Helicobacter pylori Seropositivity, ABO Blood Type, and Pancreatic Cancer Risk From 5 Prospective Cohorts

INTRODUCTION

Pancreatic cancer is the third leading cause of cancer death in the United States with 5-year survival rates of 11% (1). Research efforts over several decades have established important modifiable risk factors, including smoking, diabetes, and obesity (2). Helicobacter pylori is a Gram-negative, spiral-shaped bacterium that infects human gastric mucosa in more than 50% of the world's population (3). It is typically acquired early in childhood, causing lifelong infection unless treated (4). In its natural course, sequelae of infection can include chronic inflammation of gastric epithelia, peptic ulcer disease, intestinal metaplasia, and gastric cancer (4).

It has been suggested that H. pylori could be a risk factor for pancreatic cancer, but studies thus far have been conflicting (5–8). One proposed mechanism of carcinogenesis hypothesizes that infection by H. pylori, particularly in the gastric antrum, causes chronic hyperchlorhydria by induction of increased gastrin release and decreased or defective acid inhibitory mechanisms (9). This chronic decrease in gastric pH in turn causes increased release of secretin, one of the primary hormones that stimulate pancreatic exocrine cell secretion, which results in increased pancreatic cell hyperplasia, cell turnover, and susceptibility to carcinogens (9,10). Interestingly, stratified analyses and studies of targeted populations have demonstrated that the effect of H. pylori on pancreatic cancer risk may be strain-specific (8,11). Those strains of H. pylori containing the highly immunogenic cytotoxin-associated gene A (CagA) protein are associated with more severe gastritis, peptic ulcer disease, and up to 2-fold higher risk of gastric cancer (12,13). CagA-positive strains are also associated with relative hypochlorhydria (14). In concordance with the hyperchlorhydria theory of carcinogenesis, presence of the CagA virulence factor may thus have a protective effect against pancreatic cancer compared with CagA-negative strains.

A genome-wide association study (GWAS) among pancreatic cancer cases and controls showed significant associations between several single nucleotide polymorphisms at the ABO 9q34 gene locus and pancreatic cancer risk (15,16). Follow-up studies confirmed an increased pancreatic cancer risk among individuals with non-O blood type (17–19). H. pylori colonization of gastric epithelium occurs most efficiently through binding of an outer membrane adhesion protein to blood group antigens expressed on gastric mucins (20). Thus, it has been hypothesized that blood group antigens may play an important role in the link between H. pylori and pancreatic cancer (9).

We conducted a nested study within 5 U.S. prospective cohorts with prediagnostic blood samples to examine the association between H. pylori seropositivity and subsequent pancreatic cancer risk, including whether the association differs by CagA seropositivity or ABO blood type.

METHODS Study population

Participants were pooled from 5 prospective US cohorts—the Health Professionals Follow-up Study (HPFS), Nurses' Health Study (NHS), Physicians' Health Study (PHS), Women's Health Initiative Observational Study (WHI-OS), and Women's Health Study (WHS). HPFS was established in 1986 and enrolled 51,529 male health professionals aged 40–75 years to study nutrition and disease (21). NHS was established in 1976 and enrolled 121,700 female nurses aged 30–55 years to study women's health and contraceptive use (22). PHS is a completed randomized clinical trial initiated in 1982 to study cardiovascular disease and cancer among 22,071 male physicians aged 40–84 years (23). The WHI-OS enrolled 93,676 women aged 50–79 years from 1994 to 1998 to study diseases in postmenopausal women (24). WHS is a completed randomized clinical trial initiated in 1992 to study cardiovascular disease and cancer among 39,876 female health professionals older than 45 years (25). The trial closed in 2004, and study participants were followed as an observational cohort. The current study was approved by the institutional review boards of the Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health and those of participating registries as required, and participants provided informed consent.

Pancreatic cancer cases and matched controls

Pancreatic cancer cases consisted of individuals diagnosed with pancreatic ductal adenocarcinoma through 2008 who had provided a blood sample. Cases were identified through self-report on questionnaire or during follow-up of a participant's death. Deaths were determined by report from next-of-kin, the US Postal Service, and by searching the National Death Index among questionnaire nonrespondents. Diagnosis was confirmed by blinded study physicians' review of medical records. Controls were cohort participants who provided a blood sample and were alive and free of pancreatic cancer at the date of their matched case's diagnosis. Cases were matched to 2–3 controls on year of birth, cohort (concurrently matched on sex), smoking status (never, past, or current), fasting status at blood collection (fasting or nonfasting), and month/year of blood collection. For the current study, H. pylori and CagA serologies were measured in 485 cases and 1,122 matched controls. For H. pylori serology, 6 participants had indeterminant levels, but all were CagA-positive, so were considered H. pylori–positive. A further 32 participants were H. pylori–negative but CagA-positive and were reclassified as H. pylori–positive. A total of 485 cases and 1,122 matched controls were included in the primary analysis. For CagA serology, 39 participants were either indeterminant (n = 31) or had failure of the assay (n = 8), of whom 17 had negative H. pylori antibody so were assumed to have negative CagA. The remaining 22 participants with positive H. pylori but indeterminant or failed CagA assay were not included in the CagA-stratified analysis. A total of 478 cases and 1,107 controls were available for CagA-stratified analysis. ABO data were available for 350 cases and 566 controls.

Assessment of H. pylori and CagA antibodies

Blood samples were collected from 18,225 HPFS participants from 1993 to 1995, 32,826 NHS participants from 1989 to 1990, 14,916 PHS participants from 1982 to 1984, 93,676 WHI-OS participants from 1994 to 1998, and 28,345 WHS participants from 1992 to 1995. Samples were drawn from storage freezers, aliquoted to the appropriate volume, and sent to the reference laboratory in a blinded fashion, without identifiers of case/control status. Matched cases and controls were handled identically, shipped in the same batch, and assayed in the same analytical run. Further details on blood collection, transportation, and storage of plasma samples have been previously described (23,26–29).

H. pylori and CagA antibody titers were measured in the laboratory of Dr. Nader Rifai (Children's Hospital, Boston, MA) using reagents from ALPCO Diagnostics (Salem, NH). H. pylori was considered positive if the antibody titer was greater than 7 units/mL, negative if less than 6.25 units/mL, and otherwise indeterminant. CagA was considered positive if the antibody titer was greater than 7 units/mL, negative if less than 5.5 units/mL, and otherwise indeterminant. The 38 participants with positive CagA serology but negative or indeterminant H. pylori status were treated as H. pylori– and CagA-positive (30). The mean coefficients of variation for blinded, replicate quality control samples were 4.4% for H. pylori and 10.7% for CagA antibodies.

Assessment of ABO blood type

The G allele of rs687289 at the ABO locus has been previously shown to be highly correlated with O blood type (16). We determined O vs non-O blood type in a subset of our pooled cohort using rs687289 data from the previous PanScan GWASs (15,16,31). Details of genotyping methods by PanScan can be found elsewhere (15). When genotyped ABO data were unavailable, self-reported blood type was used in HPFS and NHS participants. In these 2 cohorts, blood type was reported on questionnaires in 1996, and a subsequent validation study showed 91% concordance between self-reported ABO blood type and laboratory assessed serologic blood type (18). Genotyped and self-reported ABO data were available in 580 and 336 participants, respectively.

Assessment of covariates

Individual characteristics of participants were obtained through baseline enrollment questionnaires in the PHS, WHI-OS, and WHS cohorts and through mailed questionnaires obtained before blood draw in the HPFS and NHS cohorts. Covariate data included age, race/ethnicity, sex, body mass index (BMI), diabetes mellitus status, smoking status, alcohol intake, physical activity level, and regular multivitamin use. Physical activity was assessed using self-reported weekly activity levels, which were converted to metabolic equivalent task-hours per week. The HPFS, NHS, and WHI questionnaires assessed use of acid-suppressing medications. H2 blocker use was assessed before blood draw in the HPFS, NHS, and WHI cohorts. Proton pump inhibitor (PPI) use was also assessed in the WHI cohort before blood draw. PPI use was not assessed in the HPFS questionnaires until 2004 and the NHS questionnaires until 2000, much after time of blood draw, so these data were not included for our analyses.

Statistical analyses

The primary exposure was history of infection by H. pylori as determined by H. pylori plasma antibody titers. We performed conditional logistic regression to compute odds ratios (ORs) and 95% confidence intervals (CIs) for incident pancreatic cancer conditioned on matching factors and adjusted for age, race (white, black, or other), BMI (<18.5, 18.5–24.9, 25–29.9, ≥30 kg/m2), history of diabetes (yes or no), and regular multivitamin use (yes or no). For stratified analyses, unconditional logistic regression was used with adjustment for matching factors and above covariates. Tests of interaction between H. pylori seropositivity and potential effect modifiers were assessed by entering the cross-product of H. pylori and the covariate into the model and assessing by the Wald test. Conditional logistic regression adjusted for the above covariates and conditioned on the matching factors was also used to perform a sensitivity analysis excluding participants with reported PPI or H2 blocker use. All statistical analyses were performed using the SAS 9.4 statistical package (SAS Institute, Cary, NC). All P values were 2-sided.

RESULTS

Baseline characteristics by H. pylori seropositivity among controls and by case/control status are shown in Table 1 and Supplementary Digital Content (see Supplementary Table 1, https://links.lww.com/CTG/A913), respectively (Table 1, see Supplementary Table 1). The median time between blood collection and cancer diagnosis was 6.7 years among cases. Among 1,122 matched controls, 377 (34%) were H. pylori–seropositive, and 172 (46%) of the H. pylori–seropositive controls were CagA-positive. As expected, cases were more likely to have obesity, a history of diabetes, and non-O blood group compared with controls (see Supplemental Table 1, https://links.lww.com/CTG/A913).

Table 1. - Baseline characteristics of nested control subjects by H. pylori seropositivity Characteristica H. pylori–seronegative (n = 745) H. pylori–seropositive (n = 377) Positive CagA virulence factor 0 (0.0) 172 (45.6) Blood type  O 171 (43.3) 83 (48.5)  Non-O 224 (56.7) 88 (51.5)  Missing 350 206 Mean age (SD), yr 62.0 (8.5) 63.9 (8.3) Female 526 (70.6) 249 (66.1) Race/ethnicity  White 705 (94.6) 326 (86.5)  Black 8 (1.1) 18 (4.8)  Other 26 (3.5) 30 (8.0)  Missing 6 (0.8) 3 (0.8) Prospective cohort  HPFS 122 (16.4) 57 (15.1)  NHS 199 (26.7) 99 (26.3)  PHS 97 (13.0) 71 (18.8)  WHI 275 (36.9) 133 (35.3)  WHS 52 (7.0) 17 (4.5) Body mass index, kg/m2  Mean (SD) 26.0 (4.8) 25.8 (4.1)  <18.5 8 (1.1) 3 (0.8)  18.5–24.9 347 (46.6) 160 (42.4)  25.0–29.9 254 (34.1) 152 (40.3)  ≥30.0 112 (15.0) 53 (14.1)  Missing 24 (3.22) 9 (2.4) Mean physical activity (SD), MET-hr/wk 18.7 (20.4) 17.3 (18.1) Tobacco use  Never 318 (42.7) 167 (44.3)  Past 323 (43.4) 166 (44.0)  Current 98 (13.2) 42 (11.1)  Missing 6 (0.8) 2 (0.5) Alcohol >1 drink/d 172 (23.1) 73 (19.4) History of diabetes mellitus 26 (3.5) 14 (3.7) Multivitamin use 282 (37.9) 165 (43.8)

CagA, cytotoxin-associated gene A; HPFS, Health Professionals Follow-up Study; MET-hr/wk, metabolic equivalent task-hour per week; NHS, Nurses' Health Study; PHS, Physicians' Health Study; WHI, Women's Health Initiative; WHS, Women's Health Study.

aData for categorical variables shown as number of participants (%).

No association was identified between H. pylori seropositivity and pancreatic cancer risk in age-adjusted (OR 0.87, 95% CI 0.69–1.11) or multivariable-adjusted (OR 0.83, 95% CI 0.65–1.06) analyses (Table 2). Furthermore, the associations were similar for H. pylori–positive, CagA-positive (OR 0.75, 95% CI 0.53–1.04) and H. pylori–positive, CagA-negative (OR 0.89, 95% CI 0.65–1.20) participants, compared with those who were H. pylori–negative. We next considered whether H. pylori seropositivity might be associated with pancreatic cancer risk in specific patient subgroups. In stratified analyses by other known pancreatic cancer risk factors, we found no statistically significant interactions with age, sex, BMI, or smoking history (Table 3). We next considered whether time between blood collection and cancer diagnosis might modify the association of H. pylori serology with pancreatic cancer risk. However, in stratified analyses by time between blood collection and diagnosis, we again identified no statistically significant interaction (Table 3). We also considered whether a pancreatic cancer diagnosis soon after blood collection might obscure an association of H. pylori with pancreatic cancer risk. Thus, we repeated the main analysis after excluding cases and matched controls who had blood collected <2 years before their cancer diagnosis. We again identified no association between H. pylori and pancreatic cancer risk (OR 0.81, 95% CI 0.62–1.05). We also performed a sensitivity analysis in which we excluded the 38 participants whose H. pylori serology was indeterminant or H. pylori and CagA serologies were discordant, and results were largely unchanged. In a second sensitivity analysis, we excluded cases and matched controls with a history of regular PPI or H2 blocker use, and results were again largely unchanged with an adjusted OR (95% CI) of 0.89 (0.68–1.16).

Table 2. - Association between H. pylori serology, CagA virulence factor serology, and pancreatic cancer risk H. pylori–seronegative H. pylori–seropositive Allc CagA− CagA+ No. of cases/controls 335/745 150/377 81/190 62/172 Age-adjusted OR (95% CI)a 1 (reference) 0.87 (0.69–1.11) 0.92 (0.68–1.25) 0.80 (0.57–1.11) Multivariable-adjusted OR (95% CI)b 1 (reference) 0.83 (0.65–1.06) 0.89 (0.65–1.20) 0.75 (0.53–1.04)

BMI, body mass index; CagA, cytotoxin-associated gene A; CI, confidence interval; OR, odds ratio.

aORs and 95% CIs estimated by conditional logistic regression conditioned on matching factors and adjusted for age at blood collection.

bMultivariable-adjusted analysis further adjusted for race (white, black, other, or missing), BMI (<18.5, 18.5–24.9, 25–29.9, or ≥30 kg/m2), history of diabetes (yes/no), and regular multivitamin use (yes/no).

cTwenty-two of the 527 H. pylori–seropositive individuals had indeterminant (20) or missing (2) CagA virulence factor serology data.


Table 3. - Stratified analyses of H. pylori serology and pancreatic cancer risk by participant characteristicsa Characteristic No. of cases/controls H. pylori–seronegative H. pylori–seropositive P interaction Age, yr 0.38  ≤63b 233/577 1 (reference) 0.94 (0.66–1.34)  >63 252/545 1 (reference) 0.75 (0.54–1.04) Sex 0.21  Female 343/775 1 (reference) 0.76 (0.57–1.02)  Male 142/347 1 (reference) 1.00 (0.66–1.53) Body mass index, kg/m2 0.35  18.5 to <25 205/507 1 (reference) 1.24 (0.86–1.78)  25 to <30 169/406 1 (reference) 0.59 (0.39–0.89)  ≥30 94/165 1 (reference) 0.73 (0.40–1.34) Tobacco use 0.95  Never 199/485 1 (reference) 0.84 (0.58–1.22)  Past 216/489 1 (reference) 0.81 (0.57–1.16)  Current 67/140 1 (reference) 0.94 (0.45–1.95) Time between blood collection and cancer diagnosis 0.80  ≤6.7 yrc 239/536 1 (reference) 0.87 (0.62–1.22)  >6.7 yr 246/586 1 (reference) 0.81 (0.58–1.13)

aUnconditional logistic regression adjusted for year of birth, cohort (which includes sex), smoking status (never, past, current, or missing), fasting status (fasting or nonfasting), month of blood draw, race (white, black, other, or missing), history of diabetes (yes/no), regular multivitamin use (yes/no), and BMI (<18.5, 18.5–24.9, 25–29.9, or ≥30 kg/m2).

bMedian age of combined cohorts at the time of blood collection.

cMedian time between blood collection and cancer diagnosis among cases.

We next considered whether the association between H. pylori serology and pancreatic cancer risk was modified by ABO blood type. First, we confirmed the association of ABO blood type and pancreatic cancer risk in the 916 nested case-control study participants with available ABO data. Participants with non-O blood type had an OR (95% CI) for pancreatic cancer of 1.33 (0.99–1.77), compared with those with O blood type. Next, we conducted a joint analysis of H. pylori serology and ABO blood type. No interaction was identified between H. pylori serology and ABO blood type in defining pancreatic cancer risk (P interaction = 0.51). Compared with the referent group who were H. pylori–seronegative and O blood type, those with non-O blood type had higher pancreatic cancer risk regardless of H. pylori serology, with ORs (95% CI) of 1.25 (0.88–1.76) for those who were H. pylori–seronegative and 1.38 (0.89–2.14) for those who were H. pylori–seropositive (Table 4).

Table 4. - Associations between H. pylori serology, ABO blood type, and pancreatic cancer risk H. pylori–seronegative (n = 642) H. pylori–seropositive (n = 274) O blood type  No. of cases/controls 95/171 41/83  Age-adjusted OR (95% CI)a 1 (reference) 0.91 (0.57–1.47)  Multivariable-adjusted OR (95% CI)b 1 (reference) 0.90 (0.55–1.46) Non-O blood type  No. of cases/controls 152/224 62/88  Age-adjusted OR (95% CI)a 1.24 (0.88–1.75) 1.38 (0.89–2.14)  Multivariable-adjusted OR (95% CI)b 1.25 (0.88–1.76) 1.38 (0.89–2.14)

CI, confidence interval; OR, odds ratio.

aUnconditional logistic regression adjusted for matching factors and age at blood collection.

bUnconditional logistic regression adjusted for matching factors, age at blood collection, race (white, black, other, or missing), Body Mass Index (<18.5, 18.5–24.9, 25–29.9, or ≥30 kg/m2), history of diabetes (yes/no), and regular multivitamin use (yes/no).


DISCUSSION

In a pooled analysis of participants from 5 prospective cohorts, we found no association between H. pylori serology and incident pancreatic cancer in age-adjusted or multivariable-adjusted analyses. The lack of association was similar when H. pylori–seropositive participants were further classified by presence or absence of the CagA virulence factor, and no effect modification was identified when considering subgroups defined by demographic factors or other exposures, such as age, BMI, or smoking history. Furthermore, results were similar when we considered time between blood collection and pancreatic cancer diagnosis. We again confirmed the association between ABO blood type and pancreatic cancer risk, but this association did not differ by H. pylori serology in our study participants.

Previous studies of H. pylori and pancreatic cancer risk have been reported with mixed results. A number of studies have suggested an increased risk of pancreatic cancer among those with positive H. pylori serology (32,33), but others have shown no association (6–8). Various mechanisms have been proposed to explain a potential association. Chronic H. pylori infection of the gastric body can cause atrophic gastritis that leads to achlorhydria and bacterial overgrowth. This bacterial overgrowth has been posited to increase catalyzation of N-nitroso compounds and production of carcinogens that translocate to the pancreas and increase risk of developing pancreatic cancer (34–37). Conversely, the hyperchlorhydria theory posits that when H. pylori infects the gastric antrum, it causes gastric hyperchlorhydria, which leads to increased pancreatic stimulation to produce bicarbonate, ductal epithelial cell proliferation, and greater risk of developing pancreatic cancer (38,39). Notably, the effect of H. pylori infection on gastric pH is complex. In the acute setting, H. pylori generally causes hypochlorhydria, but chronic infection can cause either hypochlorhydria or hyperchlorhydria, depending on the location of infection in the stomach. Although chronic antral-predominant infection is associated with hyperchlorhydria, H. pylori infection in the gastric corpus or pangastritis typically causes hypochlorhydria, and eradication can provoke hyperchlorhydria, often manifesting as development of gastroesophageal reflux disease and even Barrett's esophagus (40). Nevertheless, studies have not directly assessed pancreatic cancer risk in relation to gastric pH after H. pylori infection or location of chronic H. pylori infection within the stomach, and differences in these 2 factors may help explain differing results across previous work.

Previous studies have suggested that the association between H. pylori infection and pancreatic cancer risk may be present only for H. pylori strains that lack the CagA virulence factor, although results have been inconsistent (8,11). In line with the hyperchlorhydria theory of carcinogenesis, CagA-positive H. pylori is associated with corpus infection and hypochlorhydria, whereas CagA-negative H. pylori is more commonly associated with antral-predominant infection and hyperchlorhydria (41). We did not identify an association of H. pylori serology with pancreatic cancer regardless of CagA status in the current study. Notably, the cag genomic pathogenicity island (PAI) encodes up to 31 proteins, including the CagA protein (12), and differences in virulence may be present beyond what is identified by CagA serology (12,42). Therefore, although bacteria are deemed CagA-positive by serology, their behavior may differ with implications for disease associations.

It has been proposed that ABO blood group and H. pylori infection may interact in their associations with pancreatic cancer risk (43,44). Although it has been well established that non-O blood type is a risk factor for pancreatic cancer, the mechanism of this association remains unclear. Risch et al (9) hypothesized that 1 possible explanation for this association could involve H. pylori. The most efficient binding of H. pylori to the gastric surface occurs between H. pylori adhesins and blood group antigens on gastric mucins—primarily Lewis (b) antigens and H type 1 antigens associated with O blood type (20). Specifically, the BabA adhesin binds to the terminal Fucα1,2 residue, which is found on both of these antigen molecules. Through this binding, ABO blood group may influence H. pylori colonization of the gastric mucosa and thus affect its association with pancreatic cancer risk. However, our study showed no differential association of H. pylori and pancreatic cancer risk by ABO blood type.

The current study has several important strengths. Data were collected prospectively before cancer diagnosis, including information on lifestyle factors and comorbidities and measurement of H. pylori serologies. This prospective design, in addition to high rates of follow-up among participants, minimized confounding and selection bias. Measurement of H. pylori serologies from prediagnostic blood samples also minimized the impact of current cancer diagnosis on assay results. In sensitivity analyses, we further excluded cases diagnosed within 2 years of blood collection and their matched controls and did not see meaningful changes to risk estimates. ABO blood type was measured genetically for most participants within a large, rigorously controlled GWAS, which minimized misclassification because of locally conducted assays. Participants were drawn from 5 different large prospective U.S. cohort studies, improving generalizability of results.

There are several limitations to note. Prevalence of H. pylori, frequency of different strains, and rate of diagnosis and treatment vary around the world and even within the United States (12). This analysis included cohorts from the United States, and participants were predominantly white. Future studies might evaluate these associations in more diverse populations. We did not have data on duration of H. pylori infection or previous attempts at H. pylori treatment. Although it is known that most H. pylori infections occur in early childhood (4), we cannot be certain whether treatments for H. pylori might have lowered pancreatic cancer risk. Based on the proposed model of carcinogenesis involving chronic hyperchlorhydria from chronic H. pylori infection, it is possible that length of infection and eradication of infection may be important to fully define the relationship between H. pylori and pancreatic cancer. Similarly, use of acid-reducing medications such as PPIs and H2 blockers might be important confounders if chronic changes in stomach pH are driving the risk of carcinogenesis. We were unable to adjust for PPI and H2 blocker use in our regression models given scarcity of data. However, blood collection in our cohorts occurred in the 1980s and early to mid-1990s, likely predating common use of PPIs, the first of which was introduced in the late 1980s (45). In addition, sensitivity analysis excluding participants who reported taking these 2 classes of medications found no difference in association between H. pylori and incident pancreatic risk.

In conclusion, our findings did not support an association between history of H. pylori infection as determined by H. pylori seropositivity and risk of pancreatic cancer, regardless of CagA virulence factor status and ABO blood type. To further investigate these relationships, future studies should consider location of infection in the stomach by H. pylori and whether effective treatment for H. pylori was previously administered to eradicate infection.

CONFLICTS OF INTEREST

Guarantor of the article: Brian M. Wolpin, MD, MPH.

Specific author contributions: A.A.L., Q.W., C.S.F., C.Y., and B.M.W.: contributed to the conceptualization of this study. A.A.L., Q.W., J.K., H.D.S., J.E.B., E.L.G., M.J.S., P.K., C.S.F., C.Y., and B.M.W.: contributed to data curation. A.A.L., Q.W., and C.Y.: contributed to data analysis. H.D.S., J.E.B., J.E.M., E.L.G., M.J.S., P.K., C.S.F., and B.M.W.: contributed to funding acquisition. N.R.: contributed to sample assays. C.S.F., C.Y., and B.M.W.: contributed to supervision. A.A.L. and B.M.W.: contributed to writing the original draft. All authors contributed to reviewing and editing. All authors approved the final version of the manuscript.

Financial support: The Health Professionals Follow-up Study is supported by the National Institutes of Health (NIH) grant U01 CA167552. The Nurses' Health Study is supported by the NIH grants UM1 CA186107, P01 CA87969, and R01 CA49449. The Physicians' Health Study is supported by the NIH grants R01 CA097193, CA 34944, CA 40360, HL 26490, and HL 34595. The Women's Health Initiative program is funded by NIH through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. The Women's Health Study is supported by the NIH grants R01 CA047988, R01 HL043851, and R01 HL080467. This work was additionally supported by the NIH grant R01 CA205406 and the Broman Fund for Pancreatic Cancer Research to K.N.; by NIH grant U01 CA210171, NIH grant P50 CA127003, Hale Family Center for Pancreatic Cancer Research, Lustgarten Foundation Dedicated Laboratory Program, Stand Up To Cancer, Pancreatic Cancer Action Network, Noble Effort Fund, Wexler Family Fund, Parsons Fund for Pancreatic Cancer Early Detection, and Promises for Purple to B.M.W. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Potential competing interests: K.P. declares serving on advisory panel for Eisai and Helsinn Therapeutics/QED. C.S.F. reports consulting roles for Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi-Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck, and Taiho; he served as a Director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; he is a cofounder of EvolveImmune Therapeutics and has equity in this private company; he had provided expert testimony for Amylin Pharmaceuticals and Eli Lilly; he is an employee of Genentech and Roche. B.M.W. declares research funding from Celgene and Eli Lilly and Company and consulting for BioLineRx, Celgene, and GRAIL. Other authors declare no conflicts of interest.

IRB approval statement: The current study was approved by the institutional review boards of the Brigham and Women's Hospital and the Harvard T.H. Chan School of Public Health and those of participating registries as required, and participants provided informed consent.

Study Highlights

WHAT IS KNOWN ✓ Infection by Helicobacter pylori may act as a risk factor for pancreatic cancer, but studies have been inconsistent. ✓ The CagA virulence factor and ABO blood type may serve as important modifiers of the association between H. pylori infection and pancreatic cancer risk. WHAT IS NEW HERE ✓ A large nested case-control study of 5 prospective cohorts including 485 pancreatic cancer cases and 1122 matched controls showed no association between pre-diagnostic H. pylori antibody serology and incident risk for pancreatic cancer, regardless of CagA virulence factor status and ABO blood type. REFERENCES 1. Siegel RL, Miller KD, Fuchs HE, et al. Cancer statistics, 2022. CA Cancer J Clin 2022;72(1):7–33. 2. Klein AP. Pancreatic cancer epidemiology: Understanding the role of lifestyle and inherited risk factors. Nat Rev Gastroenterol Hepatol 2021;18(7):493–502. 3. Hooi JKY, Lai WY, Ng WK, et al. Global prevalence of Helicobacter pylori infection: Systematic review and meta-analysis. Gastroenterology 2017;153(2):420–9. 4. Herrera V, Parsonnet J. Helicobact

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