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Biomedical subjects

S C Bain

Publications and source records attributed to S C Bain.

At least 37 records · Page 2Linked to original sources
PubMed1998

Glomerular filtration rate determination in diabetic patients using iohexol clearance--comparison of single and multiple plasma sampling methods.

Use of iohexol clearance has been described as the gold standard for the measurement of glomerular filtration rate (GFR). It is suggested that multiple plasma sampling following iohexol injection is required to accurately determine GFR by area under plasma clearance curve. The aim of this study was to determine whether single plasma sampling 4 h after injection of iohexol could accurately determine GFR in diabetic patients with mild to moderate renal failure, compared to multiple plasma sampling. A total of 120 GFR determinations in 36 patients with non-insulin dependent diabetic renal disease were done over 1 year. No acute deterioration was seen in renal function following injection of contrast in any patient. Strong correlation in GFR measurement was observed between the multiple plasma sampling method and the single plasma sampling method (r2 = 0.975). Single plasma sampling 4 h after bolus injection of iohexol is a safe and accurate method of determining GFR and change in GFR in diabetic subjects with mild to moderate renal impairment.

Diabetes Mellitus, Type 2↗
PubMed1998

A search for type 1 diabetes susceptibility genes in families from the United Kingdom.

Genetic analysis of a mouse model of major histocompatability complex (MHC)-associated autoimmune type 1 (insulin-dependent) diabetes mellitus (IDDM) has shown that the disease is caused by a combination of a major effect at the MHC and at least ten other susceptibility loci elsewhere in the genome. A genome-wide scan of 93 affected sibpair families (ASP) from the UK (UK93) indicated a similar genetic basis for human type 1 diabetes, with the major genetic component at the MHC locus (IDDM1) explaining 34% of the familial clustering of the disease (lambda(s)=2.5; refs 3,4). In the present report, we have analysed a further 263 multiplex families from the same population (UK263) to provide a total UK data set of 356 ASP families (UK356). Only four regions of the genome outside IDDM1/MHC, which was still the only major locus detected, were not excluded at lambda(s)=3 and lod=-2, of which two showed evidence of linkage: chromosome 10p13-p11 (maximum lod score (MLS)=4.7, P=3x10(-6), lambda(s)=1.56) and chromosome 16q22-16q24 (MLS=3.4, P=6.5x10(-5), lambda(s)=1.6). These and other novel regions, including chromosome 14q12-q21 and chromosome 19p13-19q13, could potentially harbour disease loci but confirmation and fine mapping cannot be pursued effectively using conventional linkage analysis. Instead, more powerful linkage disequilibrium-based and haplotype mapping approaches must be used; such data is already emerging for several type 1 diabetes loci detected initially by linkage.

Adolescent↗
PubMed1998

A male-female bias in type 1 diabetes and linkage to chromosome Xp in MHC HLA-DR3-positive patients.

It is generally assumed that the male:female (M:F) ratio in patients with type 1 (insulin-dependent) diabetes mellitus (IDDM) is 1. A recent survey, however, revealed that high incidence countries (mainly European) have a high M:F ratio and low incidence ones (Asian and African) have a low M:F ratio. We have now analysed the M:F ratio according to genotype at the major locus, the major histocompatibility complex (MHC; IDDM1). There are two main IDDM1 susceptibility haplotypes, HLA-DR3 and -DR4, which are present in 95% of Caucasian cases. We report here that in medium/high incidence Caucasian populations from the United States of America, United Kingdom and Sardinia (1307 cases), the bias in male incidence is largely restricted to the DR3/X category of patients (X not = DR4) with a M:F ratio of 1.7 (P=9.3x10(-7)), compared with a ratio of 1.0 in the DR4/Y category (Y;DR3). This is additional evidence for significant heterogeneity between the aetiology of 'DR4-associated' and 'DR3-associated' diabetes. We analysed linkage of type 1 diabetes to chromosome X, and as expected, most of the linkage to Xp13-p11 was in the DR3/X affected sibpair families (n=97; peak multipoint MLS at DXS1068=3.5, P=2.7x10(-4); single point MLS=4.5, P=2.7x10(-5)). This is evidence for aetiological heterogeneity at the IDDM1/MHC locus and, therefore, in the search for non-MHC loci in type 1 diabetes, conditioning of linkage data by HLA type is advised.

Adolescent↗
PubMed1998

Fine mapping of the diabetes-susceptibility locus, IDDM4, on chromosome 11q13.

Genomewide linkage studies of type 1 diabetes (or insulin-dependent diabetes mellitus [IDDM]) indicate that several unlinked susceptibility loci can explain the clustering of the disease in families. One such locus has been mapped to chromosome 11q13 (IDDM4). In the present report we have analyzed 707 affected sib pairs, obtaining a peak multipoint maximum LOD score (MLS) of 2.7 (lambda(s)=1.09) with linkage (MLS>=0.7) extending over a 15-cM region. The problem is, therefore, to fine map the locus to permit structural analysis of positional candidate genes. In a two-stage approach, we first scanned the 15-cM linked region for increased or decreased transmission, from heterozygous parents to affected siblings in 340 families, of the three most common alleles of each of 12 microsatellite loci. One of the 36 alleles showed decreased transmission (50% expected, 45.1% observed [P=.02, corrected P=.72]) at marker D11S1917. Analysis of an additional 1,702 families provided further support for negative transmission (48%) of D11S1917 allele 3 to affected offspring and positive transmission (55%) to unaffected siblings (test of heterogeneity P=3x10-4, corrected P=. 01]). A second polymorphic marker, H0570polyA, was isolated from a cosmid clone containing D11S1917, and genotyping of 2,042 families revealed strong linkage disequilibrium between the two markers (15 kb apart), with a specific haplotype, D11S1917*03-H0570polyA*02, showing decreased transmission (46.4%) to affected offspring and increased transmission (56.6%) to unaffected siblings (test of heterogeneity P=1.5x10-6, corrected P=4.3x10-4). These results not only provide sufficient justification for analysis of the gene content of the D11S1917 region for positional candidates but also show that, in the mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is of value and that both predisposing and nonpredisposing alleles should be anticipated.

Chromosome Mapping↗
PubMed1998

Transmission of haplotypes of microsatellite markers rather than single marker alleles in the mapping of a putative type 1 diabetes susceptibility gene (IDDM6).

Allelic association methods based on increased transmission of marker alleles will have to be employed for the mapping of complex disease susceptibility genes. However, because the extent of association of single marker alleles with disease is a function of the relative frequency of the allele on disease-associated chromosomes versus non disease-predisposing chromosomes, the most associated marker allele in a region will not necessarily be closest to the disease locus. To overcome this problem we describe a haplotype-based approach developed for mapping of the putative type 1 diabetes susceptibility gene IDDM6. Ten microsatellite markers spanning a 550 kb segment of chromosome 18q21 in the putative IDDM6 region were genotyped in 1708 type 1 diabetic Caucasian families from seven countries. The most likely ancestral diabetogenic chromosome was reconstructed in a stepwise fashion by analysing linkage disequilibrium between a previously defined haplotype of three adjacent markers and the next marker along the chromosome. A plot of transmission from heterozygous parents to affected offspring of single marker alleles present on the ancestral chromosome versus the physical distance between them, was compared with a plot of transmission of haplotypes of groups of three adjacent markers. Analysing transmission of haplotypes largely negated apparent decreases in transmission of single marker alleles. Peak support for association of the D18S487 region with IDDM6 is P = 0.0002 (corrected P = 0.01). The results also demonstrate the utility of polymorphic microsatellite markers to trace and delineate extended and presumably ancient haplotypes in the analysis of common disease and in the search for identical-by-descent chromosome regions that carry an aetiological variant.

Child↗
PubMed1997

Lack of association of angiotensin II type 1 receptor gene polymorphism with diabetic nephropathy in insulin-dependent diabetes mellitus.

Several observations suggest that inherited factors are influential in the development of nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). Genetic components of the renin angiotensin system are possible candidate genes. The aim of this study was to determine the role of the hypertension associated angiotensin II type 1 receptor (AT1R) gene A1166C polymorphism in susceptibility to nephropathy in IDDM. We examined 264 Caucasoid patients with IDDM and overt nephropathy (as defined by persistent proteinuria in the absence of other causes, hypertension and retinopathy), 136 IDDM patients with long duration of diabetes and no nephropathy (LDNN group), 200 recently diagnosed IDDM patients (Sporadic Diabetic group), and 212 non-diabetic subjects. The AT1R gene polymorphism was assessed using the polymerase chain reaction and restriction isotyping. Genotype frequencies did not differ significantly between the sporadic diabetic group and the nephropathy group (p = 0.245), nor between the long duration non-nephropathy group and the nephropathy group (p = 0.250). Allele frequencies were not significantly different between the three groups (p = 0.753). We conclude that there is no significant association between the hypertension associated AT1R gene polymorphism and diabetic nephropathy in patients with IDDM in the UK.

Adolescent↗
PubMed1997

The mitochondrial tRNA[Leu(UUR)] A to G 3243 mutation is associated with insulin-dependent and non-insulin-dependent diabetes in a Chinese population.

The mitochondrial DNA tRNA[Leu(UUR)] A to G 3243 mutation is associated with maternally inherited diabetes in Caucasians and Japanese. In a Hong Kong Chinese population we have detected the 3243 mutation in 2 of 74 unrelated subjects with well characterized insulin-dependent (Type 1) diabetes mellitus (IDDM) and 2 of 75 unrelated subjects with young onset (<35 years) non-insulin-dependent diabetes (NIDDM). The 3243 mutation has only previously been associated with IDDM in Japanese. Racial differences in association of the mitochondrial 3243 mutation with IDDM suggest the influence of other genes that may increase its diabetogenic pathogenicity in Oriental races. We also found a significant excess of maternal inheritance of diabetes in the young onset NIDDM cohort, with a ratio of diabetic mothers to fathers of 2.4:1, p < 0.005. The 3243 mutation, however, only accounts for a small proportion of the observed excess maternal inheritance, and further study is needed to search for other diabetes associated mitochondrial DNA mutations.

Adolescent↗
PubMed1997

A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised bylan early age of onset (< 25 years) and an autosomal dominant mode of inheritance. MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3]. A nonsense mutation in the HNF-4 alpha gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at theta = 0) for mutations in the coding region of the HNF-4 alpha gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4 alpha gene.

Base Sequence↗
PubMed1997

Insulin VNTR allele-specific effect in type 1 diabetes depends on identity of untransmitted paternal allele. The IMDIAB Group.

The IDDM2 type 1 diabetes susceptibility locus was mapped to and identified as allelic variation at the insulin gene (INS) VNTR regulatory polymorphism. In Caucasians, INS VNTR alleles divide into two discrete size classes. Class I alleles (26 to 63 repeats) predispose in a recessive way to type 1 diabetes, while class III alleles (140 to more than 200 repeats) are dominantly protective. The protective effect may be explained by higher levels of class III VNTR-associated INS mRNA in thymus such that elevated levels of preproinsulin protein enhance immune tolerance to preproinsulin, a key autoantigen in type 1 diabetes pathogenesis. The mode of action of IDDM2 is complicated, however, by parent-of-origin effects and possible allelic heterogeneity within the two defined allele classes. We have now analysed transmission of specific VNTR alleles in 1,316 families and demonstrate that a particular class I allele does not predispose to disease when paternally inherited, suggestive of polymorphic imprinting. But this paternal effect is observed only when the father's untransmitted allele is a class III. This allelic interaction is reminiscent of epigenetic phenomena observed in plants (for example, paramutation; ref. 17) and in yeast (for example, trans-inactivation; ref. 18). If untransmitted chromosomes can have functional effects on the biological properties of transmitted chromosomes, the implications for human genetics and disease are potentially considerable.

Alleles↗
PubMed1997

ApoE genotype and Alzheimer's disease in adults with Down syndrome: meta-analysis.

The apoE gene polymorphism was examined in 100 adults with Down syndrome (with and without dementia) compared to 346 control subjects without mental retardation. Meta-analysis of available data (480 subjects) revealed that apolipoprotein E genotype distribution for people with Down syndrome was similar to that of the nonretarded population. Although no significant association between possession of the apoE epsilon 4 allele and onset of Alzheimer's disease was found, subjects with the allele had a tendency towards lower age of onset of dementia. Subjects with apoE epsilon 2 allele may not develop dementia and may have increased longevity.

Adult↗
PubMed1997

Mutations in the hepatocyte nuclear factor-1alpha gene are a common cause of maturity-onset diabetes of the young in the U.K.

Mutations in the hepatocyte nuclear factor-1alpha (HNF1alpha) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the coding region of the HNF-1alpha gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missense mutations (P129T, R131W, R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with early onset (<40 years of age) NIDDM showed the mutation in two additional families. This common mutation was present on at least three different haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that mutations in the HNF-1alpha gene are a common cause of MODY in U.K. families and result in early onset NIDDM with a progressive clinical course. Mutation-based genetic counseling can now be considered for the majority of patients with MODY.

Adolescent↗
PubMed1996

IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus.

IDDM2-encoded predisposition to type 1 diabetes has recently been mapped to the minisatellite or variable number of tandem repeat (VNTR) locus upstream of the insulin and insulin-like growth factor II genes on human chromosome 11p15.5. In a UK case-control study (n = 228 sporadic diabetics; n = 441 healthy controls), we show here that the genotype homozygous for VNTR class I alleles is predisposing to disease (RR = 2.68), and VNTR class III alleles are dominantly protective (RR = 0.37). In 722 diabetic families from the UK (n = 356), USA (n = 173), Denmark (n = 55) and Sardinia (n = 138), we have analysed the transmission of class I alleles to diabetic offspring from class I/III heterozygous parents. We confirm that in families from the USA, class I alleles are transmitted preferentially from fathers. However, in family data sets from the UK, Denmark and Sardinia, the reverse is true and maternal transmission is stronger. Furthermore, in the UK family data set, the difference between maternal and paternal transmissions is significant (P < 0.05). It is therefore unlikely that 'maternal imprinting' alone explains the parent-of-origin effects in IDDM2-encoded predisposition to type 1 diabetes, at least not in the UK. There is a relationship between VNTR class (allele length) and insulin gene expression, though some results from different studies are conflicting. In the human adult cadaveric pancreas, we confirm our preliminary results that class III alleles are associated with lower levels of insulin mRNA in vivo. Similar results have been obtained independently in human foetal pancreas samples. It is difficult to explain how these marginally lower levels of insulin expression could account for the observed VNTR class III-encoded protective effect. Perhaps the site of action of IDDM2, mediated by VNTR allelic variation, is not the pancreas but some other organ such as the thymus.

Adolescent↗
PubMed1996

Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM.

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.

Adult↗
PubMed1996

Saturation multipoint linkage mapping of chromosome 6q in type 1 diabetes.

Linkage analysis of type 1 diabetes sib pair families (n = 334) has suggested two separate regions of human chromosome 6q are linked to disease (designated IDDM5 and IDDM8). To test if these are false positive results, all available sib pair families (n = 429) were typed using a 92% informative map of chromosome 6q and multipoint analysis. The two regions still showed positive evidence of linkage, most notably the proterminal region, 6q27, corresponding to IDDM8 (MLS = 2.57, p = 0.0006; lambda s = 1.17). In addition, some evidence of transmission disequilibrium was seen with marker a046xa9 (IDDM5).

Chromosome Mapping↗