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.

Correlation between the immune responses to collagens type I, III, IV and V and Klebsiella pneumoniae in patients with Crohn's disease and ankylosing spondylitis.

BACKGROUND: Increased levels of collagen types I, III and V are found in strictures of patients with Crohn's disease (CD) compared with normal gut tissue. Type IV collagen is present in the basement membranes, basal lamina, retina and cornea. Elevated levels of antibody to Klebsiella pneumoniae are found in both active CD and active ankylosing spondylitis (AS) patients compared with healthy controls. METHODS: Reactivities for immunoglobulin class-specific antibodies (IgM, IgG and IgA) against collagen types I, III, IV, V and whole K. pneumoniae were measured by ELISA in nine patients with early CD and 10 with late CD from King's College Hospital and 12 late CD patients and 36 HLA-B27-positive AS patients from Middlesex Hospital and was compared with values for 26 healthy controls from the Blood Transfusion Service in London. RESULTS: Levels of class-specific IgM, IgG and IgA antibodies to collagen types I, III, IV, V and K. pneumoniae were significantly elevated in early and late CD patients compared with healthy controls (P<0.001). Levels of IgM, IgG antibody to the four collagen types and K. pneumoniae were also significantly elevated (P<0.001) in AS patients compared with healthy controls. In addition, the level of IgA antibody to K. pneumoniae was elevated in AS patients (P<0.001). Furthermore, a positive correlation between antibody levels to collagen types I, III, IV and K. pneumoniae was demonstrated in both early and late CD patients and in those with AS, whilst a positive correlation to type V was found in early CD. CONCLUSION: The role of K. pneumoniae and anti-collagen antibodies in the aetiopathogenesis of CD and AS requires further study.

Fibrosing colonopathy in an adult owing to over use of pancreatic enzyme supplements.

A woman, then in her late 20s, underwent a cholecystectomy in 1962 for gallstone disease and subsequent common bile duct stones were managed endoscopically. However, because of unrelenting pain, a pylorus preserving pancreaticoduodenectomy was done in 1990 and in the following years the patient took large amounts of pancreatic enzyme supplements. She developed large bowel obstruction in 1997 and a right hemicolectomy was undertaken. Histology confirmed fibrosing colonopathy of the ascending colon and caecum. Her pancreatic enzyme dose was reduced and her subsequent course has been uncomplicated.

Relatives' expressed emotion and the course of inflammatory bowel disease.

Thirty-one relatives of inflammatory bowel disease (IBD) patients referred to a specialist unit were assessed with the Camberwell Family Interview, and ratings of expressed emotion (EE) were made. These relatives were significantly less critical than relatives of psychiatric patients in previous studies (p<0.001). Outcome was assessed over a 12-month follow-up period by a clinician blinded to the EE ratings. Most patients in this study had a poor outcome, and 11 (38%) needed surgery. A significantly higher proportion of patients with low EE relatives were in the surgery outcome group (p = 0.02). Excluding the surgery group, there was a nonsignificant trend for patients with high EE relatives to have a worse outcome. Patterns of response suggested better tolerance by relatives of the more ill patients. In the group overall there was no relationship between psychiatric status and physical health, either initially or at follow-up. There was considerable agreement among relatives as to the "typical" IBD personality. A number of key findings concerning the IBD patient, patterns of relatives' EE, and how they relate to the course of the illness remain to be verified by more systematic assessment.

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.

The lactase persistence/non-persistence polymorphism is controlled by a cis-acting element.

Lactase activity is present at high levels in the small intestine of some human adults and not others. This is due to a genetically determined polymorphism which affects the developmental regulation of the expression of the lactase gene. This polymorphism is of considerable interest in relation to cultural differences in nutrition but despite exhaustive studies, the molecular basis has not yet been found. It has not even been shown whether the sequence differences reside within or adjacent to the lactase gene itself or in a trans-acting factor. We have therefore exploited known DNA 'marker' polymorphisms within the exons of the lactase gene to examine the expression of the individual lactase mRNA transcripts from persistent and non-persistent individuals in order to determine whether the regulation is in cis or trans. Our results show that in certain lactase persistent individuals one allele of the lactase gene is expressed at much lower levels than the other and these individuals tend to have intermediate lactase activities. It is proposed that these people are heterozygous for the lactase persistence and non-persistence alleles and that this means that the nucleotide substitutions responsible for the lactase persistence/non-persistence polymorphism are cis-acting. This narrows down considerably the area of the genome that needs to be searched for the relevant sequence differences.

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.

Classification of pancreatitis.

An international group of doctors interested in pancreatic disease met in Cambridge in March 1983, under the auspices of the Pancreatic Society of Great Britain and Ireland, to discuss the classification of pancreatitis in the light of developments that have taken place in the 20 years since the crucial conference in Marseille.

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 diagnosis of Ménétrier's disease.

Two cases of Ménétrier's disease are reported to illustrate the clinical presentation and diagnosis of this unusual condition. The literature has been reviewed of all the reported cases to establish the relative importance of the individual symptomatology, the value of the diagnostic methods, and to highlight the diagnostic pitfalls. Recognition of the barium meal appearances and snare biopsy at gastroscopy may avoid the necessity of diagnostic laparotomy.