Family-based Transmission Disequilibrium Test Research Articles

Relationship of Genetic Variants With Procedural Pain, Anxiety, and Distress in Children.

This study used a candidate gene approach to examine genomic variation associated with pain, anxiety, and distress in children undergoing a medical procedure. Children aged 4-10 years having an IV catheter insertion were recruited from three Midwestern children's hospitals. Self-report measures of pain, anxiety, and distress were obtained as well as an observed measure of distress. Samples were collected from children and biological parents for analysis of genomic variation. Genotyped variants had known or suspected association with phenotypes of interest. Analyses included child-only association and family-based transmission disequilibrium tests. Genotype and phenotype data were available from 828 children and 376 family trios. Children were 50% male, had a mean age of 7.2 years, and were 84% White/non-Hispanic. In family-based analysis, one single-nucleotide polymorphism (SNP; rs1143629, interleukin ( IL1B) 1β) was associated with observed child distress at Bonferroni-corrected levels of significance ( p = .00013), while two approached significance for association with high state anxiety (rs6330 Nerve Growth Factor, Beta Subunit, [ NGFB]) and high trait anxiety (rs6265 brain-derived neurotrophic factor [ BDNF]). In the child-only analysis, multiple SNPs showed nominal evidence of relationships with phenotypes of interest. rs6265 BDNF and rs2941026 cholecystokinin B receptor had possible relationships with trait anxiety in child-only and family-based analyses. Exploring genomic variation furthers our understanding of pain, anxiety, and distress and facilitates genomic screening to identify children at high risk of procedural pain, anxiety, and distress. Combined with clinical observations and knowledge, such explorations could help guide tailoring of interventions to limit procedure-related distress and identify genes and pathways of interest for future genotype-phenotype studies.

Association Between Genes Involved in Craniofacial Development and Nonsyndromic Cleft Lip and/or Palate in the Brazilian Population.

To determine the association of single-nucleotide polymorphisms (SNPs) in genes related to craniofacial development, which were previously identified as susceptibility signals for nonsyndromic oral clefts, in Brazilians with nonsyndromic cleft lip and/or palate (NSCL/P). The SNPs rs748044 (TNP1), rs1106514 (MSX1), rs28372960, rs15251 and rs2569062 (TCOF1), rs7829058 (FGFR1), rs1793949 (COL2A1), rs11653738 (WNT3), and rs242082 (TIMP3) were assessed in a family-based transmission disequilibrium test (TDT) and a structured case-control analysis based on the individual ancestry proportions. The SNPs were initially analyzed by TDT, and polymorphisms showing a trend toward excess transmission were subsequently studied in an independent case-control sample. The study sample consisted of 189 case-parent trios of nonsyndromic cleft lip with or without cleft palate (NSCL±P), 107 case-parent trios of nonsyndromic cleft palate (NSCP), 318 isolated samples of NSCL±P, 189 isolated samples of NSCP, and 599 healthy controls. Association of alleles with NSCL/P pathogenesis. Preferential transmission of SNPs rs28372960 and rs7829058 in NSCL±P trios and rs11653738 in NSCP trios (P = .04) were observed, although the structured case-control analysis did not confirm these associations. The haplotype T-C-C formed by TCOF1 SNPs rs28372960, rs15251, and rs2569062 was more frequently transmitted from healthy parents to NSCL±P offspring, but the P value (P = .01) did not withstand Bonferroni correction for multiple tests. With the modest associations, our results do not support the hypothesis that TNP1, MSX1, TCOF1, FGFR1, COL2A1, WNT3, and TIMP3 variants are risk factors for nonsyndromic oral clefts in the Brazilian population.

Family association study between melatonin receptor gene polymorphisms and polycystic ovary syndrome in Han Chinese

ObjectiveThe melatonin receptor (MTNR) gene, reported to be associated with insulin sensitivity, diabetes and metabolic syndrome, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to investigate whether an association exists between two single nucleotide polymorphism (SNP) variants (rs2119882 and rs10830963) of the MTNR gene and PCOS in Han Chinese. Study designIn total, 263 family trios (789 participants) were enrolled in this family-based transmission disequilibrium test (TDT). Genotypes were obtained by sequencing. In total, 135 trios of rs2119882 and 127 trios of rs10830963 were tested. ResultsAn association was detected between rs2119882 (p=0.0209) and PCOS, suggesting that the MTNR gene may indicate increased susceptibility to PCOS in Chinese. No significant association was found for rs10830963 (transmitted:non-transmitted=76:51, p=0.1573). The association between the MTNR gene variants and clinical characteristics of women with PCOS was investigated. CC genotype carriers had higher levels of clinical and metabolic features than the TC and TT genotypes. A significant difference in transmission of allele C of rs2119882 was found between obese and non-obese women with PCOS (Chi-squared=5.5983, p=0.018). ConclusionThis study may provide a basis for further studies of the MTNR gene in the aetiology of PCOS.

Genetic effect of transforming growth factor alpha gene variants on the risk of nonsyndromic cleft lip with or without palate in korean populations.

To identify the contribution of TGFA gene variants to the risk of nonsyndromic cleft lip with or without palate (NS-CL±P). The samples were from 142 Korean NS-CL±P families and 119 control parents having nonaffected children. Minor allele frequency, heterozygosity, and χ(2) test for Hardy-Weinberg equilibrium were calculated for each of 10 selected single-nucleotide polymorphisms (SNPs). Ten SNPs were used to examine the association of case-parent trios with the transmission disequilibrium test (TDT) and conditional logistic regression models (CLRMs). Both allelic and genotypic TDTs for individual SNPs and sliding windows of haplotypes consisting of two to five SNPs were tested using family- and haplotype-based association test programs. Genotypic odd ratios (GORs) were obtained from CLRMs using STATA software. The parent-of-origin effect was evaluated for 10 SNPs, and a comparison between 218 case parents and 119 control parents was performed to investigate paternal and maternal ORs. Family-based TDT and haplotype analysis exhibited no statistical significance, but a relatively meaningful association was shown with rs3771497 (all P < .05; two SNPs, rs3771497 and rs3755377; five SNPs, rs3771497, rs3755377, rs3771485, rs11466212, and rs3771475). G/G homozygotes at rs3771497 have a significant decreased risk of NS-CL±P (GOR = 0.30, P < .01). No SNPs showed parent-of-origin effects. However, in the comparison between case parents and control parents, a single-marker analysis of maternal line showed a significant association with NS-CL±P in rs3771497 (P < .001, recessive model). The association of the TGFA gene with NS-CL±P in Korean populations was not clearly found. However, the etiologic effect of the TGFA gene on NS-CL±P patients should be investigated in terms of maternal genotype influence.

Fibrinogen alpha and beta gene polymorphisms in pediatric stroke – Case–control and family based study

Background/purposeData on the role of the −455G > A polymorphism of the gene encoding β fibrinogen subunit (FGB) and the Thr312Ala polymorphism of the gene for the α fibrinogen subunit (FGA) in childhood ischemic stroke are insufficient. Therefore the aim of the study was to evaluate a possible association between these two polymorphisms and arterial ischemic stroke. MethodsThe study group consisted of 85 children after ischemic stroke, 146 of their parents and 159 controls. Both polymorphisms were genotyped using the restriction fragment length polymorphism method. Two study designs were used: a case–control model and a family-based transmission-disequilibrium test. Statistica 7.1 and EpiInfo 6 softwares were used in all analyses. ResultsIn the TDT test, a tendency to a higher transmission of the 312Ala allele of the FGA gene and the −455A allele of the FGB gene was observed, however, it was statistically non-significant. The frequencies of alleles and genotypes of both FGA and FGB genes polymorphisms did not differentiate children from both groups also in the case–control model. Additive or synergistic effects between FGA and FGB genes polymorphisms were not observed. ConclusionAn analysis of the results obtained in this study and a critical review of previously published data indicate that examined gene polymorphisms are not related to ischemic stroke in children.

Family-based analysis of INSR polymorphisms in Chinese PCOS

The insulin receptor (INSR), which is an indispensable component of the insulin-signalling pathway, could be a plausible candidate gene for polycystic ovary syndrome (PCOS). This study was designed to determine whether an association exists between three SNP variants (rs3786681, rs17253937 and rs2252673) of the INSR gene and PCOS in Han Chinese. A total of 224 family trios (672 participants in total) were enrolled in this family-based transmission disequilibrium test. Genotypes were obtained by sequencing. A weak association was detected in rs2252673 (P = 0.027), which indicated that INSR may confer an increased susceptibility to PCOS in Chinese. Additionally, the association between INSR gene variants and clinical and metabolic characteristics of women with PCOS was investigated. Carriers of the CG and GG genotypes in women with PCOS were slightly associated with higher cholesterol concentration (t = 2.072, P = 0.048) and lower high-density lipoprotein cholesterol concentration (t = 2.274, P = 0.026). The minor allele conferred increased odds of PCOS independently of body mass index. The present data may provide a basis for further studies of the role of the INSR in the aetiology of PCOS.

Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population

A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results. There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ(2)=4.5200, P=0.0335; rs1964081: χ(2)=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ(2)=5.3430, P=0.0208). Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.

Investigation of Parental Transmission of RUNX2 Single Nucleotide Polymorphism and Its Association with Nonsyndromic Cleft Lip with or Without Palate

To investigate the association and parental transmission of RUNX2 single nucleotide polymorphisms (SNPs) with risk of nonsyndromic cleft lip with or without cleft palate (NS-CL±P). Four RUNX2 SNPs in 142 Korean NS-CL±P families (nine cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads) were genotyped. The minor allele frequency, heterozygosity, and chi-square test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as D' and r(2) for all SNPs. Both allelic and genotypic transmission disequilibrium tests (TDTs) were performed for individual SNPs using a family-based association test program. Sliding windows of haplotypes consisting of two to four SNPs were tested using a haplotype-based association test program. Genotypic odds ratios (GORs) were calculated from conditional logistic regression models. Parent-of-origin effects were assessed using transmission asymmetry test and parent-of-origin likelihood ratio test. The family-based TDT showed significant evidence of linkage and association at rs1934328 (P = .001). In the haplotype analysis, two, three, and four haplotypes containing rs1934328 revealed significant associations (P = .0017, P = .0022, and P = .0020, respectively). The genotypes A/T and T/T at rs1934328 were significantly associated with NS-CL±P compared with the genotype A/A (GOR = 2.75, 95% confidence interval [CI] = 1.39-5.45, P =0.0019 in the dominant model; GOR = 5.38, 95% CI = 1.34-21.68, P = .0046 in the additive model). However, no parent-of origin effect was observed. These findings suggest possible involvement of RUNX2-rs194328 in the etiology of NS-CL±P in Korean cleft-parent trios without excess parental transmission.

Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts.

Parent-of-origin (PofO) effects, such as imprinting are a phenomenon where the effect of variants depends on parental origin. Conventional association studies assume that phenotypic effects are independent of parental origin, and are thus severely underpowered to detect such non-Mendelian effects. Risk of orofacial clefts is influenced by genetic and environmental effects, the latter including maternal-specific factors such as perinatal smoking and folate intake. To identify variants showing PofO effects in orofacial clefts we have used a modification of the family-based transmission disequilibrium test to screen for biased transmission from mothers and fathers to affected offspring, biased ratios of maternal versus paternal transmission, and biased frequencies of reciprocal classes of heterozygotes among offspring. We applied these methods to analyze published genome-wide single-nucleotide polymorphism (SNP) data from ∼2500 trios mainly of European and Asian ethnicity with non-syndromic orofacial clefts, followed by analysis of 64 candidate SNPs in a replication cohort of ∼1200 trios of European origin. In our combined analysis, we did not identify any SNPs achieving conventional genome-wide significance (P<5 × 10(-8)). However, we observed an overall excess of loci showing maternal versus paternal transmission bias (P=0.013), and identified two loci that showed nominally significant effects in the same direction in both the discovery and replication cohorts, raising the potential for PofO effects. These include a possible maternal-specific transmission bias associated with rs12543318 at 8q21.3, a locus identified in a recent meta-analysis of non-syndromic cleft (maternal-specific P=1.5 × 10(-7), paternal-specific P=0.17). Overall, we conclude from this analysis that there are subtle hints of PofO effects in orofacial clefting.

Genetic association of G896A polymorphism of TLR4 gene in leprosy through family-based and case-control study designs

Polymorphisms in TLR4 may change the function of the protein and alter the efficiency of immune response of host to infection. The high relevance of host gene polymorphisms with outcome of Mycobacterium leprae infection led us to study the genetic association of TLR4 G896A polymorphism in order to identify its risk among contacts of affected leprosy patients. For case-control study design a total of 628 individuals were recruited; 17 multicase leprosy families which included 32 case-parent trios were considered for family-based study. Genotyping was done using PCR-RFLP method. In case-control study AA genotype was positively associated while GA genotype was negatively associated with leprosy. In family based transmission disequilibrium test (TDT) analysis allele G was found to be over transmitted to the affected individuals. Case-control study suggests that homozygous AA genotype may confer susceptibility and heterozygous GA genotype may confer resistance to leprosy, while allele A was observed to increase risk and that of allele G may confer resistance to leprosy. No strong transmission disequilibrium was detected in family-based TDT analysis, possibly due to lower number of trios. In contrast to case-control data allele G was over transmitted to the affected ones in TDT analysis. To conclude, the frequencies of genotypes in household contacts were almost the same as in leprosy patients, suggesting that contacts with AA genotype may be at higher risk of leprosy and may therefore require prophylactic inputs.

A family-based transmission disequilibrium test of single nucleotide polymorphisms in exon 4 of ZNF804A gene in &lt;I&gt;Han&lt;/I&gt; Chinese patients with schizophrenia

A family-based transmission disequilibrium test of single nucleotide polymorphisms in exon 4 of ZNF804A gene in &lt;I&gt;Han&lt;/I&gt; Chinese patients with schizophrenia

Association betweenMSX1SNPs and Nonsyndromic Cleft Lip with or without Cleft Palate in the Korean Population

The purpose of this study was to investigate the contribution of MSX1 gene to the risk of nonsyndromic cleft lip with or without cleft palate (NS-CL ± P) in the Korean population. The samples consisted of 142 NS-CL ± P families (9 with cleft lip, 26 with cleft lip and alveolus, and 107 with cleft lip and palate; 76 trios and 66 dyads). Three single nucleotide polymorphisms (SNPs: rs3821949, rs12532, and rs4464513) were tested for association with NS-CL ± P case-parent trios using transmission disequilibrium test (TDT) and conditional logistic regression models (CLRMs). Minor allele frequency, heterozygosity, χ2 test for Hardy-Weinberg equilibrium, and pairwise linkage disequilibrium (LD) at each SNP were computed. The family- and haplotype-based association test programs were used to perform allelic and genotypic TDTs for individual SNPs and to fabricate sliding windows of haplotypes. Genotypic odds ratios (GORs) were obtained from CLRMs using R software. Although the family-based TDT indicated a meaningful association for rs3821949 (P = 0.028), the haplotype analysis did not reveal any significant association with rs3821949, rs12532, or rs4464513. The A allele at rs3821949 had a significant increased risk of NS-CL ± P (GOR, 1.64; 95% confidence interval,1.03-2.63; P = 0.038, additive model). A positive association is suggested between MSX1 rs3821949 and NS-CL ± P in the Korean population.

Associations and interactions of genetic polymorphisms in innate immunity genes with early viral infections and susceptibility to asthma and asthma-related phenotypes

The innate immune system is essential for host survival because of its ability to recognize invading pathogens and mount defensive responses. We sought to identify genetic associations of innate immunity genes with atopy and asthma and interactions with early viral infections (first 12 months of life) in a high-risk birth cohort. Three Canadian family-based studies and 1 Australian population-based case-control study (n= 5565) were used to investigate associations of 321 single nucleotide polymorphisms (SNPs) in 26 innate immunity genes with atopy, asthma, atopic asthma, and airway hyperresponsiveness. Interactions between innate immunity genes and early viral exposure to 3 common viruses (parainfluenza, respiratory syncytial virus, and picornavirus) were examined in the Canadian Asthma Primary Prevention Study by using both an affected-only family-based transmission disequilibrium test and case-control methods. In a joint analysis of all 4 cohorts, IL-1 receptor 2 (IL1R2) and Toll-like receptor 1 (TLR1) SNPs were associated with atopy after correction for multiple comparisons. In addition, an NFKBIA SNP was associated with atopic asthma. Six SNPs (rs1519309 [TLR3], rs740044 [ILIR2], rs4543123 [TLR1], rs5741812 [LBP], rs917998 [IL18RAP], and rs3136641 [NFKBIB]) were significant (P< .05, confirmed with 30,000 permutations) in both the combined analysis of main genetic effects and SNP-virus interaction analyses in both case-control and family-based methods. The TLR1 variant (rs4543123) was associated with both multiple viruses (respiratory syncytial virus and parainfluenza virus) and multiple phenotypes. We have identified novel susceptibility genes for asthma and related traits and interactions between these genes and early-life viral infections.

Association of copper‐zinc superoxide dismutase (SOD1) and manganese superoxide dismutase (SOD2) genes with nonsyndromic myelomeningocele

A common and severe neural tube defect (NTD) phenotype, myelomeningocele (MM), results from the defective closure of the caudal end of the neural tube with herniation of the spinal cord and meninges through the vertebral column. The exact mechanisms for NTDs are unknown, but excessive oxidative stress, particularly in association with maternal diabetes, has been postulated as a mechanism for MM. The SNPlex Genotyping (ABI, Foster City, CA) platform was used to investigate single nucleotide polymorphisms (SNPs) across the superoxide dismutase (SOD) 1 and 2 genes to assess their association with MM risk. The study population included 329 trio (affected child and both parents) and 281 duo (affected child and one parent) families. Only cases with documented MM were studied. Seventeen SNPs across the SOD1 and SOD2 genes met the quality-control criteria to be considered for statistical analysis. Genetic association was assessed using the family-based transmission disequilibrium test in PLINK (a genome association analysis toolset). Four SNPs in the SOD1 gene (rs 202446, rs202447, rs4816405, and rs2070424) and one SNP in the SOD2 gene ( rs5746105) [corrected] appeared to be associated with MM risk in our population. After adjusting for multiple testing, these SNPs remained significant. This study provides the first genetic evidence to support association of myelomeningocele with superoxide scavenging. The rare alleles of the five specific SNPs within SOD1 and SOD2 appear to confer a protective effect on the susceptibility for MM risk in the MM population tested. Further evaluation of the roles of superoxide scavenging and neural tube development is warranted.

Association Between PAX9 Single-Nucleotide Polymorphisms and Nonsyndromic Cleft Lip With or Without Cleft Palate

The purpose of this study was to investigate the contribution of PAX9 gene to the risk of nonsyndromic cleft lip with or without cleft palate (NS-CL/P). The samples consisted of 142 Korean NS-CL/P families (90 males and 52 females; 9 cleft lip, 26 cleft lip and alveolus, and 107 cleft lip and palate; 76 trios and 66 dyads). A total of 10 single-nucleotide polymorphisms (SNPs) were tested for association with Korean CL/P case-parent trios using transmission disequilibrium test (TDT) and conditional logistic regression models. The minor allele frequency, heterozygosity, and a χ test for Hardy-Weinberg equilibrium at each SNP were computed between parents. Pairwise linkage disequilibrium was computed as both D' and r2 for all SNPs. Both allelic and genotypic TDTs were performed for individual SNPs using family-based association test program. Sliding windows of haplotypes consisting of 2 to 8 SNPs were tested using haplotype-based association test program. Genotypic odd ratios were obtained from conditional logistic regression models using STATA software. The family-based TDT using individual SNPs and 2- to 8-SNP haplotypes of the gene indicated a significant association at rs17104928 (P = 0.014). The haplotype analysis revealed that the association was most significant for the haplotype consisting of 3 SNPs (rs2073247, rs17104928, and rs17176643; P = 0.007). G/A heterozygote at rs17104928 had a significantly increased association with NS-CL/P (genotypic odd ratio, 2.88; 95% confidence interval, 1.42-5.84; P = 0.0014, dominant model). The high-risk SNP and genotype may provide a better understanding of the etiologic role of PAX9 gene in NS-CL/P and potential options for genetic counseling.

Power comparison between population-based case-control studies and family-based transmission-disequilibrium tests: An empirical study

BACKGROUND:There are two major classes of genetic association analyses: population based and family based. Population-based case–control studies have been the method of choice due to the ease of data collection. However, population stratification is one of the major limitations of case–control studies, while family-based studies are protected against stratification. In this study, we carry out extensive simulations under different disease models (both Mendelian as well as complex) to evaluate the relative powers of the two approaches in detecting association.MATERIALS AND METHODS:The power comparisons are based on a case–control design comprising 200 cases and 200 controls versus a Transmission Disequilibrium Test (TDT) or Pedigree Disequilibrium Test (PDT) design with 200 informative trios. We perform the allele-level test for case–control studies, which is based on the difference of allele frequencies at a single nucleotide polymorphism (SNP) between unrelated cases and controls. The TDT and the PDT are based on preferential allelic transmissions at a SNP from heterozygous parents to the affected offspring. We considered five disease modes of inheritance: (i) recessive with complete penetrance (ii) dominant with complete penetrance and (iii), (iv) and (v) complex diseases with varying levels of penetrances and phenocopies.RESULTS:We find that while the TDT/PDT design with 200 informative trios is in general more powerful than a case–control design with 200 cases and 200 controls (except when the heterozygosity at the marker locus is high), it may be necessary to sample a very large number of trios to obtain the requisite number of informative families.CONCLUSION:The current study provides insights into power comparisons between population-based and family-based association studies.

Serotonin transporter gene polymorphism and psychiatric disorders: Is there a link?

Though still in infancy, the field of psychiatric genetics holds great potential to contribute to the development of new diagnostic and therapeutic options to treat these disorders. Among a large number of existing neurotransmitter systems, the serotonin system dysfunction has been implicated in many psychiatric disorders and therapeutic efficacy of many drugs is also thought to be based on modulation of serotonin. Serotonin transporter gene polymorphism is one of the most extensively studied polymorphisms in psychiatric behavioral genetics. In this article, we review the status of evidence for association between the serotonin gene polymorphism and some common mental disorders like affective disorders, post-traumatic stress disorder, obsessive-compulsive disorder, suicide, autism, and other anxiety and personality disorders. Going beyond traditional association studies, gene-environment interaction, currently gaining momentum, is also discussed in the review. While the existing information of psychiatric genetics is inadequate for putting into practice genetic testing in the diagnostic work-up of the psychiatric patient, if consistent in future research attempts, such results can be of great help to improve the clinical care of a vast majority of patients suffering from such disorders.

Polymorphisms in IL10 are associated with total Immunoglobulin E levels and Schistosoma mansoni infection intensity in a Brazilian population

Interleukin (IL)-10 is a regulatory cytokine of the helper T cell type 2 (TH2) pathway, which underlies both the host defense to helminthic infection and atopic diseases, including asthma. Although IL10 promoter polymorphisms are associated with increased atopy risk, IL10 variation has not been thoroughly explored in schistosomiasis-endemic populations. Three atopy-related IL10 promoter polymorphisms (rs1800896, rs1800871 and rs1800872), complemented by six tagging single-nucleotide polymorphisms (SNPs), were genotyped in 812 individuals in 318 nuclear families from a schistosomiasis-endemic area in Brazil. Associations between markers and total serum Immunoglobulin E (tIgE) levels, indicating non-specific activation of the TH2 pathway, and Schistosoma mansoni fecal egg counts, indicating burden of infection reflecting effectiveness of schistosomiasis host immunity, were performed using family-based transmission disequilibrium tests for quantitative traits (QTDTs). Alleles A, T and A at the three promoter SNPs rs1800896, rs1800871 and rs1800872 were associated with high tIgE levels in the same direction as in atopy populations (P=0.0008, 0.026 and 0.045), but not with egg counts. IL10 promoter polymorphisms appear to influence non-specific tIgE levels, but not schistosomiasis-specific immunity. The tagging SNP rs3024495 was associated with high S. mansoni egg counts (P=0.005), suggesting a novel locus in IL10 may influence clinically relevant burden of infection.

Role of Polymorphic Variants as Genetic Modulators of Infection in Neonatal Sepsis

This study is a retrospective, case control study involving 535 preterm infants examining the roles of sequence polymorphisms in genes that mediate host immune responses to bacterial infection in newborn infants. A total of 49 single nucleotide polymorphisms (SNPs) in 19 candidate genes including inflammatory cytokines (IL6, IL10, IL1B, and TNF), cytokine receptors (IL1RN), toll-like receptors (TLR2, TLR4, and TLR5), and cell surface receptors (CD14) were genotyped. Subjects were stratified into three groups (sepsis, suspected sepsis, and control). The data were analyzed using a family-based transmission disequilibrium test. We found that birth weight, gestational age, duration of rupture of membranes, and presence of clinical chorioamnionitis were strongly associated with sepsis. Polymorphisms in TLR2 (rs3804099), TLR5 (rs5744105), IL10 (rs1800896), and PLA2G2A (rs1891320) genes were associated with sepsis. Allelic variants in PLA2G2A and TLR2 were associated with Gram-positive infections, whereas IL10 was associated with Gram-negative infections (p < 0.05). We conclude allelic variations in PLA2G2A, TLR2, TLR5, and IL10 may moderate the predisposition to sepsis in preterm infants.

POLYMORPHISMS IN PARP, IL1B, IL4, IL10, C1INH, DEFB1, AND DEFA4 IN MENINGOCOCCAL DISEASE IN THREE POPULATIONS

The pathogenesis of meningococcal infections involves activation of the complement system, proinflammatory and anti-inflammatory mediators, antimicrobial peptides, and apoptosis. We hypothesized that variations in genes encoding these products are involved in the susceptibility to and severity of pediatric meningococcal infections. Polymorphisms in poly (adenosine diphosphate-ribose) polymerase (PARP), serine protease C1 inhibitor (C1INH), IL4, IL10 and IL1B, alpha-defensin 4, and beta-defensin 1 (DEFB1) were analyzed in two independent Caucasian case control cohorts from the United Kingdom and the Netherlands and in a family-based transmission disequilibrium test cohort from the UK. In the UK case control cohort, the DEFB1 -44 G/G homozygous genotype was overrepresented in patients with meningococcal disease compared with the G/C and C/C genotypes when combined (odds ratio, 1.57; 95% confidence interval, 1.12-2.20). The transmission disequilibrium test analysis did not confirm this, but did find an association and linkage of the IL4 -524 and the C1INH 480 polymorphisms with susceptibility to meningococcal infection. Hematological failure was present more often in UK patients with the DEFB1 -44 G/G genotype compared with the C allele carriers (odds ratio, 2.17; 95% confidence interval, 1.22-3.85). Additional studies are necessary to elucidate the conflicting results obtained for the DEFB1, IL4, and C1INH polymorphisms and their role in susceptibility to and severity of meningococcal disease.