Germline BRCA2 K3326X and CHEK2 I157T mutations increase risk for sporadic pancreatic ductal adenocarcinoma.

Rare truncating BRCA2 K3326X (rs11571833) and pathogenic CHEK2 I157T (rs17879961) variants have previously been implicated in familial pancreatic ductal adenocarcinoma (PDAC), but not in sporadic cases. The effect of both mutations in important DNA repair genes on sporadic PDAC risk may shed light on the genetic architecture of this disease. Both mutations were genotyped in germline DNA from 2,935 sporadic PDAC cases and 5,626 control subjects within the PANcreatic Disease ReseArch (PANDoRA) consortium. Risk estimates were evaluated using multivariate unconditional logistic regression with adjustment for possible confounders such as sex, age and country of origin. Statistical analyses were two-sided with p values <0.05 considered significant. K3326X and I157T were associated with increased risk of developing sporadic PDAC (odds ratio (ORdom ) = 1.78, 95% confidence interval (CI) = 1.26-2.52, p = 1.19 × 10-3 and ORdom = 1.74, 95% CI = 1.15-2.63, p = 8.57 × 10-3 , respectively). Neither mutation was significantly associated with risk of developing early-onset PDAC. This retrospective study demonstrates novel risk estimates of K3326X and I157T in sporadic PDAC which suggest that upon validation and in combination with other established genetic and non-genetic risk factors, these mutations may be used to improve pancreatic cancer risk assessment in European populations. Identification of carriers of these risk alleles as high-risk groups may also facilitate screening or prevention strategies for such individuals, regardless of family history.

Common breast cancer risk alleles and risk assessment: a study on 35 441 individuals from the Danish general population.

Background: We hypothesized that common breast cancer risk alleles are associated with incidences of breast cancer and other cancers in the general population, and identify low risk women among those invited for screening mammography. Participants and Methods: About 35 441 individuals from the Danish general population were followed in Danish health registries for up to 21 years after blood sampling. After genotyping 72 breast cancer risk loci, each with 0­2 alleles, the sum for each individual was calculated. We used the simple allele sum instead of the conventional polygenic risk score, as it is likely more sensitive in detecting associations with risks of other endpoints than breast cancer. Results: Breast cancer incidence in the 19 010 women was increased across allele sum quintiles (log-rank trend test; P = 1×10 − 12), but not incidence of other cancers (P = 0.41). Age- and study-adjusted hazard ratio for the fifth versus the first allele sum quintile was 1.82 (95% confidence interval; 1.53­2.18). Corresponding hazard ratios per allele were 1.04 (1.03­1.05) and 1.05 (1.02­1.08) for breast cancer incidence and mortality, similar across risk factors. In 50-year-old women, the starting age for screening mammography in Denmark, the average 5-year breast cancer risk was 1.5%, overall and 1.1%, 1.4%, 1.6%, 1.7%, 2.1%, for the first through fifth quintile, respectively. Based on age, nulliparity, familial history, and allele sum, 25% of women aged 50­69 years, and 94% of women aged 40­49 years, had absolute 5-year breast cancer risks ≤ 1.5%. Using polygenic risk score led to similar results. Conclusion: Common breast cancer risk alleles are associated with incidence and mortality of breast cancer in the general population, but not with other cancers. After including breast cancer allele sum in risk assessment, 25% of women currently being offered screening mammography had an absolute 5-year risk below the cutoff of average risk for a 50-year-old woman.

Asthma, other atopic conditions and risk of infections in 105 519 general population never and ever smokers.

BACKGROUND: Individuals with atopic conditions may have increased susceptibility to infections outside the organs directly affected by their atopic condition. OBJECTIVE: We tested the hypothesis that atopic conditions overall, and stratified by smoking history, are associated with increased risk of hospitalization for infections. METHODS: We collected information on smoking history and self-reported atopic conditions from 105 519 individuals from the general population and followed them for up to 23 years for infectious disease hospitalizations and deaths. For asthma, we focused on never smokers with asthma diagnosed before age 50 (early asthma) to minimize confounding by chronic obstructive pulmonary disease. RESULTS: During follow-up, 11 160 individuals had infections. Never smokers with early asthma versus no atopic conditions had significantly increased risks of any infection (hazard ratio 1.65; 95% confidence interval 1.40-1.94), pneumonia (2.44; 1.92-3.11) and any non-respiratory tract infection (1.36; 1.11-1.67); results were similar in ever smokers. Never smokers with any asthma had significantly increased risks of any infection (1.44; 1.24-1.66) and pneumonia (1.99; 1.62-2.44). Neither atopic dermatitis (1.00; 0.91-1.10) nor hay fever (1.00; 0.93-1.07) was associated with risk of any infection. In never smokers, risk estimates for any infection were comparable between asthma and diabetes, as were the population attributable fractions of 2.2% for any asthma and 2.9% for diabetes. CONCLUSION: Early asthma was associated with significantly increased risks of any infection, pneumonia and any non-respiratory tract infection in never and ever smokers. In never smokers, risk estimates as well as population attributable fractions for any infection were comparable between asthma and diabetes, suggesting that asthma may be a substantial risk factor for infections in the general population.

Role of inflammatory marker YKL-40 in the diagnosis, prognosis and cause of cardiovascular and liver diseases.

This review summarizes present evidence for the role of YKL-40 in the diagnosis, prognosis and cause of cardiovascular and alcoholic liver disease. The question of whether YKL-40 is merely a marker or a causal factor in the development of cardiovascular and liver disease is addressed, with emphasis on the Mendelian randomization design. The Mendelian randomization approach uses genetic variants associated with lifelong high plasma YKL-40 levels that are largely unconfounded and not prone to reverse causation. Thus, the approach mimics a controlled double-blind randomized trial, but it uses genetic variants rather than a drug and placebo, and like a blinded trial, it allows inference about causality. Moreover, the review also covers background on the molecular biology and functions of YKL-40, YKL-40 levels in healthy individuals and reference range, and the role of YKL-40 as a biomarker of cardiovascular and alcoholic liver disease. YKL-40 is a plasma protein named after its three N-terminal amino acids, Y (tyrosine), K (lysine) and L (leucine), and its molecular weight of 40 kDa. It is produced by local inflammatory cells in inflamed tissues, such as lipid-laden macrophages inside the vessel wall and perhaps also hepatic stellate cells. Observational studies show that plasma YKL-40 levels are elevated in patients with cardiovascular and liver disease and are associated with disease severity and prognosis. Furthermore, elevated plasma YKL-40 levels in apparently healthy individuals are associated with a 2-fold increased risk of future ischemic stroke and venous thromboembolism, but not with myocardial infarction, suggesting that YKL-40 could play a role in the formation of embolisms rather than atherosclerosis per se. Further, elevated YKL-40 levels combined with excessive alcohol consumption are associated with 10-years risk of alcoholic liver cirrhosis of up to 7%, suggesting that YKL-40 can be used as a strong noninvasive marker of predicting alcoholic liver cirrhosis. Importantly, in Mendelian randomization studies, genetically elevated plasma YKL-40 levels were not associated with risk of cardiovascular and alcoholic liver disease, thus suggesting that plasma YKL-40 does not play a causal role in the development of these diseases. Despite this, plasma YKL-40 levels may play a role in disease progression after diagnosis, and inhibition of YKL-40 activity might be a novel therapy in some cardiovascular and liver diseases.

IgE and risk of cancer in 37 747 individuals from the general population.

BACKGROUND: Immunoglobulin E (IgE) is produced by plasma cells, often as part of an allergic immune response. It is currently unknown whether plasma IgE levels are associated with risk of cancer in individuals from the general population. We tested the hypothesis that high levels of plasma total IgE are associated with overall risk of cancer and with risk of specific cancers. MATERIALS AND METHODS: Plasma total IgE was measured in 37 747 individuals from the general population, and the participants were followed prospectively for up to 30 years. All statistical tests were two-sided. RESULTS: During a mean follow-up of 7 years, a first cancer was diagnosed in 3454 participants. The multivariable adjusted hazard ratio for a 10-fold higher level of IgE was 1.05 [95% confidence interval (CI) 1.00-1.11; P = 0.04] for any cancer, 0.44 (0.30-0.64; P = 0.00002) for chronic lymphocytic leukemia (CLL), 0.53 (0.33-0.84; P = 0.007) for multiple myeloma, 1.54 (1.04-2.29; P = 0.03) for other non-Hodgkin lymphoma, 1.38 (1.04-1.84; P = 0.03) for cancer of the oral cavity and pharynx, and 1.12 (1.00-1.25; P = 0.05) for lung cancer. The findings for CLL and multiple myeloma were generally robust; however, after correcting for 27 multiple comparisons only the finding for CLL remained significant. CONCLUSION: High levels of plasma total IgE were associated with low risk of CLL and possibly of multiple myeloma, without convincing evidence for high risk of any cancer type.

Plasma testosterone in the general population, cancer prognosis and cancer risk: a prospective cohort study.

BACKGROUND: Testosterone is an important anabolic hormone in humans and in vitro testosterone stimulates growth of lung and colon cancer cells. We tested the hypothesis that plasma testosterone associate with increased risk of cancer and with increased risk of early death after cancer. MATERIALS AND METHODS: Plasma testosterone was measured in 8771 20- to 94-year-old men and women who participated in a prospective study of the general population. Participants were included in 1981-1983 and followed for a median of 22 years (range: 0-30 years). RESULTS: During follow-up, 1140 men and 809 women developed cancer. For risk of early death after cancer, for men, after adjustment for age at diagnosis, tumour stage at diagnosis, and time since blood-sampling, the hazard ratio was 1.30 [95% confidence interval (CI) 1.03-1.65] for the 2nd quintile, 1.31 (1.02-1.67) for the 3rd quintile, 1.52 (1.19-1.93) for the 4th quintile, and 1.52 (1.20-1.91) for the 5th quintile, versus the 1st quintile. For women, corresponding hazard ratios were 1.09 (0.81-1.46), 1.17 (0.86-1.59), 1.03 (0.76-1.39), and 1.80 (1.32-2.46). For risk of cancer, multifactorially adjusted hazard ratios for risk of any cancer were 1.07 (95% CI 0.98-1.18) and 1.06 (0.93-1.22) for men and women, respectively, when testosterone doubled. For both men and women, a doubling of testosterone was not associated with risk of any cancer type. CONCLUSIONS: In this prospective study of 8771 men and women from the general population followed for >30 years, increased levels of testosterone were associated with a 30%-80% increased risk of early death after cancer, but unchanged risk of incident cancer.

Telomeres and human health.

Telomeres are the tips of chromosomes and consist of proteins and hexanucleotide tandem repeats of DNA. The DNA repeats are shortened at each mitotic division of normal cells, and the telomere length chronicles how many divisions the cell has undergone. Thus, telomere length is a marker of fundamental biological pathways. It has been possible to measure telomere length for more than 20 years, and it has been established that telomere length is associated with age, sex and lifestyle factors. Here, the current knowledge of telomere length as a biomarker of disease susceptibility and mortality will be reviewed. In addition, technical difficulties and the reasons why measurement of telomeres has still not been introduced into routine clinical practice will be discussed. Findings from recent studies conducted in many thousands of individuals indicate that telomere length is not-or at best only marginally-independently associated with risk of common disorders such as cardiovascular, pulmonary and neoplastic diseases. However, in sufficiently powered studies, short telomeres are repeatedly and independently found to be associated with increased risk of early death in the general population or in subsets of individuals. This indicates that measurement of telomeres could be a valuable prognostic biomarker in many clinical settings. However, whether short telomeres are a causal factor for or simply a marker of increased risk of early death must be determined. Finally, how Mendelian randomization studies could clarify this issue, and which clinical studies might be carried out to refine this very promising biomarker for routine clinical use will be considered.

Cancer risk by combined levels of YKL-40 and C-reactive protein in the general population.

BACKGROUND: YKL-40 and C-reactive protein (CRP) are biomarkers that may reflect cancer-related subclinical inflammation. We assessed elevated YKL-40 and CRP levels as combined risk predictors for cancer. METHODS: We measured plasma YKL-40 and CRP at baseline in 8706 individuals from the Danish general population. RESULTS: Hazard ratio (HR) of gastrointestinal cancer for a doubling of YKL-40 levels was 1.37 (95% CI: 1.17-1.61) and indifferent to adjustment for CRP levels. Hazard ratio of lung cancer for a doubling of CRP levels was 1.35 (1.17-1.56) and indifferent to adjustment for YKL-40 levels. Compared to individuals with both low CRP (<1.7 mg l(-1)) and YKL-40 (<154 µg l(-1)), individuals with high YKL-40 but low CRP had an HR of gastrointestinal cancer of 3.36 (1.70-6.64), whereas individuals with high CRP but low YKL-40 had an HR of lung cancer of 2.19 (1.24-3.87). The area under the receiver operating characteristic (ROC) curve was 0.68 for the ability of YKL-40 to predict gastrointestinal cancer and 0.67 for the ability of CRP to predict lung cancer. CONCLUSION: Elevated YKL-40 levels are associated with increased risk of gastrointestinal cancer, independently of CRP levels, whereas elevated CRP levels are associated with increased risk of lung cancer, independently of YKL-40 levels.

Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population.

Glutathione-S-transferase T1 (GSTT1) and GSTM1 detoxify carcinogens and thus potentially contribute to inter-individual susceptibility to cancer. We determined the ability of GST copy number variation (CNV) to predict the risk of cancer in the general population. Exact copy numbers of GSTT1 and GSTM1 were measured by real-time PCR in 10 247 individuals, of whom 2090 had cancer. In men, the cumulative incidence of prostate cancer increased and the cumulative 5-year survival decreased with decreasing GSTT1 copy numbers (trends=0.02). The hazard ratios (HRs) (95% CIs) for prostate cancer and for death after prostate cancer diagnosis were, respectively, 1.2 (0.8-1.8) and 1.2 (0.6-2.1) for GSTT1*1/0, and 1.8 (1.1-3.0) and 2.2 (1.1-4.4) for GSTT1*0/0 versus GSTT1*1/1. In women, the cumulative incidence of corpus uteri cancer increased with decreasing GSTT1 copy numbers (trend=0.04). The HRs for corpus uteri cancer were, respectively, 1.8 (1.0-3.2) and 2.2 (1.0-4.6) for GSTT1*1/0 and GSTT1*0/0 versus GSTT1*1/1. Finally, the cumulative incidence of bladder cancer increased, and the cumulative 5-year survival decreased, with decreasing GSTM1 copy numbers (P=0.03-0.05). The HRs for bladder cancer were, respectively, 1.5 (0.7-3.2) and 2.0 (0.9-4.3) for GSTM1*1/0 and GSTM1*0/0 versus GSTM1*1/1. The HR for death after bladder cancer diagnosis was 1.9 (1.0-3.7) for GSTM1*0/0 versus GSTM1*1/0. In conclusion, exact CNV in GSTT1 and GSTM1 predict incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer.

Elevated plasma YKL-40 and risk of infectious disease: a prospective study of 94665 individuals from the general population.

OBJECTIVES: YKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population. METHODS: We prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections. RESULTS: For YKL-40 percentile category 91-100% versus 0-33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50-1.96; p 4 × 10-14) for any infection, 1.97 (1.64-2.37; p 4 × 10-13) for bacterial pneumonia, 1.62 (1.24-2.11; p 0.002) for urinary tract infection, 1.74 (1.31-2.32; p 2 × 10-4) for skin infection, 1.76 (1.25-2.46; p 0.004) for sepsis, 1.90 (1.29-2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38-5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint. DISCUSSION: Baseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.

Common polymorphisms in CYP2C9, subclinical atherosclerosis and risk of ischemic vascular disease in 52,000 individuals.

Cytochrome P450 2C9 (CYP2C9) enzymes metabolize warfarin and arachidonic acid. We hypothesized that the CYP2C9(*)2 (rs.1799853) and CYP2C9(*)3 (rs.1057910) polymorphisms with decreased enzyme activity affect risk of subclinical atherosclerosis (reduced ankle brachial index and increased C-reactive protein), ischemic vascular diseases (ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease and ischemic stroke) and death after an ischemic heart disease diagnosis. We genotyped the Copenhagen City Heart Study, a prospective study including 10 398 participants with 30-32 years of follow-up; the Copenhagen General Population Study, a cross-sectional study including 21 629 participants; and the Copenhagen Ischemic Heart Disease Study, a case-control study including 5082 cases and 14 904 controls. CYP2C9 carriers versus noncarriers did not associate with subclinical atherosclerosis. Furthermore, the odds/hazard ratios for ischemic vascular disease did not differ from 1.0 for CYP2C9 carriers versus noncarriers. Finally, we found no altered risk of early death after a diagnosis of ischemic heart disease. For all end points, we could exclude even minor changes in risk of disease with 90% power. In conclusion, in three independent studies totaling more than 52 000 individuals, we found no association between CYP2C9(*)2 and CYP2C9(*)3 polymorphisms and risk of subclinical atherosclerosis, ischemic vascular disease or death after ischemic heart disease.

Increased risk of ovarian cancer in integrin beta3 Leu33Pro homozygotes.

We previously demonstrated that integrin beta(3) Leu33Pro homozygotes have an increased risk of cancer, possibly most pronounced for ovarian cancer. We now test the latter hypothesis in case-control and prospective studies. We genotyped 463 Danish women with ovarian cancer, and 4291 women from the Danish general population. Calculation of odds ratios by conditional logistic regression was performed in the case-control study (n = 463 + 3543), and of ovarian cancer incidence, log-rank statistics and hazard ratios by Cox regression in the prospective study (n = 4291) with 9.5-year follow-up. In the case-control study matched for age and marital status, the odds ratio for ovarian cancer in homozygotes versus non-carriers was 1.6 (95% confidence interval: 1.0-2.6). In the prospective study with 28 incident ovarian cancers, non-carriers and homozygotes had incidences of 7 (4-11) and 30 (10-92) per 10 000 person-years (log-rank P = 0.02). The age-adjusted hazard ratio for ovarian cancer in homozygotes versus non-carriers was 3.9 (1.1-13). Risk of ovarian cancer did not differ between heterozygotes and non-carriers in either study. Integrin beta(3) Leu33Pro homozygotes have an increased risk of ovarian cancer.

Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome.

We report the isolation of the 5' flanking region of GRAF (GTPase regulator associated with the focal adhesion kinase), previously described as a putative tumour suppressor gene of acute myelogenous leukaemia and myelodysplastic syndrome, and demonstrate its promoter activity in reporter gene assays. Two putative protein-binding sites are identified of which one was sensitive to CpG methylation. The suppressed GRAF expression could be restored in leukaemia cell lines by treatment with a demethylating agent and an inhibitor of histone deacetylases. In contrast to normal tissues, which tested negative for GRAF promoter methylation, 11 of 29 (38%) bone marrow samples from patients with acute myeloid leukaemia or myelodysplastic syndrome were positive.

No association of breast cancer risk with integrin beta3 (ITGB3) Leu33Pro genotype.

To pursue a borderline increased risk of breast cancer for carriers of two integrin beta(3) (ITGB3) 33Pro alleles found in a recent prospective study, we conducted a case-control study of 1088 women with breast cancer and 4815 female controls. Leu33Pro heterozygotes, homozygotes and heterozygotes+homozygotes vs noncarriers had odds ratios for breast cancer of 1.0 (95% confidence interval: 0.8-1.1), 0.8 (0.5-1.2) and 1.0 (0.8-1.1), respectively. After stratification for conventional risk factors, odds ratio for breast cancer in heterozygotes, homozygotes and heterozygotes+homozygotes vs noncarriers were not increased above 1.0 in any of the 14 strata examined. This was also true after stratification for tumour histological subtype and cancer stage at the time of diagnosis.