Low concentrations of medium-sized HDL particles predict incident CVD in chronic kidney disease patients

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional CVD risk factors cannot completely explain the increased risk. Altered HDL proteome is linked with incident CVD in CKD patients, but it is unclear whether other HDL metrics are associated with incident CVD in this population. In the current study, we analyzed samples from two independent prospective case-control cohorts of CKD patients, the Clinical Phenotyping and Resource Biobank Core (CPROBE) and the Chronic Renal Insufficiency Cohort (CRIC). We measured HDL particle sizes and concentrations (HDL-P) by calibrated ion mobility analysis and HDL cholesterol efflux capacity (CEC) by cAMP-stimulated J774 macrophages in 92 subjects from the CPROBE cohort (46 CVD and 46 controls) and in 91 subjects from the CRIC cohort (34 CVD and 57 controls). We tested associations of HDL metrics with incident CVD using logistic regression analysis. No significant associations were found for HDL-C or HDL-CEC in either cohort. Total HDL-P was only negatively associated with incident CVD in the CRIC cohort in unadjusted analysis. Among the six sized HDL subspecies, only medium-sized HDL-P was significantly and negatively associated with incident CVD in both cohorts after adjusting for clinical confounders and lipid risk factors with odds ratios (per 1-SD) of 0.45 (0.22–0.93, P = 0.032) and 0.42 (0.20–0.87, P = 0.019) for CPROBE and CRIC cohorts, respectively. Our observations indicate that medium-sized HDL-P—but not other-sized HDL-P or total HDL-P, HDL-C, or HDL-CEC—may be a prognostic cardiovascular risk marker in CKD.     

Cohort case-control design and analysis for clustered failure-time data

Cohort case-control design is an efficient and economical design to study risk factors for disease incidence or mortality in a large cohort. In the last few decades, a variety of cohort case-control designs have been developed and theoretically justified. These designs have been exclusively applied to the analysis of univariate failure-time data. In this work, a cohort case-control design adapted to multivariate failure-time data is developed. A risk set sampling method is proposed to sample controls from nonfailures in a large cohort for each case matched by failure time. This method leads to a pseudolikelihood approach for the estimation of regression parameters in the marginal proportional hazards model (Cox, 1972, Journal of the Royal Statistical Society, Series B 34, 187-220), where the correlation structure between individuals within a cluster is left unspecified. The performance of the proposed estimator is demonstrated by simulation studies. A bootstrap method is proposed for inferential purposes. This methodology is illustrated by a data example from a child vitamin A supplementation trial in Nepal (Nepal Nutrition Intervention Project-Sarlahi, or NNIPS).     

Designs for synthetic case-control studies in open cohorts

Several designs are proposed for case-control studies within cohorts when the cohort is open to late entry. These and previously proposed designs are examined with respect to consistency and efficiency of relative risk parameter estimation, and a small simulation study is reported. If study costs increase in proportion to the total number of "at-risk" controls, the most efficient design, Design C, is as follows. For a case failing at time t, controls are selected at random (and without regard to "at-risk" status) from among cohort members who are (i) known not to have failed prior to t and (ii) have not been previously selected as controls. At each t, control sampling proceeds until a prespecified number of controls who are "at risk" at t have been obtained. The efficiency advantage of Design C over that of the standard case-control design proposed by Thomas (in Appendix to Liddell, McDonald, and Thomas, 1977, Journal of the Royal Statistical Society, Series B 140, 469-490) will often be small. If, on the other hand, the costs increase in proportion to the number of distinct "at-risk" controls, Design C is no longer the most efficient design. In this case, several alternative designs are proposed.     

Proton pump inhibitors on pancreatic cancer risk and survival

BackgroundHypergastrinemia may promote the development and progression of pancreatic cancer. Proton pump inhibitor (PPI) therapy is known to cause hypergastrinemia. We sought to determine the association between PPI therapy and the risk of developing pancreatic cancer as well as survival following pancreatic cancer diagnosis.MethodsWe conducted a nested case-control study and a retrospective cohort study in The Health Improvement Network (THIN), a medical records database representative of the UK population. In the case-control study, each patient with incident pancreatic cancer was matched with up to four controls based on age, sex, practice site and both duration and calendar time of follow-up using incidence density sampling. The odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer risk associated with PPI use were estimated using multivariable conditional logistic regression. The retrospective cohort study compared the survival of pancreatic cancer patients according to their PPI exposure at the time of diagnosis. The effect of PPI use on pancreatic cancer survival was assessed using a multivariable Cox regression analysis.ResultsThe case-control study included 4113 cases and 16,072 matched controls. PPI use was more prevalent in cases than controls (53% vs. 26% active users). Adjusting for diabetes, smoking, alcohol use and BMI, PPI users including both former users and active users with longer cumulative PPI use had a higher risk of pancreatic cancer compared to non-users. When assessing survival following pancreatic cancer diagnosis, only short-term, active users had a modest decrease in survival.ConclusionsLong-term PPI therapy may be associated with pancreatic cancer risk. While PPI users recently started on treatment had a slightly worse survival, this result likely is from reverse causation.     

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 ± 16.7 years (mean ± SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.     

On the design of synthetic case-control studies

A design is proposed for "case-control within cohort" studies. In this design, controls are sampled without replacement from failure-free members of the cohort at each distinct failure time. Upon selection, a subject ceases to be eligible for control selection at later failure times. Also, if a subject failing at time t had been selected as a control at t' less than t, then the matched controls at t are selected to have also been at risk at t'. In these circumstances correlation exists between score statistic contributions at t and t'. An estimator is developed for this correlation. A small simulation study compares the design just described to other possible synthetic case-control designs.     

Tobacco smoking and alcohol consumption as risk factors for thymoma – A European case-control study

PurposeHardly anything is known about the aetiology of thymoma. This paper presents data regarding tobacco smoking and alcohol consumption in relation to thymoma from the first case-control study performed on this rare tumour.MethodsA European multi-centre case-control study including incident cases aged 35–69 years with thymoma between 1995 and 1997, was conducted in seven countries. A set of controls, used in seven parallel case-control studies by the same research group was used, including population-based controls from five countries and hospital controls with colon cancer from two countries. Altogether 103 cases, accepted by a reference pathologist, 712 colon cancer controls, and 2071 population controls were interviewed.ResultsTobacco smoking was moderately related with thymoma (OR 1.4, 95% CI 0.9–2.2), and a tendency to dose-response was shown (p = 0.04), with an increased risk for heavy smokers defined as ≥41 pack-years (OR 2.1, 95% CI 1.1–3.9). A high consumption of spirits defined as ≥25 g of alcohol per day was associated with an increased risk of thymoma (OR 2.4, 95% CI 1.1–5.4), whereas no association was found with beer or wine.ConclusionsTobacco smoking and a high intake of spirits were indicated as risk factors for thymoma.     

Corticosteroid Risk Function of Severe Infection in Primary Immune Thrombocytopenia Adults. A Nationwide Nested Case-Control Study

Corticosteroid (CS)-related infection risk in immune thrombocytopenia (ITP) is unknown. The aim of this study was to assess the adjusted CS risk function of severe infection in persistent or chronic primary ITP adults. We designed a nested case-control study in the FAITH cohort. This cohort is built through the French national health insurance database named SNIIRAM and includes all treated incident persistent or chronic primary ITP adults in France (ENCePP n°4574). Patients who entered the FAITH cohort between 2009 and 2012 were eligible (n = 1805). Cases were patients with infection as primary diagnosis code during hospitalization. Index date was the date of first hospitalization for infection. A 2:1 matching was performed on age and entry date in the cohort. Various CS exposure time-windows were defined: current user, exposure during the 1/3/6 months preceding index date and from the entry date. CS doses were converted in prednisone equivalent (PEQ). The cumulative CS doses were averaged in each time-window to obtain daily PEQ dosages. Each CS exposure definition was assessed using multivariate conditional regression models. During the study period, 161 cases (9 opportunistic) occurred. The model with the best goodness of fit was CS exposure during the month before the index date (OR: 2.48, 95% CI: 1.61–3.83). The dose-effect relation showed that the risk existed from averaged daily doses ≥5 mg PEQ (vs. <5 mg: 2.09, 95% CI: 1.17–3.71). The risk of infection was mainly supported by current or recent exposure to CS, even with low doses.     

Multilocus Heterozygosity and Coronary Heart Disease: Nested Case-Control Studies in Men and Women

BackgroundGeneralized allelic heterozygosity has been proposed to improve reproductive fitness and has been associated with higher blood pressure, but its association with chronic disease is not well characterized.MethodsUsing the Affymetrix Genome-Wide Human 6.0 array, we performed whole genome scans in parallel case-control studies of coronary heart disease (CHD) nested in the Health Professionals Follow-up Study and Nurses’ Health Study. We examined ~700,000 single nucleotide polymorphisms (SNPs) in 435 men with incident CHD and 878 matched controls and 435 women with incident CHD with 931 matched controls. We examined the relationship of genome-wide heterozygosity with risk of incident of CHD and with baseline levels of cardiovascular risk factors.ResultsIn both cohorts, approximately 227650 (SD 2000) SNPs were heterozygous. The number of heterozygous SNPs was not related to risk of CHD in either men or women (adjusted odds ratios per 2000 heterozygous SNPs 1.01 [95% confidence interval, 0.91-1.13] in women and 0.94 [0.84-1.06] in men). We also found no consistent associations of genome-wide heterozygosity with levels of lipids, inflammatory markers, adhesion molecules, homocysteine, adiponectin, or body-mass index.ConclusionsIn these parallel nested case-control studies, we found no relationship of multilocus heterozygosity with risk of CHD or its major risk factors. Studies in other populations are needed to rule out associations with lower levels of heterozygosity.     

Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population

Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease-associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 × 10⁻¹⁰) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 × 10⁻¹²). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI.     

Levelling-off of the risk of lung and bladder cancer in heavy smokers: an analysis based on multicentric case-control studies and a metabolic interpretation

The shape of the dose-response relationship between carcinogenic exposure and cancer risk is a key issue, both from a theoretical (models of carcinogenesis) and practical (risk assessment) point of view. Human populations exposed to Polycyclic Aromatic Hydrocarbons (PAH) via air pollution showed a non-linear relationship between levels of exposure and WBC-DNA adducts. Among highly exposed subjects, the DNA adduct level per unit of exposure was significantly lower than measured at environmental exposures. The same exposure-dose non-linearity was observed in lung DNA from rats exposed to PAH. We have analyzed 11 case-control studies on bladder cancer (4584 incident cases and 9360 hospital controls) and eight case-control studies on lung cancer (5092 incident cases and 6083 population controls), conducted in Europe in recent years. All the studies collected detailed information on smoking histories with a similar methodology. We have estimated the relationship between the number of cigarettes smoked and the risk of cancer, with and without adjustment by duration of smoking. We have observed a levelling-off of the relationship between the number of cigarettes smoked and the relative risks for lung and bladder cancer, both in men and women. The levelling-off occurred at an odds ratio of about 5 for bladder cancer, while it occurs at about 20 for lung cancer (in men). A potential explanation for such levelling-off involves metabolic pathways and individual susceptibility. It has been suggested that some metabolic polymorphisms exert an effect that is more important at low levels of exposure.     

Is Opium a Real Risk Factor for Esophageal Cancer or Just a Methodological Artifact? Hospital and Neighborhood Controls in Case-Control Studies

Background

Control selection is a major challenge in epidemiologic case-control studies. The aim of our study was to evaluate using hospital versus neighborhood control groups in studying risk factors of esophageal squamous cell carcinoma (ESCC).

Methodology/Principal Findings

We compared the results of two different case-control studies of ESCC conducted in the same region by a single research group. Case definition and enrollment were the same in the two studies, but control selection differed. In the first study, we selected two age- and sex-matched controls from inpatient subjects in hospitals, while for the second we selected two age- and sex-matched controls from each subject''s neighborhood of residence. We used the test of heterogeneity to compare the results of the two studies. We found no significant differences in exposure data for tobacco-related variables such as cigarette smoking, chewing Nass (a tobacco product) and hookah (water pipe) usage, but the frequency of opium usage was significantly different between hospital and neighborhood controls. Consequently, the inference drawn for the association between ESCC and tobacco use did not differ between the studies, but it did for opium use. In the study using neighborhood controls, opium use was associated with a significantly increased risk of ESCC (adjusted OR 1.77, 95% CI 1.17–2.68), while in the study using hospital controls, this was not the case (OR 1.09, 95% CI 0.63–1.87). Comparing the prevalence of opium consumption in the two control groups and a cohort enrolled from the same geographic area suggested that the neighborhood controls were more representative of the study base population for this exposure.

Conclusions/Significance

Hospital and neighborhood controls did not lead us to the same conclusion for a major hypothesized risk factor for ESCC in this population. Our results show that control group selection is critical in drawing appropriate conclusions in observational studies.     

Herd-level risk factors associated with tuberculosis breakdowns among cattle herds in England before the 2001 foot-and-mouth disease epidemic

A case-control study of the factors associated with the risk of a bovine tuberculosis (TB) breakdown in cattle herds was undertaken within the randomized badger culling trial (RBCT). TB breakdowns occurring prior to the 2001 foot-and-mouth disease epidemic in three RBCT triplets were eligible to be cases; controls were selected from the same RBCT area. Data from 151 case farms and 117 control farms were analysed using logistic regression. The strongest factors associated with an increased TB risk were movement of cattle onto the farm from markets or farm sales, operating a farm over multiple premises and the use of either covered yard or 'other' housing types. Spreading artificial fertilizers or farmyard manure on grazing land were both associated with decreased risk. These first case-control results from the RBCT will be followed by similar analyses as more data become available.     

Analysis of IL-6, STAT3 and HSPA1L Gene Polymorphisms in Anti-Tuberculosis Drug-Induced Hepatitis in a Nested Case-Control Study

Objectives

To investigate the association of IL-6, STAT3 and HSPA1L polymorphisms with the risk of anti-tuberculosis drug-induced hepatitis (ATDH) in Chinese Han population.

Methods

The study was designed as a nested case-control study within a prospective cohort. Each case was matched with four controls by sex, age at baseline (±5 years), treatment history, disease severity, drug dosage and place of sample collection. Genetic polymorphisms of IL-6, STAT3 and HSPA1L were determined blindly by TaqMan single-nucleotide polymorphism (SNP) genotyping assay. Odds ratio (OR) with 95% confidence intervals (CIs) was estimated by conditional logistic regression model to measure the association between selected SNPs and the risk of ATDH.

Results

A total of 89 incident ATDH cases and 356 ATDH-free controls were genotyped for IL-6 (rs2066992, rs2069837, rs1524107), STAT3 (rs1053004, rs1053023, rs1053005) and HSPA1L (rs2227956). In genotype analysis, no significant difference was observed in genotypes frequencies of the seven selected SNPs between case and control group after Bonferroni correction. In haplotype analysis, carriers with STAT3 GAT and AGC (rs1053023-rs1053005-rs1053004) haplotypes had a significantly higher risk of ATDH compared with wild-type haplotype (P<0.0001).

Conclusion

This study suggested that genetic variants of STAT3 might contribute to ATDH susceptibility in Chinese Han population. Studies in larger, varied populations are required to confirm these findings.     

Review of moderate alcohol consumption and reduced risk of coronary heart disease: is the effect due to beer,wine, or spirits.

OBJECTIVES: To review the effect of specific types of alcoholic drink on coronary risk. DESIGN: Systematic review of ecological, case-control, and cohort studies in which specific associations were available for consumption of beer, wine, and spirits and risk of coronary heart disease. SUBJECTS: 12 ecological, three case-control, and 10 separate prospective cohort studies. MAIN OUTCOME MEASURES: Alcohol consumption and relative risk of morbidity and mortality from coronary heart disease. RESULTS: Most ecological studies suggested that wine was more effective in reducing risk of mortality from heart disease than beer or spirits. Taken together, the three case-control studies did not suggest that one type of drink was more cardioprotective than the others. Of the 10 prospective cohort studies, four found a significant inverse association between risk of heart disease and moderate wine drinking, four found an association for beer, and four for spirits. CONCLUSIONS: Results from observational studies, where alcohol consumption can be linked directly to an individual''s risk of coronary heart disease, provide strong evidence that all alcoholic drinks are linked with lower risk. Thus, a substantial portion of the benefit is from alcohol rather than other components of each type of drink.     

β3-Adrenergic receptor Trp64Arg polymorphism does not predict incident CHD or carotid intima-media thickness in a community-based sample of whites: the ARIC study

The beta3-adrenergic receptor (beta3-AR) is expressed in adipose tissue and plays a significant role in controlling energy expenditure through the regulation of lipolysis and thermogenesis. The possible clinical importance of the beta3-AR Trp64Arg polymorphism has prompted us to investigate the association between it and the extent of atherosclerosis and risk of incident coronary heart disease (CHD). The ability of the beta3-AR Trp64Arg polymorphism to predict the extent of atherosclerosis and incident CHD has been evaluated in participants of the Atherosclerosis Risk in Communities (ARIC) study. Incident CHD cases (n=271) were compared with a stratified random sample of the ARIC cohort (n=700). Comparisons were also made between a group with increased intimamedia thickness (IMT) of the carotid artery walls, but without prevalent CHD (n=324), and a thin-walled control group (n=407). The frequency of the Arg64 allele was 0.081 and 0.069 in the incident CHD cases and cohort sample, respectively, and 0.062 and 0.057 in the IMT cases and thin-walled controls, respectively. Comparison of incident CHD cases and the cohort sample by Cox proportional hazards modeling indicated that the Arg64 allele was not a significant predictor of incident CHD, either alone (RR=0.99, P=0.98) or after inclusion of body mass index (BMI) and fasting insulin and glucose measurements (RR=1.02, P=0.93). A comparison of IMT cases and thin-walled controls by multivariate logistic regression analysis suggested that the Arg64 allele was not a significant predictor of carotid artery intima-media thickness when evaluated alone (OR=1.32, P=0.29) or after BMI and fasting insulin and glucose measurements were added to the model (OR=1.28, P=0.35). We infer that the beta3-AR Trp64Arg polymorphism is not a major predictor of atherosclerosis or incident CHD in this sample of middle-aged white Americans.     

Assessment of Type 1 Diabetes Risk Conferred by HLA-DRB1, INS-VNTR and PTPN22 Genes Using the Bayesian Network Approach

Background

Determining genetic risk is a fundamental prerequisite for the implementation of primary prevention trials for type 1 diabetes (T1D). The aim of this study was to assess the risk conferred by HLA-DRB1, INS-VNTR and PTPN22 single genes on the onset of T1D and the joint risk conferred by all these three susceptibility loci using the Bayesian Network (BN) approach in both population-based case-control and family clustering data sets.

Methodology/Principal Findings

A case-control French cohort, consisting of 868 T1D patients and 73 French control subjects, a French family data set consisting of 1694 T1D patients and 2340 controls were analysed. We studied both samples separately applying the BN probabilistic approach, that is a graphical model that encodes probabilistic relationships among variables of interest. As expected HLA-DRB1 is the most relevant susceptibility gene. We proved that INS and PTPN22 genes marginally influence T1D risk in all risk HLA-DRB1 genotype categories. The absolute risk conferred by carrying simultaneously high, moderate or low risk HLA-DRB1 genotypes together with at risk INS and PTPN22 genotypes, was 11.5%, 1.7% and 0.1% in the case-control sample and 19.8%, 6.6% and 2.2% in the family cohort, respectively.

Conclusions/Significance

This work represents, to the best of our knowledge, the first study based on both case-control and family data sets, showing the joint effect of HLA, INS and PTPN22 in a T1D Caucasian population with a wide range of age at T1D onset, adding new insights to previous findings regarding data sets consisting of patients and controls <15 years at onset.     

Blood Erythrocyte Concentrations of Cadmium and Lead and the Risk of B-Cell Non-Hodgkin’s Lymphoma and Multiple Myeloma: A Nested Case-Control Study

Background

Cadmium (Cd) and lead (Pb) are hypothesised to be risk factors for non-Hodgkin’s lymphoma (NHL), a group of haematological malignancies with a suspected environmental aetiology. Within the EnviroGenoMarkers study we utilised pre-diagnostic erythrocyte concentrations of Cd and Pb to determine whether exposure was associated with risk of B-cell NHL and multiple myeloma.

Methods

194 incident cases of B-cell NHL and 76 cases of multiple myeloma diagnosed between 1990 and 2006 were identified from two existing cohorts; EPIC-Italy and the Northern Sweden Health and Disease Study. Cases were matched to healthy controls by centre, age, gender and date of blood collection. Cd and Pb were measured in blood samples provided at recruitment using inductively coupled plasma-mass spectrometry. Logistic regression was applied to assess the association with risk. Analyses were stratified by cohort and gender and by subtype where possible.

Results

There was little evidence of an increased risk of B-cell NHL or multiple myeloma with exposure to Cd (B-cell NHL: OR 1.09 95%CI 0.61, 1.93, MM: OR 1.16 95% CI: 0.40, 3.40 ) or Pb (B-cell NHL: 0.93 95% CI 0.43, 2.02, multiple myeloma: OR 1.63 95%CI 0.45, 5.94) in the total population when comparing the highest to the lowest quartile of exposure. However, gender and cohort specific differences in results were observed. In females the risk of B-cell NHL was more than doubled in those with a body burden of Cd >1µg/L (OR 2.20 95%CI; 1.04, 4.65).

Conclusions

This nested case-control study does not support a consistent positive association between Cd or Pb and NHL, but there is some indication of a gender specific effect suggesting further research is warranted.     

H. pylori Seropositivity before Age 40 and Subsequent Risk of Stomach Cancer: A Glimpse of the True Relationship?

Stomach carcinogenesis involves mucosal and luminal changes that favor spontaneous disappearance of Helicobacter pylori. Therefore, the association between the infection and cancer risk might typically be underestimated. As acquisition of the infection almost invariably occurs before adulthood, the serostatus at age 16-40 should best reflect the lifetime occurrence of the infection. We therefore conducted a case-control study nested within a historic cohort of about 400,000 individuals who donated sera before age 40 to either of two large Swedish Biobanks between 1968 and 2006, and whose records were linked to complete nationwide registers. For each stomach adenocarcinoma case occurring at least 5 years after serum donation 2 controls were selected matched on age, sex and year of donation and biobank. Serum immunoglobulin G antibodies against H. pylori cell-surface antigens (Hp-CSAs) were measured with an enzyme-linked immunosorbent assay and antibodies against CagA with an immunoblot assay. Conditional logistic regression models were used to estimate odds ratios (ORs) for stomach adenocarcinoma among H. pylori infected relative to uninfected. We confirmed 59 incident cases of stomach adenocarcinoma (41 non-cardia tumors) during follow-up. ORs for non-cardia stomach adenocarcinoma among subjects with Hp-CSA antibodies (regardless of CagA serostatus), antibodies against CagA (regardless of Hp-CSA serostatus), and antibodies to both, relative to those who were seronegative to both, were 17.1 (95% confidence interval [CI] 4.0-72.9), 10.9 (95% CI 3.2-36.9), and 48.5 (95% CI 5.8-407.4), respectively. H. pylori infection is a much stronger risk factor for non-cardia stomach adenocarcinoma than initially realized. However, further studies are needed to answer whether it is a necessary cause, as the possibility of misclassification of H. pylori status could not be ruled out in our study.