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PubMed2003

Clinical evaluation of two methods for genotyping hepatitis C virus based on analysis of the 5' noncoding region.

We compared the performance characteristics of a standardized direct sequencing method (TRUGENE HCV 5'NC; Visible Genetics Inc., Toronto, Ontario, Canada) and a reverse hybridization line probe assay (INNO-LiPA HCV II; Bayer Corp., Tarrytown, N.Y.) for genotyping of hepatitis C virus (HCV). Both methods are based on detection of sequence heterogeneity in the 5' noncoding (5'NC) region. Concordance between the genotyping methods was assessed by testing 172 samples representing the six major genotypes. Sequence analysis of the more phylogenetically informative nonstructural 5B (NS5B) region was also done with 148 (86%) samples to confirm the accuracy of and resolve discrepancies between the 5'NC genotyping results. The sensitivities of the methods were assessed by using the 5'NC amplicon from both the qualitative and quantitative AMPLICOR HCV tests (Roche Diagnostics Corp., Indianapolis, Ind.). The ability of the methods to detect mixed-genotype infections was determined with mixtures of two different genotypes at relative concentrations ranging from 1 to 50%. Both 5'NC methods were able to genotype 99.4% of the samples with type agreement for 99.5% and subtype agreement for 68.2% of the samples. No or ambiguous subtype results were found by the line probe assay for 16.5% and by the TRUGENE 5'NC test for 17.1% of the samples. Discrepancies occurred between the line probe assay and NS5B results at the type level for 1.4% of the samples and at the subtype level for 14.2% of the samples. Discrepancies also occurred between the TRUGENE 5'NC and NS5B results at the type level for 2% of the samples and at the subtype level for 8.1% of the samples. We also found two distinct strains of HCV classified as type 2 by analysis of the 5'NC region that were type 1 by analysis of the NS5B region. The sensitivities of the two 5'NC genotyping methods were comparable and dependent on the amplification test used ( approximately 10(3) IU/ml with the qualitative HCV RNA tests and approximately 10(5) IU/ml with the quantitative HCV RNA tests). Genotype mixtures were successfully identified at a relative concentration of 5% by the line probe assay and 10% by the TRUGENE 5'NC test. In conclusion, the performance characteristics of the 5'NC methods were similar and both methods produced accurate results at the genotype level but neither method should be used for subtyping.

5' Untranslated Regions↗
PubMed2003

Different cytomegalovirus glycoprotein B genotype distribution in serum and cerebrospinal fluid specimens determined by a novel multiplex nested PCR.

A novel and highly sensitive multiplex nested PCR assay has been developed for the simultaneous glycoprotein B (gB) typing of four gB genotypes of human cytomegalovirus (CMV) directly from clinical specimens. Specifically, a pair of primers to conserved regions of all gB genotypes within the gB gene (gB and gpUL55) was used for primary amplification. A mixture of nested primers to specific and conserved regions of each gB genotype was used for a secondary PCR amplification, yielding amplicons of different sizes for each gB genotype that could easily be differentiated by agarose gel electrophoresis. A total of 40 of 44 serum specimens and 26 of 26 cerebrospinal fluid (CSF) samples, which had previously tested positive for CMV in 66 of 70 AIDS patients with different CMV disease conditions, were gB genotyped by this novel assay. Significant differences in glycoprotein B genotype distribution between serum and CSF specimens were found (P = 0.001). gB genotype 3 (gB3) and gB2 were the most prevalent genotypes in sera (42.5%) and CSF (38.5%), respectively. A different distribution was also observed when only patients with CMV retinitis were studied (P = 0.005), suggesting a gB2 neuron tropism. Neither CMV disease nor any particular clinical manifestation of CMV disease was associated with gB genotypes (P > 0.05). A high incidence of mixed infection with the gB1 and gB3 genotypes (27.5%) was detected in serum specimens, indicating that reinfection and reactivation are common traits in advanced AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed2004

Longitudinal study of transmission, diversity, and stability of Streptococcus mutans and Streptococcus sobrinus genotypes in Brazilian nursery children.

The aim of this study was to perform a follow-up evaluation of the Streptococcus mutans and Streptococcus sobrinus colonization profile of children's oral cavities, which included the pattern of vertical transmission from mother to child, genotypic diversity, and stability of the strains. The subjects were 16 mother-child pairs, who were monitored for 20 months. Samples of saliva, tongue dorsum, alveolar ridge mucosa, and dental plaque from the children were collected bimonthly. Saliva samples from the mothers were also collected. After isolation and identification, the arbitrarily primed PCR method was performed for the genotypic characterization of S. mutans (968 isolates) and S. sobrinus (111 isolates). At the time the strains were acquired, the children harbored one to four distinct genotypes of S. mutans and only one genotype of S. sobrinus. Although S. mutans prevalence and genotypic diversity were greater than those of S. sobrinus, the presence of matching genotypes of S. mutans and S. sobrinus was similar (in 81.25 and 83.33% of mother-child pairs, respectively), suggesting vertical transmission for both species. This longitudinal study showed an increase in genotypic diversity of S. mutans in the oral cavity during the follow-up period: most of the initially acquired genotypes persisted, normally those genotypes transmitted by the mother, and some were lost during follow-up; new strains were also acquired. In conclusion, S. mutans and S. sobrinus genotypes acquired from maternal or alternative sources may show effective persistence in the oral cavity and/or transitory detection in the children's mouths, reflecting the continuous development of oral microbiota in children.

Adult↗
PubMed2004

Strong association between genotype F and hepatitis B virus (HBV) e antigen-negative variants among HBV-infected argentinean blood donors.

A number of reports have indicated an increased risk of cirrhosis and hepatocellular carcinoma in hepatitis B virus (HBV)-infected individuals carrying HBV e antigen (HBeAg)-negative variants. Although distinct core promoter and precore mutations distributed according to geographical locality and viral genotype have been reported, epidemiological data from South America are still scarce. The prevalences of HBV genotypes and core promoter and precore polymorphisms in 75 HBeAg-negative Argentinean blood donors were surveyed. The observed frequencies of HBV genotypes were 64.0% for genotype F, 17.3% each for genotypes A and D, and 1.3% for genotype C. Genotype F strains were widely distributed and significantly more prevalent in the northern region of the country (P < 0.001). An overall high proportion of a stop codon mutation (UAG) at precore codon 28 (66.7%) was observed. Wild-type codon 28 (UGG) was present in 29.3% of the samples, and the remaining 4.0% of samples had mixed variants. The combination of A at nucleotide (nt) 1762 and G at nt 1764 of the core promoter was found in 58.7% of the samples. The variant profiles--T at nt 1762 and A at nt 1764 or A at nt 1762 and A at nt 1764--were detected in 28.0 and 1.3% of the samples, respectively. The observed core promoter polymorphisms could not be related to the ratio of HBeAg to anti-HBeAg antibody, HBV genotype, or precore codon 28 status. Nevertheless, a clear association of genotype F and a precore stop codon mutation was found (P < 0.05). In conclusion, HBV genotype F and mutant codon 28 strains predominated and were strongly associated in a geographically broad Argentinean blood donor population.

Adult↗
PubMed2005

Identification and distribution of Acanthamoeba species genotypes associated with nonkeratitis infections.

Acanthamoeba is a free-living protozoan genus found in a wide variety of natural habitats, including water, soil, and air. Pathogenic isolates of Acanthamoeba are medically relevant as the causative agent of sight- threatening Acanthamoeba keratitis (AK), serious infections of other organs, and fatal granulomatous amebic encephalitis. Previous work employing DNA sequences of nuclear and mitochondrial small-subunit rRNA genes (SSU rRNA genes) determined the genotypic diversity of Acanthamoeba and found that many named species of Acanthamoeba are associated with particular genotypes. These studies also concluded that nearly all AK infections result from a single molecular genotype: T4. Here, we asked whether Acanthamoeba clinical isolates from non-AK infections are also associated with particular genotypes. DNA sequence determination of nuclear SSU rRNA genes was employed for genotypic identification of 29 isolates of Acanthamoeba from non-AK infections. Sequence analysis demonstrates that T4 is the predominant genotype in non-AK infections, including those in brain, cerebrospinal fluid, nasal passages, skin, and lung. Rare genotypes (T1, T10, and T12) have been isolated from brain infections. We conclude that genotype T4 is the primary genotype in non-AK Acanthamoeba infections, as was the case in AK infections. However, the genotypes that were isolated from brains have not been observed in environmental isolates of Acanthamoeba, and their natural ecological niche is unknown.

Acanthamoeba↗
PubMed2006

Comparison of conventional PCR with real-time PCR and branched DNA-based assays for hepatitis C virus RNA quantification and clinical significance for genotypes 1 to 5.

The key parameter for diagnosis and management of hepatitis C virus (HCV) infection is HCV RNA. Standardization of HCV RNA assays to IU is mainly based on genotype 1 panels. Little is known about the variability of commercially available HCV RNA assays for quantification of different genotypes. Two real-time reverse transcription (RT)-PCR assays (COBAS TaqMan HCV Test for use with the High-Pure System [HPS/CTM] and COBAS Ampliprep/COBAS TaqMan HCV Test [CAP/CTM]), one standard RT-PCR assay (COBAS Amplicor HCV Monitor 2.0 [CAM]), and one signal amplification assay (Versant Quantitative 3.0 [branched DNA [bDNA]]) were compared for quantification of genotypes 1 to 5 (n = 108). Using CAM as a reference assay for genotype 1-infected patients, the mean interassay differences compared with CAP/CTM, HPS/CTM, and bDNA were 0.16, -0.13, and -0.48 log(10) IU/ml HCV RNA, respectively. Comparison of CAM with CAP/CTM, HPS/CTM, and bDNA for the remaining genotypes showed the following results, respectively: 2a/c, -0.24, -0.78, and -0.49; 2b, -0.21, -0.18, and -0.64; 3a, 0.13, -1.04, and -0.55; 4, -0.52, -1.51, and -0.05; and 5, -0.28, -1.00, and -0.24 log IU/ml HCV RNA. A correct decision for treatment discontinuation in genotype 1 patients at week 12 was possible only when the same assay was used at baseline and week 12. Comparison of CAM with the CAP/CTM assay showed equal quantifications of genotype 1, 2, 3, and 5 samples, while genotype 4 samples were slightly underestimated. For the HPS/CTM assay, a significant underestimation of the HCV RNA concentrations of genotypes 2a/c, 3, 4, and 5 was observed. For the bDNA assay, a constant lower quantification of genotypes 1 to 3 was detected.

DNA, Viral↗
PubMed2005

Characterization of Parvovirus B19 genotype 2 in KU812Ep6 cells.

An infectious parvovirus B19 (B19V) genotype 2 variant was identified as a high-titer contaminant in a human plasma donation. Genome analysis revealed a 138-bp insertion within the p6 promoter. The inserted sequence was represented by an additional 30 bp from the end of the inverted terminal repeat adjacent to a 108-bp element found also, in inverted orientation, at the extreme right end of the unique sequence of the genome. However, despite the profound variations in the promoter region, the pattern of gene expression and DNA replication did not differ between genotype 1 and genotype 2 in permissive erythroid KU812Ep6 cells. Capsid proteins of both genotypes differ in their amino acid sequences. However, equivalent kinetics of virus inactivation at 56 degrees C or pH 4 indicated a comparable physicochemical stability of virus capsids. Sera from six individuals infected by B19V genotype 1 were investigated on cross-neutralization of B19V genotype 2 in vitro. Similar neutralization of both B19V genotypes was observed in sera from three individuals, while the sera from three other individuals showed weaker cross-neutralization for genotype 2. In conclusion, the in vitro replication characteristics and physical stability of B19V capsids are very similar between human parvovirus B19 genotypes 1 and 2, and cross-neutralization indicates a close antigenic relation of genotypes 1 and 2.

Base Sequence↗
PubMed1997

Respiratory syncytial virus genotypes and disease severity among children in hospital.

OBJECTIVES: To determine the spectrum of N and G genotypes of respiratory syncytial virus (RSV) causing respiratory tract infection and whether particular genotypes are associated with severity of infection. PATIENTS AND METHODS: Nasopharyngeal aspirates (NPAs) were obtained from 114 infants with acute respiratory tract infection due to RSV over two seasons. Viral mRNA was extracted from NPAs or cultured virus, reverse transcribed, and the cDNA amplified by the polymerase chain reaction using primers directed to parts of the N and G gene respectively. Amplicons were separately digested with four different restriction endonucleases for each gene. The fragments were separated by agarose gel, electrophoresis, and the electrophoretic patterns used to assign the various genotypes. Disease severity was assessed as very mild (upper respiratory tract signs only), mild (coryza and signs of lower respiratory tract infection), moderate (requiring nasogastric or intravenous fluids), and severe (requiring oxygen or ventilation). RESULTS: Five of the six known N genotypes were detected, but NP4 and NP2 were found most frequently. There was no association between N genotype and disease severity. Six G (SHL) genotypes were detected. Significantly (p = 0.04) more of the infants infected with the SHL2 genotype had severe or moderate disease. CONCLUSIONS: During the seasonal peaks of RSV respiratory tract infection at least 10 different RSV genotypes cocirculated. While there is no association between N genotypes and disease severity, infection with the SHL2 G genotype appears to result in moderate to severe disease.

Acute Disease↗
PubMed1997

Genotyping of Portuguese Chlamydia trachomatis urogenital isolates.

OBJECTIVE: To determine the prevalence of the different Chlamydia trachomatis genotypes in Portuguese patients. METHODS: Urogenital isolates (n = 240) derived from attenders of various clinics in the Lisbon area were differentiated into genovars by genotyping with restriction fragment length polymorphism (RFLP) analysis of the PCR amplified omp1 gene. RESULTS: Genotype E was the most common for both men (47.9%) and women (43.8%). Genotypes D and F were the second most prevalent for men (11.3%) and genotype H was the second most prevalent for women (19.5%). Genotypes F, G, D, in women and H, G, I, in men, were found in a lower percentage of cases. Genotypes B, Ba, J, K, L1 and L2 were very rarely detected. CONCLUSIONS: With one exception, the overall distribution of Chlamydia trachomatis genotypes in our study is similar to what has been observed in other western countries. The only exception is the unusual prevalence of genotype H among women. The clinical manifestations associated with this and other genotypes were similar.

Adult↗
PubMed2006

Follow-up of the prevalence of hepatitis C virus genotypes in Spain during a nine-year period (1996-2004).

BACKGROUND: Recent data suggest that the prevalence of genotype 4 HCV strains among Spanish carriers is increasing. OBJECTIVE: To assess changes in the prevalence of HCV genotypes in Spain during the last nine years. METHODS: HCV RNA was amplified by the polymerase chain reaction from 3161 serum samples from unselected, anti-HCV-positive individuals, and the HCV genotype was identified by a reverse hybridisation assay (line probe assay, LiPA). Samples came from 17 different regions of Spain and were obtained between January, 1996 and December, 2004. RESULTS: The overall prevalence of HCV genotypes was: 1b, 41.3%; 1a, 24.1%; 3, 19.6%; 4, 11.6%; 2, 3.1%; and 5, 0.3%. The prevalence of genotypes 1a, 3 and 4 increased significantly among patients born after 1950, and that of genotype 1b decreased among them. These significant differences in regard to age were also observed among patients lacking notified high-risk factors. A main switch-up in prevalence of genotypes 1a and 3 was found when patients born in 1941-1950 were compared with those born in 1951-1960, but the same finding in genotype 4 was delayed to patients born in 1961-1970. CONCLUSIONS: Two separate epidemics of HCV seem to have occurred in Spain during the last 30 years. The former one involved the spread of HCV genotypes 1a and 3. The second was more recent, and involved the spread of genotype 4.

Genotype↗
PubMed2006

Clinical significance of the genotype and core promoter/pre-core mutations in hepatitis B virus carriers.

It has been shown that clinical and virological characteristics vary among hepatitis B virus (HBV) genotypes. In this study, we measured the virus level, disease severity, and presence or absence of core promoter (CP)/pre-core (PC) mutations in 241 HBV carriers, and investigated the clinical significance of measuring the HBV genotype. In genotype C HBV carriers, the proportion of hepatitis B e antigen (HBeAg)-positive patients was significantly higher than that in genotype B HBV carriers (0 vs. 34.4%, p < 0.05), and the virus level was higher (4.9 vs. 4.05 LGE/ml). In the genotype B HBV carriers, the incidence of PC mutation was significantly higher (69 vs. 34%, p < 0.05). In the genotype C HBV carriers, the incidence of CP mutation was significantly higher (13 vs. 78%, p < 0.05). We compared patients with the wild (W)/mutant (M) pattern in the CP/PC regions to those with the M/W pattern in the CP/PC regions among the genotype C HBV carriers. Both the proportion of HBeAg-positive patients (65.8 vs. 15.4%, p < 0.05) and the alanine aminotransferase (ALT) level (48 vs. 21.5 IU, p < 0.05) were higher in the patients with the M/W pattern in the CP/PC regions, and the disease severity was deteriorated. In conclusion, genotype B HBV may more frequently induce HBe seroconversion via PC mutation compared to genotype C HBV. Among the genotype C HBV carriers, hepatitis activity and the deterioration of the disease severity were significantly inhibited in the group in which PC mutation initially occurred, in comparison to the group in which CP mutation initially occurred.

Adolescent↗
PubMed2006

Effects of differential genotyping error rate on the type I error probability of case-control studies.

OBJECTIVES: It is well known that genotyping error adversely affects the power of genetic case-control association studies but there is little research on its effects on type I error, and none that has addressed possible differences in genotype error rates between cases and controls. METHODS: We used simulations to examine the influence of genotyping error on the type I error probability given by case-control studies. The effect of genotyping error on the magnitude of type I error was explored for a single marker of varying minor allele frequency (MAF), and for haplotypic tests based on two markers with varying MAF and linkage disequilibrium (LD) measure r(2). RESULTS: We show that even with low genotyping error rates (<0.01), systematic differences in the error rate between samples can result in type I error rates substantially above 0.05. The effect was maximal for markers with small MAF, markers in strong LD, and where a common allele is more frequently misclassified as a rare allele than vice versa. The problem was also exacerbated by the use of large samples. CONCLUSIONS: Our results show that small differential genotyping error rates between cases and controls pose significant problems for association analyses. Differential genotyping error rates are particularly likely to arise where genotype data are combined from multiple sites, or where case genotypes are examined against archived reference population cohort genotypes that are being generated in several countries. Although these strategies may be necessary to obtain adequately powered samples, our data show the importance of stringent quality control. Furthermore, associations based on rare haplotypes should be treated with caution.

Alleles↗
PubMed1995

Angiotensin-converting enzyme and apolipoprotein E genotypes and restenosis after coronary angioplasty.

BACKGROUND: An insertion/deletion (I/D) polymorphism in the gene for angiotensin-converting enzyme (ACE) has been associated with myocardial infarction and other cardiac pathology. There is evidence for a role of the renin-angiotensin system in cell growth and in the repair of damaged arterial walls, so the ACE gene was postulated to be a candidate gene affecting the important clinical problem of restenosis after percutaneous transluminal balloon coronary angioplasty (PTCA). Because restenosis is influenced by the apolipoprotein E (apoE) genotype, the possibility of a relation between ACE and apoE genotypes and restenosis was also sought. METHODS AND RESULTS: Subjects (< 70 years of age) were prospectively followed and had coronary angiography 6 months after PTCA to determine the presence or absence of restenosis. Those who had angiography earlier and did not have restenosis (> or = 50% loss of gain at PTCA plus > or = 50% luminal diameter stenosis) also had angiography at 6 months. The whole group (n = 207) had a higher DD genotype frequency than did 136 population control subjects (38% versus 26%, P < .02); in PTCA patients, the frequency was the same in those with and without prior myocardial infarction. The distribution of ACE genotypes was not different in the 88 patients with and 119 patients without restenosis, while the epsilon 4/4 genotype was more frequent in those with restenosis (8 of 88 versus 3 of 118, P < .05). There was no effect of the ACE genotype in noncarriers of the epsilon 4 allele, but there was a significant effect in epsilon 4 carriers (P < .005). The combined D and epsilon 4 carrier state showed a 16-fold increase in the odds ratio for restenosis (P < .02). Multiple linear regression examining the loss of lumen as a continuous variable showed significant independent effects of the ACE and apoE genotypes. CONCLUSIONS: Overall, the ACE genotype had no clear influence on restenosis, but there was an interaction between ACE and apoE genotypes. The combined carrier state for the D and apoE epsilon 4 alleles substantially increased restenosis. For loss of lumen as a continuous variable, there were significant effects of both ACE and apoE genotypes. While the observations may not affect current management, they no doubt have implications in pathophysiology.

Angioplasty, Balloon, Coronary↗
PubMed2006

Survey of Pseudomonas aeruginosa genotypes in colonised cystic fibrosis patients.

The current authors aimed to examine whether cystic fibrosis (CF) patients in Belgium shared Pseudomonas aeruginosa genotypes and to compare the genotypes of isolates from the same patients during two consecutive years. A Belgian databank of the P. aeruginosa genotypes of all colonised CF patients was created. Sputum samples from a total of 276 P. aeruginosa colonised patients during 2003, and from a subgroup of 95 patients in 2004, were analysed. Patients were asked about any social contact between each other by questionnaire. All P. aeruginosa isolates exhibiting different colonial morphology on McConkey agar were first genotyped using arbitrarily primed PCR, whereafter single representatives of each randomly amplified polymorphic DNA-type were further genotyped by fluorescent amplified fragment length polymorphism analysis. In the 213 patients from whom P. aeruginosa could be cultured (resulting in 910 isolates), a total of 163 genotypes were found. The majority (75%) of patients harboured only one genotype. In most of the limited number of clusters, previous contacts between patients could be suspected. In 80% of the patients studied during both years, P. aeruginosa genotype remained unchanged. In conclusion, most colonised cystic fibrosis patients harbour only one Pseudomonas aeruginosa genotype, despite showing different colonial morphotypes. The number of clusters is limited, and most patients seem to retain the same genotypic strain during both years.

Adolescent↗
PubMed2006

Comparison of methods for analysis of selective genotyping survival data.

Survival traits and selective genotyping datasets are typically not normally distributed, thus common models used to identify QTL may not be statistically appropriate for their analysis. The objective of the present study was to compare models for identification of QTL associated with survival traits, in particular when combined with selective genotyping. Data were simulated to model the survival distribution of a population of chickens challenged with Marek disease virus. Cox proportional hazards (CPH), linear regression (LR), and Weibull models were compared for their appropriateness to analyze the data, ability to identify associations of marker alleles with survival, and estimation of effects when all individuals were genotyped (full genotyping) and when selective genotyping was used. Little difference in power was found between the CPH and the LR model for low censoring cases for both full and selective genotyping. The simulated data were not transformed to follow a Weibull distribution and, as a result, the Weibull model generally resulted in less power than the other two models and overestimated effects. Effect estimates from LR and CPH were unbiased when all individuals were genotyped, but overestimated when selective genotyping was used. Thus, LR is preferred for analyzing survival data when the amount of censoring is low because of ease of implementation and interpretation. Including phenotypic data of non-genotyped individuals in selective genotyping analysis increased power, but resulted in LR having an inflated false positive rate, and therefore the CPH model is preferred for this scenario, although transformation of the data may also make the Weibull model appropriate for this case. The results from the research presented herein are directly applicable to interval mapping analyses.

Genotype↗
PubMed2006

Extending the clinical heterogeneity of iodide transport defect (ITD): a novel mutation R124H of the sodium/iodide symporter gene and review of genotype-phenotype correlations in ITD.

CONTEXT: Iodide transport defect (ITD) is an autosomal recessive disorder resulting in varying degrees of congenital hypothyroidism (CH) with goiter and low or absent radioiodide uptake (RIUT), as determined by thyroid scintigraphy, and low iodide saliva to plasma ratio. Defects of the sodium/iodide symporter gene (NIS) have been shown to cause ITD. OBJECTIVE: We describe molecular studies of NIS in a patient with ITD and genotype-phenotype correlation analysis in 31 patients with NIS defects reported worldwide. DESIGN: NIS sequencing and functional studies of the new NIS mutation in vitro were performed. RESULTS: In a newborn with symptomatic CH and a large goiter, thyroid scintigraphy showed no RIUT (0%). NIS sequencing identified the new homozygous mutation, R124H, in exon 2. This mutation was associated with abolition of iodide uptake in vitro when transfected in COS-7 cells. Immunocytochemical studies documented correct targeting of the mutated protein to the plasma membrane of transfected cells. Genotype-phenotype correlation analysis showed that the onset of hypothyroidism occurred during the neonatal period with four NIS mutations (neonatal onset of hypothyroidism genotype), during infancy with three NIS mutations (infancy onset of hypothyroidism genotype), and during childhood with three NIS mutations (childhood onset of hypothyroidism genotype). RIUT is a direct measure of residual NIS activity in vivo. Mean RIUT was lower in patients with the neonatal onset of hypothyroidism genotype (0.88 +/- 0.2%) than in the infancy onset of hypothyroidism (1.9 +/- 0.4%; P < 0.05) and childhood onset of hypothyroidism (2.6 +/- 0.7%; P < 0.05) genotypes. CONCLUSIONS: We identified a new NIS mutation, R124H, in a newborn with the complete clinical ITD phenotype. Genotype-phenotype correlations suggest that age at hypothyroidism onset may be genotype specific and may depend on genotype-specific residual NIS activity.

Age of Onset↗
PubMed2002

Adrenomedullary function may predict phenotype and genotype in classic 21-hydroxylase deficiency.

Classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is characterized by decreased synthesis of glucocorticoids and mineralocorticoids, adrenal hyperandrogenism, and impaired development and function of the adrenal medulla. Although genotype can usually predict phenotype, genotype-phenotype discordance has been described. We investigated the association between adrenomedullary function, disease severity, and genotype in 37 children [22 males and 15 females; age range, 4.7-14.9 yr; 28 salt-wasting (SW) and 9 simple virilizing (SV) CAH] with classic 21-hydroxylase deficiency. Plasma and 24-h urinary catecholamines and their metabolites, and the 21-hydroxylase genotype were determined in all patients. The disease-causing mutations were divided into 4 groups (Null, A, B, and C) according to in vitro 21-hydroxylase activity as previously described. Genotype groups Null (n = 9) and A (n = 15) were predicted to result in SW CAH, group B (n = 8) was predicted to have the SV phenotype, and group C (n = 1) was predicted to have nonclassic CAH. A fifth group, D (n = 4), included patients in whom mutations were detected in only 1 allele. Plasma total metanephrine (420.1 +/- 60.0 vs. 657.7 +/- 67.8 pg/ml; P = 0.04) and free metanephrine (13.4 +/- 1.7 vs. 24.0 +/- 4.1 pg/ml; P = 0.008) concentrations were significantly lower in children with SW CAH than in those with the SV form of the disease. Plasma free metanephrine concentrations best predicted phenotype, with accuracy similar to that of genotype. Concordance rates between genotype and phenotype were higher in the most severely affected patients (Null, 88.9%; A, 93.3%; B, 75%; plasma free metanephrine, <18.5 pg/ml: SW, 92%). The plasma free metanephrine concentration correlated with the expected 21-hydroxylase activity based on genotype, and there was a significant trend for free metanephrine concentrations across the three genotype groups (P < 0.0001). Our findings indicate that measurement of adrenomedullary function, best assessed by the free metanephrine concentration, is a useful biomarker of disease severity in 21-hydroxylase deficiency. Molecular genotype and plasma free metanephrine concentration predict phenotype with similar accuracy. Both methods are more accurate in the most severe forms of the disease.

Adolescent↗
PubMed2003

Strong association between N-acetyltransferase 2 genotype and PD in Hong Kong Chinese.

BACKGROUND: The slow acetylator genotype for N-acetyltransferase 2 (NAT2 genotype) may be associated with PD in white subjects and the genotype is common in both white and Chinese populations. Whether there is a relationship between NAT2 genotype and PD in Chinese subjects is not known. OBJECTIVE: To investigate the association between the slow acetylator genotype for N-acetyltransferase 2 and PD in a Chinese population. METHODS: The authors obtained DNA samples and documented sex, age, and smoking history in 99 Chinese patients with PD and in 126 control subjects from two major Hong Kong hospitals. PCR-restriction fragment length polymorphism was used to identify M1, M2, and M3 mutant polymorphisms of the slow acetylator genotype for N-acetyltransferase 2. Logistic regression analyses were carried out to investigate the relationships between the different variables and PD. RESULTS: The frequency of the slow acetylator genotype for N-acetyltransferase 2 in the PD group was significantly higher than that of the control group (68.7% vs 28.6%) with an OR of 5.53 (95% CI 3.08 to 9.92) after adjusting for age, sex, and smoking history. In a subgroup analysis smoking had no modifying effect on the association between genotype and PD. CONCLUSIONS: There is a significant association between PD and the slow acetylator genotype for N-acetyltransferase 2 in Hong Kong Chinese. The OR found is among the highest reported so far in all susceptibility gene studies for PD in both Chinese and white subjects and provides evidence for a possible functional relationship between NAT2 slow acetylator genotype and PD in both racial groups.

Acetylation↗