CISH and susceptibility to infectious diseases.

BACKGROUND: The interleukin-2-mediated immune response is critical for host defense against infectious pathogens. Cytokine-inducible SRC homology 2 (SH2) domain protein (CISH), a suppressor of cytokine signaling, controls interleukin-2 signaling. METHODS: Using a case-control design, we tested for an association between CISH polymorphisms and susceptibility to major infectious diseases (bacteremia, tuberculosis, and severe malaria) in blood samples from 8402 persons in Gambia, Hong Kong, Kenya, Malawi, and Vietnam. We had previously tested 20 other immune-related genes in one or more of these sample collections. RESULTS: We observed associations between variant alleles of multiple CISH polymorphisms and increased susceptibility to each infectious disease in each of the study populations. When all five single-nucleotide polymorphisms (SNPs) (at positions -639, -292, -163, +1320, and +3415 [all relative to CISH]) within the CISH-associated locus were considered together in a multiple-SNP score, we found an association between CISH genetic variants and susceptibility to bacteremia, malaria, and tuberculosis (P=3.8x10(-11) for all comparisons), with -292 accounting for most of the association signal (P=4.58x10(-7)). Peripheral-blood mononuclear cells obtained from adult subjects carrying the -292 variant, as compared with wild-type cells, showed a muted response to the stimulation of interleukin-2 production--that is, 25 to 40% less CISH expression. CONCLUSIONS: Variants of CISH are associated with susceptibility to diseases caused by diverse infectious pathogens, suggesting that negative regulators of cytokine signaling have a role in immunity against various infectious diseases. The overall risk of one of these infectious diseases was increased by at least 18% among persons carrying the variant CISH alleles.

Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore.

BACKGROUND: Schools are important foci of influenza transmission and potential targets for surveillance and interventions. We compared several school-based influenza monitoring systems with clinic-based influenza-like illness (ILI) surveillance, and assessed the variation in illness rates between and within schools. METHODS: During the initial wave of pandemic H1N1 (pdmH1N1) infections from June to Sept 2009 in Singapore, we collected data on nation-wide laboratory confirmed cases (Sch-LCC) and daily temperature monitoring (Sch-DTM), and teacher-led febrile respiratory illness reporting in 6 sentinel schools (Sch-FRI). Comparisons were made against age-stratified clinic-based influenza-like illness (ILI) data from 23 primary care clinics (GP-ILI) and proportions of ILI testing positive for pdmH1N1 (Lab-ILI) by computing the fraction of cumulative incidence occurring by epidemiological week 30 (when GP-ILI incidence peaked); and cumulative incidence rates between school-based indicators and sero-epidemiological pdmH1N1 incidence (estimated from changes in prevalence of A/California/7/2009 H1N1 hemagglutination inhibition titers ≥ 40 between pre-epidemic and post-epidemic sera). Variation in Sch-FRI rates in the 6 schools was also investigated through a Bayesian hierarchical model. RESULTS: By week 30, for primary and secondary school children respectively, 63% and 79% of incidence for Sch-LCC had occurred, compared with 50% and 52% for GP-ILI data, and 48% and 53% for Sch-FRI. There were 1,187 notified cases and 7,588 episodes in the Sch-LCC and Sch-DTM systems; given school enrollment of 485,723 children, this represented 0.24 cases and 1.6 episodes per 100 children respectively. Mean Sch-FRI rate was 28.8 per 100 children (95% CI: 27.7 to 29.9) in the 6 schools. We estimate from serology that 41.8% (95% CI: 30.2% to 55.9%) of primary and 43.2% (95% CI: 28.2% to 60.8%) of secondary school-aged children were infected. Sch-FRI rates were similar across the 6 schools (23 to 34 episodes per 100 children), but there was widespread variation by classrooms; in the hierarchical model, omitting age and school effects was inconsequential but neglecting classroom level effects led to highly significant reductions in goodness of fit. CONCLUSIONS: Epidemic curves from Sch-FRI were comparable to GP-ILI data, and Sch-FRI detected substantially more infections than Sch-LCC and Sch-DTM. Variability in classroom attack rates suggests localized class-room transmission.

Hepatocyte growth factor and retinal arteriolar diameter in Singapore Chinese.

OBJECTIVE: To assess if natural genetic variation in hepatocyte growth factor (HGF) is associated with altered retinal vessel diameter. DESIGN: Two-stage cohort study. PARTICIPANTS AND CONTROLS: Discovery set (set 1, n = 682 children) and confirmatory set (set 2, n = 1293 adults). METHODS: Children in the discovery set were genotyped for a panel of genetic markers within HGF. Markers that were found to be associated significantly with altered retinal vessel diameter then were genotyped in the confirmatory set. MAIN OUTCOME MEASURES: Increased or decreased retinal vessel diameter. RESULTS: In the discovery set (n = 682 Chinese children aged 7 to 12 years), the variant allele of 4 HGF single nucleotide polymorphisms (SNPs) demonstrated association with larger retinal arteriolar diameter. The effect of the variant allele seems to be strongest within a recessive model of inheritance (P(min) = 4.6x10(-3)) for all 4 SNPs. When these 4 SNPs were assessed in a confirmatory study comprising 1293 Chinese adults, successful replication was observed for one of them (HGF +63962; rs5745752); the variant allele was observed to correlate with significantly larger retinal arteriolar diameter, with its effect again strongest within a model of recessive inheritance (P = 0.049). Analyzed as a quantitative trait, recessive carriage at HGF +63962 resulted in on average a 3.5-microm increase in retinal arteriolar diameter among children and a 2.5-microm increase in adults (P = 7.0x10(-3), analysis of variance; P = 3.0x10(-3), Kruskal-Wallis test). CONCLUSIONS: This study suggests that natural variation within HGF is involved in the control of retinal arteriolar diameter and may be important in the pathogenesis of microvascular disease in individuals of Chinese descent.

cMET and refractive error progression in children.

OBJECTIVE: To assess whether genetic variation in cMET is associated with refractive error or change in refractive error over time. DESIGN: Cohort study. PARTICIPANTS AND CONTROLS: Discovery set (Set 1: N = 579 children; 403 cases, 176 controls). Confirmatory set (Set 2: N = 547 children; 338 cases, 209 controls). METHODS: Children in the discovery set were genotyped for a panel of genetic markers within cMET. Markers that were found to be significantly associated with the presence of refractive error or more rapid change in refractive error were then genotyped in the confirmatory set. MAIN OUTCOME MEASURES: Presence or absence of myopia and the rate of change in refractive error over a 3-year follow-up period. RESULTS: Carriage of the variant cMET +110703 A allele was found to associate with increased susceptibility to myopia. The variant was also found to associate with a faster rate of change in refractive error in both the discovery set and the confirmatory cohort regardless of the initial refractory ability (School 1; chi(2) for trend P = 0.014) (Schools 2 and 3; chi(2) for trend = 5.42, P = 0.020) (combined N = 1126, overall chi(2) for trend = 10.90, P = 9.6 x 10(-4)). Carriage of the variant allele was also found to be significantly overrepresented in children within the fastest changing quartile (Q4: mean change of -3.01 D over 3 years) compared with the slowest (Q1: mean change of -0.28 D over 3 years) (P(Set1) = 0.004, P(Set2) = 0.02, Combined N = 559, P = 3.0 x 10(-4)). CONCLUSIONS: Our data implicate the involvement of cMET in the pathogenesis of myopia in general, as well as more rapid progression in refractive error regardless of the initial refractory ability. These results underline the importance of eye growth genes in the development of common myopia.

Novel CFTR gene mutation in a patient with CBAVD.

We report a novel mutation detected in a 33 year old Chinese man with congenital bilateral absence of the vas deferens (CBAVD), a past history of pulmonary meliodosis infection and a past history of bronchiolitis obliterans organising pneumonia. A novel splice site mutation in intron 6b (1001+5 G-->A) in the homozygous state was identified, and was predicted to lead to inefficient splicing. He was also homozygous at all intragenic and flanking polymorphic markers. Quantitative realtime PCR analysis showed that there were 2 copies of the CFTR gene present, ruling out the possibility of a deletion, and strongly suggesting the possibility of uniparental isodisomy involving at least a part of chromosome 7.

Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asians with chronic pulmonary disease: a pilot study.

BACKGROUND: Little is known about the relationship between cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in Asian patients and severe asthma or idiopathic bronchiectasis. We investigated this potential relationship in the Singaporean Chinese. METHODS: Twenty patients with chronic pulmonary disease, 14 with severe asthma and 6 with idiopathic bronchiectasis, were screened for CFTR mutations by direct gene sequencing. The frequencies of identified putative mutations were compared against 40 unaffected controls and 96 unselected population samples. RESULTS: Three missense mutations (I125T, I556V, and Q1352H) and 1 splice site variant (intron 8 12TG5T) were identified in a total of 10 patients, representing a combined mutant/variant allele frequency of 0.25. These alleles were also observed in the controls, but at a significantly lower allele frequency of 0.09 (P<0.01). Furthermore, the I125T mutation was significantly associated with the idiopathic bronchiectasis sub-group (P<0.05). CONCLUSIONS: The significantly higher frequency of CFTR mutations among patients with chronic pulmonary disease compared with unaffected controls suggests that these mutations may increase risk for disease. The association of I125T with idiopathic bronchiectasis alone suggests that different mutations predispose to different disease.

Molecular cytogenetic characterization of a subtle interstitial del(3)(p25.3p26.2) in a patient with deletion 3p syndrome.

Deletion 3p syndrome is associated with characteristic facial features, growth failure, and mental retardation. Typically, individuals with deletion 3p syndrome have terminal deletions that result in loss of material from 3p25 to 3pter. We present a child with a clinical phenotype consistent with deletion 3p syndrome (ptosis, microcephaly, growth retardation, and developmental delay) and a subtle interstitial deletion in the distal portion of the short arm of chromosome 3, del(3)(p25.3p26.2). Fluorescence in situ hybridization (FISH) studies using 3p subtelomeric probes confirmed the terminal region of chromosome 3 was present. Sequence tagged sites (STS)-linked BAC clones mapping to chromosomal region 3p25-p26 were used to characterize the interstitial deletion by FISH. The results indicate the deletion is within a region of approximately 4.5 Mb between STS markers D3S3630 and D3S1304. This interstitial deletion lies within all previously reported terminal deletions in deletion 3p syndrome individuals, and represents the smallest reported deletion associated with deletion 3p syndrome. Characterization of the deletion may help identify genes important to growth and development that contribute to the deletion 3p syndrome phenotype when present in a hemizygous state.

Genotype-phenotype correlation in patients with bicuspid aortic valve and aneurysm.

OBJECTIVES: Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction. METHODS: All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence. RESULTS: Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13 families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm. CONCLUSIONS: These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management.

Fatty Acid oxidation defects.

Fatty acid oxidation defects (FAODs) are a group of inborn errors of metabolism that carry a risk for morbidity and mortality. Successful management of these conditions involves early diagnosis, proper management of clinical situations that predisposes to metabolic crisis as well as adequate treatment of a metabolic crisis. The advent of tandem mass spectrometry based newborn screening has reduced the morbidity and mortality in some FAODs. This article discusses how to recognise FAODs and how to manage them.

Familial thoracic aortic dilation and bicommissural aortic valve: a prospective analysis of natural history and inheritance.

The autosomal dominant inheritance of bicommissural aortic valve (BAV) (Online Mendelian Inheritance in Man #109730) in some families is well-documented; however, the inheritance of BAV with thoracic aortic aneurysm (TAA) is less clear. Whether the aneurysm is secondary to hemodynamic perturbation related to the valve abnormality or a primary manifestation of the disorder remains controversial. Guidelines are needed regarding the follow-up and treatment of these patients and their families. Thirteen families with at least one individual with TAA and BAV (BAV/TAA) were evaluated prospectively by standard echocardiographic methods or clinical history. Affected status was determined by the presence of BAV or TAA or a history of dissection, rupture, or surgical repair. Six of 13 families had at least two family members with both BAV and TAA, often in successive generations. Informatively, all 13 families had at least one family member with TAA in the absence of BAV. Thirty-five percent (39/110) of family members had BAV/TAA or TAA, and the majority of families (11/13) had maximal dilatation above the sinotubular junction (STJ). Vascular dissection or rupture occurred in seven of 13 families and in individuals with structurally normal aortic valves. Two families had non-manifesting, obligate carriers. Three families have members with other left heart outflow tract anomalies. This study confirms autosomal dominant inheritance with incomplete penetrance for BAV/TAA in these families. Furthermore, our data suggest that the component features, BAV and TAA, are independent manifestations of a single gene defect. To avoid the risk of early death, it is essential that all first-degree relatives receive echocardiographic follow-up at regular intervals regardless of the presence or absence of a BAV. This assessment must include imaging of the aortic region above the STJ.

Characterization of the human gene encoding alpha-aminoadipate aminotransferase (AADAT).

In mammals, the conversion of alpha-aminoadipate to alpha-ketoadipate by alpha-aminoadipate aminotransferase (AADAT) is an intermediate step in lysine degradation. A gene encoding for alpha-aminoadipate aminotransferase and kynurenine aminotransferase activities had been previously identified in the rat (KAT/AadAT). We identified the human gene (AADAT) encoding for AADAT. It has a 2329 bp cDNA, a 1278 bp open-reading frame, and is predicted to encode 425 amino acids with a mitochondrial cleavage signal and a pyridoxal-phosphate binding site. AADAT is 73% and 72% identical to the mouse and rat orthologs, respectively. The genomic structure spans 30 kb and consists of 13 exons. FISH studies localized the gene to 4q32.2. Two transcripts (approximately 2.9 and approximately 4.7 kb) were identified, with expression highest in liver. Bacterial expression studies confirm that the gene encodes for AADAT activity. The availability of the DNA sequence and enzyme assay will allow further evaluation of individuals suspected to have defects in this enzyme.