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Biomedical subjects

D A Savage

Publications and source records attributed to D A Savage.

At least 19 recordsLinked to original sources
PubMed2002

The IL12B 3' untranslated region DNA polymorphism is not associated with early-onset type 1 diabetes.

A recent study employing Australian and UK type 1 diabetes families has demonstrated significant transmission bias to affected offspring of a polymorphism (1188A allele; termed allele 1) in the 3' untranslated region (3'UTR) of the interleukin 12B (IL12B) gene which encodes the IL-12p40 subunit of the pro-inflammatory cytokine IL-12. However, results from replication studies in other populations have been controversial. We performed both case-control (n=120 cases; n=330 controls) and family-based (n=307 families) association studies, using the transmission disequilibrium test, to investigate if allele 1 is associated with early-onset type 1 diabetes in Northern Ireland. No association was observed between allele 1 and type 1 diabetes in either case-control (80.8% vs 80.8%; P=0.98) or family-based (49.7% transmissions; P=0.94) studies. Our results do not support earlier reports of an association between allele 1 in the 3'UTR of the IL12B gene and type 1 diabetes.

3' Untranslated Regions↗
PubMed2001

Possible association between CTLA4 DNA polymorphisms and early onset type 1 diabetes in a UK population.

Linkage and association has been reported between CTLA4 DNA markers and susceptibility to type 1 diabetes in some populations, but not others. We performed case-control and family-based association studies to assess if the CTLA4 A49G and intron 1 C/T polymorphisms were associated with development of early onset type 1 diabetes in the Northern Ireland population. The distribution of A49G and C/T alleles in cases (n = 144) was similar to those observed in controls (n = 307). In contrast, significant distortions in allele transmissions from informative parents to probands were observed for both the A49G (P = 0.02) and C/T (P = 0.01) polymorphisms employing 297 nuclear families. Our results suggest that the CTLA4 gene may play a minor role in the overall genetic predisposition to type 1 diabetes in this UK population.

Abatacept↗
PubMed2001

Analysis of the association between diabetic nephropathy and polymorphisms in the aldose reductase gene in Type 1 and Type 2 diabetes mellitus.

AIMS: To investigate the association between polymorphisms of the aldose reductase gene and diabetic nephropathy in both Type 1 and Type 2 diabetes mellitus, and to carry out a meta-analysis of published results. METHODS: We have investigated the role of two aldose reductase polymorphisms in four independent cohorts of cases and controls (two each with Type 1 and Type 2 diabetes) drawn from two ethnic populations, including 471 patients with nephropathy and 494 control diabetic patients without nephropathy. A C/T transition at position -106, and a (CA)n microsatellite marker 2.1 kb from the start site of the aldose reductase gene were genotyped in nephropathic patients and non-nephropathic controls from each cohort. RESULTS: Carriage of the -106 T allele was significantly associated with diabetic nephropathy in three of the four study groups. The Mantel-Haenszel combined odds ratio was 2.22 (95% CI 1.69, 2.94), P = 1.05 x 10(-8). We found no evidence for association of the microsatellite marker with nephropathy, despite moderate levels of disequilibrium between the two markers. Meta-analysis of published data yielded no evidence for association of the microsatellite marker with diabetic nephropathy in Type 2 diabetes, but varying degrees of association with diabetic nephropathy in Type 1 diabetes. CONCLUSIONS: Meta-analyses provide more convincing evidence of a role for the ALR2-106 marker than for the microsatellite marker in diabetic nephropathy (DN). More studies are now required to confirm these results and to establish whether the ALR2-106 polymorphism has a functional role in DN.

Adolescent↗
PubMed2000

Association of serum AACT levels and AACT signal polymorphism with late-onset Alzheimer's disease in Northern Ireland.

alpha1-antichymotrypsin (AACT) is a serine protease inhibitor that has been associated with amyloid plaques in the brains of patients with Alzheimer's disease (AD). It has been reported that AACT serum levels are higher in AD patients than in age and sex matched controls. In addition, polymorphisms in the signal peptide and 5' of the AACT gene have been reported to increase the risk of developing AD. Serum AACT has also been suggested to be associated with cognitive decline in elderly subjects. Our objective was to investigate whether a relationship existed between serum AACT levels, AACT genotypes and risk for AD in a case control association study using 108 clinically well defined late onset AD cases and 108 age and sex matched controls from Northern Ireland. We also wished to determine whether higher serum AACT affected levels of cognition as had been previously reported. Serum AACT levels were found to be significantly raised in cases compared to controls (t=3.8, df=209, p<0.001). However, we detected no relationship between serum AACT levels and cognitive decline. We report allelic association of the AACT signal polymorphism with AD (chi(2)=3.70, df=1, p=0.04) but we failed to show any correlation between AACT serum levels and genotype.

Age Factors↗
PubMed2000

HLA class II typing of whole genome amplified mouth swab DNA.

Postal collection of mouth swabs provides a cheap and convenient means of DNA sampling but hitherto has not provided sufficient genetic material for HLA typing by polymerase chain reaction using sequence-specific primers (PCR-SSP). This study examined the feasibility of collecting mouth swabs from a test population by post, amplifying the DNA by whole genome amplification and genotyping for selected HLA class II alleles. We optimised a strategy for whole genome amplification or primer extension preamplification using a random 15 base pair primer which resulted in a 1,000-fold increase in DNA template. The amplified DNA was of sufficient quality for analysis of selected HLA Class II alleles by PCR-SSP and PCR using sequence-specific oligonucleotide probes. To test the reliability of our data, blood DNA from 30 individuals in 10 families, previously tested for all DRB1 alleles in a routine diagnostic laboratory, was then tested in our laboratory for DRB1 *03 and *04 following whole genome amplification. Further whole genome amplified product from another 10 families was tested for DRB1 *03, *04 in our laboratory and then tested for all DRB1 alleles in a routine diagnostic laboratory. One repeat typing was required to achieve 100% concordance between laboratories. Amplification of whole genome amplified DNA by PCR-SSP was then extended successfully to low-resolution HLA DRB1, DQA1, DQB1 and DPB1 typing. Mouth swab collection by post, followed by whole genome amplification of DNA provides an effective strategy for genetic analysis of large cohorts. We have optimised conditions for HLA class II typing on whole genome amplified DNA collected by mouth swab, but this method could potentially be applied to low concentrations of DNA from other sources.

Adult↗
PubMed2000

Is there an association between angiotensin-converting enzyme gene variants and chronic nonproductive cough?

BACKGROUND: It is unclear why some patients develop a chronic nonproductive cough. Angiotensin-converting enzyme (ACE) inactivates tussive peptides in the airways such as bradykinin and tachykinins. An insertion/deletion polymorphism in the ACE gene accounts for variation in ACE levels, and patients with the II genotype have lowest serum ACE levels compared with ID and DD genotypes. We hypothesized that the II genotype would be associated with increased risk of developing a chronic cough. MATERIALS AND METHODS: We recruited 47 patients (33 women), referred for evaluation of cough (median cough duration, 24 months; range, 2 to 240 months). Cough patients were evaluated using a comprehensive diagnostic protocol, and cough reflex sensitivity was measured using a capsaicin inhalation challenge. ACE genotyping was performed on DNA samples from patients using the polymerase chain reaction followed by agarose gel electrophoresis. ACE genotypes in patients with chronic cough were compared with those in 199 healthy control subjects. Serum ACE levels were determined using a colorimetric assay. RESULTS: Genotype frequencies for the ACE gene were similar between patients and control subjects. There was no correlation between capsaicin sensitivity and ACE genotypes or serum ACE levels. CONCLUSION: Susceptibility to develop chronic cough is not associated with ACE genotype.

Adolescent↗
PubMed1999

Risk of Alzheimer's disease is associated with a very low-density lipoprotein receptor genotype in Northern Ireland.

The epsilon-4 allele of apolipoprotein E (APOE) is associated with increased risk of Alzheimer's disease (AD), but the pathogenic mechanism is unknown. The 5-repeat allele of a CGG repeat polymorphism in the 5' untranslated region of the very low-density lipoprotein receptor (VLDL-R) gene, a receptor for apoE, has been found to be associated with increased risk of AD in a Japanese population. Other groups have been unable to replicate this in American Caucasian populations. A case-control study utilizing a clinically well-defined group of late-onset AD patients (n = 108) and age- and sex-matched control subjects (n = 108) from Northern Ireland was performed to test this association in a relatively homogeneous population. The 9,9 genotype of the VLDL-R was found to be significantly increased in patients compared to controls (P = 0.003; Pcorr = 0.035), leading to an increased risk of AD to subjects with this genotype (OR = 3.9; 95% CI, 1.52-11.25). In contrast to results from the Japanese study, the 5-repeat allele was found to be significantly reduced in the patient group when compared to controls (P = 0.008; Pcorr = 0.047). The results from this study suggest that individuals who have the 9,9 genotype of the VLDL-R gene are at increased risk of AD in Northern Ireland.

Aged↗
PubMed1999

Paraoxonase polymorphisms are not associated with cardiovascular risk in renal transplant recipients.

BACKGROUND: Paraoxonase (PON1) gene variants have been identified as risk factors for cardiovascular disease (CVD). There are two common PON1 polymorphisms at position 55 (Leu-Met change) and 192 (Gln-Arg change) of the amino acid chain. Leucine at position 55 and arginine at position 192 have been associated with increased cardiovascular risk. The increased prevalence of CVD in renal transplant recipients can be only partly explained by the increased prevalence of conventional risk factors. METHODS: We therefore investigated PON1 polymorphisms in renal transplant recipients (N = 491) with (N = 103) and without CVD (N = 388) using polymerase chain reaction-restriction fragment length analysis. PON1 polymorphisms and their associated PON1/arylesterase activities were also assessed in a subgroup of patients (N = 165). RESULTS: The genotype distribution and allele frequencies for both polymorphisms were similar in both groups. The frequencies for LL, LM, and MM genotypes for the 55 position in patients with CVD were 0.39, 0.51, and 0.10, respectively, compared with 0.43, 0.43, and 0.14 in patients without CVD (P = 0.31). The distribution for the QQ, QR, and RR genotypes at the 192 position were 0.48, 0.43, and 0.09, respectively, in patients with CVD compared with 0.46, 0.46, and 0.08 in patients without CVD (P = 0.8). There were highly significant differences in serum activities of PON1/arylesterase between genotypes defined by 55 and 192 polymorphisms. Leucine at position 55 and arginine at position 192 were associated with higher activities. CONCLUSION: These data indicate that there is no association between the PON1 gene variants, conferring higher enzyme activity, and the increased cardiovascular risk in renal transplant recipients.

Adult↗
PubMed1999

Risk of developing diabetic nephropathy is not associated with synergism between the angiotensin II (type 1) receptor C1166 allele and poor glycaemic control.

BACKGROUND: It has recently been reported that the risk of developing nephropathy in patients with insulin dependent (type 1) diabetes mellitus is strongly associated with synergism between poor glycaemic control and carriage of the hypertension associated angiotensin II (type 1) receptor C1166 allele. The same report also revealed an increase in risk of nephropathy in diabetic patients carrying a specific angiotensin II (type 1) receptor haplotype, i.e. C1166/140-bp microsatellite allele (major allele). METHODS: In order to replicate these findings we performed PCR-based genotyping for the A1166-->C DNA polymorphism and the CA repeat at the 3' end of the angiotensin II (type 1) receptor gene employing validated groups of type 1 diabetic patients with (cases, n = 95) and without (controls, n = 97) nephropathy. HbA1 values above the median (10.5) were used as an index of poor glycaemic control. RESULTS: The risk of nephropathy in carriers of the C1166 allele with HbA1 > 10.5 was 2.1 (95% CI 0.8-5.2) compared to 1.1 (95% CI 0.4-2.6) for non-carriers of the C1166 allele; however, these odds ratios were not significantly different. No difference in the frequency of the high-risk haplotype was found in cases compared to controls (12.4 vs 11.5%; chi2=0.0, P=0.938 with 1 df). CONCLUSIONS: The results of this study do not support previous findings that the risk of diabetic nephropathy is associated with synergism between poor glycaemic control and carriage of the C1166 allele or inheritance of the C1166/major microsatellite haplotype.

Adult↗
PubMed1998

An interluekin 1B allele, which correlates with a high secretor phenotype, is associated with diabetic nephropathy.

Induction of interleukin 1 activates vascular endothelial and kidney mesangial cells, and increases production of type IV (basement membrane) collagen. Hence, genes within the interleukin 1 gene cluster are potential candidates in the pathogenesis of diabetic nephropathy. In a previously validated case-control study from Northern Ireland, consisting of 95 patients with insulin-dependent (type 1) diabetes and nephropathy (cases) and 96 patients with insulin-dependent (type 1) diabetes without nephropathy (controls), the authors performed PCR-based genotyping of specific DNA polymorphisms within the interleukin 1A, interleukin 1B, interleukin 1 (type 1) receptor and interleukin 1 receptor antagonist genes. The groups were matched for age at onset and duration of diabetes. A statistically significant increase was found in the allele frequency of the interleukin 1B*2 allele in cases compared to controls (chi2=7. 19, df.=1; P=0.007, Pcorr=0.028). The results of this study suggest that the interleukin 1B*2 allele, or a susceptibility factor in linkage disequilibrium with this allele, is associated with diabetic nephropathy in the Northern Ireland population.

Alleles↗
PubMed1996

A rapid HLA-DRB1*04 subtyping method using PCR and DNA heteroduplex generators.

We describe here a rapid polymerase chain reaction (PCR)-based method for the identification of HLA-DRB1*0401-*0412 alleles. The method is based on the generation of specific DNA heteroduplex patterns between PCR products derived from selective group-specific amplification of the various DRB1*04 alleles and PCR products derived from two synthetic DNA heteroduplex generator (DHG) molecules following non-denaturing polyacrylamide minigel electrophoresis. One DHG was designed to detect DRB1*0401, *0405, *0407, *0408, and *0409 alleles, whilst the other was designed to detect DRB1*0402, *0403, *0404, *0406, *0410, *0411, and *0412 alleles. Characteristic heteroduplex patterns were obtained for all DRB1*04 alleles tested both in homozygous and heterozygous situations. Both DHG and PCR-SSP (sequence-specific primer) typing were performed on 41 DRB1*04 positive DNAs from Singaporean Chinese blood donors and complete concordance in results was obtained. HLA-DRB1*0403, *0405, and *0406 were found to account for 95% of the DRB1*04 alleles in the population studied. The DHG technique described is technically simple and rapid since it essentially involves only two PCR amplifications per individual subtyping. The technique is particularly useful for resolving DRB1*04 combinations which are indistinguishable by PCR-SSO (sequence-specific oligonucleotide) or PCR-SSP subtyping.

Alleles↗
PubMed1995

Detection of beta-thalassaemia mutations using DNA heteroduplex generator molecules.

In this report we describe a rapid polymerase chain reaction (PCR) based method for the detection of beta-thalassaemia (beta-thal) mutations. This method is based on the visualization of unique DNA heteroduplex banding patterns, following non-denaturing polyacrylamide gel electrophoresis, resulting from hybridization between mutant PCR products and synthetic DNA heteroduplex generator molecules. Using the Singaporean population, which consists of Chinese, Malay and Asian Indian ethnic groups, as a model, we have constructed and evaluated three DNA heteroduplex generator molecules for the detection of the common beta-thalassaemia mutations found in this population. The results show that these three molecules are capable of detecting approximately 95% of the mutations found in the Singaporean population. We propose that this technology may be applied as an alternative screening strategy for beta-thalassaemia mutations because it is technically simple, flexible, cost-effective, and requires only minimal laboratory resources.

Base Sequence↗
PubMed1995

HLA-DRB1*01 subtyping by heteroduplex analysis.

In this report we describe an alternative method for the identification of the four known HLA-DRB1*01 alleles, which is based on the generation of unique heteroduplex patterns between the different DRB*01 alleles and a synthetic DNA heteroduplex generator (DHG) molecule. The method is technically simple, rapid and cost-effective, as it essentially involves only a single polymerase chain reaction (PCR) followed by polyacrylamide gel electrophoresis. This technique allows the rapid discrimination of the various known HLA-DRB1*01 subtypes, both in homozygous and heterozygous situations. We propose that this technology can potentially be applied to most HLA class I and class II subtyping.

Alleles↗
PubMed1994

TAP1 and TAP2 polymorphism in multiple sclerosis patients.

The frequency of TAP1 and TAP2 gene polymorphisms in MS patients was compared with that of a normal population. A significant increase in TAP2-379-VAL homozygosity and TAP2-565-ALA homozygosity was found in HLA-DRB1*1501-DQB1*0602-negative patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗