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PubMed1986

Evolutionary principles for general frequency-dependent two-phenotype models in sexual populations.

The evolutionary dynamics in general two-sex two-phenotype frequency-dependent selection models are studied with respect to underlying multi-allele one-locus genetic systems. Two classes of equilibria come into play: genotypic equilibria, with equilibrium allelic frequencies independent of the phenotype, and phenotypic equilibria, which are characterized by equal mean phenotypic fitnesses. The exact conditions for genotypic equilibria to exist and be stable and for phenotypic equilibria to exist and be evolutionarily attractive are examined. Using adequate definitions of mean fitnesses in general contexts of frequency-dependent selection in dioecious populations, we show that two phenotypes, when they can coexist in the population, tend to balance their fitnesses as far as is allowed by the genetic system as more alleles responsible for phenotype determination are introduced into the population.

Alleles↗
PubMed1996

The effect of physical activity on serum total and low-density lipoprotein cholesterol concentrations varies with apolipoprotein E phenotype in male children and young adults: The Cardiovascular Risk in Young Finns Study.

Apolipoprotein E (apo E) determines serum total (TC) and low-density lipoprotein (LDL-C) cholesterol concentrations and is thus associated with coronary heart disease (CHD) risk. We studied if the effect of physical activity (PA) on serum TC and LDL-C concentrations varies with apo E phenotype in a population-based sample of children and young adults with regular PA. The study cohort consisted of subjects aged 9, 12, 15, 18, 21, and 24 years in 1986 (N = 1,498) participating in a large multicenter study of cardiovascular risk factors in children and young adults. Serum lipid concentrations were determined enzymatically, and apo E phenotypes by isoelectric focusing and immunoblotting. The composition of the diet was determined by a 48-hour recall method, and a PA index was calculated on the basis of frequency, intensity, and duration of activity assessed by a questionnaire. LDL-C (P = .0082), TC (P = .014), and the high-density lipoprotein cholesterol (HDL-C)/TC ratio (P = .0004) responses to exercise varied with apo E phenotype. The effect of PA on LDL-C, TC, or HDL/TC was not found in apo E phenotype E4/4. A moderate inverse effect of PA on TC and LDL-C and a positive effect on HDL/TC was found in subjects with E4/3 and E3/3 phenotypes. Similar but stronger associations were found between these variables within the group of E3/2 males. The effect of PA on serum lipid levels was strongest within the phenotype E3/2. These associations were not explained by dietary habits. Apo E phenotype partly determines the effect of PA on serum TC and LDL-C in Finnish male children and young adults with regular PA.

Adolescent↗
PubMed2000

Relationship between lipoprotein(a) phenotypes and plaminogen activator inhibitor type 1 in diabetic patients.

It has been demonstrated in vitro that lipoprotein(a) [Lp(a)] increases the endothelial synthesis of plasminogen activator inhibitor 1 (PAI-1). However, this effect in vivo is controversial, and the possible relationship between PAI-1 and Lp(a) phenotypes has not been evaluated. The aim of the study was to determine the influence of Lp(a) and its phenotypes on PAI-1 serum concentrations in diabetic patients. For this purpose we include 75 Caucasian diabetic patients (34 consecutive type I and 41 consecutive type II) without late diabetic complications. Lp(a) and PAI-1 were assessed by ELISA. Lp(a) phenotypes were determined by SDS-PAGE followed by immunoblotting, and grouped according to size in small (F,B,S1,S2), big (S3,S4), and null. A linear correlation between Lp(a) and PAI-1 was not observed either as a whole or when type I and type II diabetic patients were analyzed separately. However, significant differences were detected in PAI-1 levels when Lp(a) phenotypes were considered (small: 42.1+/-31.8 ng/mL; big: 37.2+/-26.1 ng/mL; null: 14.4+/-14.4; p< 0.05). The significant differences were due to the low PAI-1 concentrations observed in patients with null phenotype. Our results suggest that fibrinolytic activity might be preserved in diabetic patients with null Lp(a) phenotype. Furthermore, it could be speculated that diabetic patients with null phenotype should be considered at low risk to develop cardiovascular disease.

Adult↗
PubMed2001

Glyoxalase I phenotype as a potential risk factor for prostate carcinoma.

OBJECTIVES: To elicit a possible link between glyoxalase I (Gly-I), a detoxifying enzyme, and the incidence of prostate cancer (PCa), we investigated Gly-I phenotypic expression in the prostatic tissue and red blood cells (RBCs) from patients with PCa. METHODS: Eighty-seven clinical specimens, including 42 PCa tissue samples, 20 RBC samples, and 25 matched pair (prostate and RBC) samples from patients at prostatectomy were examined. The Gly-I phenotypes in these specimens were assessed by nondenaturing starch-polyacrylamide gel electrophoresis. RESULTS: Of the 87 patients, 63 (72.4%) were white, 15 (17.2%) were black, and 9 (10.4%) were another ethnicity (eg, Hispanic, Asian, Indian). Three Gly-I phenotypes were detected in these specimens as fast, intermediate, and slow-moving bands on the gel. The fast phenotype was the most common form found in the white (34 [54%] of 63) and black (8 [53.3%] of 15) patients, but the third ethnic group was too small for proper analysis. To validate this finding, the data from the white patients were compared with the Gly-I phenotypic frequencies in U.S. populations. The data analysis confirmed that a higher incidence (54%) of the fast type in our white patients was statistically significant (P <0.0001) compared with its phenotypic frequency of 30.6% in the general U.S. white population. CONCLUSIONS: The significantly high frequency (P <0.0001) of the fast Gly-I phenotype was detected among patients with PCa, suggesting it is a potential risk factor for PCa. Whether its increased incidence in whites reflects the lack of sample numbers for other ethnic groups needs additional investigation.

ABO Blood-Group System↗
PubMed2006

Asthma: defining of the persistent adult phenotypes.

The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes that overlap. Although clinicians have recognised these different phenotypes for many years, they have remained poorly characterised, with little known about the underlying pathobiology contributing to them. Development of targeted therapies for asthma, and phenotype-specific clinical trials have raised interest in these phenotypes. Improved understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specific genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised method to define asthma phenotypes. This Review analyses some of the methods that have been used to define asthma phenotypes and proposes an integrated method of classification to improve our understanding of these phenotypes.

Adrenal Cortex Hormones↗
PubMed1994

Lumbar vertebral and femoral neck bone mineral density are higher in postmenopausal women with the alpha 2HS-glycoprotein 2 phenotype.

alpha 2HS-glycoprotein (AHSG) is a plasma protein which becomes concentrated in the organic matrix of bone. The two most common alleles, AHSG*1 and AHSG*2, give rise to three common phenotypes. A recent report showed that a group of postmenopausal white North American women with different AHSG phenotypes differed significantly with respect to their oestrogen status. We have studied variations in bone mineral density, measured by DEXA, and levels of sex hormones and biochemical markers of bone metabolism in a group of 88 post-menopausal women unselected as to their health status. Lumbar vertebral and femoral neck bone mineral density (BMD), and the free oestradiol index were all significantly higher (P < 0.05) in women with the AHSG 2 phenotype. Values of these three parameters were lowest in the AHSG 1 phenotype and intermediate in the AHSG 2-1 phenotype. Because the differences in BMD between the AHSG 2 and 1 phenotypes represent at least a 40% difference in fracture risk, the AHSG phenotype may be of some clinical relevance as a risk factor for osteoporosis.

Aged↗
PubMed2002

Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes: The Strong Heart Study.

OBJECTIVES: The goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM). BACKGROUND: Cardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications. METHODS: We sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years. RESULTS: In multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype. CONCLUSIONS: This study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient.

Aged↗
PubMed2002

Macrolide resistance phenotypes in Streptococcus pneumoniae in Santiago, Chile.

The mechanism of resistance was investigated in 39 macrolide-resistant clinical isolates of Streptococcus pneumoniae isolated from January 1997 to July 1999 in Santiago, Chile. Our results showed that 22 (56.5%) were macrolide-resistant, clindamycin-susceptible isolates (M phenotype) and 17 (43.5%) were macrolide and clindamycin resistant (MLS(B) phenotype). mefE gene was detected in all M phenotype, while ermB gene was detected in all MLS(B)-phenotype strains. Serotype 14 was the most frequent serotype among M-phenotype strains, and serotypes 19 and 23F were the most frequent serotypes in MLS(B) strains. These results demonstrate that both phenotypes of macrolide-resistant S. pneumoniae are found in Santiago, Chile, with the M phenotype predominating.

Adult↗
PubMed1996

Phenotypic variation of clinical Serratia marcescens isolates repeatedly recovered from individual patients.

A total of 129 selected isolates of Serratia marcescens which had been recovered from 50 patients during the 1980-1995 period and which revealed phenotypic variation in terms of bacteriocin (phage tail) susceptibility, carbon source assimilation, or serotype, were reexamined with these three phenotypic methods. Seven isolates (5.4%) were bacteriocin nontypable; all 129 isolates utilized carbon sources and could be serotyped. Fourty-eight isolates from 20 patients yielded unambiguous results with these 3 phenotypic methods and were excluded from further analysis. Among the remaining 81 isolates from 30 patients, isolates from 2 patients revealed phenotypic variation in bacteriocin susceptibility only, whereas isolates from 6 patients showed variant bacteriocin types and variant biochemical profiles, but were of identical serotype. Isolates from 20 patients revealed variant biochemical profiles only. Three patients had become superinfected with strains of S. marcescens of different phenotype and genotype. In 4 patients, previously motile (H12) isolates had become nonmotile (H-). PFGE analysis of XbaI and SpeI-restricted genomic DNA of the 81 isolates of the 30 patients demonstrated the isolates of 22 patients to be genotypically identical. The isolates from 3 patients were closely related by genotype, and those from an additional patient proved to be possibly related. PFGE analysis demonstrated one patient to have become infected by two genotypically different strains of S. marcescens of identical serotype, which, however, differed in bacteriocin type and biochemical profile. It was concluded that PFGE analysis of restricted genomic S. marcescens DNA was superior to the three phenotypic methods examined comparatively. Serotyping was more reliable than bacteriocin typing, and the latter technique yielded fewer phenotypic variants than determination of biochemical profiles among consecutively recovered isolates from patients with long-lasting S. marcescens infection.

Bacterial Typing Techniques↗
PubMed1997

Relationships among strains classified with the ruminant Pasteurella haemolytica-complex using quantitative evaluation of phenotypic data.

The phenotypic relationships among 246 trehalose-negative strains classified under the [Pasteurella] haemolytica-complex in ruminants were investigated by clustering and multidimensional ordinations based upon 79 phenotypic characters. A quantitative evaluation of phenotypic data using a 5-level scoring system is presented permitting a comprehensive utilization of the recorded phenotypic variation among the strains in the analyses. Clustering and ordination analyses display complementary aspects of data which has been clearly demonstrated in this investigation. The main clusters revealed by the numerical techniques could be related to distinctive phenotypic differences and showed an extensive correlation with the recognized biogroups. This classification was based only upon 4 characters (fermentation of L-arabinose, D-sorbitol, glucosides and ornithine decarboxylase). In contrast, there was no obvious interpretation of the clusters formed by using binary scores. Phenotypic subgroups within the recognized biogroups have been described as well as a new, related group of bacteria, tentatively named Bisgaard taxon 36. Quantitative interpretation of phenotypic data seems to represent a promising method for finding relations among affiliated strains of bacteria and to assist in forming hypotheses for subsequent genotypic investigations.

Animals↗
PubMedDate not supplied

The complexity of the genotype-phenotype relationship and the limitations of using genetic "markers" at the individual level.

Many associations have recently been discovered between phenotypic variation and genetic loci, causing some to advocate what Robert Sinsheimer has called "a new eugenics" that would treat genetic "defects" in individuals prone to a disease. The first premise of this vision is that genetic association studies reveal the biological cause of the phenotypic variation. Once the responsible genes are known, the second premise is that we should focus upon changing "nature" rather than "nurture" by correcting the "defective" genes. The first premise is flawed because associations between genetic markers and phenotypes can be spurious, as shown by an example. Moreover, it is shown that using non-causative but associated genetic markers one at a time (the normal practice) can lead to incorrect predictions of disease risk for many individuals. Going from association to causation is a non-trivial step scientifically that has rarely been done in much of the human genetic research. Even when a particular locus does contribute to the phenotypic variation of interest, the first premise remains flawed because phenotypes in general arise from complex interactions among genes and between genes and environments as shown for genes associations with coronary artery disease (CAD). The ability of current molecular genetic tools to "fix" defective genotypes is extremely limited, but even if the technological problems could be overcome, the studies on CAD reveal no obvious "defective" gene to fix because the genetic effects are so context dependent (upon both other genes and environmental factors). Contrary to the second premise of the new eugenics, the more we learn about how different genotypes show variable responses to environments, the more important the environment becomes for individual treatment. The paradigm of a "defective gene" may work for classical Mendelian genetic diseases that are due to loss-of-function mutations. However, such mutations affect only a small portion of humanity. When the focus is changed to common disease and behavioral phenotypes, the "defective gene" paradigm is biologically meaningless and often harmful when applied to individuals. Thus, even when genes clearly do influence common phenotypic variation, the premises of the "new eugenics" are biologically indefensible.

Alzheimer Disease↗
PubMed1984

Distribution of apolipoprotein E phenotypes in Friedreich's ataxia.

Allelic polymorphism at the apolipoprotein E (apo E) gene locus (alleles epsilon 2, epsilon 3, and epsilon 4) is responsible for the existence of 6 discrete electrophoretic phenotypes of plasma apo E. Since the presence of the epsilon 2 allele in the genotype tends to be associated with higher triglyceride levels, a study was undertaken to determine if a higher frequency of this allele could account for the presence of higher plasma triglycerides in subsets of patients with Friedreich's Ataxia. The frequency of the apo E phenotypes was determined in 37 subjects with Friedreich's Ataxia and compared with that of 102 normolipidemic and 102 hyperlipidemic individuals. There was no increased prevalence of the E3/2 phenotype and the epsilon 2 allele in the Friedreich's sample as is found in a hyperlipidemic sample. Furthermore, the epsilon 2 subset did not have significantly higher plasma triglycerides than the non-epsilon 2 subset and the hypothesis was rejected. On the other hand, there was a trend for a decreased frequency of the E4/3 phenotype in the Friedreich's sample relative to the hyperlipidemic group but the difference did not reach statistical significance. The apo E phenotype distribution was also measured in a smaller sample of Charlevoix-Saguenay disease; this led to the discovery of two siblings with the relatively rare E2/2 phenotype and unexpectedly low levels of plasma lipid and lipoprotein concentrations. Plasma apolipoprotein E concentrations in both diseases were within the normal range except for subjects bearing the E2/2 phenotype.

Adolescent↗
PubMed2001

Correspondence of soldier defense secretion mixtures with cuticular hydrocarbon phenotypes for chemotaxonomy of the termite genus Reticulitermes in North America.

Soldier defense secretions from samples of Reticulitermes collected in California, Nevada, Arizona, New Mexico, and Georgia were characterized and correlated with cuticular hydrocarbon phenotypes. Twenty-seven cuticular hydrocarbon phenotypes have been defined, and soldier defense secretion (SDS) phenotypes have been described for 25 of these. Forty-five terpenoid compounds were found, including monoterpenes, sesquiterpenes, and a few diterpenes. The monoterpenes include (-)-alpha-pinene, (-)-beta-pinene, (-)-camphene, myrcene, (Z)- and (E)-ocimene, and (-)-limonene. The major sesquiterpenes produced are (+)-gamma-cadinene, (+)-gamma-cadinene aldehyde, (-)-germacrene A, germacrene B, gamma-himachalene, and beta-bisabolene. Some SDS phenotypes pair with more than one cuticular hydrocarbon phenotype; however, with two exceptions, each hydrocarbon phenotype is associated with only one SDS phenotype. These chemical characterizations lend support to the conclusion that there are numerous undescribed species of Reticulitermes in North America.

Adaptation, Physiological↗
PubMed1998

Frequency and significance of phenotypes for alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis.

To evaluate the frequency and significance of alpha1-antitrypsin deficiency in type 1 autoimmune hepatitis, 181 Caucasian patients were assessed for variant phenotypes. Three hundred three Caucasian patients with various other chronic liver diseases were similarly evaluated. Twenty-one of the 181 patients (12%) had heterozygous deficiencies, including the MS (6%) and MZ (6%) phenotypes. These patients were indistinguishable from those with normal phenotypes. Immediate outcomes after corticosteroid therapy were also similar in both groups. Variant phenotypes were present in 34 of the 303 patients with other chronic liver diseases (11%). Patients with nonalcoholic steatohepatitis had a significantly greater frequency of deficiency phenotypes than patients with chronic hepatitis C (20% vs 7%, P = 0.03). In conclusion, deficiency phenotypes are common in type 1 autoimmune hepatitis and they have no clinical or prognostic importance. In certain liver diseases, such as nonalcoholic steatohepatitis, variant phenotypes may be comorbid factors.

Adult↗
PubMed2003

Linkage analysis of candidate regions using a composite neurocognitive phenotype correlated with schizophrenia.

As schizophrenia is genetically and clinically heterogeneous, systematic investigations are required to determine whether ICD-10 or DSM-IV categorical diagnoses identify a phenotype suitable and sufficient for genetic research, or whether correlated phenotypes incorporating neurocognitive performance and personality traits provide a phenotypic characterisation that accounts better for the underlying variation. We utilised a grade of membership (GoM) model (a mathematical typology developed for studies of complex biological systems) to integrate multiple cognitive and personality measurements into a limited number of composite graded traits (latent pure types) in a sample of 61 nuclear families comprising 80 subjects with ICD-10/DSM-IV schizophrenia or schizophrenia spectrum disorders and 138 nonpsychotic first-degree relatives. GoM probability scores, computed for all subjects, allowed individuals to be partly assigned to more than one pure type. Two distinct and contrasting neurocognitive phenotypes, one familial, associated with paranoid schizophrenia, and one sporadic, associated with nonparanoid schizophrenia, accounted for 74% of the affected subjects. Combining clinical diagnosis with GoM scores to stratify the entire sample into liability classes, and using variance component analysis (SOLAR), in addition to parametric and nonparametric multipoint linkage analysis, we explored candidate regions on chromosomes 6, 10 and 22. The results indicated suggestive linkage for the familial neurocognitive phenotype (multipoint MLS 2.6 under a low-penetrance model and MLS>3.0 under a high-penetrance model) to a 14 cM area on chromosome 6, including the entire HLA region. Results for chromosomes 10 and 22 were negative. The findings suggest that the familial neurocognitive phenotype may be a pleiotropic expression of genes underlying the susceptibility to paranoid schizophrenia. We conclude that use of composite neurocognitive and personality trait measurements as correlated phenotypes supplementing clinical diagnosis can help stratify the liability to schizophrenia across all members of families prior to linkage, allow the search for susceptibility genes to focus selectively on subsets of families at high genetic risk, and augment considerably the power of genetic analysis.

Adolescent↗
PubMed1997

Evidence of a dominant transcriptional pathway which regulates an undifferentiated and complete metastatic phenotype.

The highly metastatic amelanotic C8161 human melanoma line was found to exhibit complete dominance of its undifferentiated and metastatic phenotype in multiple somatic cell hybridization studies designed to bypass the presence of potential tumor suppressor genes. In a three armed approach involving somatic cell fusions of C8161 with recipient lines of greater differentiation, different lineage, and different tumorigenicity status, the metastatic and undifferentiated phenotype of C8161 was promiscuously dominant. In somatic cell hybrids produced between the C8161 and a group of non-metastatic human melanoma lines which exhibited melanocyte differentiation markers including S100, HMB-45, NKI/C3, and melanin, the fusions were uniformly metastatic and undifferentiated. In somatic cell hybrids of C8161 and MCF-7 the fusions exhibited an estrogen independent and unresponsive, estrogen receptor (ER) negative, and highly metastatic phenotype. In fusions between C8161 and HMS-1, an immortalized 'benign' human myoepithelial line which produced an abundant extracellular matrix (ECM) and high levels of protease and angiogenic inhibitors including maspin, tissue inhibitor of metalloproteinase-1 (TIMP-1), alpha1-antitrypsin (alpha1-AT), protease nexin II (PN-II), thrombospondin-1 and soluble basic fibroblast growth factor (bFGF) receptors, the hybrids showed complete absence of matrix, absent maspin expression, markedly decreased protease inhibitor and angiogenic inhibitor production, high levels of proteases and angiogenic factors, and a highly metastatic phenotype. In our somatic cell fusions, the human-human hybrids represented true and complete fusions and not hybrid clones selected for by loss of dominant-acting growth suppressor genes. This finding was supported by detailed comparative genomic hybridization (CGH) studies, Q-banding karyotype analysis, and autofusions of representative clones. The purposeful creation of inherently unstable human-murine fusions between C8161 and B16-F1 where loss of putative suppressor loci would be expected, resulted in fusions exhibiting decreased growth and non-metastatic behavior with progressive chromosomal loss. Neither p53, nm23, DNA methyltransferase, activated ras, fibroblast growth factor-4 (FGF-4), or epidermal growth factor receptor (EGFR) mediated the acquisition of the metastatic or undifferentiated phenotype within the C8161-human fusions. These studies are the first studies ever to successfully transfer the complete metastatic phenotype by somatic cell fusion and support the presence of a new high level regulatory pathway(s) involving dominant trans-acting factors which act pleiotropically to regulate an undifferentiated and highly metastatic phenotype.

Animals↗
PubMed2002

Evidence for separate disease phenotypes in intestinal Crohn's disease.

BACKGROUND: This study investigated the hypothesis that separate phenotypes of Crohn's disease exist which display differing patterns of recurrence with a tendency to preservation of phenotype between serial operations. METHODS: Some 483 abdominal operations (278 patients) were identified from a prospectively compiled database. Patterns of recurrence (reoperation) were analysed by Kaplan-Meier plots and log rank tests according to disease phenotype (perforated, stenosed or ulcerated). Serial operations were analysed by agreement of phenotype and microscopic features of disease using kappa statistics and correlation coefficients. RESULTS: There was no significant difference in recurrence according to disease phenotype (median reoperation-free survival time 43.0, 50.2 and 47.9 months for perforated, stenosed and ulcerated types respectively; log rank chi(2) = 3.5, P = 0.18). There was poor agreement in phenotype between serial operations (kappa = 0.22 for first/second operation and kappa= 0.15 for second/third operation) and no significant correlation between pathological features was identified (r between -0.19 and 0.48). CONCLUSION: No evidence was found for the existence of separate disease phenotypes with differing natural histories or underlying pathological characteristics.

Crohn Disease↗
PubMed2003

Slow acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole hypersensitivity.

AIMS: To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV-positive patients with sulphamethoxazole (SMX) hypersensitivity. METHODS: Forty HIV-positive patients (32 of whom were SMX-hypersensitive), and 26 healthy volunteers, were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis, and phenotyped using dapsone (50 mg) as a probe, for acetylator status. Sequencing of the NAT2 exon was performed where discrepancy between phenotyping and genotyping was detected. Our results were also pooled with published studies addressing slow acetylator status in HIV-positive SMX-hypersensitive patients. RESULTS: Slow acetylator genotype and phenotype frequencies did not differ between HIV-positive SMX-hypersensitive and nonhypersensitive patients, and healthy controls, which was further confirmed in a meta-analysis of published studies (pooled odds ratio 2.25, 95% confidence interval 0.45, 11.17). Discordance between phenotype and genotype was resolved in four of the subjects by sequencing of the whole NAT2 exon, which revealed rare mutations, leaving three (9%) HIV-positive SMX-hypersensitive patients and one (4%) healthy volunteer who continued to demonstrate the discordance. CONCLUSIONS: Slow acetylator phenotype or genotype is unlikely to predispose to SMX hypersensitivity in HIV-positive patients, although a minor role cannot be excluded. Phenotype-genotype discrepancies are partly due to nondetection of all rare alleles by PCR methodology, and can be circumvented by sequencing of the gene in patients showing a discrepancy.

Acetylation↗