Help
Subscribe


All of GastroHep is now free access! - Click here to register Read For FREE - Our full range of review articles
GastroHep.com - the global online resource for all aspects of gastroenterology, hepatology and endoscopy
GastroHep.com - the global online resource for all aspects of gastroenterology, hepatology and endoscopy Profile of Guido Tytgat Profile of Pete Peterson Profile of Peter Cotton Profile of Roy Pounder

Home

News
Journals
Review Articles
Slide Atlas
Video Clips
Online Books
Advanced Digestive Endoscopy
Classical Cases
Conference Diary
PubMed
International GH Links
USA GH Links
National GH Links
National GI Societies
Other Useful Links




Emails on Gastroenterology and Hepatology
the National AIDS Treatment Advocacy Project
Visit the gastroenterology section of the EUMS

Personal View

GastroenterologyEsophagus

Barrett's esophagus

Click a heading in the right-hand column to see the selected articles in that subject area

See any comments for this Personal View

S. Rajendra, C Mohan and R Ackroyd Barrett's oesophagus - ulcerative colitis, sarcoidosis, Indian ethnicity and the HLA-7 1 ancestral haplotype: shared immunogenetics?
S. Rajendra, C Mohan and R Ackroyd, 27 November 2006

Abstract

In South-East Asia and Britain, a predilection for Indian ethnicity has been reported in several studies relating to Barrett's oesophagus and/or gastro-oesophageal reflux disease (GERD), ulcerative colitis and sarcoidosis.

Moreover, the risk of ulcerative colitis, reflux disease and sarcoidosis is highest in monozygotic twins. Interestingly, a common Human Leucocyte Antigen i.e. HLA-B*07 and/or a common ancestral haplotype, i.e. 7.1 AH (A*03, B*07 and DRB1*15) association has been reported in all three diseases, which are thought to be due to a complex interplay of immunogenetic and environmental factors.

A racial predilection and the HLA-7 [1]. ancestral haplotype as a potential common denominator lead us to speculate that these diseases may have a common aetiology.

Furthermore, familial clustering is well documented in all three diseases, which may reflect a genetic influence and/or a common environment and lifestyle. Studies and case reports documenting the coexistence of at least two of these disorders within the same patients lend further credence to an association between them.

Nevertheless, despite the interesting and intriguing data presented here, much more evidence is required by way of epidemiological, linkage, genetic association, immunogenetic and animal studies to explore the potential link (if any) between these three inflammatory conditions. Understanding the aetiology of any one of these diseases may in turn explain the pathogenesis of the others.

Indian ethnicity

Independent studies on GERD and Barrett's oesophagus [1-4], ulcerative colitis (UC) [5-7] and sarcoidosis [8-9] in multiethnic Asian patient populations in Malaysia and Singapore have revealed a striking common denominator, i.e. an over-representation of Indian (South Asian) ethnicity. This predilection for Indians is even more striking when one considers that they make up less than 8% of the multiracial populations of these South-East Asian nations [10,11] though they account for 45% of patients diagnosed with Barrett's oesophagus [1] 18-35% of those with ulcerative colitis [5-7] and 50-70% of reported cases of sarcoidosis. [8,9]. In Britain, a recent community study revealed that South Asian origin was a risk factor for gastro-oesophageal reflux disease (GERD) [12]. Nevertheless, Indian ethnicity has not been shown to be a risk factor for Barrett's oesophagus (a complication of GERD) in British patients [13]. In the Malaysian patient population, we have demonstrated that Helicobacter pylori infection and gastric corpus atrophy is highest in Indians, which somewhat ameliorates the risk for developing Barrett's oesophagus (Rajendra et al., manuscript submitted).

We speculate that this may also apply to British Asian individuals with GERD. Interestingly, Montgomery et al. reported that South Asians born in Britain had a significantly higher risk of developing inflammatory bowel disease (IBD) than the indigenous European population [14]. The authors postulated that this may reflect a greater genetic predisposition to IBD that is uncovered by exposure to environmental factors. In Britain, sarcoidosis has been found to be more common, more severe and more extensive in both Blacks and Asians when compared with Caucasians [15].

A comparative study of sarcoidosis in South Africa between 1969 and 1975 revealed that the minimum incidence was 23.2/100,000 in Blacks, 11.6/100,000 in Asians and 3.7/100,000 in Whites [16]. Racial differences in disease frequency suggest a genetic causal factor, though social, cultural and environmental factors could equally account for the observed differences.

HLA

The HLA system located on chromosome 6 is the most polymorphic region in the human genome. It contains 224 genes, many of which encode proteins essential for antigen presentation and processing. The HLA complex is also an excellent marker for population genetic analyses and disease association studies. The highly polymorphic genes located in the Major Histocompatibility Complex (MHC) are inherited en bloc in haplotypes. Haplotypes which are alleles found at different loci on a chromosome are maintained by linkage disequilibrium (LD). Some of these DNA segments occur frequently in the population and have been conserved over time as extended [17] or ancestral haplotypes [18] which can be traced to a common ancestor. Equally intriguing and strongly suggestive of a genetic basis for Barrett's oesophagus, ulcerative colitis and sarcoidosis is the fact that a common Human Leucocyte Antigen, i.e. HLA-B*07 and/or a common ancestral haplotype (7.1 AH) association has been reported in all three diseases.

Immunogenetics of Barrett's oesophagus

Chronic gastro-oesophageal reflux (GERD) predisposes to Barrett's oesophagus, which is a precursor lesion for oesophageal adenocarcinoma [19]. It has been hypothesized that Barrett's metaplasia develops as an adaptive epithelium in response to chronic damage by gastro-oesophageal refluxate [20]. The immune profiles that characterize the varied phenotypic responses to GERD [21] in response to a common antigenic stimulus may be important in modulating disease. Tumour cells often express new antigens as a result of the multiple genetic alterations that are associated with cell transformation [22] and immune recognition of these neo-antigens is a key event in the history of a cancer [23]. Host cytotoxic (CTL) and helper T (TH) cells can potentially recognize these neo-antigens presented by human leucocyte antigen (HLA) Class I or II molecules, respectively [24].

We recently reported that the inheritance of the HLA B7 gene incurs an increased risk for Barrett's oesophagus in South Asians (predominantly South Indians) but not Orientals (Malays and Chinese) [25], though it must be stressed that these results are only preliminary given the small number of patients studied.

In addition, the HLA B07 positive patients with Barrett's oesophagus had a significantly greater family history of heartburn, compared to their HLA-B07 negative counterparts, indicating that this genetic component could possibly be associated with particular disease manifestations of GERD. Racial differences in reflux disease, [1-4] familial aggregations of GERD symptoms/Barrett's oesophagus [26-29] and twin studies [30,31] lead us to speculate that there may well be one or more GERD genes. One of these key genes for the development of GERD could be the HLA-B07 allele or other gene(s) tightly linked to this allele.

HLA molecules perform a crucial function in the regulation of the immune response. The observed association with major histocompatibility complex (MHC) class I genes may reflect linkage disequilibrium to other MHC or non-MHC genes or may reflect a role for MHC class I molecules in disease pathogenesis. [25]. Malignant transformation of cells is frequently associated with altered HLA class I expression and/or function. These abnormalities provide tumour cells with escape routes from immune recognition. Class I molecules are also important to fight some viral and bacterial infections, although no infective aetiology has yet been implicated in the pathogenesis of Barrett's oesophagus. Recently, we investigated MHC expression in patients with Barrett's oesophagus and in controls with a healthy oesophagus and no reflux symptoms. [32]. It was found that HLA class I expression was downregulated and class II upregulated in Barrett's oesophagus. As these changes predate malignant transformation, we believe that this altered MHC expression might be an essential step in disease progression, possibly by facilitating evasion from immune surveillance [32].

Ulcerative colitis and HLA associations

Ulcerative colitis is a chronic inflammatory mucosal disease of the colon, which is thought to be due to a complex interplay of immunogenetic and environmental factors. In this regard, Barrett's metaplasia, which arises in a background of reflux-induced chronic inflammation and ulceration, bears some similarity to that seen in inflammatory bowel disease [33]. Furthermore, both conditions predispose to malignancy at a rate of approximately 0.4% per annum which is reduced by chemoprevention with non-steroidal anti-inflammatory drugs. [34,35]. As with reflux disease, risk of ulcerative colitis is highest in identical twins [36], suggesting that genetic factors may be involved in pathogenesis. In addition, familial association is well documented, [37-39], though this may indicate a common environment and lifestyle rather than a genetic influence. A number of susceptibility loci for inflammatory bowel disease have been identified on chromosomes 2,3,6, 7,12,14,16, and 19 [40-42]. Linkage and association studies reveal that the HLA complex (on chromosome 6) is important in conferring genetic susceptibility to ulcerative colitis [43]. Many of the described associations are specific to particular ethnic groups implying linkage disequilibrium (LD) with other polymorphisms in the HLA region [44]. The most widely replicated associations are those between HLA-DRB1*0103 [45-49] DRB1*1501 and DRB1*1502 and extensive disease. [45,46,50,51].

Interestingly, HLA-B*07 is in linkage disequilibrium with DRB1*15 as part of the ancestral haplotype (7.1 AH i.e. HLA-A3, B7, DR15). Not surprisingly, a Spanish group has reported that the HLA-B*07 allele was over-represented in distal UC [52], reinforcing the emerging notion that HLA might have a greater role in modifying IBD phenotype than in overall disease susceptibility. In this study, all patients carrying the B7 allele also had the MICA-A5.1 gene. Both these genes are in linkage disequilibrium with HLA-DR15 in Caucasians as part of the extended haplotype EH7.1 (DR15/MICA5.1/B7) and thus explain the associations previously described [45,53,54]. Moreover, the HLA-DRB1*0103 allele, which is a susceptibility locus for UC, has been reported to be associated with MICA-A5 in the same populations. Relatively recently, a central MHC gene (HLA class III) susceptibility locus has been reported [51]. The inhibitor of KB-like gene (IKBL) + 738 C has been linked to extensive and more severe colitis in Spanish but not British patients [45, 51].

In Caucasians, the IKBL + 738C gene is found predominantly in haplotypes carrying the DRB1*1501 and HLA B7 alleles (7.1 AH).55 A very recent study from Spain has found that the allelic combination DRB1*0103/D6S273-5/BAT_2-8/TNFa11b4c1d3e3/IKBL+738(C)/MICA5.1 that includes the telomeric class III markers of the 7.1 ancestral haplotype is very significantly increased in patients with UC compared to controls [56].

Mapping studies suggest that the MICA and MICB genes (two of seven members of the MIC gene family whose genomic structure is similar to HLA class I genes) located 53.4 kb and 141.2 kb centromeric from the HLA-B locus may be additional genes implicated in the development of UC. These genes are expressed on the gastrointestinal epithelium [57], and encode proteins that bind to NKG2D, which is expressed on NK cells, CDa▀ T cells, ?dT cells and macrophages [58, 59]. The MICA gene is in tight linkage disequilibrium with the human leucocyte antigen-B (HLA-B). In fact, MICA*5.1 has been associated with peripheral arthropathy in Caucasian patients with UC [60], though this was not replicated in a subsequent study by the same group [44]. MICA*6 has been linked with UC in Japanese [61, 62], though a German group were unable to replicate these findings in their UC population [63]. It is unclear how HLA genes exert their influence in IBD.

It has been postulated that HLA molecules bind peptides which may be derived from bacteria, thus stimulating inflammatory responses. In addition, molecular mimicry might exist between a bacterial peptide presented on a specific HLA allele and a gut antigen, thus stimulating T cells and consequent gut inflammation. It has been suggested that this process is facilitated by the increased expression of HLA class II molecules in UC [64].

Immunopathology of sarcoidosis

Sarcoidosis is a multisystem disease of unknown aetiology that is characterized pathologically by the presence of non-caseating granulomas [65], not dissimilar to Crohn's disease. It has immunopathological features of being antigen-driven and Th-1 cell-dependent [66]. As in Barrett's oesophagus and ulcerative colitis, hereditary susceptibility to sarcoidosis is suggested by familial clustering [67, 68], ethnic differences [69], reports of sarcoidosis in monozygotic twins [70-74] and substantial HLA gene contributions [75-77]. Both HLA Class I (HLA-B8 and B7) and II (HLA-DR5,- DR8 and -DR9 in Japanese, -DR5 in Germans and HLA-DRB1*15 in Scandinavians) alleles have been strongly associated with sarcoidosis [66]. Amongst the class I alleles, HLA-B7 and HLA-B8 are the most frequently linked to disease [66]. Grunewald et al. from Sweden recently reported that HLA-B*07 independently increased the risk for persistent sarcoidosis as well as for resolving disease.78 HLA-DRB1*15 was associated with persistent disease, which confirmed their previous findings [79]. The ancestral haplotype of A*03, B*07 and DRB1*15 was very strongly associated with persistent disease, i.e. this combination was found in 25% of patients with sarcoidosis as opposed to 7% of healthy subjects. HLA-B*07 and HLA-B*08 may predispose to early events in inflammation and granuloma formation [78]. Both these alleles may also influence the inflammatory response through presentation of distinct antigen peptides.

Sarcoidosis may also be a disease involving immune reactions against self- structures which are modulated by HLA class I alleles. As in ulcerative colitis, molecular mimicry might exist between viral peptides presented on various class I alleles and self antigens, thus generating T cell clones and consequent tissue inflammation [78, 80]. Another mechanism may involve class I derived peptides that influence both the selection of the T cell repertoire and the capacity to generate specific immune responses [81]. Also, exogenous antigens can be presented by HLA class I molecules [82], incriminating CD8+ T cells in the pathogenesis of sarcoidosis. Finally, it has also been suggested that the ancestral haplotype A*03, B*07 and DRB1*15 might be linked to other immunomodulatory genes which could influence and modulate inflammation [78].

Coexistence of at least two disorders

Studies and case reports documenting the coexistence of at least two of these disorders within the same patients lend further credence to an association between the diseases. Thus, it has been reported that patients with active UC had a higher prevalence of reflux compared with controls (60% v 17%, P < 0.001) [83]. In a series of 680 patients with ulcerative colitis, pulmonary or extra-pulmonary sarcoidosis was present in eight [84]. Three of the patients had the HLA B8 DR3 phenotype. The authors concluded that patients with ulcerative colitis who possess this HLA phenotype may possibly be more susceptible to developing sarcoidosis. Several case reports documenting the co-existence of ulcerative colitis and sarcoidosis have also been published [85-88]. Interestingly, sarcoidosis presenting with the macroscopic appearance of Barrett's oesophagus has also been described [89].

Conclusion

Currently, there is no data on HLA B7 allele association with ulcerative colitis or sarcoidosis in Indians. Nevertheless, we speculate that this allele may be robust across racial boundaries (i.e. Caucasian and South Asian) for the following reasons. HLA-B7 is one of the most frequently found HLA-B specificities in American Caucasians (allele frequency 0.142) and, European Caucasians (0.136) as well as North and South Indians (0.076 and 0.192 respectively) [90]. Furthermore, phylogenetic tree and correspondence analysis on HLA-B and HLA-C allele frequencies indicate that the Indians share a strong European lineage [91, 92]. Not surprisingly, Risch et al. categorize Caucasians and Indians together as a major world (continental) racial grouping; the others being Africans, Pacific Islanders, Asians and Native Americans [93].

In summary, therefore, we have described three inflammatory conditions with some uncanny similarities in immunogenetics. A strong genetic basis, the predilection for Indians and the HLA-7.1 ancestral haplotype or sub-loci within this allele as a potential common denominator lead us to speculate that these diseases may share a common aetiology and pathogenesis. In view of the limited evidence provided here, higher resolution genetic analyses, linkage and genetic association investigations as well as epidemiological and randomized case-control studies are required to ascertain the potential link (if any) between these three inflammatory conditions. Furthermore, patho-physiology and animal studies might also help. Unravelling the pathogenesis of any one of these diseases may in turn illuminate our understanding of the aetiology of the others.

We declare no conflicts of interest.

References

1 Rajendra S, Kutty K, Karim N. Ethnic differences in the prevalence of endoscopic oesophagitis and Barrett's oesophagus: the long and short of it all. Dig Dis Sci, 2004 (49), 237-42. PubMed CrossRef

2 Rajendra S, Alahuddin S. Racial differences in the prevalence of heartburn. Aliment Pharmacol Ther, 2004 (19), 375-6. PubMed CrossRef

3 Rosaida MS, Goh KL. Gastroesophageal reflux disease, reflux oesophagitis and non-erosive reflux disease in a multiracial Asian population: a prospective, endoscopy based study. Eur J Gastroenterol Hepatol, 2004 (16), 495-501. PubMed CrossRef

4 Ho KY, Kang JY, Seow A. Prevalence of gastrointestinal symptoms in a multiracial Asian population, with particular reference to reflux-type symptoms. Am J Gastroenterol 1998, 93, 1816-22. PubMed CrossRef

5 Thein-Htut Kudva MV. Ulcerative colitis in Malaysians: a review of 23 patients. Sing Med J 1989, 30, 385-7.

6 Teh LB, Koh D, Ng HS et al. Ulcerative colitis in Singapore: a clinical study of sixty-one patients. Ann Acad Med Singapore 1987, 16, 480-7. PubMed

7 Ling KL, Ooi CJ, Luman W, Cheong WK, Choen FS, Ng HS. Clinical characteristics of ulcerative colitis in Singapore, a multiracial city state. J Clin Gastroenterol, 2002 (35), 144-8. PubMed CrossRef

8 Liam CK, Menon A. Sarcoidosis: a review of cases seen at the University Hospital, Kuala Lumpur. Sing Med J 1993, 34, 153-6.

9 Chong WS, Tan HH, Tan SH. Cutaneous sarcoidosis in Asians: a report of 25 patients from Singapore. Clin Exp Dermatol, 2005 (30), 120-4. PubMed

10 Shaari AR. Population distribution and basic demographic characteristics. In: The 2000 Population and Housing Census of Malaysia. Putrajaya: Department of Statistics; 2000.

11 Chief Statistician. Key indicators of Resident Population by Ethnic Group. In: Census 2000 Singapore Department of Statistics. Singapore: 2000.

12 Mohammed I, Nightingale P, Trudgill NJ. Risk factors for gastro-oesophageal reflux disease symptoms: a community study. Aliment Pharmacol Ther, 2005 (21), 821-7. PubMed CrossRef

13 Ford AC, Forman D, Reynolds PD, Cooper BT, Moayyedi P. Ethnicity, gender and socioeconomic status as risk factors for esophagitis and Barrett's esophagus. Am J Epidemiol, 2005 (162), 454-60. PubMed CrossRef

14 Montgomery SM, Morris DL, Pounder RE, Wakefield AJ. Asian ethnic origin and the risk of inflammatory bowel disease. Eur J Gastroenterol Hepatol 1999, 11, 543-6. PubMed CrossRef

15 Edmondstone WM, Wilson AG. Sarcoidosis in Caucasians, Blacks and Asians in London. Br J Dis Chest 1985, 79, 27-36. PubMed CrossRef

16 Benatar SR & . Sarcoidosis in South Africa. A comparative study in Whites, Blacks and Coloureds. S Afr Med J 1977, 52, 602-6. PubMed

17 Egea GE, Yunis I, Spies T et al. Association of polymorphisms in the HLA-B region with extended haplotypes. Immunogenetics 1991, 33, 4-11. PubMed CrossRef

18 Dawkins RL, Christiansen FT, Kay PH et al. Disease associations with complotypes, supratypes and haplotypes. Immunol Rev 1983, 70, 1-22. PubMed CrossRef

19 Hameeteman W, Tytgat GNJ, Houthoff HJ, Van Den Tweel JG. Barrett's esophagus: Development of dysplasia and adenocarcinoma. Gastroenterology 1989, 96, 1249-56. PubMed

20 Jankowski J. Gene expression in Barrett's mucosa: acute and chronic adaptive responses in the oesophagus. Gut 1993, 34, 1649-50. PubMed

21 Fitzgerald RC, Onwuegbusi BA, Bajaj-Elliott M et al. Diversity in the oesophageal phenotypic response to gastro-oesophageal reflux: immunological determinants. Gut, 2002 (50), 451-9. PubMed CrossRef

22 Little AM, Stern PL, Does HLA type predispose some individuals to cancer? Mol Med Today 1999, 5, 337-42. PubMed CrossRef

23 Scanlan MJ, Chen YT, Williamson B et al. Characterization of human colon cancer antigens recognized by autologous antibodies. Int J Cancer 1998, 76, 652-8. PubMed CrossRef

Join the debate! Click here to post your comments about this Personal View Speech.

24 Townsend A, Ohlen C, Bastin J, Ljunggren HG, Foster L, Karre K. Association of class I major histocompatibility heavy and light chains induced by viral peptides. Nature 1989, 340, 443-8. PubMed CrossRef

25 Rajendra S, Ackroyd R, Murad S, et al. HLA, determinants of susceptibility to Barrett's oesophagus in Asians: a preliminary report. Aliment Pharmacol Ther, 2005, 21: 1377-83.

26 Trudgill NJ, Kapur KC, Riley SA. Familial clustering of reflux symptoms. Am J Gastroenterol 1999, 94, 1172-8. PubMed

27 Chak A, Lee T, Kinnard MF et al. Familial aggregation of Barrett's oesophagus, oesophageal adenocarcinoma, and oesophagogastric junctional adenocarcinoma in Caucasian adults. Gut, 2002 (51), 323-8. PubMed

28 Romero Y, Cameron AJ, Locke GR et al. Familial aggregation of gastroesophageal reflux in patients with Barrett's esophagus and esophageal adenocarcinoma. Gastroenterology. 1997 (113), 1449-56. PubMed CrossRef

29 Crabb DW, Berk MA, Hall TR et al. Familial gastroesophageal reflux and development of Barrett's esophagus. Ann Intern Med 1985, 103, 52-4. PubMed

30 Cameron AJ, Lagergren J, Henriksson C et al. Gastroesophageal reflux disease in monozygotic and dizygotic twins. Gastroenterology, 2001 (122), 55-9.

31 Mohammed I, Cherkas LF, Riley SA et al. Genetic influences in gastro-oesophageal reflux disease: a twin study. Gut, 2003 (52), 1085-9. PubMed CrossRef

32 Rajendra S, Ackroyd R, Karim N, Mohan C, Ho JJ, Kutty MK. Loss of HLA class I and gain of class II expression are early events in carcinogenesis-clues from a study of Barrett's oesophagus. J Clin Pathol, 2006 (59), 952-7. PubMed CrossRef

33 Mason RJ, Bremner CG. Gastritis in Barrett's oesophagus. World J Surg 1995 (19), 96-101. PubMed CrossRef

34 Velayos FS, Terdiman JP, Walsh JM., Effect of, 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and meta-analysis of observational studies. Am, J, Gastroenterol 2005; 100: 1345-6. CrossRef

35 Corley DA, Kerlikowske K, Verma R, Buffler P. Protective association of aspirin/NSAID's and oesophageal cancer: a systematic review and meta-analysis. Gastroenterology, 2003 (124), 47-56. PubMed

36 Halfvarson J, Bodin L, Tysk C et al. Inflammatory bowel disease in a Swedish twin cohort: a long-term follow-up of concordance and clinical characteristics. Gastroenterology, 2003 (124): 1767- 73.

37 Mathew CG, Lewis CM. Genetics of inflammatory bowel disease: progress and prospects. Hum Mol Genet, 2004, 13: R161-8.

38 Halme L, Turunen U, Helio T et al. Familial and sporadic inflammatory bowel disease: comparison of clinical features and serological markers in a genetically homogeneous population. Scand J Gastroenterol, 2002 (37), 692-8. PubMed

39 Peeters M, Cortot A, Vermiere S et al. Colombel JF. Familial and sporadic inflammatory bowel disease: different entities? Inflamm Bowel Dis. 2000 (6), 314-20. PubMed

40 Barmada MM, Brant SR, Nicolae DL et al. A genome scan in 260 inflammatory bowel disease-affected relative pairs. Inflamm Bowel Dis, 2004 (10), 513-20.

41 Van Heel DA, Fischer SA, Kirby A et al. Inflammatory bowel disease susceptibility loci defined by genome scan meta-analysis of 1952 affected relative pairs. Hum Mol Genet, 2004 (13), 763-70. PubMed CrossRef

42 Brant SR, Shugart YY. Inflammatory bowel disease gene hunting by linkage analysis: rationale, methodology and present status of the field. Inflamm Bowel Dis, 2004 (10), 300-11. PubMed

43 Ahmad T, Satsangi J, McGovern D, Bunce M, Jewell D. The genetics of inflammatory bowel disease. Aliment Pharmacol Ther, 2001 (15), 731-48. PubMed CrossRef

44 Ahmad T, Marshall SE, Mulcahy-Hawes K et al. High resolution MIC genotyping: Design and application to the investigation of inflammatory bowel disease susceptibility. Tissue Antigens, 2002 (60), 164-79. PubMed CrossRef

45 Ahmad T, Armuzzi A, Neville M et al. The contribution of human leucocyte antigen complex genes to disease phenotype in ulcerative colitis. Tissue Antigens, 2003 (62), 527-35. PubMed CrossRef

46 Trachtenberg EA, Yang H, Hayes E et al. HLA class II haplotype associations with inflammatory bowel disease in Jewish (Ashkenazi) and non-Jewish Caucasian populations. Hum Immunol 2000 (61), 326-33. PubMed CrossRef

47 Satsangi J, Welsh KI, Bunce M et al. Contribution of genes of the major histocompatibility complex to susceptibility and disease phenotype in inflammatory bowel disease. Lancet 1996, 347, 1212-7. PubMed CrossRef

48 Roussomoustakaki M, Satsangi J, Welsh K et al. Genetic markers may predict disease behaviour in patients with ulcerative colitis. Gastroenterology 1997, 112, 1845-53. PubMed CrossRef

49 de la Concha EG, Fernandez-Arquero M, Lopez-Nava G et al. Susceptibility to severe ulcerative colitis is associated with polymorphism in the central MHC gene IKBL. Gastroenterology 2000, 119, 1491-5. PubMed CrossRef

50 Toyoda H, Wang SJ, Yang HY et al. Distinct associations of HLA class II genes with inflammatory bowel disease. Gastroenterology 1993, 104, 741-8. PubMed

51 de la Concha EG, Fernandez-Arquero M, Santa Cruz S et al. Positive and negative associations of distinct HLA-DR2 subtypes with ulcerative colitis (UC). Clin Exp Immunol 1997, 108, 392-5. PubMed CrossRef

52 Fdez-Morera JL, Rodrigo L, Lopez-Vazquez A. MHC class I chain-related gene A transmembrane polymorphism modulates the extension of ulcerative colitis. Hum Immunol, 2003 (64), 816-22. PubMed CrossRef

53 Futami S, Aoyama N, Honsako Y et al. HLA-DRB1*1502 allele, subtype of DR15, is associated with susceptibility to ulcerative colitis and its progression. Dig Dis Sci 1995 (40), 814-8. PubMed CrossRef

54 Yamamoto-Furusho JK, Uscanga LF, Vargas-Alarcon G et al. Clinical and genetic heterogeneity in Mexican patients with ulcerative colitis. Hum Immunol, 2003 (64), 119-23. PubMed CrossRef

55 Allcock RJ, Christiansen FT, Price P. The central MHC gene IKBL carries a structural polymorphism that is associated with HLA-A3,B7,DR15. Immunogenetics 1994 (49), 660-5.

56 Fernandez L, Nunez C, Mendoza JL et al. A recombined haplotype in the major histocompatibility region contains a cluster of genes conferring high susceptibility to ulcerative colitis in the Spanish population. Inflamm Bowel Dis, 2005 (11), 785-91. PubMed CrossRef

57 Groh V, Bahram S, Bauer S, Herman A, Beauchamp M, Spies T. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium. Proc Natl Acad Sci USA 1996 (93), 12445-50. PubMed CrossRef

58 Diefenbach A, Jamieson AM, Liu SD et al. Ligands for the murine NKG2D receptor: expression by tumour cells and activation of NK cells and macrophages. Nature Immunol 2000, 1, 119-26. CrossRef

59 Bauer S, Groh V, Wu J et al. Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA. Science 1999, 285, 727-9. PubMed

60 Orchard TR, Dhar A, Simmons JD, Vaughan R, Welsh KI, Jewell DP MHC, class I chain-like gene A (MICA) and its associations with inflammatory bowel disease and peripheral arthropathy. Clin Exp Immunol, 2001 (126), 437-40. PubMed CrossRef

61 Sugimura K, Ota M, Mtsuzawa J et al. A close relationship of triplet repeat polymorphism in MHC class I chain-related gene A (MICA) to the disease susceptibility and behaviour in ulcerative colitis. Tissue Antigens, 2001 (57), 9-14. PubMed CrossRef

62 Seki S, Sugimura K, Ota M et al. Stratification of MICA triplet repeat polymorphisms and HLA antigens associated with ulcerative colitis in Japanese. Tissue Antigens, 2001 (58), 71-6. PubMed CrossRef

63 Glas J, Martin K, Brunnler G et al. MICA, MICB and C1-4-1 polymorhism in Crohn's disease and ulcerative colitis. Tissue Antigens, 2001 (58), 243-9. PubMed CrossRef

64 Yap LM, Ahmad T, Jewell DP. The contribution of HLA genes to IBD susceptibility and phenotype. Best Pract Res Clin Gastroenterol, 2004 (18), 577-96. PubMed CrossRef

65 Statement on sarcoidosis. Joint statement of the American Thorarcic Society (ATS), the European Respiratory Society (ERS) and the World Assocation of Sarcoidosis and Other Granulamatous Disorders (WASOG). Am J Respir Crit Care Med 1994 (160), 736-55.

66 Du Bois RM, Goh N, McGrath D, Cullinan P. Is there a role for microorganisms in the pathogenesis of sarcoidosis. J Intern Med, 2003 (253), 4-17. PubMed CrossRef

67 Rybicki BA, Iannuzzi MC, Frederick MM et al. Familial aggregation of sarcoidosis. A case-control etiologic study of sarcoidosis (ACCESS). Am J Respir Crit Care Med, 2001 (164): 2085-91. PubMed

68 McGrath DS, Daniil Z, Foley P et al. Epidemiology of familial sarcoidosis in the UK. Thorax 2000, 55, 751-4. PubMed CrossRef

69 Rybicki BA, Major M, Popovich J Jr, Maliarik MJ, Iannuzzi MC. Racial differences in sarcoidosis incidence: a 5-year study in a health maintenance organization. Am J Epidemiol 1997, 145, 234-41. PubMed

70 Grunewald I, Eklund A. Specific bronchoalveolar lavage fluid T cells associate with disease in a pair of monozygotic twins discordant for sarcoidosis. J Intern Med, 2001 (250), 535-9. PubMed CrossRef

71 Nakamura H, Hashimoto T, Kashiwabara K et al. Sarcoidosis synchronously detected in identical twins. Nihon Kokyuki Gakkai Zasshi. 1994 (37), 406-9.

72 Swale VJ, Spector TD, Bataille VA. Sarcoidosis in monozygotic twins. Br J Dermatol 1998, 139, 350-2. PubMed CrossRef

73 Kneitz C, Wilhelm M, Kraus MR et al. Sarcoidosis in monozygotic twins. Dtsch Med Wochenschr 1995, 120, 867-73. PubMed

74 Yoshikawa T, Yamamoto M, Inaba S et al. Sarcoidosis in identical twins. Nihon Kyobu Shikkan Gakkai Zasshi 1994, 32, 610-5. PubMed

75 Schurmann M, Lympany PA, Reichel P et al. Familial sarcoidosis is linked to the major histocompatibility complex region. Am J Respir Crit Care Med 2000, 162, 861-4. PubMed

76 Schurmann M, Reichel P, Muller-Myhsok B, Schlaak M, Muller-Quernheim J, Schwinger E. Results from a genome-wide search for predisposing genes in sarcoidosis. Am J Respir Crit Care Med, 2001 (164), 840-6. PubMed

77 Martinetti M, Luisetti M, Cuccia M. HLA and sarcoidosis: new pathogenetic insights. Sarcoidosis Vasc Diffuse Lung Dis, 2002 (19), 83-95. PubMed

78 Grunewald J, Eklund A, Olerup O. Human leukocyte antigen class I alleles and the disease course in sarcoidosis patients. Am J Respir Crit Care Med, 2004 (169), 696-702. PubMed CrossRef

79 Berlin M, Fogdell-Hahn A, Olerup O, Eklund A, Grunewald J. HLA-DR predicts the prognosis in Scandinavian patients with pulmonary sarcoidosis. Am J Respir Crit Care Med 1997 (156), 1601-5. PubMed

80 Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995, 80, 695-705. PubMed

81 Rammensee HG, Friede T, Stevanoviic S. MHC ligands and peptide motifs: first listing. Immunogenetics 1995, 41, 178-228. PubMed CrossRef

82 Lanzavecchia A. Mechanisms of antigen uptake for presentation. Curr Opin Immunol 1996, 8, 348-54. PubMed CrossRef

83 Katz J, Shenkman A, Stavropoulos F, Melzer E. Oral signs and symptoms in relation to disease activity and site of involvement in patients with inflammatory bowel disease. Oral Dis, 2003 (9), 34-40. PubMed CrossRef

84 Barr GD, Shale DJ, Jewell DP. Ulcerative colitis and sarcoidosis. Postgrad Med. J. 1986 (62), 341-5. PubMed

85 Yoshioka K, Nishimura S, Kitai S, Kondo M. Association of sarcoidosis, insulin-dependent diabetes mellitus, and ulcerative colitis. Arch Intern Med 1997, 157, 465-7. PubMed CrossRef

86 Nilubol N, Taub PJ, Venturero M, Lichtiger S, Bauer JJ. Ulcerative colitis and sarcoidosis. Mt Sinai J Med, 2001 (686), 400-2. PubMed

87 Storch I, Rosoff L, Katz S. Sarcoidosis and inflammatory bowel disease. J Clin Gastroenterol, 2001 (33), 345. PubMed CrossRef

88 Vaiphei K, Gupta N, Sinha SK, Nagi B, Singh K Association of ulcerative colitis with pulmonary sarcoidosis subcutaneous lipomatosis and appendiceal adenocarcinoma. Indian J Gastroenterol, 2003 (22), 193-4. PubMed

89 Murdock A, Jacob G., Sarcoidosis of the esophagus presenting macroscopically as Barrett's esophagitis. Am, J & Gastroenterol 2003 (98): 1661-2.

90 Gjertson DW, Lee SH. HLA-A/B and DRB1/DQB1 allele-level haplotype frequencies. 1998 In Gjertson, DW & Terasaki, PI, eds. HLA Lenexa, KS. American Society for Histocompatibility and Immunogenetics, pp. 365-450.

91 Thomas R, Nair SB, Banerjee M. HLA-B and HLA-C alleles and haplotypes in the Dravidian tribal populations of southern India. Tissue Antigens, 2004 (64), 58-65. PubMed CrossRef

92 Basu A, Mukherjee N, Roy S et al. Ethnic India: a genomic view, with special reference to peopling and structure. Genome Res, 2003 (13), 2277-90. PubMed

93 Risch N, Burchard E, Ziv E, Tang H. Categorization of humans in biomedical research: genes, race and disease. Genome Biol 2002; 3: comment 2007. PubMed CrossRef

Go to top of page

YourComments

Go to top of page Email this page Email this page to a colleague

 03 September 2014

Advanced search
Close folder Gastroenterology
Mouth
  Esophagus
Stomach & duodenum
Helicobacter pylori
Small intestine
Colo-rectum and anus
Pancreas
Inflammatory bowel disease
Functional bowel disorders
Nutrition
Symptoms/signs of gastrointestinal disease
Basic science
Close folder Hepatology
Biliary tract
Viral hepatitis
Liver diseases
Cirrhosis and portal hypertension
Liver transplantation
Liver & other diseases
Pediatric hepatology
Basic science
Close folder Endoscopy
Upper endoscopy
ERCP
Colonoscopy
Endoscopic ultrasound
Technology
Practice issues

Blackwell Publishing


GastroHep.com is a Blackwell Publishing registered trademark
© 2014 Wiley-Blackwell and GastroHep.com and contributors
Privacy Statement
Disclaimer
About Us