.61,95％ CI 1.06～2.43,显性模型OR 1.57,95％口1.01 ～2.48).3)单体型T-G/T-A与乙肝易感性及感染后病毒自发清除相关.结论 HLA-DQ基因多态性与乙肝易感性及感染后病毒的自发清除密切相关.     

Alcohol use disorder and GABAB receptor gene polymorphisms in an Italian sample: haplotype frequencies,linkage disequilibrium and association studies

Background: Alcohol use disorder (AUD) is a complex trait with genetic and environmental influences. Several gene variants have been associated with the risk for AUD, including genes encoding the sub-units of the γ-aminobutyric acid (GABA) receptors.

Aim: This study evaluated whether specific single nucleotide polymorphisms (SNPs) in genes encoding GABA_B receptor sub-units can be considered as candidates for the risk of AUD.

Subjects and methods: Seventy-four AUD subjects and 128 Italian controls were genotyped for 10 SNPs in genes encoding GABA-B1 and GABA-B2 sub-units (GABBR1 and GABBR2). Allele, genotype, and haplotype frequencies were tested for the association with the AUD trait.

Results: A significant difference between AUD individuals and controls was observed at genotype level for rs2900512 of GABBR2 gene. The homozygous T/T genotype was not found in the controls, whereas it was over-represented in the AUD individuals. Under the recessive model (T/T vs C/T?+?C/C) this result was statistically significant, as well as the Odds Ratio for the association with the AUD trait.

Conclusions: The results provide preliminary data on the association between GABA_B receptor gene variation and risk of AUD. To confirm this finding, studies with larger samples and additional characterisation of the phenotypic AUD trait are required.     

Association of an intronic haplotype of the LIPC gene with hyperalphalipoproteinemia in two independent populations

Hepatic lipase (HL) plays a major role in the regulation of plasma lipids. Several groups seeking to find association between the gene encoding HL (LIPC) and plasma concentrations of high-density lipoprotein cholesterol (HDLc) using various methods and populations have reported conflicting results. We have approached the problem of demonstrating a relationship between the LIPC locus and HDLc by means of haplotype association using four single nucleotide polymorphisms (SNPs) (rs12594375G/A, rs8023503C/T, rs4775047C/T, and rs11634134T/A) located in intron 1 of the LIPC gene in two independent Japanese populations consisting of 2,970 and 1,638 individuals, respectively. Significant association between hyperalphalipoproteinemia and a specific haplotype in this intron was detected in both populations. When HDLc levels among the three haplotypic categories were analyzed [haplotype rs8023503C/rs12594375G (haplotype-1; H1) homozygotes (H1H1), haplotype rs8023503T/rs12594375A (haplotype-2; H2) homozygotes (H2H2), and heterozygotes (H1H2)], HDLc levels were lowest among H1H1 [mean ± standard error (SE) = 58.4 ± 0.4 mg/dl], highest among H2H2 (62.5 ± 0.8 mg/dl), and intermediate among H1H2 (59.2 ± 0.4 mg/dl) (P = 0.00011), indicating that H2 haplotype elevates plasma HDLc levels. This association was validated in the second population (n = 1,638) (P = 0.00070). The results provide convincing evidence that the LIPC locus influences HDL metabolism.     

IL-23R基因多态性与吉林人群强直性脊柱炎易感性的关联研究

目的:探讨吉林人群IL-23R基因rs7517847和rs10489629位点的单核苷酸多态性与强直性脊柱炎易感性的关系。方法:采用PCR-RFLP方法对188例强直性脊柱炎患者进行IL-23R基因多态性检测,与100例健康者对照分析。结果:两个SNP位点(rs7517847和rs10489629)各基因型频率和等位基因频率在AS组与对照组之间的分布差异均有统计学意义(P0.05),并在假设遗传方式下,rs7517847位点的纯合突变GG基因型与(TG+TT)基因型比较;rs10489629位点的纯合突变AA基因型与(GA+GG)基因型比较,其频率分布差异在AS组与对照组之间也具有统计学意义(P0.05)。结论:IL-23R基因rs7517847和rs10489629位点的多态性均与吉林人群AS易感性有关;携带G等位基因(或A等位基因)且为GG(或AA)基因型的个体患AS的倾向性增大,可能是患AS的易感因素之一。     

Positive association of the <Emphasis Type="Italic">FTSJ1</Emphasis> gene polymorphisms with nonsyndromic X-linked mental retardation in young Chinese male subjects

To investigate the possible genetic association of nonsyndromic X-linked mental retardation (NS-XLMR) with FTSJ1 gene polymorphisms, a case-control association study was performed focusing on the Chinese Han population in the Qinba mountain region. Three common single nucleotide polymorphisms (SNPs) (rs2268954, rs2070991, rs5905692) in the gene were selected and genotyped using the polymerase chain reaction single-strand confirmation polymorphism (PCR-SSCP) method. Pairwise linkage disequilibrium (LD) analysis showed that the three SNPs were in strong LD (all D' > 0.8). There were significant differences between cases and controls in allele frequency distribution of rs2268954 (P = 0.036), rs2070991 (P = 0.043), and rs5905692 (P = 0.014) and in the distributions of common haplotypes combined by these SNPs (global P = 0.01236) in male subjects. In female subjects, however, no positive results were found. Our results suggest a positive association between the genetic variants of the FTSJ1 gene and NS-XLMR in young male subjects in the Chinese Han population in the Qinba region.     

The T &gt; A (rs11646213) gene polymorphism of cadherin-13 (CDH13) gene is associated with decreased risk of developing hypertension in Mexican population

Hypertension is a major public health problem affecting about 30% of the adult population and is associated with an increased risk of developing metabolic and cardiovascular disease. Recent reports have shown that the T-cadherin receptor characteristically expressed on endothelial and vascular smooth muscle cells is involved in hypertension. The aim of the present study was to evaluate the role of cadherin-13 (CDH13) gene polymorphisms as susceptibility markers for hypertension in Mexican population. Six CDH13 polymorphisms (rs11646213, rs11646411, rs6563943, rs3096277, rs3784990 and rs254340) were genotyped by 5′ exonuclease TaqMan assays in a group of 644 hypertensive and 765 non-hypertensive individuals. Under co-dominant, recessive, and additive models, the CDH13 T > A (rs11646213) polymorphism was associated with decreased risk of developing hypertension when compared to non-hypertensive individuals (OR = 0.61, 95% CI: 0.42–0.89, P_co-dom = 0.019; OR = 0.63, 95% CI: 0.46–0.87, P_res = 0.005; OR = 0.80, 95% CI: 0.66–0.96, P_add = 0.016, respectively). All models were adjusted by gender, age, body index mass, type II diabetes mellitus, alcohol consumption, dyslipidemia and smoking habit. Linkage disequilibrium analysis showed one haplotype (TCACGG) with decreased frequency in hypertensive when compared to non-hypertensive individuals (OR = 0.52, 95% CI: 0.33–0.82, P = 0.0053). In summary, our data suggests that the CDH13 T > A (rs11646213) polymorphism is associated with decreased risk of developing hypertension in the Mexican population. In addition, it was possible to distinguish one haplotype associated with decreased risk and two for increased risk of develop hypertension.     

A conserved linkage group on chromosome 6, the 8.1 ancestral haplotype,is a predisposing factor of chronic rhinosinusitis associated with nasal polyposis in aspirin-sensitive Hungarians

Inflammation plays a central role in the pathogenesis of chronic rhinosinusitis (CRS), and TNFα is a key pro-inflammatory cytokine in the pathogenesis of this disease. In our previous studies, we showed that the TNFA −308A allele is a genetic predisposition factor in a subgroup of aspirin-sensitive (ASA+) CRS patients suffering from nasal polyps (NP) in the Hungarian population.To determine whether the TNF −308A allele or the presence of a complex, extended ancestral haplotype (8.1AH) located on chromosome 6 is responsible for the previously observed genetic effect, we performed a case–control study for examining the frequency of 8.1AH carriers in controls and in subgroups of CRS patients.Our novel observations demonstrate that the presence of the 8.1AH may be responsible for the development of severe forms of CRS (CRSwNP, ASA+) and strengthen the clinical observation that CRS patients can be classified into clinically and genetically different subgroups.     

Association between single nucleotide polymorphisms in the hMSH3 gene and sporadic colon cancer with microsatellite instability

The association between three single nucleotide polymorphisms (SNPs) in the hMSH3 gene and sporadic colon cancer with microsatellite instability (MSI) was analyzed. Of the three SNPs observed in this population, SNPs at residues 235 and 693 were novel, while that at residue 3133 was previously described. The SNPs at residues 235 and 3133 caused amino acid substitutions, V79I and T1045A, respectively. We analyzed the allele frequencies of the three SNPs in samples from 19 patients with sporadic colon cancer with MSI and 90 healthy controls. We found that the V79 allele frequency was significantly higher in the tumor samples than in controls. In addition, the frequency of the G693 allele showed a higher trend in the tumor samples than in controls. These results indicated that some SNPs in the hMSH3 gene were associated with colon cancer with MSI. Received: February 16, 2000 / Accepted: February 25, 2000     

汉族人群脂联素基因-11377C/G多态性与子痫前期的相关性研究

目的探讨福建莆田地区汉族人群脂联素基因（APN）单核苷酸多态性（SNP）和子痫前期（pre-eclampsi-a）及其血脂水平的关联性。方法研究对象516例,包括对照组260例,子痫前期病例组256例。采用聚合酶链反应一限制性片段长度多态性（PCR-RFLP）法鉴定APN基因启动子-11377C/G单核苷酸多态性并测定血脂水平。结果 APN基因启动子-11377C/G位点G等位基因频率和GG＋CG基因型频率在子痫前期病例组明显升高,差异有统计学意义（P〈0.05）。子痫前期病例组内GG＋CG基因型患者血清甘油三酯（TG）、血浆总胆固醇（TC）和低密度脂蛋白（LDL）值均高于CC基因型（P〈0.05）。结论 APN基因启动子-11377C/G位点GG＋CG基因型与子痫前期及其血浆TG、TC和LDL水平升高关联,C-G多态性提高了子痫前期合并血脂代谢紊乱的风险性。     

Association analysis of vitamin D receptor gene polymorphisms in North England population with Type 2 diabetes mellitus

BackgroundNumerous diabetes susceptibility loci, include a region consisting vitamin D receptor gene found in chromosome 12q, have been known using genome wide screens.AimThe aim of present study is to probe the relationship between polymorphism of vitamin D receptor gene (single nucleotide polymorphisms) and type 2 diabetes mellitus (T2DM). Five hundred T2DM patients and 200 healthy subjects with normal HbA1c (≤ 5.0 %), fasting blood sugar (≤ 120 mg/dL) and random blood sugar (≤ 140 mg/dL) were enrolled.MetholodgyThe genotypes were found by polymerase chain reaction restriction fragment length polymorphism and DNA sequencing.Resultsrevealed that no considerable differences in frequencies of genotype and allele of the Bsm I and Fok I polymorphisms between healthy and patients in the North England (For Fok I: OR = 1.11, 95% CI: 0.72–1.12; for Bsm I: OR = 1.35, 95% CI: 0.79–1.98).ConclusionIt is recommended that both following polymorphisms of vitamin D receptor gene may not considerably add to the progression of T2DM in the North England.     

A promoter SNP (-1323T>C) in G-substrate gene (GSBS) correlates with hypercholesterolemia

Factors predisposing to the phenotypic features of higher total cholesterol (TC) have not been clearly defined. Here we report an association between a promoter SNP (–1323T>C) in G-substrate gene (GSBS) and TC levels in 368 adult individuals from an east-central area of Japan. Age and gender-adjusted levels of LDL-cholesterol, TG, TC, and HDL-cholesterol were analyzed. When we separate the subjects into two genotypic groups regarding T allele, those who bear the T allele had significantly higher plasma TC levels than the others who lack the T allele (mean; 239.6 mg/dl vs. 210.6 mg/dl; p=0.003; Mann–Whitney test). Of the 341 individuals with the T allele, approximately 80% individuals presented with hypercholesterolemia, whereas only 44% were hypercholesterolemic among the 27 individuals without the T allele (p=0.0001). These results indicate a significant elevating effect of plasma TC levels by a SNP in the putative regulatory region of the G-substrate gene in our studied population. These data suggest that genetic variation at the G-substrate gene may be one of the determinants for plasma lipoprotein levels.