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A K Daly

Publications and source records attributed to A K Daly.

At least 37 records · Page 2Linked to original sources
PubMed2000

The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects.

AIMS: To establish whether gender or N-acetyltransferase 2 (NAT2) genotype influence the urinary 17 U+17X/137X ratio after dosing with caffeine. METHODS: Ninety-two nonsmoking individuals underwent caffeine phenotyping. NAT2 genotype was determined by the polymerase chain reaction followed by a restriction digest (PCR-RFLP). RESULTS: The median ratio for urinary 17 U+17X/137X was 6.7 (range 1.45-18. 65). 55% of subjects were slow acetylators. Gender did not affect the metabolic ratio or NAT2 genotype. Mean 17 U+17X/137X ratio differed between fast (6.75) and slow (8.69) acetylators (95% CI for the difference, 0.32-3.56). CONCLUSIONS: The findings are further evidence that the 17 U+17X/137X urinary ratio is not a robust measure of CYP1A2 activity. A possible mechanism by which the ratio might be influenced by NAT2 genotype is suggested.

Adolescent↗
PubMed2000

CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system.

AIMS: Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S-mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity. METHODS: Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups. RESULTS: One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035). CONCLUSIONS: These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.

Aged↗
PubMed2000

Variation in induced CYP1A1 levels: relationship to CYP1A1, Ah receptor and GSTM1 polymorphisms.

The genotypic basis of interindividual variation in levels of induced CYP1A1 activity has been investigated by screening both the CYP1A1 gene and the Ah receptor gene (AhR) for both previously described and novel polymorphisms. A 103-fold level of interindividual variation in induced CYPlA1 activity [ethoxyresorufin O-deethylase (EROD)] was observed in lymphocytes from a group of 30 Caucasian volunteers. High levels of induced EROD activity did not correlate with the presence of CYP1A1*2 or CYP1A1*4 alleles or with the GSTM1 null genotype. Novel CYP1A1 alleles with the base substitutions C4151T, G-469A and C-459T respectively, were detected by screening the coding exons and approximately 1 kb of upstream sequence in 20 individuals by single-strand conformational polymorphism (SSCP) analysis but none of the three novel alleles appeared to be associated with high induced CYP1A1 activity in the study group. Screening of the 11 exons of the AhR gene by SSCP analysis confirmed the existence of the previously described G1721A polymorphism in a Caucasian population and a novel allele (G1768A which results in the amino acid substitution V5701) was also detected. The novel allele was very rare in Caucasians though more common in African-Americans. Individuals with at least one copy of the G1721A AhR variant allele showed a significantly higher level of induced CYP1A1 activity compared with individuals negative for the polymorphism (P = 0.0001). A similar finding was obtained for induced CYP1A1 protein levels determined by immunoblotting. Levels of induced CYP1A1 activity were also found to show a sex difference with women showing a significantly lower induced activity compared with men. We conclude that genotypes for the G1721A AhR polymorphism and gender appear to be determinants of levels of induced CYP1A1 activity and that interindividual variation in levels of induced CYP1A1 activity appears to be associated more with regulatory factors than polymorphism in the CYP1A1 gene.

Adult↗
PubMed2000

Relationship of polymorphism in CYP2C9 to genetic susceptibility to diclofenac-induced hepatitis.

The mechanism by which diclofenac-induced hepatotoxicity occurs is unclear, even though covalent modification of proteins by diclofenac metabolites appears to be important in pathogenesis, either by altering protein function or by eliciting an immune response. Adduct formation may be due to metabolism of diclofenac via an alternative pathway rather than via its major 4'-hydroxylation pathway mediated by the cytochrome P450 CYP2C9. We hypothesized that possession of variant CYP2C9 alleles might be a risk factor for diclofenac-induced hepatotoxicity, since the allelic variants CYP2C9*2 and CYP2C9*3 may be associated with impaired metabolism compared to the wild-type (CYP2C9*1). To investigate in more detail the effects of the polymorphisms on diclofenac metabolism in human liver, the kinetics of diclofenac 4-hydroxylation by human liver microsomes of known CYP2C9 >genotype were examined. An overall difference in Vmax and Vmax/Km between samples homozygous for CYP2C9*1 and heterozygous for CYP2C9*2 or CYP2C9*3 was detected (P = 0.044). However, on subgroup analysis, there was no significant difference between samples homozygous for CYP2C9*1 and heterozygous for CYP2C9*2, although there was a borderline difference between the samples homozygous for CYP2C9*1 and those heterozygous for CYP2C9*3 (P = 0.057). The relationship between CYP2C9 genotype and susceptibility to diclofenac-induced hepatotoxicity was further examined by genotyping 24 patients with diclofenac-induced hepatotoxicity together with 100 healthy controls for the CYP2C9*2 and CYP2C9*3 alleles. CYP2C9 genotype frequencies for CYP2C9*2 and CYP2C9*3 were similar in patients and controls. To assess whether diclofenac-induced hepatotoxicity was due to rare CYP2C9 mutations, the upstream sequence (-1 to -1000) and all exons and exon-intron boundaries of CYP2C9 from four subjects who had suffered severe hepatotoxicity was determined. However, no new polymorphisms were detected. We therefore found no evidence that polymorphism in CYP2C9 is a determinant of diclofenac-induced hepatotoxicity.

Adult↗
PubMed2000

Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease.

BACKGROUND: The factors determining why less than 10% of heavy drinkers develop advanced alcoholic liver disease (ALD) remain elusive, although genetic factors may be important. Interleukin 10 (IL-10) is an important cytokine with anti-inflammatory, anti-immune, and antifibrotic functions. Several polymorphisms have been identified in the IL-10 promoter and recent evidence suggests that some of these may have functional effects on IL-10 secretion. AIMS: To test the hypothesis that IL-10 promoter region polymorphisms are associated with susceptibility to ALD. METHODS: The allele frequencies for the two single base pair substitutions at positions -627 (C-->A) and -1117 (A-->G) in the IL-10 promoter were determined in 287 heavy drinkers with biopsy proved advanced ALD, 107 heavy drinkers with no evidence of liver disease or steatosis only on biopsy, and 227 local healthy volunteers. RESULTS: At position -627, 50% of patients with advanced ALD had a least one A allele compared with 33% of controls (p<0.0001) and 34% of drinkers with no or mild disease (p=0.017). At position -1117, the slight excess of the A allele in drinkers with advanced disease was because of linkage disequilibrium between the A alleles at the two sites. CONCLUSIONS: Among heavy drinkers, possession of the A allele at position -627 in the IL-10 promoter is associated with an increased risk of advanced liver disease. This is consistent with recent functional data that the -627*A allele is associated with low IL-10 expression which will favour inflammatory, immune mediated, and profibrotic mechanisms of alcohol related liver injury.

Alleles↗
PubMed1999

Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.

BACKGROUND: The cytochrome P450 CYP2C9 is responsible for the metabolism of S-warfarin. Two known allelic variants CYP2C9*2 and CYP2C9*3 differ from the wild type CYP2C9*1 by a single aminoacid substitution in each case. The allelic variants are associated with impaired hydroxylation of S-warfarin in in-vitro expression systems. We have studied the effect of CYP2C9 polymorphism on the in-vivo warfarin dose requirement. METHODS: Patients with a daily warfarin dose requirement of 1.5 mg or less (low-dose group, n=36), randomly selected patients with a wide range of dose requirements from an anticoagulant clinic in north-east England (clinic control group, n=52), and 100 healthy controls from the community in the same region were studied. Genotyping for the CYP2C9*2 and CYP2C9*3 alleles was done by PCR analysis. Case notes were reviewed to assess the difficulties encountered during the induction of warfarin therapy and bleeding complications in the low-dose and clinic control groups. FINDINGS: The odds ratio for individuals with a low warfarin dose requirement having one or more CYP2C9 variant alleles compared with the normal population was 6.21 (95% CI 2.48-15.6). Patients in the low-dose group were more likely to have difficulties at the time of induction of warfarin therapy (5.97 [2.26-15.82]) and have increased risk of major bleeding complications (rate ratio 3.68 [1.43-9.50]) when compared with randomly selected clinic controls. INTERPRETATION: We have shown that there is a strong association between CYP2C9 variant alleles and low warfarin dose requirement. CYP2C9 genotyping may identify a subgroup of patients who have difficulty at induction of warfarin therapy and are potentially at a higher risk of bleeding complications.

Aged↗
PubMed1999

Tumour necrosis factor-alpha promoter polymorphisms in primary biliary cirrhosis.

BACKGROUND/AIMS: The incidence of primary biliary cirrhosis (PBC) is increased in the close relatives of patients, suggesting that genetic factors play a role in disease susceptibility. Decreased in vitro production of tumour necrosis factor (TNF)-alpha has been reported in PBC patients, suggesting a potential aetiological role for this cytokine. The aim of this study was to examine two biallelic polymorphisms in the promoter region of the TNF-alpha gene, which may play a role in the control of TNF-alpha secretion, as candidate susceptibility loci in PBC. METHODS: The polymorphisms at positions -238 and -308 in the TNF-alpha promoter region were analysed by polymerase chain reaction in 168 unrelated PBC patients and 145 local unrelated, geographically matched normal individuals. All PBC subjects were also genotyped for HLA DR8, a previously identified susceptibility locus in PBC. RESULTS: The -308 TNF1/TNF1 genotype was seen in a similar proportion of PBC patients (66%) and controls (60%). However, this genotype was found significantly more frequently in the 95 PBC patients with more advanced disease (histological stage III/IV) (77%) than in either controls (p<0.01, OR = 2.2 [1.2-4.0]) or the PBC patients with earlier disease (38/73 (52%), p = 0.001 OR 3.1 [1.6-5.9]). Linkage between TNF -308 and HLA DR8 was not seen. No association was found between PBC and the biallelic -238 TNF-alpha polymorphism, either in the whole PBC population or the histological Stage III/IV subgroup. CONCLUSIONS: Our study provides no evidence for involvement of the TNF-alpha -308 or -238 promoter polymorphisms in genetic predisposition to PBC. However, the significantly increased frequency of the -308 TNF1/TNF1 genotype seen in 95 patients with more advanced disease raises the possibility that this allele may be linked to disease progression rather than susceptibility. The finding of different allele frequencies in PBC patients in different disease subgroups emphasises the importance of clinical phenotype/casemix in the design of disease association studies.

Aged↗
PubMed1999

Genetic epidemiology of environmental toxicity and cancer susceptibility: human allelic polymorphisms in drug-metabolizing enzyme genes, their functional importance, and nomenclature issues.

Pharmacogenetics is the study of idiosyncratic drug responses that have an hereditary basis and usually reflect differences in drug-metabolizing enzymes (DMEs) and the receptors that control DME levels. The purpose of this review is to provide a brief overview of recent findings concerning more than a dozen clinically important polymorphisms and to emphasize the need to standardize the nomenclature of these alleles in each polymorphism, as quickly as possible. This nomenclature system should be consistent with the Human Gene Nomenclature Guidelines. Because DMEs have existed before divergence of prokaryotes and eukaryotes more than 2 billion years ago, it is clear that DME genes first must have evolved for critical life functions and that, more recently in animals, DME genes expanded to include the role of detoxification of dietary products, evolving plant metabolites, and, of course, pharmaceutical drugs. Many human DME polymorphisms are relevant to clinical problems in that they represent the basis of risk factors in the development of cancer, toxicity, and other diseases associated with drug, chemical, or dietary exposure. The study of the relationship among human genetic polymorphisms, cancer susceptibility, toxicity, and environmental exposure is a new and exciting area of research--which will undoubtedly have increasingly important implications for risk assessment and the prevention, early diagnosis, and intervention of clinical disease.

Cytochrome P-450 Enzyme System↗
PubMed1999

CYP2D6 is associated with Parkinson's disease but not with dementia with Lewy Bodies or Alzheimer's disease.

The similarities between the clinical and pathological findings of dementia with Lewy Bodies (DLB) with Alzheimer's disease and Parkinson's disease are complex, and their significance for pathogenesis is unresolved. It is likely that DLB shares common disease determinants with both Alzheimer's disease and Parkinson's disease. Clinically DLB shows the presence of dementia similar, though not identical, to that found in Alzheimer's disease. A parkinsonian movement disorder is present in a proportion of DLB cases. Pathologically DLB shows senile plaques, as with Alzheimer's disease, and also substantia nigra neurone loss and Lewy bodies, as with Parkinson's disease. At a genetic level, DLB shows an elevated Apolipoprotein E epsilon4 frequency as described in Alzheimer's disease, but this is absent in Parkinson's disease. An elevated frequency of the CYP2D6*4 allele has been found in Parkinson's disease and we have therefore genotyped a large series of clinically and neuropathologically confirmed cases of DLB, Alzheimer's disease, Parkinson's disease and age-matched control individuals for the CYP2D6*4 allele. Whilst an elevated frequency of the CYP2D6*4 allele was found in Parkinson's disease, no such elevations were found in DLB or Alzheimer's disease. Stratification of the CYP2D6*4 allele with respect to the Apolipoprotein E epsilon4 also did not show any significant associations with the CYP2D6*4 allele. The CYP2D6*4 allele is not a major genetic determinant of DLB and the results place DLB with Alzheimer's disease rather than Parkinson's disease on a genetic level.

Aged↗
PubMed1999

Low frequency of CYP2A6 gene polymorphism as revealed by a one-step polymerase chain reaction method.

Human cytochrome P450 2A6 (CYP2A6) has been shown to metabolically activate carcinogens and mutagens. Genetic polymorphisms for CYP2A6 have been reported previously in different ethnic groups using a two-step polymerase chain reaction (PCR) method to identify CYP2A6*1, CYP2A6*2 and CYP2A6*3. Moreover, a new truncated allele has been recently identified in a Japanese population. We report here a one-step PCR amplification of the CYP2A6 gene from human genomic DNA and the detection of intact CYP2A6 alleles by restriction enzyme digestion. The diagnostic exon (exon 3) of the CYP2A6 gene was amplified from human genomic DNA with a primer pair. The forward primer is unique to the CYP2A6 gene, which eliminates previous problems in amplifying two highly homologous CYP2A genes, CYP2A7 and CYP2A13, in humans. The resulting PCR products (214 bp) were digested with XcmI or DdeI to detect the presence of CYP2A6*2 or CYP2A6*3 alleles, respectively. The allelic frequencies for CYP2A6*2 were 2.3% (n = 320) in the Caucasian and 0.7% (n = 71) in the Chinese populations, respectively. CYP2A6*3 allelic frequency in the Chinese population was 0.7%; while no CYP2A6*3 allele was detected in the Caucasian population. The allelic frequencies are relatively low and the reason for this discrepancy between different methods is discussed.

Aryl Hydrocarbon Hydroxylases↗
PubMed1999

Detailed modelling of caffeine metabolism and examination of the CYP1A2 gene: lack of a polymorphism in CYP1A2 in Caucasians.

The cytochrome P450 CYP1A2 is important in the metabolism of both drugs and procarcinogens such as heterocyclic amines. We aimed to clarify the existence of a phenotypic polymorphism and explore the molecular basis of such a polymorphism. Ninety-two non-smoking individuals underwent caffeine phenotyping. The distribution of the 1,7-dimethylxanthine + 1,7-dimethyluracil/caffeine (17U + 17X/137X) ratio and log-transformed data were determined. Probit plots were constructed and the distribution fitted using maximum likelihood method. The CYP1A2 gene, including upstream regulatory regions, was examined for sequence polymorphisms using the single-strand conformation polymorphism technique in 19 individuals and by complete DNA sequencing in two individuals from the extremes of the distribution. We found a similar range (1.45-18.65) and median (6.7) for the 17U + 17X/137X ratio to that found in previous studies of non-smoking Caucasians and no effect of sex. The 17U + 17X/137X ratio gave a normal distribution when log-transformed. Maximum likelihood analysis showed that the log-normal and bimodal distributions had similar deviances but the log-normal distribution was favoured because it has fewer parameters. There was no evidence for significant DNA sequence differences between fast and slow metabolizers, although some differences from published sequences including a silent polymorhpism in exon 7 which were unlikely to be of functional significance were found. We therefore conclude that CYP1A2 does not show functionally significant polymorphism but that the wide interindividual variation in activity may be due to environmental factors.

Adolescent↗
PubMed1999

The effect of fluconazole on cyclophosphamide metabolism in children.

Fluconazole is increasingly used in children receiving chemotherapy. Many of these patients are being treated with cyclophosphamide, which must undergo hepatic metabolism to produce active alkylating species. As a consequence of the cytochrome P-450 inhibitory properties of fluconazole, a potential interaction exists between these two agents that could influence the therapeutic effect of cyclophosphamide. To investigate this interaction, a retrospective case series of patients was chosen from a population of children with a previously established profile of cyclophosphamide metabolism. Twenty-two children who were not receiving other therapy known to influence drug metabolism were selected and analyzed in terms of fluconazole treatment; of these, nine were receiving fluconazole and thirteen were identified as controls. Study design was not randomized. The plasma clearance of cyclophosphamide was lower in patients receiving fluconazole [mean(SD) 2.4(0.71) versus 4.2(1.2) l/h/m2, p =.001]. In vitro studies were performed to characterize the interaction between fluconazole and cyclophosphamide in six human liver microsomes. The concentration of fluconazole required to reduce the production of 4-hydroxycyclophosphamide to 50% of control values (IC50) varied between 9 and 80 microM (median 38 microM). Further studies of the effect of fluconazole on 4-hydroxycyclophosphamide production in vivo are warranted to determine whether this interaction reduces the therapeutic effect of cyclophosphamide in clinical practice.

Adolescent↗
PubMed1999

Polymorphisms in GSTP1, GSTM1, and GSTT1 and susceptibility to colorectal cancer.

Polymorphisms in glutathione S-transferase (GSTs) may predispose to colorectal cancer through deficient detoxification of environmental carcinogens, although previous results are conflicting. A study with 178 matched case-control pairs was conducted to determine the effect of the GSTT1 and GSTM1 null genotypes and polymorphisms in GSTP1 on colorectal cancer susceptibility. In a secondary analysis, we examined interactions between genotypes and with the N-acetyltransferase 2 (NAT2) genotype. Heterogeneity by age, sex, site, and stage of cancer was also examined. No effect of any genotype for GSTM1, GSTT1, or GSTP1 on colorectal cancer susceptibility was detected. Secondary end points showed that individuals with both the GSTT1 null and NAT2 slow genotypes combined appeared to be at increased risk of colorectal cancer (odds ratio = 2.33; 95% confidence interval, 1.1-5.0). We conclude that GST polymorphisms alone do not predispose to colorectal cancer in northeast England. We also observed possible effects of the GSTT1 null genotype on the age and stage at presentation, and these, together with the findings of an apparent interaction with NAT2 genotypes, need to be confirmed in further studies.

Adult↗
PubMed1998

Recent advances in understanding the molecular basis of polymorphisms in genes encoding cytochrome P450 enzymes.

The cytochrome P450 superfamily is known to exhibit a high degree of genetic polymorphism and polymorphisms associated with absent or low enzyme activity in CYP2D6, CYP2C19 and CYP2C9 are particularly well studied. However, despite early reports of strong disease associations for particular CYP2D6 phenotypes, these have not been confirmed in recent, more detailed studies and it now appears that analysis of CYP2D6, CYP2C19 and CYP2C9 genotype is of most value in predicting metabolism of specific drugs. Polymorphisms in other cytochrome P450 genes are less well studied and appear not to be associated with complete absence of enzyme activity. We have recently carried out studies of polymorphism in both CYP1A1 and CYP2E1. The molecular basis of the apparent CYP1A1 'high inducibility' polymorphism was investigated by studying CYP1A1 and Ah receptor polymorphisms in a group of phenotyped individuals who were genotyped both for known and novel CYP1A1 and Ah receptor polymorphisms. Three novel polymorphisms in CYP1A1 (C(-459)T, G(-469)A and C(4151)T) and one in the Ah receptor (G(1768)A; V(570)I) were detected by single strand conformational polymorphism analysis and DNA sequencing. Among both novel and previously known polymorphisms, only the Ah receptor G(1721)A polymorphism, which has an allele frequency of 0.12 in Caucasians and was detected previously in a Japanese population, was significantly associated with high induced CYP1A1 activity. In the case of CYP2E1, we have detected three polymorphisms in the promoter region (A(-316)G, T(-297)A and G(-35)T) and one in the coding sequence (G(4804)A; V(179)I) by screening Caucasian DNA samples. The significance of these alleles has been investigated but only G(-35)T combined with T(-297)A, which has an allele frequency of 0.05, appears to be of functional significance, with an apparent 1.8-fold increase in levels of transcriptional activity compared with the wild-type.

Animals↗
PubMed1998

Heterozygosity for hereditary hemochromatosis is associated with more fibrosis in chronic hepatitis C.

Hepatic iron has been associated with more aggressive liver disease in chronic viral hepatitis. We evaluated whether the recently described C282Y mutation of the hemochromatosis gene, designated HFE (responsible for at least 83% of hereditary hemochromatosis), was associated with more advanced liver disease in chronic hepatitis C. One hundred thirty-seven patients with biopsy-proven chronic hepatitis C were studied and liver biopsies scored for necroinflammation (grade 0-18) and fibrosis (stage 0-6). Genomic DNA was amplified by polymerase chain reaction and the C282Y mutation identified by restriction with RsaI and electrophoretic separation of restriction fragments. Ten (7.3%) patients had the C282Y mutation. No C282Y homozygous patients were identified. Age, sex distribution, and estimated weekly alcohol consumption were not significantly different between those with and without the mutation. Serum ferritin was higher in the heterozygotes (mean, 339 microg/L) compared with homozygous wild types (153 microg/L; P = .0005). In the majority of patients, liver iron was graded 0 out of 4, but hepatocyte iron staining was more commonly present in heterozygotes compared with homozygous normals (30% compared with 4% [P = .02]). Liver disease was more advanced in those with the mutant allele (mean fibrosis stage: 3.6, compared with wild type: 1.5 [P = .01]). Cirrhosis was found more often in those with the mutation (40%) compared with those without (8.7%) (P = .01; odds ratio: 7.6 [1.9-31.2]). There was no significant difference in inflammation scores between heterozygotes and wild type (mean, 5.4 compared with 4.1). Hepatitis C virus (HCV)-RNA titers were measured by branched DNA assay (HCV RNA 2.0-Chiron), and there was no difference between heterozygous and homozygous normal patients. Thus, despite relatively minor increases in iron stores, individuals who are heterozygous for hemochromatosis appear to develop more fibrosis in chronic hepatitis C. Venesection may be useful therapy in this subgroup.

Adult↗
PubMed1998

Tumour necrosis factor-alpha gene promoter polymorphism and decreased insulin resistance.

Insulin resistance is a feature of non-diabetic relatives of non-insulin-dependent diabetic (NIDDM) families. Tumour necrosis factor-alpha (TNF alpha) expression is linked with insulin resistance, and is under strong genetic control. We examined the relationship between insulin resistance and two polymorphisms of the TNF alpha promoter region (positions -238 and -308). Non-diabetic relatives (n = 123) of NIDDM families and control subjects (n = 126) with no family history of diabetes were studied. Insulin resistance was determined by homeostasis model assessment (HOMA) and short insulin tolerance test (ITT), and genotyping was by restriction digest. The -238 polymorphism (TNFA-A allele) was carried by 14 relatives and 11 control subjects, and all were heterozygotes. To examine the relationship between the -238 polymorphism and insulin resistance independent of potentially confounding factors, the relatives with the TNFA-A allele were individually pair-matched for age, sex, waist-hip ratio, body mass index, and glucose tolerance with relatives homozygous for the wild-type allele. Relatives with the TNFA-A allele had decreased insulin resistance (HOMA index: 2.0, 3.6 +/- 2.1 [means +/- SD of differences], p = 0.03), and this was true for comparable pair-matched control subjects (HOMA index: 1.1, 1.9 +/- 0.8, p = 0.01). Combining relative (n = 7) and control (n = 4) pairs that had undergone an ITT, subjects with the TNFA-A allele had an increased K(ITT) (3.8, 3.0 +/- 1.0%/min, p = 0.04) similarly indicating decreased insulin resistance. There was no significant relationship between the -308 polymorphism and insulin resistance. We conclude that the TNFA-A allele is associated with decreased insulin resistance as assessed by two independent methods, and may protect against the future development of NIDDM in susceptible individuals.

Adult↗