抑郁症与cAMP反应元件结合蛋白基因的关联研究

目的 探讨cAMP反应元件结合蛋白(cyclic adenosine monophosphate response elementbinding protein,CREB1)基因与抑郁症的关联关系.方法 采用聚合酶链反应-限制性片段长度多态性方法检测105个抑郁症核心家系CREB1基因上单核苷酸多态性(single nucleotide polymorphisms,SNP)rs10932201和rs6740584的等位基因与基因型分布情况.进行单位点及单倍型的传递/不平衡检验(transmission disequilibrium test,TDT).结果 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,TDT χ2 值分别为2.700(P=0.1004)和0.458(P=0.4986),差异均无统计学意义.单倍型TDT分析结果显示由rs10932201和rs6740584构成的单倍型与抑郁症存在显著性关联,差异有统计学意义(总χ2=23.458,df=3,P=0.00003241).单个单倍型A-C和A-T与抑郁症也均有显著性关联,差异有统计学意义(χ2 值分别为5.405和13.623,P值分别为0.020和0.00022).结论 CREB1基因上SNP位点rs10932201和rs6740584与抑郁症均无显著性关联,但由这2个SNP位点构成的单倍型与抑郁症存在显著性关联,提示CREB1基因rs10932201-rs6740584单倍型可能在抑郁症的遗传学发病机制中具有重要作用.     

Family-based association study between autism and glutamate receptor 6 gene in Chinese Han trios.

The glutamate pathways are involved in diverse processes such as learning and memory, epilepsy, and they play important roles in neural plasticity, neural development, and neurodegeneration. It has been proposed that autism could be a hypoglutamatergic disorder. Recently, Jamain et al. reported that the glutamate receptor 6 (GluR6 or GRIK2) is in linkage disequilibrium with autism. In the present study, the transmission disequilibrium test (TDT) and the haplotype transmission were performed to analyze the four SNPs (SNP1: rs995640; SNP2: rs2227281; SNP3: rs2227283; SNP4: rs2235076) of GluR6 in 174 Chinese Han parent-offspring trios. The TDT demonstrated that the two SNPs (SNP2 and SNP3) showed preferential transmission (TDT P = 0.032). The global chi(2) test for haplotype transmission also revealed an association between GluR6 and autism (chi(2) = 10.78, df = 3, P = 0.013). Our results suggested that GluR6 is in linkage disequilibrium with autism.     

FXYD6基因遗传多态性在精神分裂症患者核心家系中的传递不平衡检验

目的 探讨FXYD6基因单核苷酸多态性(single nucleotide polymorphisms,SNP)和精神分裂症(schizophrenia)之间的相关性.方法 采用等位基因特异性PCR的方法对FXYD6基因6个SNPs(rs10790212、rs11544201、rs555577、rs1815774、rs4938446和rs497768)位点的基因型在101个三口之家中进行传递不平衡检验(transmission disequilibrium test,TDT).结果 遗传标记rs10790212和rs11544201显示了显著的传递不平衡(P＜0.05),而单倍型分析的结果表明单倍型rs10790212-rs11544201与精神分裂症显著性关联(P＜0.05).结论 FXYD6基因与中国汉族人群精神分裂症遗传易感性相关,有必要进一步开展对FXYD6基因的功能学研究.     

Lipoprotein lipase variants associated with an endophenotype of hypertension: hypertension combined with elevated triglycerides

Previously, we observed that young-onset hypertension was independently associated with elevated plasma triglyceride(s) (TG) levels to a greater extent than other metabolic risk factors. Thus, focusing on the endophenotype--hypertension combined with elevated TG--we designed a family-based haplotype association study to explore its genetic connection with novel genetic variants of lipoprotein lipase gene (LPL), which encodes a major lipid metabolizing enzyme. Young-onset hypertension probands and their families were recruited, numbering 1,002 individuals from 345 families. Single-nucleotide polymorphism discovery for LPL, linkage disequilibrium (LD) analysis, transmission disequilibrium tests (TDT), bin construction, haplotype TDT association and logistic regression analysis were performed. We found that the CC- haplotype (i) spanning from intron 2 to intron 4 and the ACATT haplotype (ii) spanning from intron 5 to intron 6 were significantly associated with hypertension-related phenotypes: hypertension (ii, P=0.05), elevated TG (i, P=0.01), and hypertension combined with elevated TG (i, P=0.001; ii, P<0.0001), according to TDT. The risk of this hypertension subtype increased with the number of risk haplotypes in the two loci, using logistic regression model after adjusting within-family correlation. The relationships between LPL variants and hypertension-related disorders were also confirmed by an independent association study. Finally, we showed a trend that individuals with homozygous risk haplotypes had decreased LPL expression after a fatty meal, as opposed to those with protective haplotypes. In conclusion, this study strongly suggests that two LPL intronic variants may be associated with development of the hypertension endophenotype with elevated TG.     

支气管哮喘易感区域5q31-33内Tim-3基因单体型分析

目的： 探讨染色体上支气管哮喘易感区域5q31-33内Tim-3基因多态性与支气管哮喘的关系。方法：应用限制性片段长度多态性技术方法,分析了118个儿童变应性哮喘核心家系Tim-3基因4个SNPs(rs10053538、rs10515746、rs13170556和rs9313441)的基因型;采用基于家系传递不平衡检验（TDT）,分析基因分型数据;应用TRANSMIT软件构建单体型并进行单体型关联分析。结果：①基于家系的TDT分析显示,Tim-3基因的4个SNPs由杂合子父母传递给患病子代的等位基因频率不比预期值高,与哮喘无关（P>0.05）。②Transmit多个位点单体型分析结果显示由Tim-3基因rs10053538、 rs13170556、 rs9313441构建的单体型与支气管哮喘有关联（Global 2=10.83,P<0.05）。父母传递给患病子女GGG单体型的观察值小于期望值,差异显著（2=8.24,P<0.01）。结论：中国汉族人群中,位于染色体5q31-33区域的Tim-3基因本身或其附近的基因可能与儿童变应性哮喘的易感性相关。     

基于家系的Tim-3基因多态性与儿童变应性哮喘的关联研究

目的 以家系资料为基础,利用遗传不平衡原理探讨染色体5q33.2区Tim-3基因启动子两个多态性位点rs10053538和rs10515746与中国湖北地区汉族儿童变应性哮喘的关系.方法 应用限制性片段长度多态性技术结合测序方法,分析了118个儿童变应性哮喘核心家系Tim-3基因rs10053538和rs10515746的基因型;采用基于家系的关联分析方法,包括单体型相对风险分析(HRR)和传递不平衡检验(TDT),分析基因分型数据;应用Transmit软件构建单体型并进行单体型关联分析.结果 118个核心家庭HRR分析显示Tim-3基因启动子区两个多态性位点rs10053538和rs10515746不使病人具有更高的发病风险(X2=2.430,P>0.05;x2=1.368,P>0.05).118个满足经典TDT分析的核心家庭中,杂合子父母传递给患病子代的等位基因频率不比预期值高(x2=2.042,P>O.05;x2=0.750,P>O.05).Transmit双位点单体型分析也未见父母传递给子女各个单体型的观察值和期望值有明显差异(P>O.05).结论 中国湖北地区汉族人群中,Tim-3基因启动子区两个多态性位点rs10053538和rs10515746与儿童变应性哮喘不具有相关性.     

The transmission disequilibrium analysis between neuronal nicotinic acetylcholine receptor alpha 7 subunit gene polymorphisms and schizophrenia]

OBJECTIVE: To investigate the association between neuronal nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) gene and schizophrenia. METHODS: The three polymorphisms rs2337980, rs1909884, rs883473 in CHRNA7 gene were detected based on PCR and polyacrylamide gel microarray in 129 schizophrenic trios. The results of genotyping were analyzed by haplotype relative risk analysis based on haplotype(HHRR), transmission disequilibrium test(TDT) and hyplotype analysis. RESULTS: (1)The HHRR analysis suggested that there was significant differences in rs2337980 allele frequencies between schizophrenia group and dummy control group(P= 0.017); (2)In TDT test, there may be transmission disequilibrium between rs2337980 and schizophrenia, the heterozygous parents excessively transferred the C allele to patients (P= 0.021); (3)The haplotype between rs2337980 and rs1909884 as well as the hyplotype among rs2337980, rs1909884 and rs883473 may have significant association with schizophrenia (global P= 0.034; global P= 0.027), the T-C and T-C-T hyplotype may have transmission disequilibrium with schizophrenia. CONCLUSION: There may be association between CHRNA7 gene polymorphisms and schizophrenia, the variant allele T in rs2337980 may have a protective effect to schizophrenia.     

Neuregulin 1基因多态性与中国汉族精神分裂症关联分析

目的 探讨Neuregulin 1(NRG1)基因多态性与精神分裂症的关联.方法 在258个中国汉族精神分裂症核心家系(患者及其亲生父母)中,应用实时定量PCR技术检测位于NRGl基因5'端的4个单核苷酸多态(single nucleotide polymorphism,SNP)位点:rs221533(C/T)、rs7820838(C/T)、433E1006 (A/G)和rs3924999(C/T),进行基因分型,应用传递不平衡检测(transmission disequilibrium test,TDT)分析等位基因传递情况,分析该基因与精神分裂症易感性的关联.结果 在258个中国汉族核心家系中,rs221533、433E1006、rs3924999三个SNP均存在有统计学意义的传递不平衡,优先传递的等位基因分别是:C、A、T(rs221533:X2=27.45,P=0.000;433E1006:X2=56.08,P=0.000;rs3924999:X2=10.53,P=0.001).rs7820838未检到不平衡传递(X2=3.31,P=0.081).频率大于1%单倍型进行分析,rs221533-rs7820838-433E1006联合分析,单倍型C/C/G和C/C/A优先传递(C/C/G:X2=5.26,P=45.08;C/C/A:X2=0.026,P=0.000);rs221533-rs7820838-433E1006-rs3924999联合分析,单倍型C/C/G/T、C/C/A/C和C/C/A/T优势传递(C/C/G/T:X2=10.71,P=0.001;C/C/A/C:.)X2=8.83,P=0.006、C/C/A/T:X2=27.00,P=0.000).213个阳性亚型的精神分裂症核心家系中传递不平衡得出基本一致的结果 .结论 Nrg1基因多态性与中国汉族人群精神分裂症存在关联,尤其是支持与阳性亚型精神分裂症存在关联.     

Family-based association study between GRIK2 polymorphisms and autism spectrum disorders in the Korean trios

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with strong genetic components. The present study comprises the detection of four single nucleotide polymorphisms (SNPs) in GRIK2 followed by a family-based association analysis of the SNPs in 126 Korean ASD trios by using the transmission disequilibrium test (TDT) and haplotype analysis. We found preferential transmission of the C allele at the rs3213607 (P<0.001) of GRIK2 in ASD and haplotype analysis revealed that one haplotype demonstrated a significant association (P=0.023). These results suggest a potential association between GRIK2 and ASD in the Korean population.     

神经型烟碱乙酰胆碱受体α7亚单位基因多态性与精神分裂症的传递不平衡研究

目的 探讨神经型烟碱乙酰胆碱受体α7亚单位基因(neuronal nicotinic acetyleholine receptor α7 subunit gene,CHRNA7)多态性与精神分裂症的关系.方法 应用聚合酶链反应及聚丙烯酰胺凝胶芯片技术检测129个精神分裂症先证者核心家系CHRNA7基因的rs2337980、rs1909884、rs883473三个单核苷酸多态性,并采用基于单倍型的单倍型相对风险检验(haplotype relative risk,HHRR)、传递不平衡检验(transmission disequilibrium test,TDT)及单倍型分析进行统计.结果 (1)HHRR分析结果显示rs2337980位点精神分裂症患者组与虚拟对照组之间等位基因频率差异有统计学意义(P=0.017);(2)TDT分析发现,rs2337980位点与精神分裂症之间可能存在传递不平衡,杂合子父母过多的传递等位基因C给患病子女(P=0.021).(3)单倍型分析发现,rs2337980、rsl909884及rs2337980、rsl909884、rs883473组成的单倍型与精神分裂症有显著相关(总体P=0.034;glohal P=0.027),其中T-C,T-C-T两个单倍型与精神分裂症可能存在传递不平衡.结论 CHRNA7 基因多态性可能与精神分裂症存在关联,rs2337980的变异等位基因T可能是精神分裂症的保护性因子.     

The KPNA3 gene may be a susceptibility candidate for schizophrenia

The present study investigated the possible association of the KPNA3 locus in the 13q14 region with schizophrenia. We detected 7 single nucleotide polymorphisms (SNPs) on 13q14, one (rs6313) present at the HTR2A locus and the other 6 at the KPNA3 locus, among 124 British family trios consisting of mother, father and affected offspring with schizophrenia. The transmission disequilibrium test (TDT) showed allelic association for rs3736830 (chi(2)=8.66, P=0.003), rs2181185 (chi(2)=3.86, P=0.049) and rs626716 (chi(2)=5.82, P=0.016), but not for rs6313 (chi(2)=0.009, P=0.926). The global P-value was 0.029 for 1000 permutations with the TDT. The 2-SNP haplotype analysis showed a disease association for the rs2273816-rs3736830 haplotypes (chi(2)=7.63, d.f.=2, P=0.022), the rs3736830-rs2181185 haplotypes (chi(2)=10.30, d.f.=2, P=0.006) and the rs2181185-rs3782929 haplotypes (chi(2)=9.26, d.f.=2, P=0.01). The global P-value was 0.034 for 1000 permutations with the 2-SNP haplotype analysis. The 6-SNP haplotype system also showed a weak association with the illness (chi(2)=15.62, d.f.=8, P=0.048), although the 1-d.f. test did not show the association for nine individual haplotypes when a P-value was corrected by the Bonferroni corrections. The present study suggests that the KPNA3 may contribute genetically to schizophrenia in a small effect size.     

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.     

Association between nonsyndromic cleft lip with or without cleft palate and the glutamic acid decarboxylase 67 gene in the Japanese population

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the most common craniofacial malformations. Both genetic and environmental factors are involved in the pathogenesis. In addition to its role as an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) synthesized by glutamic acid decarboxylase (GAD) is presumed to play a role in normal embryonic, especially facial, development. This notion has been substantiated by the fact that Gad67 knockout mice have been shown to have cleft palate. We hypothesized that GAD67 may be involved in the development of NSCLP and investigated the possible association between the GAD67 gene (GAD67) and NSCLP in Japanese patients. We screened 50 probands for single nucleotide polymorphisms (SNPs) in GAD67 using denaturing high performance liquid chromatography (DHPLC) and found seven SNPs. Since two SNPs showed complete linkage disequilibrium (LD) to the other SNPs, we constructed a 5-locus haplotype of GAD67. The frequency distribution of the haplotype differed between NSCLP patients and controls (P = 0.0028). The frequency of -445A, -292A, -147G, 111C, and IVS9-39T haplotype in the NSCLP patients was significantly lower than that in controls (P = 0.00098). In a transmission disequilibrium test (TDT) in 99 parent-offspring trios, we found -445C, -292C, -147G, 111C, and IVS9-39C haplotype was preferentially transmitted to the patients with cleft lip and palate (P = 0.0077). Our data suggest that GAD67 is involved in the pathogenesis of NSCLP in the Japanese population.     

Genetic variants of RANTES are associated with serum RANTES level and protection for type 1 diabetes

RANTES (regulated on activation, normal T-cell expressed and secreted) is a T-helper type 1 (Th1) chemokine that promotes T-cell activation and proliferation. RANTES is genetically associated with asthma, sarcoidosis and multiple sclerosis. The concentration of RANTES is increased at inflammation sites in different autoimmune diseases. Type 1 diabetes (T1D) is a Th1-mediated disease with complex genetic predisposition. We tested RANTES as a candidate gene for association with T1D using three single-nucleotide polymorphism (SNP) variants (rs4251719, rs2306630 and rs2107538) to capture haplotype information. The minor alleles of all SNPs were transmitted less frequently to T1D offspring (transmission rates 37.3% (P=0.002), 38.7% (P=0.007) and 41.0% (P=0.01)) and were less frequently present in patients compared to controls (P=0.009, 0.03 and 0.04, respectively). A similar protective effect was observed for the haplotype carrying three minor alleles (transmission disequilibrium test (TDT): P=0.003; odds ratio (OR)=0.55; confidence interval (CI): 0.37-0.83; case/control: P=0.03; OR=0.74; CI: 0.55-0.98). Both patients and controls carrying the protective haplotype express significantly lower serum levels of RANTES compared to non-carriers. Subsequently, we tested a cohort of 310 celiac disease patients, but failed to detect association. RANTES SNPs are significantly associated with RANTES serum concentration and development of T1D. The rs4251719*A-rs2306630*A-rs2107538*A haplotype associated with low RANTES production confers protection from T1D. Our data imply that RANTES is associated with T1D both genetically and functionally, and contributes to diabetes-prone Th1 cytokine profile.     

STK11基因多态性与家族性热性惊厥关联研究

目的研究丝氨酸/苏氨酸蛋白激酶11(serine/threonine kinase 11,STK11)基因单核苷酸多态性(single nucleotide polymorphisms,SNPs)位点与家族性热性惊厥(familial febrile convulsions,FC)的关系.方法用关联分析的方法,结合传递不平衡检验(transmission disequilibrium test,TDT),对来自中国北方的家族性热性惊厥病人和对照组进行分析.结果 SNPs位点的基因型频率在惊厥患儿和对照组中分布均符合Hardy-Weinberg平衡.前期实验位点rs741764的基因型频率和基因频率及rs2075604的基因型频率在两组人群中分布差异有显著性(P＜0.05),后期选择一般人群作为对照组进行的关联分析,除rs741764基因型频率在两组间差异有显著性(P＜0.05)外,其余差异均无显著性.进一步用TDT得到3个位点都没有发现传递不平衡现象.结论 STK11基因的四个SNPs位点均与家族性热性惊厥不相关,STK11基因可能不是中国北方人家族性热性惊厥的易感基因.     

A study of the PEMT gene in schizophrenia

The phospholipid hypothesis of schizophrenia is becoming popular because of the findings from the niacin flush test, the treatment with polyunsaturated fatty acids (PUFAs), biochemical studies for the phospholipid metabolism pathway and genetic studies of phospholipase A2. The present study attempted to investigate the gene coding for phosphatidylethanolamine N-methyltransferase (PEMT), which is an important enzyme for the synthesis of membrane phospholipids. We recruited 271 Chinese parent-offspring trios of Han descent and detected 3 single nucleotide polymorphisms (SNPs) at the PEMT locus. The transmission disequilibrium test (TDT) showed allelic association for rs464396 (X2=9.4, P=0.002), but not for the other two. The 2-SNP haplotype analysis showed haplotypic association for both the rs936108-rs464396 haplotypes (X2=25.7, d.f.=3, P=0.00001) and the rs464396-rs4244593 haplotypes (X2=17.3, d.f.=3, P=0.0006). The 3-SNP haplotype analysis also showed a haplotypic association (X2=24.4, d.f.=7, P=0.0006). The present results suggest that the PEMT gene may contribute to the etiology of schizophrenia.     

Association of the TSHR gene with Graves' disease: the first disease specific locus

The development of autoimmune thyroid disease (AITD) is associated with autoantibodies directed against the thyroid stimulating hormone receptor (TSHR). Previous studies have failed to demonstrate a consistent association between the TSHR and AITD, or any of its sub-phenotypes. In the present study, we analysed the linkage disequilibrium (LD) structure encompassing the TSHR, to identify LD 'blocks' and SNPs, which capture the majority of intra-block haplotype diversity. The haplotype tagging SNPs, plus all common SNPs reported in previous studies were genotyped in 1,059 AITD Caucasian cases and 971 Caucasian controls. A haplotype, across two LD blocks, showed association (P<1 x 10(-6), OR 1.7) with Graves' disease (GD) but not autoimmune hypothyroidism (AIH). We replicated these findings by genotyping the most associated GD SNP, rs2268458, in a separate UK Caucasian cohort of 1,366 AITD cases and 1,061 controls (GD, P=2 x 10(-6), OR 1.3; AIH, P=NS). These results in two independent Caucasian data sets suggest that the TSHR is the first replicated GD-specific locus meriting further fine mapping and functional analysis to identify the aetiological variants.     

Genetic association of SNPs in the FTO gene and predisposition to obesity in Malaysian Malays

The common variants in the fat mass- and obesity-associated (FTO) gene have been previously found to be associated with obesity in various adult populations. The objective of the present study was to investigate whether the single nucleotide polymorphisms (SNPs) and linkage disequilibrium (LD) blocks in various regions of the FTO gene are associated with predisposition to obesity in Malaysian Malays. Thirty-one FTO SNPs were genotyped in 587 (158 obese and 429 non-obese) Malaysian Malay subjects. Obesity traits and lipid profiles were measured and single-marker association testing, LD testing, and haplotype association analysis were performed. LD analysis of the FTO SNPs revealed the presence of 57 regions with complete LD (D'' = 1.0). In addition, we detected the association of rs17817288 with low-density lipoprotein cholesterol. The FTO gene may therefore be involved in lipid metabolism in Malaysian Malays. Two haplotype blocks were present in this region of the FTO gene, but no particular haplotype was found to be significantly associated with an increased risk of obesity in Malaysian Malays.     

Association of the MMP9 gene with childhood cedar pollen sensitization and pollinosis

Matrix metalloproteinase 9 (MMP9) gene has been shown to be involved in the pathogenesis of allergic rhinitis (AR) and asthma. Previous studies suggested that single-nucleotide polymorphisms (SNPs) of the MMP9 gene conferred a risk for childhood asthma. However, whether the SNPs confer a risk for AR has not been previously investigated. The objective of this study was to investigate whether SNPs of the MMP9 gene are associated with risk of seasonal AR (pollinosis), perennial AR and allergen sensitization. A total of 670 school children were recruited in Japan and genotyped for functional polymorphism in the promoter (-1590C/T: rs3918242) and three amino-acid substitutions (R297Q: rs17576; P574R: rs2250889; R668Q: rs17577). Serum levels of total and specific IgE were determined. Disease status and other clinical characteristics of the subjects were investigated using a questionnaire. Associations between the MMP9 SNPs and both AR and serum IgE levels were evaluated. -1590C/T showed significant association with cedar pollinosis (corrected P (Pcor)=0.039). R668Q was in strong linkage disequilibrium (LD) with -1590C/T and showed significant association with cedar pollinosis (Pcor=0.023) and serum cedar pollen-specific IgE level (Pcor=0.022). A haplotype associated with -1590T and 668Q showed a significant association with cedar pollinosis, orchard grass pollinosis and cedar pollen-specific IgE (Pcor=0.0012, Pcor=0.0059 and Pcor=0.0041, respectively). R297Q and P574R were in weak LD with the rest of the SNPs and did not show significant association with disease. Compared with wild-type MMP9 protein (279R-574P-668R), a variant enzyme (279R-574P-668Q) that showed association with pollinosis had lower activity. However, lower enzyme activity was not associated with disease risk because another variant (279Q-574R-668R) showed lower enzyme activity but was not associated with pollinosis. The -1590T allele and its corresponding haplotype was associated with higher promoter activity and with pollen-specific IgE levels and pollinosis, suggesting that -1590C/T may have more impact on sensitization and disease development than R668Q. Our results suggest that the MMP9 gene confers susceptibility to cedar pollinosis in Japanese children. The MMP9 gene may be associated with pollinosis through sensitization processes.