Computational sentiment analysis of an online left ventricular assist device support forum: positivity predominates.

BACKGROUND: The impact of left ventricular assist device (LVAD) complications on the individual patient, overall sentiment, and its effect on referral patterns, is not fully understood. We sought to better understand patient attitudes towards LVAD therapy using a computational sentiment analysis approach. METHODS: Posts, comments, and titles were parsed from MyLVAD.com's HTML as a text file using custom Python scripts (version 3.6). Individual word frequency was computed with word classification as 'positive', 'negative', or 'neutral'. Data transformation and cleaning, sentiment determination, and analysis was performed with a binary dictionary package using R software (version 3.6). RESULTS: Sixty-six thousand eight hundred and twenty-one unique words were noted, including 4,623 (6.9%) with positive sentiment and 3,248 (4.8%) with negative sentiment. Net sentiment ratio [(number of positive words - number of negative words)/(number of total words)] was 2.1%. Positive sentiment dominated the 20 most commonly used words. Odds ratio of non-neutral words [(number of positive words/number of negative words)] was 1.42, indicating a less obvious disparity in sentiment when expanding analysis beyond the top 20 words. Word cloud analysis of positive and negative sentiments was performed, indicating common use of "infection" (208 mentions) compared to other complications such as "stroke" (29 mentions), "bleeding" (30 mentions), and "thrombosis" or "clot" (32 mentions). CONCLUSIONS: Positive sentiment dominates the most frequently used words, yet this disparity decreases when considering the totality of words. "Infection" is mentioned a disproportionate number of times compared to other LVAD complications. Further research is required to address analysis limitations, including selection bias.

Utilization of extracorporeal life support for diffuse alveolar damage and diffuse alveolar hemorrhage: A systematic review.

Modern extracorporeal life-support (ECLS) technology has been successfully utilized to treat patients with diffuse alveolar damage (DAD) and diffuse alveolar hemorrhage (DAH); however, reports in the literature remain scarce. We sought to pool existing evidence to better characterize ECLS use in these patients. An electronic search was conducted to identify all studies in the English literature reporting the use of ECLS for DAD/DAH. Thirty-two articles consisting of 38 patients were selected, and patient-level data were extracted and pooled for analysis. Median patient age was 36 [IQR: 27, 48] years, and the majority (63.2%) were female. Most common etiological factors included granulomatosis with polyangiitis (8/38, 21.1%), systemic lupus erythematosus (8/38, 21.1%), Goodpasture's syndrome (4/38, 10.5%), and microscopic polyangiitis (4/38, 10.5%). Immunologic markers included anti-neutrophil cytoplasmic antibody (ANCA) in 15/38 (39.5%), anti-nuclear antibody (ANA) in 6/38 (15.8%), and anti-glomerular basement membrane (anti-GBM) antibodies in 4/38 (10.5%). DAH was present in 32/38 (84.2%) of cases and DAD without evidence of DAH was present in 6/38 (15.8%) of cases. ECLS strategies included extracorporeal membrane oxygenation of veno-venous type (VV-ECMO) in 28/38 (73.7%), veno-arterial type (VA-ECMO) in 5/38 (13.2%), and one case of right ventricular assist device with oxygenator (RVAD-ECMO). Heparin was utilized in 18/38 (47.4%) of cases with no difference in use between DAH versus no DAH (P = .46) or VA- versus VV-ECLS (P = 1). Median duration of ECLS was 10 [5, 14] days. Pre- versus post-ECLS comparison of blood gases showed improvement in median PaO2 (49 [45, 59] mm Hg vs. 80 [70, 99] mm Hg, P < .001), PaO2:FiO2 ratio (48.2 [41.4, 54.8] vs. 182.0 [149.4, 212.2], P < .01), and pulse oximetry values (76% [72, 80] vs. 96% [94, 97], P = .086). Overall, 94.7% (36/38) of patients survived to decannulation while 30-day mortality was 10.5% (4/38) with no differences between VA- and VV-ECMO (P = 1 and P = .94, respectively). DAD/DAH occurs in a younger, predominantly female population, and tends to be associated with systemic autoimmune processes. ECLS, independent of its type, appears to result in favorable short-term survival.

Outcomes of Extracorporeal Life Support Use in Accidental Hypothermia: A Systematic Review.

BACKGROUND: Extracorporeal life support (ECLS) has been used in the treatment of accidental hypothermia with hemodynamic instability, with promising outcomes. This systematic review examines ECLS treatment of accidental hypothermia to assess outcomes. METHODS: An electronic search was performed to identify articles reporting ECLS use for treatment of accidental hypothermia. Only reports describing patients aged more than 16 years after January 1, 2005, were included. Nineteen studies were identified comprising 47 patients. Demographic information, perioperative variables, and outcomes were extracted for analysis. RESULTS: Median patient age was 48 years (interquartile range (IQR), 29 to 56), and 72.3% (34 of 47) were male. On presentation, median body temperature was 24.6°C (IQR, 22.2° to 26°C), median potassium level 4.3 mmol/L (IQR, 3.4 to 4.6 mmol/L), and median Glasgow Coma Scale score 3 (IQR, 3 to 7). Cardiac arrest occurred in 35 of 47 patients (74.5%). Median time to ECLS initiation from scene was 155 minutes (IQR, 113 to 245). Median ECLS duration was 18 hours (IQR, 4 to 27), with median rewarming rate of 2°C per hour (IQR, 1.5° to 4°). Median intensive care unit stay and hospital length of stay were 8 days (IQR, 2 to 16) and 17 days (IQR, 10 to 36), respectively. Inhospital mortality was 19.1% (9 of 47). Median discharge Glasgow Coma Scale score was 15 (IQR, 15 to 15) with minor long-term cognitive impairments noted in 6 of 47 patients (19.4%). Survival was significantly associated with potassium on presentation (P < .001), initial body temperature (P < .001), and ECLS rewarming rate (P < .001). CONCLUSIONS: Extracorporeal life support is a viable cardiac support option for rewarming patients with accidental hypothermia, and initial potassium level, initial body temperature, and ECLS rewarming rate appear to be significantly associated with survival.

Domino heart transplant following heart-lung transplantation: a systematic review and meta-analysis.

BACKGROUND: The domino-donor operation occurs when a "conditioned" heart from the heart-lung transplant (HLT) recipient is transplanted into a separate heart transplant (HT) recipient. The purpose of this systematic review was to investigate the indications and outcomes associated with the domino procedure. METHODS: An electronic search was performed to identify all prospective and retrospective studies on the domino procedure in the English literature. Eight studies reported 183 HLT recipients and 263 HT recipients who were included in the final analysis. RESULTS: HLT indications included cystic fibrosis in 58% (95% CI: 27-84%) of recipients, primary pulmonary hypertension (PPH) in 17% (95% CI: 12-24%), bronchiectasis in 5% (95% CI: 3-10%), emphysema in 5% (95% CI: 0-45%), and Eisenmenger's syndrome in 4% (95% CI: 2-8%). HT indications included ischemic heart disease in 40% (95% CI: 33-47%), non-ischemic disease in 39% (95% CI: 25-56%), and re-transplantation in 10% (95% CI: 1-59%). The pooled mean pulmonary vascular resistance (PVR) in HT recipients was 3.05 Woods units (95% CI: 0.14-5.95). The overall mortality in the HLT group was 28% (95% CI: 18-41%) at an average follow-up of 15.68 months (95% CI: 0.82-30.54), and 35% (95% CI: 17-58%) in the HT group at an average follow-up of 37.26 months (95% CI: 6.68-67.84). Freedom from rejection in HT was 94% (95% CI: 75-99%) at 1 month, 77% (95% CI: 30-96%) at 6 months, and 41% (95% CI: 33-50%) at 1 year. CONCLUSIONS: The domino procedure appears to be a viable option in properly selected patients that can be performed safely with acceptable outcomes.

Age of initiation of cigarette smoking and smokeless tobacco use among western Alaska Native people: Secondary analysis of the WATCH study.

OBJECTIVE: This study examined self-reported age of tobacco initiation (cigarette smoking and smokeless tobacco [ST] use) and explored potential sex and generational group influences on tobacco use onset among Alaska Native (AN) adult ever tobacco users. METHODS: Secondary analysis of consolidated data from the Western Alaska Tribal Collaborative for Health (WATCH) study comprised 2800 AN adult ever tobacco users (1490 women, 1310 men; mean age = 39.2 years) from two rural western Alaska regions. ST use data were limited to one region. Logistic regression was used to examine potential sex and generational group (age 18-29, 30-49, ≥50) effects on initiation at ≤13 years of age. RESULTS: Thirty-seven percent of the sample reported using any tobacco product by age 13 years. Initiation of any ST use by age 13 was greater than for cigarette smoking (52.7% vs. 18.2%), and women were more likely than men to report initiation of any ST use at ≤13 years (52.6% vs. 38.4%). Nearly one-third of ever smokers (31%) initiated in young adulthood (ages 18-29). For ST use, logistic regression analyses revealed significant sex differences (women more likely to initiate by 13 years of age than men) and generational group effects with younger and middle age groups more likely to report initiation ≤13 years compared to the eldest participants. For smoking, no sex differences were observed but the youngest generational group was more likely to report initiation by age 13 compared to the eldest group. CONCLUSIONS: Earlier age of tobacco initiation is found among younger generations of AN people. Findings highlight the need to focus prevention efforts on initiation of smoking in young adulthood and uptake of ST use among girls.

Association between iq'mik smokeless tobacco use and cardiometabolic risk profile among Yup'ik Alaska Native people.

OBJECTIVE: The traditional lifestyle of Yup'ik Alaska Native people, including a diet abundant in marine-based foods and physical activity, may be cardio-protective. However, iq'mik, a traditional form of smokeless tobacco used by >50% of Yup'ik adults, could increase cardiometabolic (CM) risk. Our objective was to characterize the associations between iq'mik use and biomarkers of CM status (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], triglycerides [TG], systolic blood pressure [SBP] and diastolic blood pressure [DBP], glycated hemoglobin [HbA1c], fasting blood glucose [FBG], waist circumference [WC], and body mass index [BMI]). DESIGN: We assessed these associations using data from a cross-sectional sample of Yup'ik adults (n = 874). Current iq'mik use, demographic, and lifestyle data were collected through interviews. Fasting blood samples were collected to measure LDL-C, HDL-C, TG, HbA1c, and FBG. SBP, DBP, WC, and BMI were obtained by physical examination. We characterized the association between current iq'mik use and continuous biomarkers of CM status using multiple approaches, including adjustment for measures of Yup'ik lifestyle and a propensity score. RESULTS: Based on either adjustment method, current iq'mik use was significantly and positively associated with at least 5% higher HDL-C, and significantly associated but in an inverse direction with multiple biomarkers of CM status including 7% lower TG, 0.05% lower HbA1c, 2% lower FBG, 4% lower WC, and 4% lower BMI. Observed associations for LDL-C, SBP, and DBP varied by adjustment method. CONCLUSIONS: This inverse association between iq'mik use and cardiometabolic risk status has not been previously reported. Additional research is needed to replicate these findings and explore physiological mechanisms and/or confounding factors.

High tobacco use prevalence with significant regional and sex differences in smokeless tobacco use among Western Alaska Native people: the WATCH study.

Tobacco use prevalence among Alaska Native (AN) people living in Alaska is greater than the general population prevalence statewide and nationally. Better understanding of regional tobacco use is needed to improve cessation efforts and reduce prevalence. Using self-reported baseline data from the Western Alaska Tribal Collaborative for Health study, we describe tobacco use patterns among AN people in two western Alaska regions. Data were stratified by age group and sex. Dual- and multi-product use in the Yukon-Kuskokwim (Y-K) region was stratified by concurrent vs sequential use. Overall, 87% of the cohort reported having used tobacco. In Norton Sound, cigarette (98%) was the predominant tobacco type. In Y-K 71% smoked, 76% used smokeless tobacco (ST), with 47% reporting use of both products. ST use in Y-K consisted of commercial ST and homemade iqmik. Y-K women reported more ST product use, while men reported more cigarette use. Among dual- and multi-product users, the majority reported concurrent use, with no significant differences between men and women. Distinct regional differences include high smoking prevalence in Norton Sound and frequent use of smoking and ST products in Y-K. Findings support modification of cessation programmes to address regional variations in tobacco use patterns.

Bi-cultural dynamics for risk and protective factors for cardiometabolic health in an Alaska Native (Yup'ik) population.

Alaska Native people experience disparities in mortality from heart disease and stroke. This work attempts to better understand the relationships between socioeconomic, behavioral, and cardiometabolic risk factors among Yup'ik people of southwestern Alaska, with a focus on the role of the socioeconomic, and cultural components. Using a cross-sectional sample of 486 Yup'ik adults, we fitted a Partial Least Squares Path Model (PLS-PM) to assess the associations between components, including demographic factors [age and gender], socioeconomic factors [education, economic status, Yup'ik culture, and Western culture], behavioral factors [diet, cigarette smoking and smokeless tobacco use, and physical activity], and cardiometabolic risk factors [adiposity, triglyceride-HDL and LDL lipids, glycemia, and blood pressure]. We found relatively mild associations of education and economic status with cardiometabolic risk factors, in contrast with studies in other populations. The socioeconomic factor and participation in Yup'ik culture had potentially protective associations with adiposity, triglyceride-HDL lipids, and blood pressure, whereas participation in Western culture had a protective association with blood pressure. We also found a moderating effect of participation in Western culture on the relationships between Yup'ik culture participation and both blood pressure and LDL lipids, indicating a potentially beneficial additional effect of bi-culturalism. Our results suggest that reinforcing protective effects of both Yup'ik and Western cultures could be useful for interventions aimed at reducing cardiometabolic health disparities.

Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for Thirteen Cancer Types.

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

My family medical history and me: feasibility results of a cardiovascular risk reduction intervention.

OBJECTIVE: Evaluate the feasibility and acceptability of a behaviorally focused intervention designed to increase perceived cardiovascular disease (CVD) and coronary heart disease (CHD) risk in young adults with a family history (FH) of CVD/CHD. DESIGN AND SAMPLE: Single group, pre-post-test design. Fifteen, mostly female (n = 13, 86.7%), White, young adults (mean age 20.8 years) with a minimum of a high school education with a FH of CVD/CHD. MEASURES: Feasibility examined the recruitment strategy, study procedures, appropriateness and quality of the study instruments, and problems that occurred during delivery of the intervention. Acceptability examined participants' engagement in the in person sessions and at home exercises and their feedback about the intervention. INTERVENTION: Two, in person sessions provided personalized, tailored messages about 10-year and lifetime CHD risk based on risk factors, FH from a three-generation pedigree, lipid levels, blood pressure, and smoking status, and brief counseling about how to engage in a healthy lifestyle to decrease CVD/CHD risk. RESULTS: The intervention was feasible and acceptable. Participants requested more information on healthy food choices, including which foods to avoid and which exercises most improve cardiovascular health. CONCLUSIONS: Although requiring refinement, the intervention has potential public health implications and deserves further testing.

Genome-wide association study identifies multiple susceptibility loci for pancreatic cancer.

We performed a multistage genome-wide association study including 7,683 individuals with pancreatic cancer and 14,397 controls of European descent. Four new loci reached genome-wide significance: rs6971499 at 7q32.3 (LINC-PINT, per-allele odds ratio (OR) = 0.79, 95% confidence interval (CI) 0.74-0.84, P = 3.0 × 10(-12)), rs7190458 at 16q23.1 (BCAR1/CTRB1/CTRB2, OR = 1.46, 95% CI 1.30-1.65, P = 1.1 × 10(-10)), rs9581943 at 13q12.2 (PDX1, OR = 1.15, 95% CI 1.10-1.20, P = 2.4 × 10(-9)) and rs16986825 at 22q12.1 (ZNRF3, OR = 1.18, 95% CI 1.12-1.25, P = 1.2 × 10(-8)). We identified an independent signal in exon 2 of TERT at the established region 5p15.33 (rs2736098, OR = 0.80, 95% CI 0.76-0.85, P = 9.8 × 10(-14)). We also identified a locus at 8q24.21 (rs1561927, P = 1.3 × 10(-7)) that approached genome-wide significance located 455 kb telomeric of PVT1. Our study identified multiple new susceptibility alleles for pancreatic cancer that are worthy of follow-up studies.

Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Genetic factors affecting statin concentrations and subsequent myopathy: a HuGENet systematic review.

Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, have proven efficacy in both lowering low-density-lipoprotein levels and preventing major coronary events, making them one of the most commonly prescribed drugs in the United States. Statins exhibit a class-wide side effect of muscle toxicity and weakness, which has led regulators to impose both dosage limitations and a recall. This review focuses on the best-characterized genetic factors associated with increased statin muscle concentrations, including the genes encoding cytochrome P450 enzymes (CYP2D6, CYP3A4, and CYP3A5), a mitochondrial enzyme (GATM), an influx transporter (SLCO1B1), and efflux transporters (ABCB1 and ABCG2). A systematic literature review was conducted to identify relevant research evaluating the significance of genetic variants predictive of altered statin concentrations and subsequent statin-related myopathy. Studies eligible for inclusion must have incorporated genotype information and must have associated it with some measure of myopathy, either creatine kinase levels or self-reported muscle aches and pains. After an initial review, focus was placed on seven genes that were adequately characterized to provide a substantive review: CYP2D6, CYP3A4, CYP3A5, GATM, SLCO1B1, ABCB1, and ABCG2. All statins were included in this review. Among the genetic factors evaluated, statin-related myopathy appears to be most strongly associated with variants in SLCO1B1.

All-cause, cardiovascular, and cancer mortality in western Alaska Native people: western Alaska Tribal Collaborative for Health (WATCH).

OBJECTIVES: We determined all-cause, cardiovascular disease (CVD), and cancer mortality in western Alaska Native people and examined agreement between death certificate information and adjudicated cause of deaths. METHODS: Data from 4 cohort studies were consolidated. Death certificates and medical records were reviewed and adjudicated according to standard criteria. We compared adjudicated CVD and cancer deaths with death certificates by calculating sensitivity, specificity, predictive values, and κ statistics. RESULTS: Men (n = 2116) and women (n = 2453), aged 18 to 95 years, were followed an average of 6.7 years. The major cause of death in men was trauma (25%), followed by CVD (19%) and cancer (13%). The major cause of death in women was CVD (24%), followed by cancer (19%) and trauma (8%). Stroke rates in both genders were higher than those of US Whites. Only 56% of deaths classified as CVD by death certificate were classified as CVD by standard criteria; discordance was higher among men (55%) than women (32%; κs = 0.4 and 0.7). CONCLUSIONS: We found lower rates for coronary heart disease death but high rates of stroke mortality. Death certificates overestimated CVD mortality; concordance between the 2 methods is better for cancer mortality. The results point to the importance of cohort studies in this population in providing data to assist in health care planning.

Family history of diabetes and pancreatic cancer as risk factors for pancreatic cancer: the PACIFIC study.

Genetic association studies have identified more than a dozen genes associated with risk of pancreatic cancer. Given this genetic heterogeneity, family history can be useful for identifying individuals at high risk for this disease. The goal of this analysis was to evaluate associations of family history of diabetes and family history of pancreatic cancer with risk of pancreatic cancer. PACIFIC is a case-control study based on two large health plans. Cases were diagnosed with pancreatic ductal adenocarcinoma (PDA) and controls were selected from the health plan enrollment databases and frequency matched to cases. Family history data were collected using an interviewer-administered questionnaire and were available on 654 cases and 697 controls. Logistic regression was used for the association analyses. First-degree relative history of diabetes was statistically significantly associated with increased risk of PDA [OR, 1.37; 95% confidence interval (CI), 1.10-1.71]. The highest risk of PDA was observed for an offspring with diabetes (OR, 1.95; 95% CI, 1.23-3.09). In addition, history of pancreatic cancer increased risk for PDA with an OR of 2.79 (95% CI, 1.44-4.08) for any first-degree relative history of pancreatic cancer. This population-based analysis showed that family history of diabetes was associated with increased risk of PDA and confirmed previous studies showing that first-degree family history of pancreatic cancer is associated with PDA. These results support the need for ongoing studies of genetic influences on pancreatic cancer in large samples and investigations of possible pleiotropic genetic effects on diabetes and pancreatic cancer.

Association study of type 2 diabetes genetic susceptibility variants and risk of pancreatic cancer: an analysis of PanScan-I data.

OBJECTIVE: To examine associations between recently identified common type 2 diabetes (T2D) susceptibility genetic variants and pancreatic cancer risk. METHODS: Using data on individuals of European ancestry from the Cancer Genetic Markers of Susceptibility PanScan-I study (1,763 pancreatic cancer cases and 1,802 controls), we tested associations for 37 T2D susceptibility variants with pancreatic cancer risk. Associations with pancreatic cancer were also tested for three composite T2D susceptibility measures, incorporating data on all 37 variants, and for ten additional variants related to T2D-related phenotypes, including fasting glucose and beta-cell function. RESULTS: Of the 37 T2D risk alleles, two showed nominally significant positive associations with pancreatic cancer risk (FTO rs8050136 per-allele OR = 1.12; CI: 1.02-1.23; MTNR1B rs1387153 OR = 1.11; CI: 1.00-1.23) and one showed an inverse association (BCL11A rs243021 OR = 0.88; CI: 0.80-0.97). The composite T2D susceptibility measures were not associated with pancreatic cancer. The glucose-raising allele of MADD rs11039149 was associated with increased risk of pancreatic cancer (OR = 1.14; CI: 1.03-1.27). CONCLUSIONS: Overall, these results do not provide strong evidence that common variants underling T2D or related phenotypes also affect pancreatic cancer risk; however, associations for FTO, MTNR1B, BCL11A, and MADD variants warrant further investigation in larger studies. Hypothesis-driven analyses of existing genome-wide genetic data can be cost-efficient and promising approaches for investigating genetic susceptibility to complex diseases.

Variant ABO blood group alleles, secretor status, and risk of pancreatic cancer: results from the pancreatic cancer cohort consortium.

BACKGROUND: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk. METHODS: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression. RESULTS: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63). CONCLUSIONS: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk. IMPACT: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34.

Association of diabetes susceptibility gene calpain-10 with pancreatic cancer among smokers.

OBJECTIVE: The objective of this study was to test the association between calpain-10 (CAPN10), a diabetes susceptibility gene, with risk of pancreatic cancer (PC). METHODS: DNA samples from 83 incident exocrine PC cases and 166 controls, all of whom were smokers, were genotyped for four markers of CAPN10 in a nested case-control study based on the Beta-Carotene and Retinol Efficacy Trial (CARET), a randomized chemoprevention trial of subjects at high risk of lung cancer. Controls were matched on sex, race, age, CARET intervention arm, duration of exposure to asbestos, and smoking history. Conditional logistic regression was used for statistical analyses. RESULTS: The minor allele of SNP-43 (rs3792267) in intron 3 was associated with increased risk of PC with an odds ratio of 1.57 (95%CI 1.03-2.38, p = 0.035) per allele. The three markers of the highest risk haplotype had an odds ratio of 1.98 (95%CI 1.12-3.49, p = 0.019) for risk of PC compared to the most common haplotype. There was no evidence of interaction between either of these associations by diabetes status. CONCLUSION: These results suggest that variation in CAPN10 may be associated with increased risk of PC among smokers. Thus, studies of genes associated with diabetes risk in PC are warranted in a larger population.

Association between the peroxisome proliferator-activated receptor gamma Pro12Ala variant and haplotype and pancreatic cancer in a high-risk cohort of smokers: a pilot study.

OBJECTIVES: The Pro12Ala variant in the peroxisome proliferator-activated receptor gamma (PPARG) gene has been associated with diabetes and several cancers. This pilot study tested for the association between Pro12Ala and pancreatic cancer risk in a high-risk sample of smokers. METHODS: A nested case-control study was conducted in 83 incident cases of pancreatic cancer and 166 matched controls originally recruited into a cohort chemoprevention study of lung cancer. Associations between Pro12Ala and pancreatic cancer risk were measured using conditional logistic regression. RESULTS: Carriers of the G allele (Ala) of the Pro12Ala variant had a borderline increased relative risk of pancreatic cancer compared with homozygous carriers of the C allele (Pro), with an odds ratio of 1.79 (95% confidence interval [CI], 0.96-3.33; P=0.06). Among subjects randomized to high-dose vitamin A, the odds ratio was 2.80 (95% CI, 1.16-6.74; P=0.02) versus 1.20 (95% CI, 0.45-3.23; P=0.71) in the placebo group. A haplotype including Pro12Ala was also significantly associated with pancreatic cancer risk in all subjects and in subjects randomized to vitamin A. CONCLUSIONS: This analysis presents the first evidence that PPARG may be associated with pancreatic cancer risk, and this candidate gene should be investigated in future, larger studies.