Serum pepsinogen, ui-antitrypsin (ui-AT) and blood groups were studied as genetic markets in 32 patients with endoscopically proven duodenal ulcer and 44 control subjects with no family history of ulcer disease. Serum pepsinogen was detennined by the modified method of Edward et al7, a1-AT by single radial hnmunodiffusion8 (RID) and phenotyping was carried out by isoelectric focusing (IEF)9. Duodenal ulcer patients with hyper- pepsinogenemia (28%) and low serum ui-AT (35%) had a dominant blood group 0, lower mean age, an early onset of disease, a higher frequency of gastrointestinal (CI) bleeding and ulcer perforation. These parameters were found considerably different in patients with normal serum pepsi­nogen and ui-AT. Phenotype analysis of a1-AT revealed that four duodenal ulcer patients had partial deficiency of the protease inhibitor and none of the normal exhibited the deficiency pattern. The etiology of the disease appears to be genetic anomaly in 28% of patients while the rest (72%) had ulcers as a result of neuroendocrinological or environmental factors (JPMA 47:135,1997)

Muhamined A. Waqar, Muhamined A. Waqar Muhamined A. Waqar

Shahid, Anjum

Siddiqui, Anwar Ali

Zuberi, Sarwar J

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eCommons@AKUDepartment of Biological & Biomedical Sciences Medical College, PakistanMay 1997Genetic Markers and Duodenal UlcerAnjum ShahidJinnab Postgraduate Medical Centre, Karachi.Sarwar J. ZuberiJinnab Postgraduate Medical Centre, KarachiAnwar Ali SiddiquiAga Khan University, anwar.siddiqui@aku.eduMuhamined A. Waqar Muhamined A. Waqar Muhamined A. WaqarAga Khan UniversityFollow this and additional works at: http://ecommons.aku.edu/pakistan_fhs_mc_bbsPart of the Life Sciences Commons, and the Medical Education CommonsRecommended CitationShahid, A., Zuberi, S. J., Siddiqui, A., Muhamined A. Waqar, M. M. (1997). Genetic Markers and Duodenal Ulcer. Journal Of PakistanMedical Association, 47(135), 135-137.Available at: http://ecommons.aku.edu/pakistan_fhs_mc_bbs/269Genetic Markers and Duodenal UlcerPages with reference to book, From 135 To 137 Anjum Shahid, Sarwar J. Zuberi ( PMRC Research Centre, Jinnab Postgraduate Medical Centre, Karachi. ) Anwar A. Siddiqui, Muhamined A. Waqar ( Department of Biochemistry, The Aga Khan University, Karachi. ) Abstract Serum pepsinogen, ui-antitrypsin (ui-AT) and blood groups were studied as genetic markets in 32patients with endoscopically proven duodenal ulcer and 44 control subjects with no family history ofulcer disease. Serum pepsinogen was detennined by the modified method of Edward et al7, a1-AT bysingle radial hnmunodiffusion8 (RID) and phenotyping was carried out by isoelectric focusing (IEF)9.Duodenal ulcer patients with hyper- pepsinogenemia (28%) and low serum ui-AT (35%) had adominant blood group 0, lower mean age, an early onset of disease, a higher frequency ofgastrointestinal (CI) bleeding and ulcer perforation. These parameters were found considerablydifferent in patients with normal serum pepsinogen and ui-AT. Phenotype analysis of a1-AT revealedthat four duodenal ulcer patients had partial deficiency of the protease inhibitor and none of the normalexhibited the deficiency pattern. The etiology of the disease appears to be genetic anomaly in 28% ofpatients while the rest (72%) had ulcers as a result of neuroendocrinological or environmental factors(JPMA 47:135,1997).Introduction Duodenal ulcer is a common disorderwhich is believed to have existed in families. Due to itsheterogeneity1 and multiple causative factors it often becomes difficult to assign a single agentresponsible for this disease. It is therefore, widely accepted that interaction of certain environmental,genetic and other factors such as stress might collectively produce alteration of gastric secretions tosuch extent that it leads to low resistance of gastric mucosal cells which in turn detennines thepredisposition to the development of duodenal ulcer. The genetic markers that have been proposed tobe linked withthis disorderinclude ABO blood groups2, secretor and non-secretor status3, I{LA typing4,serum pepsinogen5 and serum alpha 1 antitrypsin6. Those who have been considered prone to developduodenal ulcer include individuals with blood group 0 (35%) and non-secretors (50%). In addition tothese, persons with raised serum pepsinogen, low levels of ui-AT and increased frequency of HLA, B-5have also been identified among the predisposed group2-6. Like many of the well known disonlers ofgenetic origin, researchers have also been lookingfor suitable markers for this disease. If one or moresuitable markers can be identified for the duodenal ulcer it is hoped that this information would provideconsiderable help not only in the successful management of patients, but also in the development ofstrategies for control and prevention of disease. This study was conducted to find out whether theetiology of duodenal ulcerinourpopulation is genetic or some other factors play a role in causation ofthe disease.Patients and Methods Thirty-two patients with endoscopically proven duodenal ulcerand forty-fourheaithy subjects with nohistory of peptic ulcer disease were selected as patients and controls respectively. Patients writtenconsent and an approval of the Ethical Conunittee, Jinnah Postgraduate Medical Centre, Karachi weretaken, All sera were stored at -70°C until analysed. Serum pepsinogen was determined by the modifiedmethod of Edward et af. Quantitative measurement of serum a-1AT was carried out by single RIDtechnique using M. Partigen immunodiffusion plates (Behring Diagnostic, Germany)8 and phenotypingwas perfonnedby ultrathin layer polyacrylamide gel IEF9. We used gels containing 2% ampholytes inthe pH range 4.2-4.9. At the end of IEF run, pH at each 1 cm segment across the gel lengthwasmeasured using a surface pH electrode. a1-AT bands were visualized by staining the gels withCoomassie Blue R-250. Further confirmation of ui-AT phenotyping was done by immunofixation9. Forthis purpose cellulose acetate membrane presoaked in 1:2 diluted antiserum to ui-AT, was layered overthe surface of JEF gel. After an hour the membrane was washed exhaustively in saline and stainedwithamido-black to locate ui-AT-antibody complexes.Results Serum pepsinogen, ui-AT and blood groups were determined in32 patients with duodenal ulcer and 44controls. The patients age ranged between 18-77 years (mean 41 years) and in controls from 18-82yçars (mean 35 years). There were 26 males and 6 females with a male to female ratio of 4.3:1. Themeanvalues and ranges fortotal semmpepsinogen, serum ui-AT and blood groups in controls andpatients with duodenal ulcer are shown in Table I. The range of serum pepsinogen in controls was 9-140 units/mi. Considering this as normal range, 72% patients were normal pepsinogenemic and 28%were hyperpepsinogenemic. The values of controls and patients with duodenal ulcer do not appearsignificantly different (Table I).Subjects having values less than 2 gm/i of serum ui-AT were regarded as being ui-AT deficient. Amongthe patients 65% had normal and 35% below normal ui-AT levels. A significant difference (P<0.00l)was observed betweenthemeanvalues of controls and patients (Table I). IEF patterns indicated that fourduodenal ulcer patients with low semm ui-AT had atleast partial deficiency of the protease inhibitor.Blood group 0 was dominant among patients with raised serum pepsinogen and low cu-AT. Comparingpatients with blood group 0 versus those with groups other than 0 indicates thatthesepatients hadalowermeanage, raised mean serum pepsinogen and low mean ai-AT (Table II).Discussion Duodenal ulcer manifesting raised serum pepsinogen and low a1 -AT is reported to be a geneticallydetermined entity. Other characteristic features among these patients include dominant blood gmup 0,lower mean age, an early onset of the disease and an increased frequency of gastrointestinal bleedingand perforation10. These findings confirm the strong association of duodenal ulcer with geneticmarkers, which in the present study seems to hold true only in a small number of patients i.e., only 28%of the patients had raised serum pepsinogen while 35% had low ai-AT Among these patients, bloodgroup 0 was found dominant. Role of genetic factors in duodenal ulcer disease has been suspectedsince long because of an increased incidence of the disease among first degree relatives of patients3. Agreater concordance for duodenal ulcer in monozygotic than in dizygotic twins11 and an increasedfrequency of blood group 0 and blood group non-sector status inpatients with duodenal ulce? have beenreported. Blood group 0 and non-sector status although associated with the disease, are not useful forthis purpose as the magnitude of the association appears very weak2, however, an elevated serumpepsinogen level occurs with increased frequency in patients with established duodenal ulcer12,13 andhas been found to identify those at an increased risk for the development of the disease14.15. Hereditarydeficiency of the protease inhibitor, resulting in low levels of ai -AT (synthesized by hepatocytes) isanother factor reported induodenal ulcer6. Recognizing phenotypes of cu-AT is clinically important asit is an acute phase reactant protein and its quantitative estimation induodenal ulcer and in otherinflammatory conditions can be misleading16.Duodenal ulceration is a common gastrointestinal problem but to date no studies have been conductedon local population in screening various genetic markers and establishing the etiology of the diseaseeither to be of genetic or non-genetic in origin. An earlier study5 reported a high percentage (83%) ofduodenal ulcer patients with hyperpepsinogenemia. Such an ulcer was considered to be of geneticetiology termed as primary duodenal ulcer. The observations are different in our study, only 28% of thepatients had raised serum pepsinogen while serum alpha-i antitiypsin was low in 35% of the patients.Other findings in the patients include dominant blood group 0, lower mean age, an early onset of thedisease, an increased frequency of gastrointestinal bleeding and ulcer perforation, thereby confirmingthe strong association of duodenal ulcer with all the markers. But this association seems to hold trueonly in a small number of patients included in this study. From the preceding discussion it appears thatthe genetic etiology of the disease existed in just 28% of the patients while the rest comprising a largemajority of the patients (72%) had ulcers which could be the result of neuroendocrinological orenvironmental factors which are also known to cause the disease. Individual differences in charactertendencies, psychological and emotional adaptability, responses and adaptive abilities of. the humoralsystem to stress are also closely related with the development of ulcer. Severe psychological stressesimposed upon children and adults because of the complex psycho-social circumstances may be the rootcause of the disease and should be seriously considered.References 1. Rotter, S. I. The genetics of gastritis and peptic ulcer. S. Clin. Gastroenterol., 1981;3 (Suppl. 2):35-43.2. Langman, M.J.S. Blood groups and alimentary disorders. Clin. Gastroenterol., 1973;2:497-506.3. McConnell, RB. Gastric and duodenal ulcer. The genetics of the gastrointestinal disorders. London.Oxford University Press. 1966, pp. 76-104.4. Ellis, AC, and Woodrow, S.C. HLA and duodenal ulcer. Gut, 1979;20:760-762.5. Habibullsh, CM, Ali, MM, Ishsq, M. et al. Study of duodenal ulcer disease in 100 families using totalserum pepsinogen as a genetic marker. Gut, 1984;25:1380- 1383.6. Kishore, N. Alpha I antitrypsin deficiency in duodenal ulcer. Trop. Gastroenterol., 1980;1:193-196.7. Edward, K., Jepson, R.P. and Wood, KR Modified serum pepsinogen. varley’s practical clinicalbiochemistry by Harold varley. vth edition, London, William Hcinemann, 1980, pp. 1003-1004.8. Mancini, 0, Carbonarer, AG. and Heremans, J.F Immunochemical quantitation of antigens by singleradial immunodiffusion. Immunochem., 1965,2:235-254.9. Jeppson, JO. and Franzen,B. Typing ofgenetic variants of alpha I antitrypsin by electrofocusing.Clin. Chem., 1982;28:219-225.10. Habibullah, C.M. and Radha, V. The genetics of peptic ulcer disease. Trop. Gastroenterol.,19856:132-140.11. Gotlieb-Jensen, K. Peptic ulcer Genetic and cpidemiological aspects based on twin studies.Copenhagen, Munksgaard, 1972.12. Mirsky, IA., Futterman, P. and Kaplaro, S. Blood plasma pcpsinogen 11. The activity with duodenalulcer and patients with perinicious anaemia,J. Lab. Clin. Med., 1952;401 :188-189,13. Spiro. EM., Ryan, A.E. and Jones, C.M The utility of the blood pepsin assay in clinical medicine.N. EngI. J. Med., 1955:253:261-266.14. Mirsky, IA. Physiologic, psychologic and social determinants in the etiology of duodenal ulcer Am.J. Dig. Dis., 1958;3:285-314.IS. Niederman, S.C., Spiro, H.M. and Sheldon, WH. Blood pepsin as marker of susceptibility toduodenal ulcer disease. Arch. Environ. Health, 1964;8:540-546.16. Fagerhol, MS. and Cox, D.W. The pi polymorphism: genetic, biochemical and clinical aspects ofhuman alpha I antitrypsin. Adv. Hum. Genet., 1981; 11:1-62.

Genetic Markers and Duodenal Ulcer

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Genetic Markers and Duodenal Ulcer

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