American Journal of Gastroenterology ISSN 0002-9270C© 2007 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2006.00885.xPublished by Blackwell Publishing

Ethnicity and H. Pylori as Risk Factors for Gastric Cancerin Malaysia: A Prospective Case Control StudyKhean-Lee Goh, M.B.B.S., F.R.C.P., M.D., F.A.C.G.,1 Phaik-Leng Cheah, M.B.B.S., F.R.C.Path., M.D.,2

Noorfaridah Md, M.B.B.S., M.Path.,2 Kia-Fatt Quek, Ph.D.,3 and Navaratnam Parasakthi, M.B.B.S.,F.R.C.Path.4

Departments of 1Medicine, 2Pathology, 3Biostatistics, and 4Medical Microbiology, University of Malaya, KualaLumpur, Malaysia

OBJECTIVE: To determine the risk factors for gastric cancer (GCA), with particular emphasis on ethnicity in ourmultiracial population.

METHODS: A prospective case control study with ratio of cancer:controls of 1:2. Diagnosis of H. pylori wasmade by serology using the ELISA technique. Dietary intake was assessed by dietary recall over thepreceding 6 months.

RESULTS: Eighty-seven cases of GCA were enrolled. The cancers were predominantly distal in location and ofthe intestinal type. Risk factors identified following multiple logistic regression analysis were:Chinese race (OR 10.23 [2.87–36.47]), H. pylori (OR 2.54 [1.16–5.58]), low level of education (OR9.81 [2.03–47.46]), smoking (OR 2.52 [1.23–5.15]), and high intake of salted fish and vegetables(OR 5.18 [1.35–20.00]) were identified as significant independent risk factors for GCA, while highintake of fresh fruits and vegetables was protective for GCA (OR 0.15 [0.04–0.64]). Chili intake wasnot a significant protective factor following multivariate analysis.

CONCLUSIONS: Chinese race was a strong independent predictor of GCA. H. pylori was an important predictor ofGCA with a 2.5-fold greater risk in our patients. Despite a high prevalence of H. pylori, the prevalenceof GCA among Indians was low and this paradox can be appropriately called the “Indian enigma.”

(Am J Gastroenterol 2007;102:40–45)

INTRODUCTION

Gastric cancer (GCA) remains one of the most common can-cers in Asia (1, 2). Although the incidence rates are decliningin Asia as they are worldwide, the cancer burden of GCAremains huge (3, 4). In Malaysia, it is the second most com-mon gastrointestinal cancer after colorectal cancer for menand women (5).

Multiple factors contribute to the pathogenesis of GCA.In 1994, the IARC classified H. pylori as a definite carcino-gen in GCA (6). Ecological comparison studies have shownan association between high prevalence areas and high GCAincidence (7, 8). However anomalies occur. For example, theH. pylori prevalence in India is high (9, 10), but the GCA in-cidence is one of the lowest in the world (11). It is importantto note that while H. pylori may be a major factor in gastriccarcinogenesis, there is an interplay with other host and en-vironmental factors that may modulate the development ofcancer. Marked differences in GCA incidence among differ-ent ethnic groups living in the same geographical area havebeen observed, which point to host genetic factors or socioen-vironmental factors peculiar to a particular racial group (12).Malaysia epitomizes the multiraciality of an Asian popula-

tion and comprises three major Asian races: Malay, Chinese,and Indian. These races have remained relatively distinct de-spite living together for close to two generations and allowobservations of differences in disease prevalence and patternsamong races.

The aim of this study was to determine the risk factors forGCA, with particular emphasis on ethnicity in our multiracialpopulation.

MATERIALS AND METHODS

A prospective age- and sex-matched, hospital-based case-control study was performed at the University Hospital, KualaLumpur. Consecutive patients presenting with GCA were re-cruited for the study. All cases had undergone gastroscopicexamination where the location of tumor could be assessed aswell as biopsies taken for histopathological study. Biopsieswere read by experienced histopathologists, and all cases wereconfirmed to be adenocarcinoma. The histological type wasclassified according to Lauren’s classification (13). Controlswere chosen from patients who attended the general medicalclinics and who did not have any gastrointestinal complaints.

40

Ethnicity and H. Pylori as Risk Factors 41

Controls were age matched to cases ±5 yr and were chosenin a ratio of 2:1.

Patients and controls were subjected to a detailed question-naire and sera were taken for H. pylori serology. H. pyloriserology was performed using a locally validated serologicaltest: HEL-p II test (AMRAD, Victoria, Australia), which hasbeen shown to have a high sensitivity and specificity (14).

Dietary intakes of fresh fruits and vegetables and of saltedfish and vegetables were assessed by recall over the preced-ing 6 months and graded according to frequency of intake—never, occasional (less than 3–4 times per week), frequent(3–4 times per week), and daily. “Frequent” and daily intakewas classified as high intake and none and occasional as lowintake. Intake of chilies was graded according to frequencyand quantity—never, light (chilis as condiments only), fre-quent (3–4 chili or curry dishes per week), and daily intake ofchili or curry dishes. “Frequent” and daily intake was classi-fied as high intake and never and light as low intake. Smokingand alcohol consumption were classified as never or ever.

This study was approved by the ethic committee of theUniversity Hospital, Kuala Lumpur, and was performed inaccordance to GCP/ICH guidelines.

Sample SizeDetermination of sample size was based on the following:2 sample type at alpha of 0.05 and power of 80% with aratio of case to control of 1:2 and the assumption that theproportion of H. pylori in cases is 0.70 and in controls is0.50. The calculated sample size requirement for cases = 78and controls = 156.

Statistical AnalysisComparisons between cases and controls were made using aχ2 test or Fisher’s exact test where appropriate. A 2-tailed testwas used and a P value of <0.05 was taken as significant. Theprevalence of GCA was analyzed in relation to the followingvariables: race, H. pylori status, level of education, smoking,alcohol intake, intake of chilis, consumption of fresh fruitsand vegetables, and consumption of salted fish and vegeta-bles. Odds ratios (OR) of GCA in the presence of a particularfactor were used as a measure of the strength of associationand are presented with 95% CI. Variables with a P valueof <0.20 were then subjected to multivariate analysis usingmultiple logistic regression analysis. Statistical analysis wasperformed using the SPSS 11.5 statistical program.

RESULTS

Eighty-seven cases of GCA and 174 controls were recruitedfor the study. The mean age of controls was 58.9 + 10.8 andcases 61.4 + 13.0 yr. The demographic features of cases andcontrols are as shown in Table 1.

GCA PatientsThe age at diagnosis of GCA is as shown in Figure 1 anda sharp rise in incidence is diagnosed after the age of 50 yr

Table 1. Basic Demographic Data and Characteristics of GCA Pa-tients, N (%)

Patients ControlsN = 87 N = 174

Mean age (SD) 61.4 + 13.0 58.9 + 10.8Male:female ratio 42:45 86:88Race

Malay 4 (4.6) 48 (27.6)Chinese 66 (75.9) 58 (33.3)Indian 17 (19.5) 68 (39.1)

Education levelHigh 2 (2.3) 29 (16.7)Medium 11 (12.6) 70 (40.2)Low 74 (85.1) 75 (43.1)

H. pylori +ve 69 (79.3) 94 (54.0)Smoking 50 (57.5) 62 (35.6)Alcohol 9 (10.3) 10 (5.7)Chili intake 48 (55.2) 152 (87.4)

(moderate and heavy)Fresh fruits and 20 (23.0) 169 (97.1)

vegetables (frequent)Salted vegetables 16 (18.4) 8 (4.6)

and fish (frequent intake)

in our patients. All tumors were confirmed histologically tobe adenocarcinoma. The location of tumor was as follows:distal 66 (75.9%), proximal 15 (17.2%), and total stomachinvolvement 6 (6.9%). Histological classification accordingto Lauren’s classification showed that 59 (67.8%) belongedto the intestinal type and 28 (32.2%) to the diffuse type.

H. Pylori Prevalence and RacesThe prevalence of H. pylori in GCA patients and controls is asshown in Table 2. For all races, the H. pylori prevalence washigh in GCA patients. For controls, the prevalence was sig-nificantly higher among the Chinese (P = 0.005) and Indians(P = 0.015) compared to the Malays. The proportion of pa-tients and controls with H. pylori developing GCA is shownin Table 3. A lower percentage of H. pylori-positive Indian

AGE

888278757067646158555247443526

Cum

ulat

ive

Fre

quen

cy

100

80

60

40

20

0

Figure 1. Cumulative frequency of GCA cases by age.

42 Goh et al.

Table 2. H. Pylori-Positive Status Among Different Races in Pa-tients and Controls

Patients H. Pylori Controls H. Pylori+ve (%)∗ +ve (%)†

Malay 3/4 (75.0) 14/48 (29.2)Chinese 52/66 (78.8) 34/58 (58.6)Indian 14/17 (82.3) 46/88 (52.3)

∗Chinese vs Malay (NS, P = 1.000), Indian vs Malay (NS, P = 1.000).†Chinese vs Malay (P = 0.005), Indian vs Malay (P = 0.015).

subjects develop GCA compared to Chinese and Malays andthis was highly statistically significant (P < 0.001).

Predictive Factors for GCAUnivariate analysis of predictive factors is as shown in Table4. The following factors were found to be significant: Chineserace, H. pylori infection, low level of education, smoking, andheavy intake of salted fish and vegetables. Conversely, intakeof chilies and fresh fruits and vegetables was found to beprotective for GCA.

Following multivariate analysis using multiple logistic re-gression analysis, Chinese race (OR 10.23 [2.87–36.47]), H.pylori (OR 2.54 [1.16–5.58]), low level of education (OR 9.81[2.03–47.46]), smoking (OR 2.52 [1.23–5.15]), and high in-take of salted fish and vegetables (OR 5.18 [1.35–20.00])were identified as significant independent risk factors forGCA, while high intake of fresh fruits and vegetables wasprotective for GCA (OR 0.15 [0.04–0.64]) (Table 5).

DISCUSSION

In this study, we have shown that the characteristics of GCApatients are very similar to those reported in the developingworld. There was a slight male preponderance, and the meanage at diagnosis was above 60 yr. The majority of our cancerswere located distally and they belonged to the intestinal typeaccording to Lauren’s classification.

In our carefully conducted case control study, we have iden-tified Chinese race as an independent risk factor. Cancer in-cidence from our National Cancer Registry (3) and that ofneighboring Singapore has consistently showed a higher agestandard incidence rate (ASR) among Chinese compared tothe Indians and Malays (15). This is further supported by thecomparatively high ASR from cancer registries in China andthe low ASR from registries in India (15).

Table 3. Proportion of H. Pylori +ve Subjects (Patients and Con-trols) with GCA by Race

GCA (%)∗

Malay 14/17 (82.3)Chinese 52/86 (60.5)Indian 14/60 (23.3)

∗Malay vs Indian (P < 0.001), Chinese vs Indian (P < 0.001).

Table 4. Univariate Analysis of Risk Factors for GCA

Gastric Univariate ORVariable Cancer (95% CI) P Value

RaceChinese 66/124 (53.2) 13.66 (4.36–47.61) <0.001Indian 17/85 (20.0) 3.0 (0.87–11.31) 0.090Malay 4/52 (7.7)

H. pyloriYes 69/163 (42.3) 3.26 (1.73–6.21) <0.001No 18/98 (18.4)

EducationMedium 11/70 (15.7) 2.28 (0.43–15.9) 0.510Low 74/149 (49.7) 14.31 (3.15–90.06) <0.001High 2/31 (6.5)

SmokingYes 50/112 (44.6) 2.4 (1.40–4.28) 0.001No 37/149 (24.8)

AlcoholYes 9/19 (47.4) 1.89 (0.67–5.29) 0.273No 78/242 (32.2)

Chili intakeHeavy 48/200 (24.0) 0.18 (0.09–0.34) <0.001Low/None 39/61 (63.9)

Fresh vegetables/fruitsFrequent 67/236 (28.4) 0.10 (0.03–0.29) <0.001Low/None 20/25 (40.0)

Salted fish/vegetablesHeavy 16/24 (66.7) 4.68 (1.78–12.56) <0.001Low/None 71/237 (30.0)

The other important risk factor, which has been definedas definite carcinogen by the IARC, is H. pylori (16). In ourstudy, we have shown a threefold greater risk with H. pyloriinfection. We have used serology as the H. pylori diagnostictest, which would give a more accurate diagnosis than biopsy-based tests, as it also detects past infection. The findings oflower risk of GCA among Indians appear paradoxical, as H.pylori prevalence is high among this racial group as previ-ously documented (9, 10, 17). When we subanalyzed data inour study, among H. pylori-positive subjects (both patientsand control combined), we found 23.3% of Indians havingGCA compared to 60.5% and 82.3% of Chinese and Malays.In a seroprevalence study from Singapore, a significant lin-ear correlation was found for Chinese and Malay subjectsbut not for Indians (18). We have previously noted this para-dox with peptic ulcer disease where a larger proportion of H.pylori-positive Indian patients had nonulcer dyspepsia com-pared to Chinese and Malays (19). The lower frequency ofGCA among Indians despite the high H. pylori prevalencecan indeed be termed the “Indian enigma” and suggests theinfluence and interaction with other, probably protective fac-tors.

This difference in disease outcome between Chinese andIndians, who both have high H. pylori prevalence, couldbe related to differences in infecting bacterial strains be-tween races. Bacterial virulence factors in our different races,Malay, Chinese, and Indians, have been previously studied byTan et al. (20). With respect to Cag A status using PCR in situhybridization, we reported a high Cag A prevalence among allthree major races in Malaysia (Malay 76.6%, Chinese 86.4%,

Ethnicity and H. Pylori as Risk Factors 43

Table 5. Multivariate analysis of risk factors for GCA

95% CIOdds

Variable B SE Wald df Sig. (P) Ratio Lower Upper

Race 17.173 2 0.000Chinese 2.325 0.649 12.854 1 0.000 10.229 2.869 36.467Indian 0.921 0.638 2.082 1 0.149 2.513 0.719 8.782

Education 23.125 2 0.000Medium 0.487 0.864 0.318 1 0.573 1.627 0.299 8.846

Low 2.284 0.804 8.067 1 0.005 9.814 2.029 47.455Low intake of fresh fruits and vegetables 1.896 0.737 6.608 1 0.010 6.658 1.569 28.251High intake of salted foods 1.645 0.688 5.717 1 0.017 5.182 1.345 19.965H. pylori +ve 0.932 0.402 5.372 1 0.020 2.538 1.155 5.580Smoking 0.925 0.364 6.441 1 0.011 2.521 1.234 5.147Chili 0.595 0.456 1.699 1 0.192 1.812 0.741 4.432

Indian 86.8%). However, the Cag E prevalence was signifi-cantly lower among Chinese (39.0%) compared to the Indians(81.6%) and Malays (70.0%), which appears paradoxical, assome studies have suggested that the Cag E gene is a morereliable virulence marker (21). Other virulence factors haveto be studied to see if there were indeed bacterial strain dif-ferences between races, which could account for the discor-dant GCA prevalence between the Chinese and Indians. Atthe same time, host genetic proinflammatory polymorphismscould play an important role in these observed differencesand is a crucially important area for further investigations.Preliminary studies in our population show significant dif-ferences in interleukin-1 polymorphisms among races andfurther work needs to be done to correlate this with diseaseoutcome (22).

With regards to environmental factors, diet has always beena subject of interest, particularly with regards to gastroin-testinal cancers. Among Indians, intake of curries, which isa staple of the Indian diet, is high. Curcumin, which is an ac-tive ingredient of turmeric powder used in curries, has beenshown to have a protective effect against GCA (23, 24). In ourstudy, we have attempted to define the amount of chili takenby patients and controls, which we have defined broadly asdaily intake, occasional intake versus no intake, or chiliesused as condiments only. In our multiracial society, sociocul-tural influence has affected diets most, and while curries andchilies are commonplace in the Indian and Malay diets, theyare also becoming more common with the Chinese. How-ever, we were unable to confirm that high chili intake wasprotective for GCA although it was significant on univariateanalysis. As with all dietary studies, there will be criticisms asto the accurate recall of patients, especially those who are illand as to the method of quantification of intake. Conversely,there have also been studies that have incriminated chilies asa risk factor for GCA (25, 26).

We have also taken a careful history for the intake of freshfruits and vegetables, as well as salted fish and vegetables.High intake of fresh fruits and vegetables was found to beprotective for GCA, while high salt intake was found to be asignificant risk factor for GCA. The protective role of fresh

fruits and vegetables has been noted for a long time and hasbeen postulated for the north–south difference in GCA withina particular country such as China, where the tropical south-ern parts with year-round consumption of fresh fruits andvegetables have less cancer than the temperate northern parts(27). Among elderly Chinese (and not among the Malays andIndians) in Malaysia, there is a belief that fresh fruits andvegetables are “cold” and many avoid taking them believingthat they will aggravate “rheumatism” and other geriatric ail-ments. The presence of high salt content and preservatives,such as nitrites in salted fish and vegetables, which are oftenconsumed by Chinese but not by the Malays and Indians, isbelieved to be responsible for the higher prevalence of GCA inChinese. For both dietary factors, significance was obtainedeven after adjustment for confounding factors. In general,Chinese, Japanese, and Korean diets have a high salt content,salt being used to preserve food over the winter months inthe past. Salted and preserved foods, such as the Japanesemiso soup and the Korean Kim chi, have now become staplesand their intake perpetuated. Studies have shown salted andpreserved foods to be carcinogenic (28–30).

We have also identified low level of schooling, which wehave used as an indicator of lower social class, to be a signif-icant risk factor for GCA. This is in keeping with reportedliterature, which has consistently shown that GCA is a canceraffecting the lower social classes (27, 31, 32).

CONCLUSIONS

Chinese race was identified as a strong independent predictorof GCA. H. pylori was also a significant risk factor for GCA.Despite a high prevalence of H. pylori, the prevalence of GCAamong Indians was low and this paradox can be appropriatelycalled the “Indian enigma.” Race could be a surrogate markerfor certain sociocultural practices, including dietary habitssuch as high intake of salted or preserved foods, which arethought to be carcinogenic. Further work needs to be done toinvestigate the role of different infecting bacterial strains andhost genetic polymorphisms in the pathogenesis of GCA inour multiracial population.

44 Goh et al.

STUDY HIGHLIGHTS

What Is Current Knowledge

� Helicobacter pylori is a major risk factor for gastriccancer (GCA). GCA is more frequently seen in certainethnic groups.

What Is New Here

� The distinct differences in H. pylori and GCA preva-lence among three major Asian races: Malay, Chi-nese, Indians. In a multiracial Asian society such asin Malaysia, the Indians have a low prevalence of GCAdespite a high rate of infection with H. pylori. Thisis an extremely interesting observation and an enigmaand suggests a host-environment interaction in diseaseoutcome.

Reprint requests and correspondence: Prof. Khean-Lee Goh, De-partment of Medicine, Faculty of Medicine, University of Malaya,50603 Kuala Lumpur, Malaysia.

Received February 23, 2006; accepted July 30, 2006.

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CONFLICT OF INTEREST

Guarantor of the article: Khean-Lee Goh, MBBS, FRCP,MD, FACG.

Specific author contributions: Khean-Lee Goh conceivedthe idea of the study, collected patient data, biopsies,and blood samples and analyzed the data and wrote themanuscript. Noorfaridah Md and Phaik-Leng Cheah per-formed the histopathological examination, Kia-Fat Quekadvised and helped perform the statistical analysis, andNavaratnan Parasakthi carried out serology and advise onthe manuscript.Financial support: Government of Malaysia IRPA researchvote: 06-02-03-0311.Potential competing interests: None.