基于核心家系的EGR3基因与精神分裂症的关联研究

研究表明位于染色体8p21.3区域的EGR3(Early growth response 3)是精神分裂症(Schizophrenia)的重要易感基因,然而,仍有两个病例-对照研究未能验证上述发现。为了研究EGR3基因在我国患者中是否与疾病关联,文章在中国汉族的核心家系中选择EGR3基因座位上的5个SNPs位点(rs1996147、rs1877670、rs3750192、rs35201266和rs7009708)进行基因分型和传递不平衡检验(Transmission disequilibrium test,TDT)。结果表明遗传标记rs1996147和rs3750192分别显示出显著的传递不平衡(2>4.40,P<0.05)。在连锁不平衡分析中,由2个(rs3750192和rs35201266)、3个(rs1877670、rs3750192和rs7009708)以及4个(rs1996147、rs1877670、rs3750192和rs7009708)SNPs位点构建的单倍型均显示与精神分裂症显著性关联(2>7.10,整体P<0.05)。总之,EGR3基因与中国汉族人群精神分裂症遗传易感性相关,后续关于EGR3基因进一步的功能研究将会更好的帮助我们了解该基因在疾病病理学机制中的作用。     

基于核心家系的EGR3基因与精神分裂症的关联研究

研究表明位于染色体8p21.3区域的EGR3(Early growth response 3)是精神分裂症(Schizophrenia)的重要易感基因, 然而, 仍有两个病例-对照研究未能验证上述发现。为了研究EGR3基因在我国患者中是否与疾病关联, 文章在中国汉族的核心家系中选择EGR3基因座位上的5个SNPs位点(rs1996147、rs1877670、rs3750192、rs35201266和rs7009708)进行基因分型和传递不平衡检验(Transmission disequilibrium test, TDT)。结果表明遗传标记rs1996147和rs3750192分别显示出显著的传递不平衡(c²>4.40, P<0.05)。在连锁不平衡分析中, 由2个(rs3750192和rs35201266)、3个(rs1877670、rs3750192和rs7009708)以及4个(rs1996147、rs1877670、rs3750192和rs7009708)SNPs位点构建的单倍型均显示与精神分裂症显著性关联(c²>7.10, 整体P<0.05)。总之, EGR3基因与中国汉族人群精神分裂症遗传易感性相关, 后续关于EGR3基因进一步的功能研究将会更好的帮助我们了解该基因在疾病病理学机制中的作用。     

Thinking and doing: the effects of dopamine and oxytocin genes and executive function on mothering behaviours

Animal and human studies suggest that initial expression of maternal behaviour depends on oxytocin and dopamine systems. However, the mechanism by which these systems affect parenting behaviours and the timing of these effects are not well understood. This article explores the role of mothers' executive function in mediating the relation between oxytocin and dopamine gene variants and maternal responsiveness at 48 months post‐partum. Participants (n = 157) were mothers recruited in the Maternal Adversity, Vulnerability and Neurodevelopment Study, which assesses longitudinally two cohorts of mothers and children in Canada. We examined single nucleotide polymorphisms (SNPs) related to the dopamine and oxytocin systems (DRD1 rs686, DRD1 rs265976, OXTR rs237885 and OXTR rs2254298), assessed mothers' decision‐making at 48 months using the Cambridge Neurological Automated Testing Battery (CANTAB) and evaluated maternal responsiveness from videotaped interactions during the Etch‐A‐Sketch co‐operation task. Mediation analyses showed that OXTR rs2254298 A‐carriers had an indirect effect on positive parenting which was mediated by mothers' performance on decision‐making task (estimate = 0.115, P < 0.005), while OXTR rs2254298 A‐carriers had both direct and indirect effects on physically controlling parenting, also mediated through enhanced performance on decision‐making (estimate = ?0.059, P < 0.005). Dopamine SNPs were not associated with any measure of executive function or parenting (all P > 0.05). While oxytocin has previously been associated with only the early onset of maternal behaviour, we show that an OXTR polymorphism is involved in maternal behaviour at 48 months post‐partum through mothers' executive function. This research highlights the importance of the oxytocin system to maternal parenting beyond infancy.     

Genetic susceptibility to obsessive-compulsive hoarding: the contribution of neurotrophic tyrosine kinase receptor type 3 gene

Recent work suggests that neurotrophic factors may contribute to the genetic susceptibility to obsessive-compulsive disorder (OCD). Among other clinical dimensions, the presence of hoarding obsessions and compulsions has been shown to be correlated with a number of clinical and neuroimaging findings, as well as with a different pattern of genetic inheritance. We used a linkage disequilibrium (LD)-mapping approach to investigate whether neurotrophic tyrosine kinase receptor type 3 (NTRK3), the high-affinity receptor of neurotrophin 3 (NT-3), plays a role in increasing susceptibility to hoarding in OCD. We performed an association study of 52 tag single nucleotide polymorphisms (tagSNPs) covering the whole NTRK3 gene in a sample comprising 120 OCD patients and 342 controls. Single nucleotide polymorphism association and haplotype analysis were performed. Thirty-six of our patients (30%) exhibited significant hoarding obsessions and compulsions. A significant association of two SNPs in the 3' downstream region of NTRK3 gene and obsessive-compulsive hoarding was identified: rs1017412 [odds ratio (OR) = 2.16; P = 0.001] and rs7176429 (OR = 2.78; P = 0.0001), although only the latter remained significant after Bonferroni correction. Although the haplotype analysis did not show significant results, a more extended block of LD in the OCD hoarders with respect to the control group was observed, suggesting a lower haplotype diversity in these individuals. Our findings suggest that NTRK3 may contribute to the genetic susceptibility to hoarding in OCD and may constitute an interesting gene to focus on in studies of the genetic basis of obsessive-compulsive hoarding.     

Interaction between Oxytocin Genotypes and Early Experience Predicts Quality of Mothering and Postpartum Mood

Individual differences in maternal behavior are affected by both early life experiences and oxytocin, but little is known about genetic variation in oxytocin genes and its effects on mothering. We examined two polymorphisms in the oxytocin peptide gene OXT (rs2740210 and rs4813627) and one polymorphism in the oxytocin receptor gene OXTR (rs237885) in 187 Caucasian mothers at six months postpartum. For OXT, both rs2740210 and rs4813627 significantly associated with maternal vocalizing to the infant. These polymorphisms also interacted with the quality of care mothers experienced in early life, to predict variation in maternal instrumental care and postpartum depression. However, postpartum depression did not mediate the gene-environment effects of the OXT SNPs on instrumental care. In contrast, the OXTR SNP rs237885 did not associate with maternal behavior, but it did associate with pre-natal (but not post-natal) depression score. The findings illustrate the importance of variation in oxytocin genes, both alone and in interaction with early environment, as predictors of individual differences in human mothering. Furthermore, depression does not appear to have a causal role on the variation we report in instrumental care. This suggests that variation in instrumental care varies in association with a gene-early environment effect regardless of current depressive symptomatology. Finally, our findings highlight the importance of examining multiple dimensions of human maternal behavior in studies of genetic associations.     

Variants of the human PPARG locus and the susceptibility to chronic periodontitis

Apart from its regulatory function in lipid and glucose metabolism, peroxisome proliferator-activated receptor (PPAR)γ has impact on the regulation of inflammation and bone metabolism. The aim of the study was to investigate the association of five polymorphisms (rs10865710, rs2067819, rs3892175, rs1801282, rs3856806) within the PPARG gene with chronic periodontitis. The study population comprised 402 periodontitis patients and 793 healthy individuals. Genotyping of the PPARG gene polymorphisms was performed by PCR and melting curve analysis. Comparison of frequency distribution of genotypes between individuals with periodontal disease and healthy controls for the polymorphism rs3856806 showed a P-value of 0.04 but failed to reach significance after correction for multiple testing (P??0.90). A 3-site analysis (rs2067819-rs1801282-rs3856860) revealed five haplotypes with a frequency of ≥1% among cases and controls. Following adjustment for age, gender and smoking, none of the haplotypes was significantly different between periodontitis and healthy controls after Bonferroni correction. This study could not show a significant association between PPARG gene variants and chronic periodontitis.     

多NER基因多态的交互作用与移植排斥的发病风险相关

基因间SNP-SNP的交互作用较单一SNP对于疾病的预警作用可能会达到更优的检测效能。本研究探讨了核苷酸切除修复(NER)系统基因中SNP交互作用对移植排斥反应发病风险的预警作用。通过Sequenom MassARRAY平台进行基因分型,对8个NER基因中的38个多态进行了检测,包括XPA、XPC、DDB2、XPB (ERCC3)、XPD (ERCC2)、ERCC1、XPF (ERCC4)和XPG (ERCC5)基因。单体型分析结果显示,XPA rs3176629-rs2808668 C-T单体型以及ERCC5 G-C-C-T和G-C-T-C单体型可以增加移植排斥反应的发病风险(分别为OR = 1.81,OR=7.72和OR=3.46),而ERCC5 rs2094258-rs751402-rs2296147-rs1047768 A-C-T-T单体型降低了该风险(OR = 0.35)。多因素Logistic回归与多因子降维(MDR)分析均表明,ERCC2 rs50871、ERCC5 rs1047768和XPC rs2228001多态对于发生移植排斥反应存在基因间SNP-SNP的交互作用。因此,XPC rs2228001、ERCC2 rs50871、ERCC5 rs1047768三者的交互作用与移植排斥反应的发病风险相关。     

Association of the insulin-like growth factor1 gene with myocardial infarction in Japanese subjects

During adult life, the insulin/insulin-like growth factor1 (IGF1) signaling pathway plays an important role in cardiovascular function. Several reports have suggested that low baseline levels of IGF1 increase the risk of fatal ischemic heart disease. Thus, IGF1 may be involved in cardiovascular disease. The aim of the present study was to investigate the relationship between the human IGF1 gene and myocardial infarction (MI) in the Japanese population via the use of single nucleotide polymorphisms (SNPs). After selecting six SNPs in the human IGF1 gene (rs2162679, rs7956547, rs2288378, rs2072592, rs978458 and rs6218), we performed a case-control study using each of the SNPs and haplotypes in 320 MI patients and 307 non-MI controls. Multiple logistic regression analysis demonstrated that the GG+GA variant of rs2162679 (p=0.009) and the AA+GA variant of rs2072592 (p=0.026) exhibited a resistant effect for MI. The haplotype-based case-control study revealed that the frequency of the A-T-G-G haplotype for rs2162679-rs7956547-rs2072592-rs978458 was significantly higher in the MI group (47.3%) as compared to the non-MI group (41.4%) (p=0.037, odds ratio=1.270). The frequency of the A-T-G-T haplotype for rs2162679-rs7956547-rs978458-rs6218 was also significantly higher in the MI group (47.3%) as compared to the non-MI group (41.3%) (p=0.033, odds ratio=1.276). The current results suggest that specific SNPs and haplotypes can be utilized as genetic markers for MI risk or MI resistance. In addition, IGF1 or a neighboring gene might be associated with increased or decreased susceptibility to MI.     

Association of amyloid precursor protein-binding protein,family B,member 1 with nicotine dependence in African and European American smokers

Although epidemiological studies reveal that cigarette smoking is inversely associated with Alzheimer’s disease (AD) and Parkinson’s disease (PD), the underlying mechanism remains largely unknown. Considering the facts that amyloid precursor protein-binding protein, family B, member 1 (APBB1) is mapped to a suggestive linkage region on chromosome 11 for nicotine dependence (ND), and has been implicated in the pathogenesis of AD and PD, it represents a plausible candidate for genetic study of ND. Five single nucleotide polymorphisms (SNPs) within APBB1 were genotyped in a sample consisting of 2,037 participants of either African-American (AA) or European-American (EA) origin, and examined their associations with ND assessed by three commonly used measures: Smoking Quantity (SQ), the Heaviness of Smoking Index (HSI), and the Fagerström Test for ND (FTND). Individual SNP-based association analysis showed that all five SNPs are associated with at least one ND measure in one of the three samples; however, only the association of SNP rs4758416 with SQ and HSI remained significant after correction for multiple testing in the pooled sample. Haplotype analysis demonstrated three major haplotypes significantly associated with ND after Bonferroni correction. Formed by rs4758416-rs10839562-rs1079199, haplotype C-C-T showed positive association with FTND in the AA and pooled samples, and conversely, haplotype G-C-T showed negative association with SQ and HSI in AA and EA samples. Another haplotype, C-T-G, formed by rs10839562-rs1079199-rs8164, was significantly associated with HSI in the EA sample. Based on these findings, we conclude that APBB1 represents an important candidate gene in the genetic study on ND and neurodegenerative diseases and warrants further investigation in future.     

Single- and multilocus allelic variants within the GABA(B) receptor subunit 2 (GABAB2) gene are significantly associated with nicotine dependence

Twelve single-nucleotide polymorphisms (SNPs) in the human gamma-aminobutyric acid type B (GABA(B)) receptor subunit 2 gene (GABAB2) were tested for association with nicotine dependence (ND) in an extensively phenotyped cohort of 1,276 smokers and nonsmokers, representing approximately 404 nuclear families of African American (AA) or European American (EA) origin. The GABAB2 gene encodes a subunit of the GABA(B) receptor for GABA, an inhibitory neurotransmitter involved in the regulation of many physiological and psychological processes in the brain. The gene is located within a region of chromosome 9q22 that showed a "suggestive" linkage to ND. Individual SNP analysis performed using the PBAT-GEE program indicated that two SNPs in the AAs and four SNPs in the EAs were significantly associated with ND. Haplotype analysis using the Family-Based Association Test revealed that, even after Bonferroni correction, the haplotype C-C-G of rs2491397-rs2184026-rs3750344 had a significant positive association with ND in both the pooled and the AA samples. In the EAs, we identified two haplotypes, C-A-C-A and T-A-T-A, formed by SNPs rs1435252-rs378042-rs2779562-rs3750344, that showed a highly significant negative and positive association with ND, respectively. In summary, our findings provide evidence of a significant association of GABAB2 variants with ND, implying that this gene plays an important role in the etiology of this drug addiction.     

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.     

Genetic variability of the gene cluster CALHM1–3 in sporadic Creutzfeldt-Jakob disease

Perturbations of calcium homeostasis have been associated with several neurodegenerative disorders. A common polymorphism (rs2986017) in the CALHM1 gene, coding for a regulator of calcium homeostasis, is a genetic risk factor for the development of Alzheimer disease (AD). Although some authors failed to confirm these results, a meta-analysis has shown that this polymorphism modulates the age at disease onset. Furthermore, a recent association study has explored the genetic variability of CALHM1 gene and two adjacent paralog genes (CALHM3 and CALHM2) in an Asian population. Since several lines of evidence suggest that AD and prion diseases share pathophysiologic mechanisms, we investigated for the first time the genetic variability of the gene cluster formed by CALHM1 and its paralogs in a series of 235 sporadic Creutzfeldt-Jakob disease (sCJD) patients, and compared the genotypic and allelic frequencies with those presented in 329 controls from the same ancestry. As such, this work also represents the first association analysis of CALHM genes in sCJD. Sequencing analysis of the complete coding regions of the genes demonstrated the presence of 10 single nucleotide polymorphisms (SNP) within the CALHM genes. We observed that rs4918016-rs2986017-rs2986018 and rs41287502-rs41287500 polymorphic sites at CALHM1 were in linkage disequilibrium. We found marginal associations for sCJD risk at CALHM1 polymorphic sites rs41287502 and rs41287500 [coding for two linked missense mutations (p.(Met323Ile); (Gly282Cys)], and rs2986017 [p.(Leu86Pro)]. Interestingly, a TGG haplotype defined by the rs4918016-rs2986017-rs2986018 block was associated with sCJD. These findings underscore the need of future multinational collaborative initiatives in order to corroborate these seminal data.     

Association between Oxytocin Receptor Gene Polymorphisms and Self-Rated ‘Empathic Concern’ in Schizophrenia

The nonapeptide oxytocin (OXT) and its receptor (OXTR) have been implicated in social cognition, empathy, emotion and stress regulation in humans. Previous studies reported associations between OXT and OXTR genetic polymorphisms and risk for disorders characterized by impaired socio-emotional functioning, such as schizophrenia and autism. Here we investigate the influence of two single nucleotide polymorphisms (SNPs) within the OXTR gene on a measure of socio-emotional functioning in schizophrenic patients. OXTR SNPs that were previously investigated in other studies were genotyped in 145 patients diagnosed with schizophrenia according to DSM-IV and 145 healthy controls matched for age and gender. The Interpersonal Reactivity Index (IRI) was used to assess cognitive (‘perspective taking’), affective (‘empathic concern’) and self-related (‘personal distress’) dimensions of empathy. No group differences in genotype frequencies were observed. MANCOVA revealed a significant main (F [1,282] = 10.464; p<0.01) and interaction effect (genotype by diagnosis: F [1,282] = 4.329; p<0.05) of OXTR SNP rs2254298(A>GG) with ‘empathic concern’. Within the schizophrenia group, linear regression analysis determined OXTR rs2254298 genotype, PANSS negative and general symptom score, and age of disease onset as being significantly associated with ‘empathic concern’. OXTR rs2254298 significantly impacted PANSS general psychopathology scores. No associations were found for OXTR rs53576, IRI ‘perspective taking’ or ‘personal distress’ ratings. Our preliminary findings support hypotheses about an involvement of OXTR rs2254298 in emotional empathy in schizophrenic and healthy individuals, warranting independent replication.     

CNR1、GAD1和BDNF基因多态性与云南傣族男性海洛因依赖的相关性分析

为了探讨大麻素受体1基因(Cannabinoid receptor 1,CNR1)3个SNP位点(rs6454674、rs1049353和rs806368)、谷氨酸脱羧酶1基因(Glutamate decarboxylase 1,GAD1)3个SNP位点(rs1978340、rs3791878和rs11542313)、脑源性神经营养因子基因(Brain-derived neurotrophic factor,BDNF)2个SNP位点(rs6265和rs13306221)与云南傣族男性海洛因依赖的相关性,文章采用病例对照关联分析,建立8-SNPs复合扩增体系,应用SNaPshot方法检测165例傣族男性海洛因依赖患者和170例健康傣族男性CNR1、GAD1和BDNF基因8个SNPs位点基因型,采用SPSS17.0、Haploview4.2、PHASE2.1和MDR软件进行统计学分析。结果显示,rs13306221基因型频率在海洛因依赖组和对照组中的差异具有统计学意义(P<0.025),海洛因依赖组rs6265 A等位基因显著高于对照组(P<0.05),由rs1978340-rs3791878-rs11542313构建的T-A-C、C-C-C、C-C-T和T-C-C单体型及rs6265-rs13306221构建的A-G单体型频率在海洛因依赖组及对照组中差异具有统计学意义(P<0.05),海洛因依赖组T-A-C、C-C-T和A-G单体型频率明显高于对照组,GAD1基因rs1978340与rs3791878之间可能存在强协同的交互作用。结果表明,CNR1基因rs1049353多态性、GAD1基因rs1978340和rs11542313多态性以及BDNF基因rs6265和rs13306221多态性与云南傣族男性海洛因依赖相关联,并且携带rs6265 A等位基因的个体可能更容易对海洛因产生依赖。     

PPARGC1A基因Thr394Thr/Gly482Ser多态性与2型糖尿病的关联研究

对344例2型糖尿病患者和307名正常人的PPARGC1A基因单核苷酸多态性rs2970847(Thr394Thr)和rs8192678(Gly482Ser)与2型糖尿病的关系进行了单标记和单体型关联分析以及Logistic回归分析。在单标记分析中,对照组与病例组Thr394Thr的基因型和等位基因频率有显著差异(基因型, P =0.006; 等位基因, P < 0.001); Logistic回归和单体型分析表明, Thr394Thr的AA基因型及Thr394(ACA)-Ser482单体型增加患2型糖尿病的风险。Gly482Ser的基因型和等位基因频率在对照组与病例组间无显著差异。PPARGC1A基因是湖北汉人的一个2型糖尿病易感基因。     

Association between the oxytocin receptor (OXTR) gene and children's social cognition at 18 months

At 18 months, children engage in a variety of social behaviors that reflect their nascent ability to understand the intentions of other people (e.g. joint attention, empathy, cooperation and self‐recognition). Although numerous contextual factors have been shown to predict social cognition in young children, the genetic underpinnings of social‐cognitive traits has been understudied in this age group. Owing to the known effects of oxytocin on adult social cognition and psychopathology, this study hypothesized that variability in the oxytocin receptor gene (OXTR) would be associated with social cognition in children at 18 months. Participants consisted of 350 children (182 males; 168 females) who were part of an ongoing longitudinal study that aimed to assess environmental and genetic contributions to children's cognitive and socio‐emotional functioning. At 18 months, social cognition was measured using previously validated and developmentally sensitive tasks assessing children's joint attention, empathy, cooperation and self‐recognition. Five potentially functional OXTR variants were genotyped: rs1042778, rs2254298, rs11131149, rs237897 and rs237899. A family‐based association design was used to control for population admixture and stratification, and additional non‐genomic covariates were controlled. Results showed that variability in rs11131149 was significantly associated with social cognition (P = 0.009), with more copies of the major allele related to higher social cognition, and more copies of the minor (risk) allele associated with lower social cognition. A haplotype consisting of rs11131149–rs2254298 was also associated with social cognition (P = 0.020). Implications for normative and pathological development are discussed, and key areas for future research are proposed.     

Analysis of Interleukin-8 Gene Variants Reveals Their Relative Importance as Genetic Susceptibility Factors for Chronic Periodontitis in the Han Population

Interleukin (IL)-8, an important chemokine that regulates the inflammatory response, plays an important role in periodontitis. Previous studies indicate that certain IL-8 gene polymorphisms are associated with periodontitis susceptibility in some populations. However, the literature is somewhat contradictory, and not all IL-8 polymorphisms have been examined, particularly in Han Chinese individuals. The aim of this study was to investigate the association of every IL-8 SNP with chronic periodontitis in Han Chinese individuals. We analyzed 23 SNPs with minor allele frequency (MAF)≥0.01, which were selected from 219 SNPs in the NCBI dbSNP and preliminary HapMap data analyses from a cohort of 400 cases and 750 controls from genetically independent Han Chinese individuals. Single SNP, haplotype and gender-specific associations were performed. We found that rs4073 and rs2227307 were significantly associated with chronic periodontitis. Further haplotype analysis indicated that a haplotype block (rs4073-rs2227307-rs2227306) that spans the promoter and exon1 of IL-8 was highly associated with chronic periodontitis. Additionally, the ATC haplotype in this block was increased 1.5-fold in these cases. However, when analyzing the samples by gender, no significant gender-specific associations in IL-8 were observed, similar to the results of haplotype association analyses in female and male subgroups. Our results provide further evidence that IL-8 is associated with chronic periodontitis in Han Chinese individuals. Furthermore, our results confirm previous reports suggesting the intriguing possibilities that IL-8 plays a role in the pathogenesis of chronic periodontitis and that this gene may be involved in the etiology of this condition.     

The association between GAD1 gene polymorphisms and cerebral palsy in Chinese infants

Studies suggest that GAD1 gene was a functional candidate susceptibility gene for cerebral palsy (CP). In order to investigate the contribution of GAD1 gene to the etiology of CP in Chinese infants, we carried out a case-control association study between GAD1 gene and CP. In this study, 374 health controls and 392 infants with CP were recruited. Genomic DNA was extracted from venous blood and all three single nucleotide polymorphisms in GAD1 (rs3791874, rs3791862 and rs16858977) were genotyped by Sequenom’s MassARRAY system. There were no significant differences in allele or genotype frequencies between CP or mixed CP patients and controls at any of the three genetic polymorphisms. Through haplotype analysis we found that haplotype GG (rs3791862, rs16858977) frequency demonstrated significantly statistical difference between mixed CP patients and controls (p = 0.0371). Our positive findings of haplotype GG suggested that variation of GAD1 gene was an important risk factor for mixed CP.     

Host Genetic Factors and Vaccine-Induced Immunity to HBV Infection: Haplotype Analysis

Hepatitis B virus (HBV) infection remains a significant health burden world-wide, although vaccines help decrease this problem. We previously identified associations of single nucleotide polymorphisms in several candidate genes with vaccine-induced peak antibody level (anti-HBs), which is predictive of long-term vaccine efficacy and protection against infection and persistent carriage; here we report on a haplotype-based analysis. A total of 688 SNPs from 117 genes were examined for a two, three and four sliding window haplotype analysis in a Gambian cohort. Analysis was performed on 197 unrelated individuals, 454 individuals from 174 families, and the combined sample (N = 651). Global and individual haplotype association tests were carried out (adjusted for covariates), employing peak anti-HBs level as outcome. Five genes (CD44, CD58, CDC42, IL19 and IL1R1) had at least one significant haplotype in the unrelated or family analysis as well as the combined analysis. Previous single locus results were confirmed for CD44 (combined global p = 9.1×10⁻⁵ for rs353644-rs353630-rs7937602) and CD58 (combined global p = 0.008 for rs1414275-rs11588376-rs1016140). Haplotypes in CDC42, IL19 and IL1R1 also associated with peak anti-HBs level. We have identified strong haplotype effects on HBV vaccine-induced antibody level in five genes, three of which, CDC42, IL19 and IL1R1, did not show evidence of association in a single SNP analyses and corroborated the majority of these effects in two datasets. The haplotype analysis identified associations with HBV vaccine-induced immunity in several new genes.