Iron, haemochromatosis genotypes, and risk of infections: a cohort study of 142,188 general population individuals.

It is unclear whether risk of infection is increased in individuals with hereditary haemochromatosis and in individuals with low or high plasma iron, transferrin saturation, or ferritin. Therefore, we tested whether high and low iron, transferrin saturation, and ferritin are associated with risk of infections observationally and genetically through HFE genotypes. We studied 142,188 Danish general population individuals. Iron, transferrin saturation, and ferritin were measured in 136,656, 136,599, and 38,020 individuals, respectively. HFE was genotyped for C282Y and H63D in 132,542 individuals. Median follow-up after study enrolment was 8 years(range:0-38years) for hospital and emergency room admissions with infections(n=20,394 individuals) using the National Patient Register, covering all Danish hospitals. Hazard ratios for any infection were 1.20(95%CI:1.12-1.28) and 1.14(1.07-1.22) in individuals with plasma iron≤5th or ≥95th percentile compared to individuals with iron from 26th-74th percentiles. Findings for transferrin saturation were similar, while infection risk was not increased in individuals with ferritin≤5th or ≥95th percentile. Hazard ratios in C282Y homozygotes versus non-carriers were 1.40(1.16-1.68) for any infection, 1.69(1.05-2.73) for sepsis, and 2.34(1.41-3.90) for death from infectious disease. Risk of infection was increased in C282Y homozygotes with normal plasma iron, transferrin saturation, or ferritin, and in C282Y homozygotes without liver disease, diabetes, and/or heart failure. In summary, low and high plasma iron and transferrin saturation were independently associated with increased infection risk. C282Y homozygotes had increased risk of any infection, sepsis, and death from infections. Even C282Y homozygotes with normal iron, transferrin saturation, or ferritin, not currently recommended for genotyping, had increased infection risk.

Attitudes towards risk-stratified breast cancer screening: a population-based survey among 5,001 Danish women.

BACKGROUND: The individual woman's risk of being diagnosed with breast cancer can now be estimated more precisely, and screening can be stratified accordingly. The risk assessment requires that women are willing to provide a blood test, additional personal information, to know their risk, and alter screening intervals. This study aimed to investigate Danish women's attitudes towards risk-stratified breast cancer screening. METHODS: An online, cross-sectional survey was conducted among Danish women aged 52-67 years. We used logistic regression analyses to assess how personal characteristics were associated with the women's attitudes. RESULTS: 5,001 women completed the survey (response rate 44%) of which 74% approved of risk estimation to potentially alter their screening intervals. However, only 42% would accept an extended screening interval if found to have low breast cancer risk, while 89% would accept a reduced interval if at high risk. The main determinants of these attitudes were age, education, screening participation, history of breast cancer, perceived breast cancer risk and to some extent breast cancer worry. CONCLUSION: This study indicates that women are positive towards risk-stratified breast cancer screening. However, reservations and knowledge among subgroups of women must be carefully considered and addressed before wider implementation of risk-stratified breast cancer screening in a national program.

Development and validation of a model to predict incident chronic liver disease in the general population: The CLivD score.

BACKGROUND & AIMS: Current screening strategies for chronic liver disease focus on detection of subclinical advanced liver fibrosis but cannot identify those at high future risk of severe liver disease. Our aim was to develop and validate a risk prediction model for incident chronic liver disease in the general population based on widely available factors. METHODS: Multivariable Cox regression analyses were used to develop prediction models for liver-related outcomes with and without laboratory measures (Modellab and Modelnon-lab) in 25,760 individuals aged 40-70 years. Their data were sourced from the Finnish population-based health examination surveys FINRISK 1992-2012 and Health 2000 (derivation cohort). The models were externally validated in the Whitehall II (n = 5,058) and Copenhagen City Heart Study (CCHS) (n = 3,049) cohorts. RESULTS: The absolute rate of incident liver outcomes per 100,000 person-years ranged from 53 to 144. The final prediction model included age, sex, alcohol use (drinks/week), waist-hip ratio, diabetes, and smoking, and Modellab also included gamma-glutamyltransferase values. Internally validated Wolbers' C-statistics were 0.77 for Modellab and 0.75 for Modelnon-lab, while apparent 15-year AUCs were 0.84 (95% CI 0.75-0.93) and 0.82 (95% CI 0.74-0.91). The models identified a small proportion (<2%) of the population with >10% absolute 15-year risk for liver events. Of all liver events, only 10% occurred in participants in the lowest risk category. In the validation cohorts, 15-year AUCs were 0.78 (Modellab) and 0.65 (Modelnon-lab) in the CCHS cohort, and 0.78 (Modelnon-lab) in the Whitehall II cohort. CONCLUSIONS: Based on widely available risk factors, the Chronic Liver Disease (CLivD) score can be used to predict risk of future advanced liver disease in the general population. LAY SUMMARY: Liver disease often progresses silently without symptoms and thus the diagnosis is often delayed until severe complications occur and prognosis becomes poor. In order to identify individuals in the general population who have a high risk of developing severe liver disease in the future, we developed and validated a Chronic Liver Disease (CLivD) risk prediction score, based on age, sex, alcohol use, waist-hip ratio, diabetes, and smoking, with or without measurement of the liver enzyme gamma-glutamyltransferase. The CLivD score can be used as part of health counseling, and for planning further liver investigations and follow-up.

Risk of ulcerative colitis and Crohn's disease in smokers lacks causal evidence.

Smoking has been associated with opposing risks of ulcerative colitis and Crohn's disease. Whether these observational associations reflect actual causal associations, confounding, or reverse causation is unclear. Using a Mendelian randomization approach, we tested the hypothesis that smoking protects against ulcerative colitis and is a cause of Crohn's disease. We included 118,683 white Danes aged ≥ 20 from the Copenhagen General Population Study (2003-2015) and the Copenhagen City Heart Study (1991-94 and 2001-03). During follow-up until 2018, we investigated the association of smoking and CHRNA3 rs1051730, where the T-allele is strongly associated with nicotine dependence, with risk of ulcerative colitis and Crohn's disease. We identified 1312 cases of ulcerative colitis and 671 cases of Crohn's disease. Compared to never-smokers, multivariable adjusted hazard ratios (HRs) for ulcerative colitis were 1.69(95% confidence interval [CI] 1.32-2.15) in former smokers and 2.27(1.74-2.96) in current smokers. Corresponding HRs for Crohn's disease were 1.31(0.93-1.84) and 1.93(1.34-2.78), respectively. Among ever-smokers when compared to non-carriers of the CHRNA3 rs1051730 T-allele, age and sex adjusted HRs for risk of ulcerative colitis were 1.03(95%CI 0.89-1.18) in heterozygotes and 0.91(0.72-1.16) in homozygotes. Corresponding HRs for Crohn's disease were 1.05(0.87-1.28) and 1.02(0.74-1.41), respectively. In a meta-analysis combined with UK Biobank, there was no evidence that CHRNA3 rs1051730 was associated with risk of ulcerative colitis or Crohn's disease. In conclusion, current versus never-smoking was associated with unexpected 2.3-fold risk of ulcerative colitis and expected 1.9-fold risk of Crohn's disease in prospective analyses; however, genetic evidence of lifelong increased smoking intensity did not support causal relationships.

Traditional and Non-traditional Cardiovascular Risk Factors and Cardiovascular Disease in Women with Psoriasis.

Women with cardiovascular disease are underdiagnos-ed, undertreated and under-represented in research. Even though the increased risk of cardiovascular disease among patients with psoriasis is well establi-shed, only a few studies have examined women with psoriasis. This study examined the prevalence of cardio-vascular risk factors and cardiovascular disease among women with psoriasis. Using the Copenhagen City Heart Study and the Copenhagen General Population Study, 66,420 women were included in a cross-sectional design. Of these, 374 (0.56%) women had hospital-diagnosed psoriasis. Women with vs with-out hospital-diagnosed psoriasis had higher odds ratios of having traditional cardiovascular risk factors, including hypertriglyceridaemia, smoking, obesity, type 2 diabetes, and low physical activity, and of having non-traditional cardiovascular risk factors, including low level of education, high level of psycho-social stress, and low-grade inflammation. Compared with women from the general population, the multi-variable adjusted odds ratio of heart failure and ischaemic cerebrovascular disease in women with hospital-diagnosed psoriasis was 2.51 (95% confidence interval 1.33-4.73) and 2.06 (1.27-3.35). In conclusion, women with hospital-diagnosed psoriasis have a higher prevalence of traditional and non- traditional cardiovascular risk factors, and increased risk of heart failure and ischaemic cerebrovascular disease, even after adjusting for these cardiovascular risk factors.

Reference intervals for 12 clinical laboratory tests in a Danish population: The Lolland-Falster Health Study.

Reference intervals (RIs), developed as part of the Nordic Reference Interval Project 2000 (NORIP) are widely used in most European laboratories. We aimed to examine the validity of the NORIP RIs by establishing RIs for 12 frequently used laboratory tests based on data from a local Danish population and compare these local RIs with the NORIP RIs. Using an a posteriori direct sampling approach, blood sample data were assessed from 11,138 participants aged 18+ years in the Lolland-Falster Health Study (LOFUS), of whom 2154 turned out to meet criteria for being healthy for inclusion in establishing RIs according to the NORIP methodology. The 2.5th and 97.5th percentiles were calculated for alanine aminotransferase (ALAT), albumin, alkaline phosphatase, bilirubin, creatinine, hemoglobin, high-density lipoprotein cholesterol, iron, low-density lipoprotein cholesterol, thrombocytes, total cholesterol, and triglycerides. When comparing our estimates with the NORIP, the lower reference limits (RLs) for bilirubin and iron were lower, and higher for ALAT, thrombocytes and triglycerides. Upper RLs were lower for albumin (males and females ≥70 years), bilirubin and iron, but higher for alkaline phosphatase, triglycerides and for creatinine in men. In LOFUS, approximately 20% of the participants were healthy and qualified for inclusion in the establishment of RIs. Several of the local RIs differed from the NORIP RIs.

Smoking and Increased White and Red Blood Cells.

Objective- Whether tobacco smoking causally affects white and red blood cells and thrombocyte counts is unknown. Using a Mendelian randomization approach, we tested the hypothesis that smoking causes increases in these blood cell indices. Approach and Results- We included 104 607 white Danes aged 20 to 100 years from the Copenhagen General Population Study with information on blood cell indices, smoking habits, and CHRNA3 (alpha 3 nicotinic cholinergic receptor) rs1051730 genotype, where the T allele causes higher tobacco consumption; 41 759 were former smokers and 17 852 current smokers. In multivariable adjusted observational analyses and compared with never smokers, white blood cells were associated with up to 19% increases, thrombocytes with up to 4.7% increases, and red blood cell indices with up to 2.3% increases in former and current smokers. All associations were dose dependent, with tobacco consumption but for white blood cells and thrombocytes also dependent on smoking cessation time in former smokers; highest increases were for <1-year smoking cessation and lowest increases for >10-year smoking cessation. In age- and sex-adjusted genetic analyses, percent differences per T allele increase in current smokers were 1.15% (95% CI, 0.61%-1.68%) for leukocytes, 1.07% (0.38%-1.76%) for neutrophils, 1.34% (0.66%-2.02%) for lymphocytes, 1.50% (0.83%-2.18%) for monocytes, -0.60% (-1.91% to 0.74%) for eosinophils, 0.17% (-0.94% to 1.29%) for basophils, 0.38% (-0.17% to 0.93%) for thrombocytes, 0.04% (-0.14% to 0.23%) for erythrocytes, 0.34% (0.17% to 0.50%) for hematocrit, 0.26% (0.09% to 0.43%) for hemoglobin, and 0.29% (0.18% to 0.41%) for mean corpuscular volume. Conclusions- Smoking causes increased blood leukocytes, neutrophils, lymphocytes, and monocytes, as well as increased hematocrit, hemoglobin, and mean corpuscular volume. The observational smoking relationships were long term for white blood cells and short term for red blood cell indices.

Incidental lymphopenia and mortality: a prospective cohort study.

BACKGROUND: It is unknown if incidental lymphopenia detected in the general population is associated with higher all-cause and cause-specific mortality. We aimed to identify the associations between lymphopenia and all-cause and cause specific mortality. METHODS: In a prospective cohort study, we examined and followed participants enrolled in the Copenhagen General Population Study between November 2003 and April 2015. In our analysis, we modelled risks using Cox proportional hazards regression for 3 groups: participants with a lymphocyte count below the 2.5th percentile; those with a lymphocyte count at or between the 2.5th and 97.5th percentiles (reference category); and those with a lymphocyte count above the 97.5th percentile. RESULTS: The cohort included 108 135 participants with a median age of 68 years. During a median follow-up of 9 (interquartile range [IQR] 0-14) years, 10 372 participants died. We found that participants with lymphopenia (lymphocyte count < 1.1 × 109/L) compared with those with a lymphocyte count in the reference range (1.1-3.7 × 109/L) had higher mortality with multivariable adjusted hazard ratios (HRs) of 1.63 (95% confidence interval [CI] 1.51-1.76) for all causes, 1.67 (95% CI 1.42-1.97) for nonhematologic cancers, 2.79 (95% CI 1.82-4.28) for hematologic cancers, 1.88 (95% CI 1.61-2.20) for cardiovascular diseases, 1.88 (95% CI 1.55-2.29) for respiratory diseases, 1.86 (95% CI 1.53-2.25) for infectious diseases, and 1.50 (95% CI 1.19-1.88) for other causes. For all-cause mortality, the highest absolute 2-year risks of death were observed in women (61%) and men (75%) who smoked and were aged 80 years or older with lymphocyte counts less than 0.5 × 109/L. Participants with a lymphocyte count higher than the reference category had increased mortality (adjusted HR 1.17, 95% CI 1.04-1.31). INTERPRETATION: We found that lymphopenia was associated with an increased risk of all-cause and cause-specific mortality.

Burden of prediabetes, undiagnosed, and poorly or potentially sub-controlled diabetes: Lolland-Falster health study.

BACKGROUND: This study aimed to investigate prevalence and risk factors for prediabetes, undiagnosed diabetes mellitus, poorly and potentially sub-controlled diabetes in a rural-provincial general adult population in Denmark. METHODS: Using cross-sectional data from the Lolland-Falster Health Study, we examined a total of 10,895 individuals aged 20 years and above. RESULTS: Prevalence of prediabetes was 5.8% (men: 6.1%; women: 5.5%); of undiagnosed diabetes 0.8% (men: 1.0%; women: 0.5%); of poorly controlled diabetes 1.2% (men: 1.5%; women: 0.8%); and of potentially sub-controlled diabetes 2% (men: 3.0%; women: 1.3%). In total, 9.8% of all participants had a diabetes-related condition in need of intervention; men at a higher risk than women; RR 1.41 (95% CI 1.26-1.58); person aged + 60 years more than younger; RR 2.66 (95% CI 2.34-3.01); obese more than normal weight person, RR 4.51 (95% CI 3.79-5.38); smokers more than non-smokers, RR 1.38 (95% CI 1.19-1.62); persons with self-reported poor health perception more than those with good, RR 2.59 (95% CI 2.13-3.15); low leisure time physical activity more than those with high, RR 2.64 (95% CI 2.17-3.22); and persons with self-reported hypertension more than those without, RR 3.28 (95% CI 2.93-3.68). CONCLUSIONS: In the Lolland-Falster Health Study, nearly 10% of participants had prediabetes, undiagnosed diabetes, poorly controlled, or potentially sub-controlled diabetes. The risk of these conditions was more than doubled in persons with self-reported poor health perception, self-reported hypertension, low leisure time physical activity, or measured obesity, and a large proportion of people with diabetes-related conditions in need of intervention can therefore be identified relatively easily.

Lymphopenia and risk of infection and infection-related death in 98,344 individuals from a prospective Danish population-based study.

BACKGROUND: Neutropenia increases the risk of infection, but it is unknown if this also applies to lymphopenia. We therefore tested the hypotheses that lymphopenia is associated with increased risk of infection and infection-related death in the general population. METHODS AND FINDINGS: Of the invited 220,424 individuals, 99,191 attended examination. We analyzed 98,344 individuals from the Copenhagen General Population Study (Denmark), examined from November 25, 2003, to July 9, 2013, and with available blood lymphocyte count at date of examination. During a median of 6 years of follow-up, they developed 8,401 infections and experienced 1,045 infection-related deaths. Due to the completeness of the Danish civil and health registries, none of the 98,344 individuals were lost to follow-up, and those emigrating (n = 385) or dying (n = 5,636) had their follow-up truncated at the day of emigration or death. At date of examination, mean age was 58 years, and 44,181 (44.9%) were men. Individuals with lymphopenia (lymphocyte count < 1.1 × 109/l, n = 2,352) compared to those with lymphocytes in the reference range (1.1-3.7 × 109/l, n = 93,538) had multivariable-adjusted hazard ratios of 1.41 (95% CI 1.28-1.56) for any infection, 1.31 (1.14-1.52) for pneumonia, 1.44 (1.15-1.79) for skin infection, 1.26 (1.02-1.56) for urinary tract infection, 1.51 (1.21-1.89) for sepsis, 1.38 (1.01-1.88) for diarrheal disease, 2.15 (1.16-3.98) for endocarditis, and 2.26 (1.21-4.24) for other infections. The corresponding hazard ratio for infection-related death was 1.70 (95% CI 1.37-2.10). Analyses were adjusted for age, sex, smoking status, cumulative smoking, alcohol intake, body mass index, plasma C-reactive protein, blood neutrophil count, recent infection, Charlson comorbidity index, autoimmune diseases, medication use, and immunodeficiency/hematologic disease. The findings were robust in all stratified analyses and also when including only events later than 2 years after first examination. However, due to the observational design, the study cannot address questions of causality, and our analyses might theoretically have been affected by residual confounding and reverse causation. In principle, fluctuating lymphocyte counts over time might also have influenced analyses, but lymphocyte counts in 5,181 individuals measured 10 years after first examination showed a regression dilution ratio of 0.68. CONCLUSIONS: Lymphopenia was associated with increased risk of hospitalization with infection and increased risk of infection-related death in the general population. Notably, causality cannot be deduced from our data.

Telomere length and depression: prospective cohort study and Mendelian randomisation study in 67 306 individuals.

BACKGROUND: Depression has been cross-sectionally associated with short telomeres as a measure of biological age. However, the direction and nature of the association is currently unclear. AIMS: We examined whether short telomere length is associated with depression cross-sectionally as well as prospectively and genetically. METHOD: Telomere length and three polymorphisms, TERT, TERC and OBFC1, were measured in 67 306 individuals aged 20-100 years from the Danish general population and associated with register-based attendance at hospital for depression and purchase of antidepressant medication. RESULTS: Attendance at hospital for depression was associated with short telomere length cross-sectionally, but not prospectively. Further, purchase of antidepressant medication was not associated with short telomere length cross-sectionally or prospectively. Mean follow-up was 7.6 years (range 0.0-21.5). The genetic analyses suggested that telomere length was not causally associated with attendance at hospital for depression or with purchase of antidepressant medication. CONCLUSIONS: Short telomeres were not associated with depression in prospective or in causal, genetic analyses.

Risk of breast cancer in relation to combined effects of hormone therapy, body mass index, and alcohol use, by hormone-receptor status.

BACKGROUND: Alcohol consumption, increased body mass index (BMI), and hormone therapy are risk factors for postmenopausal breast cancer, but their combined effects are not well understood. Because hormone therapy is effective for the relief of menopausal symptoms, the identification of "high-risk" users is important for therapeutic reasons. We investigated interactions between hormone therapy use and alcohol-use/high BMI status in relation to invasive breast cancer risk, both overall and according to estrogen receptor (ER) status. METHODS: Two Danish prospective cohorts were pooled, including 30,789 women ages 50+ years (study period 1981 to 2009). Information on risk factors was obtained in baseline questionnaires. We performed analyses using the Aalen additive hazards model. Serum estradiol and testosterone measurements were obtained in a subsample of approximately 1000 women. RESULTS: During 392,938 person-years of follow-up, 1579 women developed invasive breast cancer. Among nonusers of hormone therapy, the risk of breast cancer was slightly increased with overweight/obesity and increasing alcohol consumption. Compared with normal-weight nonusers, the risk of breast cancer was higher in hormone therapy users across all BMI strata (P for interaction = 0.003). A markedly higher risk of breast cancer was also observed for alcohol combined with hormone therapy use compared with abstinent nonusers (P for interaction = 0.02). These effects were primarily restricted to ER-positive cases. Combined effects of hormone therapy/high BMI and hormone therapy/alcohol on serum estradiol and testosterone supported the hypothesis of a hormonal pathway linking these exposures to breast cancer. CONCLUSION: These analyses suggest an increased risk of breast cancer associated with hormone therapy use-a risk that may be particularly strong among women consuming alcohol.

Self-Reported Health as Predictor of Allostatic Load and All-Cause Mortality: Findings From the Lolland-Falster Health Study.

Objectives: The aim was to determine the association between self-reported health (SRH), allostatic load (AL) and mortality. Methods: Data derived from the Lolland-Falster Health Study undertaken in Denmark from 2016-2020 (n = 14,104). Median follow-up time for death was 4.6 years where 456 participants died. SRH was assessed with a single question and AL by an index of ten biomarkers. Multinomial regression analysis were used to examine the association between SRH and AL, and Cox regression to explore the association between SRH, AL and mortality. Results: The risk of high AL increased by decreasing level of SRH. The ratio of relative risk (RRR) of having medium vs. low AL was 1.58 (1.11-2.23) in women reporting poor/very poor SRH as compared with very good SRH. For men it was 1.84 (1.20-2.81). For high vs. low AL, the RRR was 2.43 (1.66-3.56) in women and 2.96 (1.87-4.70) in men. The hazard ratio (HR) for all-cause mortality increased by decreasing SRH. For poor/very poor vs. very good SRH, the HR was 6.31 (2.84-13.99) in women and 3.92 (2.12-7.25) in men. Conclusion: Single-item SRH was able to predict risk of high AL and all-cause mortality.

Tumor suppressor p53 Arg72Pro polymorphism and longevity, cancer survival, and risk of cancer in the general population.

p53 is an important tumor suppressor, normally preventing cancer development via apoptosis. A genomic Arg72Pro substitution in the p53 protein has important influence on cell death via apoptosis, which could be beneficial. We therefore tested the hypotheses that this polymorphism influences longevity, survival after a cancer diagnosis, and risk of cancer in the general population. We examined a cohort of 9,219 participants ages 20-95 from the Danish general population with 100% follow-up. The overall 12-yr survival was increased in p53 Arg/Pro heterozygotes with 3% (P = 0.003) and in Pro/Pro homozygotes with 6% (P = 0.002) versus Arg/Arg homozygotes, corresponding to an increase in median survival of 3 yr for Pro/Pro versus Arg/Arg homozygotes. We also demonstrated an increased survival after the development of cancer, or even after the development of other life-threatening diseases, for Pro/Pro versus Arg/Arg homozygotes. The Arg72Pro substitution did not associate with decreased risk of cancer. In conclusion, in this large cohort from the general population, we show that a well-known functional single nucleotide polymorphism in the tumor suppressor p53 protein leads to increased longevity, but not to decreased risk of cancer. The increased longevity may be due to increased survival after a diagnosis of cancer or other life-threatening diseases.

Smoking is an independent but not a causal risk factor for moderate to severe psoriasis: A Mendelian randomization study of 105,912 individuals.

Background: Smoking is strongly associated with higher risk of psoriasis in several observational studies; however, whether this association is causal or can be explained by confounding or reverse causation is not fully understood. Randomized controlled trials are the gold standard when examining causality; however, when this method is not feasible, the Mendelian randomization design is an alternative. Herein genetic variants can be used as robust proxies for modifiable exposures and thereby avoiding confounding and reverse causation.In this study, we hypothesized that smoking is an independent and causal risk factor for psoriasis and tested this using a Mendelian randomization design. Methods: We used data from the Copenhagen General Population Study including 105,912 individuals with full information on lifestyle factors, biochemistry, and genotype data. In total, 1,240 cases of moderate to severe psoriasis were included to investigate the association between smoking and psoriasis. To assess causality of the association, we used the genetic variant CHRNA3 rs1051730, where the T-allele is strongly associated with high lifelong cumulative smoking, as a proxy for smoking. Results: In observational analyses, the multivariable adjusted hazard ratio of developing moderate to severe psoriasis was 1.64 (95% confidence interval: 1.35-2.00) in ever smokers with ≤ 20 pack-years and 2.23 (1.82-2.73) in ever smokers with > 20 pack-years compared to never smokers. In genetic analyses, the odds ratio of developing moderate to severe psoriasis was 1.05 (0.95-1.16) per CHRNA3 rs10511730 T-allele in ever smokers. Conclusion: Smoking was an independent risk factor for moderate to severe psoriasis in observational analyses. However, using a genetic variant as a robust proxy for smoking, we did not find this association to be causal.

Changing Smoking Behavior and Epigenetics: A Longitudinal Study of 4,432 Individuals From the General Population.

BACKGROUND: Hypomethylation of the aryl hydrocarbon receptor repressor (AHRR) gene indicates long-term smoking exposure and might therefore be a monitor for smoking-induced disease risk. However, studies of individual longitudinal changes in AHRR methylation are sparse. RESEARCH QUESTION: How does the recovery of AHRR methylation depend on change in smoking behaviors and demographic variables? STUDY DESIGN AND METHODS: This study included 4,432 individuals from the Copenhagen City Heart Study, with baseline and follow-up blood samples and smoking information collected approximately 10 years apart. AHRR methylation at the cg05575921 site was measured in bisulfite-treated leukocyte DNA. Four smoking groups were defined: participants who never smoked (Never-Never), participants who formerly smoked (Former-Former), participants who quit during the study period (Current-Former), and individuals who smoked at both baseline and follow-up (Current-Current). Methylation recovery was defined as the increase in AHRR methylation between baseline and follow-up examination. RESULTS: Methylation recovery was highest among participants who quit, with a median methylation recovery of 5.58% (interquartile range, 1.79; 9.15) vs 1.64% (interquartile range, -1.88; 4.96) in the Current-Current group (P < .0001). In individuals who quit smoking, older age was associated with lower methylation recovery (P < .0001). In participants who quit aged > 65 years, methylation recovery was 5.9% at 5.6 years after quitting; methylation recovery was 8.5% after 2.8 years for participants who quit aged < 55 years. INTERPRETATION: AHRR methylation recovered after individuals quit smoking, and recovery was more pronounced and occurred faster in younger compared with older interim quitters.

Development and validation of a simple general population lung cancer risk model including AHRR-methylation.

INTRODUCTION: Screening reduces lung cancer mortality of high-risk populations. Currently proposed screening eligibility criteria only identify half of those individuals, who later develop lung cancer. This study aimed to develop and validate a sensitive and simple model for predicting 10-year lung cancer risk. METHODS: Using the 1991-94 examination of The Copenhagen City Heart Study in Denmark, 6,820 former or current smokers from the general population were followed for lung cancer within 10 years after examination. Logistic regression of baseline variables (age, sex, education, chronic obstructive pulmonary disease, family history of lung cancer, smoking status and cumulative smoking, secondhand smoking, occupational exposures to dust and fume, body mass index, lung function, plasma C-reactive protein, and AHRR(cg05575921) methylation) identified the best predictive model. The model was validated among 3,740 former or current smokers from the 2001-03 examination, also followed for 10 years. A simple risk chart was developed with Poisson regression. RESULTS: Age, sex, education, smoking status, cumulative smoking, and AHRR(cg05575921) methylation identified 65 of 88 individuals who developed lung cancer in the validation cohort. The highest risk group, consisting of less educated men aged >65 with current smoking status and cumulative smoking >20 pack-years, had absolute 10-year risks varying from 4% to 16% by AHRR(cg05575921) methylation. CONCLUSION: A simple risk chart including age, sex, education, smoking status, cumulative smoking, and AHRR(cg05575921) methylation, identifies individuals with 10-year lung cancer risk from below 1% to 16%. Including AHRR(cg05575921) methylation in the eligibility criteria for screening identifies smokers who would benefit the most from screening.

Non-alcoholic fatty liver disease is not a causal risk factor for psoriasis: A Mendelian randomization study of 108,835 individuals.

Background: Psoriasis is observationally associated with a higher risk of non-alcoholic fatty liver disease (NAFLD); however, the causal relationship between the two diseases remains unclear. Objective: We hypothesized that individuals with NAFLD or elevated liver fat content have higher risk of psoriasis and that NAFLD is a causal risk factor for psoriasis. We tested this using a Mendelian randomization approach. Methods: We included 108,835 individuals from the Danish general population, including 1,277 individuals with psoriasis and 802 individuals with NAFLD according to ICD codes. To estimate liver fat content, a subset of the participants (N = 7,416) also had a CT scan performed. First, we tested whether a diagnosis of NAFLD or elevated liver fat content was observationally associated with risk of psoriasis. Subsequently, we used the genetic variants PNPLA3 and TM6SF2, both strongly associated with NAFLD and high liver fat content, to test whether NAFLD was causally associated with increased risk of psoriasis. Results: Observationally, individuals with vs. without a diagnosis of NAFLD had higher risk of psoriasis with an odds ratio of 2.03 (95% confidence interval 1.28-3.21). The risk of psoriasis increased in a stepwise manner with increasing liver fat content with an odds ratio of 5.00 (2.63-9.46) in individuals in the highest quartile of liver fat content compared to individuals in the lowest quartile. In genetic analyses, PNPLA3 and TM6SF2 were both associated with increased risk of NAFLD but not with increased risk of psoriasis. Conclusion: Observationally, a diagnosis of NAFLD or elevated liver fat content was associated with higher risk of psoriasis. However, using genetic variants as a proxy for NAFLD, we did not find evidence of a causal relationship between NAFLD and psoriasis. Thus, the observational association between NAFLD and psoriasis is presumably a result of shared confounding factors or reverse causation.

Allostatic load as predictor of mortality: a cohort study from Lolland-Falster, Denmark.

OBJECTIVES: The purposes of the present study were to determine the association between (1) 10 individual biomarkers and all-cause mortality; and between (2) allostatic load (AL), across three physiological systems (cardiovascular, inflammatory, metabolic) and all-cause mortality. DESIGN: Prospective cohort study. SETTING: We used data from the Lolland-Falster Health Study undertaken in Denmark in 2016-2020 and used data on systolic blood pressure (SBP) and diastolic blood pressure (DBP), pulse rate (PR), waist-hip ratio (WHR) and levels of low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), triglycerides, glycated haemoglobin A1c (HbA1c), C-reactive protein (CRP) and serum albumin. All biomarkers were divided into quartiles with high-risk values defined as those in the highest (PR, WHR, triglycerides, HbA1c, CRP) or lowest (HDL-c, albumin) quartile, or a combination hereof (LDL-c, SBP, DBP). The 10 biomarkers were combined into a summary measure of AL index. Participants were followed-up for death for an average of 2.6 years. PARTICIPANTS: We examined a total of 13 725 individuals aged 18+ years. PRIMARY OUTCOME MEASURE: Cox proportional hazard regression (HR) analysis were performed to examine the association between AL index and mortality in men and women. RESULTS: All-cause mortality increased with increasing AL index. With low AL index as reference, the HR was 1.33 (95% CI: 0.89 to 1.98) for mid AL, and HR 2.37 (95% CI: 1.58 to 3.54) for high AL. CONCLUSIONS: Elevated physiological burden measured by mid and high AL index was associated with a steeper increase of mortality than individual biomarkers.

Pre- and Perioperative Inflammatory Biomarkers in Older Patients Resected for Localized Colorectal Cancer: Associations with Complications and Prognosis.

The association between pre- and perioperative inflammatory biomarkers, major complications, and survival rates after resection of colorectal cancer (CRC) in older patients is largely unknown. The aim was to investigate age-dependent differences in these associations. Serum CRP, IL-6, and YKL-40 were measured preoperatively and on the first and second day after resection of CRC (stages I-III) in 210 older (≥70 years) and 191 younger patients (<70 years). The results from the complications was presented as an odds ratio (OR, with a 95% confidence interval (CI)) with logistic regression. Results from the mortality rates were presented as a hazard ratio (HR, with a 95% CI) using Cox proportional hazards regression. The preoperative inflammatory biomarkers were higher in the older vs. the younger patients. The risk of complications was increased in older patients with a high preoperative CRP (OR = 1.25, 95% CI 1.03-1.53), IL-6 (OR = 1.57, 95% CI 1.18-2.08), and YKL-40 (OR = 1.66, 95% CI 1.20-2.28), but not in younger patients. Mortality was higher in younger patients with high preoperative YKL-40 (HR = 1.66, 95% CI 1.06-2.60). This was not found in older patients. Elevated preoperative inflammatory biomarkers among older patients were associated with an increased risk of complications, but not mortality. Preoperative inflammatory biomarkers may be useful in assessing the risk of a complicated surgical course in older patients with CRC.