Martin Sarner

Analgesic ingestion and other factors preceding relapse in ulcerative colitis.

To investigate factors which predispose to relapse in patients with ulcerative colitis, we conducted a survey to compare the events occurring in the four weeks preceding the clinic attendance of 62 outpatients in remission with those taking place in the same period before the onset of relapse in 21 patients attending with active disease. The only event which occurred significantly more often in patients who subsequently relapsed was ingestion of paracetamol and other inhibitors of prostaglandin synthesis (76% (16/21) relapse vs 39% (24/62) remission, p less than 0 . 01). Recent upper respiratory tract infection (38% vs 26%) was not significantly more common in patients in relapse than in remission, and emotional stress, atopic events, antibiotic treatment, dietary indiscretions, foreign travel, and gastroenteritis were relatively rare in both groups. The surprisingly high prevalence of analgesic ingestion before relapse itself requires confirmation but does lend indirect support to the theory that colonic mucosal prostaglandin deficiency induces relapse in some patients with ulcerative colitis.

The Causal Element for the Lactase Persistence/ non-persistence Polymorphism is Located in a 1 Mb Region of Linkage Disequilibrium in Europeans

Expression of lactase in the intestine persists into adult life in some people and not others, and this is due to a cis‐acting regulatory polymorphism. Previous data indicated that a mutation leading to lactase persistence had occurred on the background of a 60 kb 11‐site LCT haplotype known as A ( Hollox et al. 2001 ). Recent studies reported a 100% correlation of lactase persistence with the presence of the T allele at a CT SNP at −14 kb from LCT, in individuals of Finnish origin, suggesting that this SNP may be causal of the lactase persistence polymorphism, and also reported a very tight association with a second SNP (GA –22 kb) ( Enattah et al. 2002 ). Here we report the existence of a one megabase stretch of linkage disequilibrium in the region of LCT and show that the –14 kb T allele and the –22 kb A allele both occur on the background of a very extended A haplotype. In a series of Finnish individuals we found a strong correlation (40/41 people) with lactose digestion and the presence of the T allele. The T allele was present in all 36 lactase persistent individuals from the UK (phenotyped by enzyme assay) studied, 31/36 of whom were of Northern European ancestry, but not in 11 non‐persistent individuals who were mainly of non‐UK ancestry. However, the CT heterozygotes did not show intermediate lactase enzyme activity, unlike those previously phenotyped by determining allelic transcript expression. Furthermore the one lactase persistent homozygote identified by having equally high expression of A and B haplotype transcripts, was heterozygous for CT at the −14 kb site. SNP analysis across the 1 megabase region in this person showed no evidence of recombination on either chromosome between the –14 kb SNP and LCT. The combined data shows that although the –14 kb CT SNP is an excellent candidate for the cause of the lactase persistence polymorphism, linkage disequilibrium extends far beyond the region searched so far. In addition, the CT SNP does not, on its own, explain all the variation in expression of LCT, suggesting the possibility of genetic heterogeneity.

INDIUM-111 TAGGED LEUCOCYTES IN THE DIAGNOSIS OF INFLAMMATORY BOWEL DISEASE

The distribution of autologous leucocytes labelled with the gamma-ray emitting radioisotope indium-111 was studied in 25 patients with inflammatory bowel disease, 15 with Crohns disease, and 10 with ulcerative colitis. In all instances the bowel lesion was identified. Radioactivity rapidly accumulated in the lesions over the first 2 h and then passed into the lumen of the bowel within the next 48 h, being redistributed from the liver and spleen. Normally, about 1% of the radioactivity passes into the stools in the 48 h after injection whereas approximately 20% of the administered radioactivity was found in the stools of the patients with inflammatory bowel disease. This noninvasive technique can show the extent of disease in patients too ill for conventional procedures. It can display abscesses and other lesions, and can be performed in outpatients.

Lactase haplotype frequencies in Caucasians: association with the lactase persistence/non-persistence polymorphism.

A genetic polymorphism is responsible for determining that some humans express lactase at high levels throughout their lives and are thus lactose tolerant, while others lose lactase expression during childhood and are lactose intolerant. We have previously shown that this polymorphism is controlled by an element or elements which act in cis to the lactase gene. We have also reported that 7 polymorphisms in the lactase gene are highly associated and lead to only 3 common haplotypes (A, B and C) in individuals of European extraction. Here we report the frequencies of these polymorphisms in Caucasians from north and south Europe and also from the Indian sub‐continent, and show that the alleles differ in frequency, the B and C haplotypes being much more common in southern Europe and India. Allelic association studies with lactase persistence and non‐persistence phenotypes show suggestive evidence of association of lactase persistence with certain alleles. This association was rather more clear in the analysis of small families, where haplotypes could be determined. Furthermore haplotype and RNA transcript analysis of 11 unrelated lactase persistent individuals shows that the persistence (highly expressed) allele is almost always on the A haplotype background. Non‐persistence is found on a variety of haplotypes including A. Thus it appears that lactase persistence arose more recently than the DNA marker polymorphisms used here to define the main Caucasian haplotypes, possibly as a single mutation on the A haplotype background. The high frequency of the A haplotype in northern Europeans is consistent with the high frequency of lactase persistence.

Studies on the expression of intestinal lactase in different individuals.

Sixty one duodenal biopsy specimens were examined for the expression of lactase at the level of enzyme activity, protein, and messenger RNA. Of the 51 samples with normal villous architecture, 39 were lactase persistent, 11 were nonpersistent (adult type hypolactasia), and one was of indeterminate status. All the lactase persistent individuals showed high mRNA and a high level of the lactase protein as detected by sodium dodecyl sulphate polyacrylamide gel electrophoresis. All the 11 non-persistent individuals tested showed a low level of lactase protein. Nine of the 10 samples tested showed low mRNA and one high mRNA. These results suggest that the lactase persistence polymorphism is controlled at the level of the expression of the lactase gene, though there may be some heterogeneity of the lactase non-persistence phenotype.

Lactase haplotype frequencies in Caucasians: Association with the lactase persistence/non-persistence polymorphism

A genetic polymorphism is responsible for determining that some humans express lactase at high levels throughout their lives and are thus lactose tolerant, while others lose lactase expression during childhood and are lactose intolerant. We have previously shown that this polymorphism is controlled by an element or elements which act in cis to the lactase gene. We have also reported that 7 polymorphisms in the lactase gene are highly associated and lead to only 3 common haplotypes (A, B and C) in individuals of European extraction. Here we report the frequencies of these polymorphisms in Caucasians from north and south Europe and also from the Indian sub-continent, and show that the alleles differ in frequency, the B and C haplotypes being much more common in southern Europe and India. Allelic association studies with lactase persistence and non-persistence phenotypes show suggestive evidence of association of lactase persistence with certain alleles. This association was rather more clear in the analysis of small families, where haplotypes could be determined. Furthermore haplotype and RNA transcript analysis of 11 unrelated lactase persistent individuals shows that the persistence (highly expressed) allele is almost always on the A haplotype background. Non-persistence is found on a variety of haplotypes including A. Thus it appears that lactase persistence arose more recently than the DNA marker polymorphisms used here to define the main Caucasian haplotypes, possibly as a single mutation on the A haplotype background. The high frequency of the A haplotype in northern Europeans is consistent with the high frequency of lactase persistence.