Shoaib Afzal

Mortality Attributable to Smoking Among HIV-1–Infected Individuals: A Nationwide, Population-Based Cohort Study

BACKGROUND We assessed mortality attributable to smoking among patients with human immunodeficiency virus (HIV). METHODS We estimated mortality rates (MRs), mortality rate ratios (MRRs), life expectancies, life-years lost, and population-attributable risk of death associated with smoking and with HIV among current and nonsmoking individuals from a population-based, nationwide HIV cohort and a cohort of matched HIV-negative individuals. RESULTS A total of 2921 HIV patients and 10 642 controls were followed for 14 281 and 45 122 person-years, respectively. All-cause and non-AIDS-related mortality was substantially increased among smoking compared to nonsmoking HIV patients (MRR, 4.4 [95% confidence interval {CI}, 3.0-6.7] and 5.3 [95% CI, 3.2-8.8], respectively). Excess MR per 1000 person-years among current vs nonsmokers was 17.6 (95% CI, 13.3-21.9) for HIV patients and 4.8 (95% CI, 3.2-6.4) for controls. A 35-year-old HIV patient had a median life expectancy of 62.6 years (95% CI, 59.9-64.6) for smokers and 78.4 years (95% CI, 70.8-84.0) for nonsmokers; the numbers of life-years lost in association with smoking and HIV were 12.3 (95% CI, 8.1-16.4) and 5.1 (95% CI, 1.6-8.5). The population-attributable risk of death associated with smoking was 61.5% among HIV patients and 34.2% among controls. CONCLUSIONS In a setting where HIV care is well organized and antiretroviral therapy is free of charge, HIV-infected smokers lose more life-years to smoking than to HIV. The excess mortality of smokers is tripled and the population-attributable risk of death associated with smoking is doubled among HIV patients compared to the background population.

Low 25-Hydroxyvitamin D and Risk of Type 2 Diabetes: A Prospective Cohort Study and Metaanalysis

BACKGROUND Vitamin D deficiency has been implicated in decreased insulin secretion and increased insulin resistance, hallmarks of type 2 diabetes mellitus. We tested the hypothesis that low plasma 25-hydroxyvitamin D [25(OH)D] is associated with increased risk of type 2 diabetes in the general population. METHODS We measured 25(OH)D in 9841 participants from the general population, of whom 810 developed type 2 diabetes during 29 years of follow-up. Analyses were adjusted for sex, age, smoking status, body mass index, income, physical activity, HDL cholesterol, and calendar month of blood draw. RESULTS Lower 25(OH)D concentrations, by clinical categories or seasonally adjusted quartiles, were associated with higher cumulative incidence of type 2 diabetes (trend, P = 2×10(-7) and P = 4×10(-10)). Multivariable adjusted hazard ratios of type 2 diabetes were 1.22 (95% CI 0.85-1.74) for 25(OH)D <5 vs ≥20 μg/L and 1.35 (1.09-1.66) for lowest vs highest quartile. Also, the multivariable adjusted hazard ratio of type 2 diabetes for a 50% lower concentration of 25(OH)D was 1.12 (1.03-1.21); the corresponding hazard ratio for those ≤58 years old was 1.26 (1.15-1.41). Finally, in a metaanalysis of 16 studies, the odds ratio for type 2 diabetes was 1.50 (1.33-1.70) for the bottom vs top quartile of 25(OH)D. CONCLUSIONS We observed an association of low plasma 25(OH)D with increased risk of type 2 diabetes. This finding was substantiated in a metaanalysis.

Genetically low vitamin D concentrations and increased mortality: mendelian randomisation analysis in three large cohorts

Objective To test the hypothesis that genetically low 25-hydroxyvitamin D concentrations are associated with increased mortality. Design Mendelian randomisation analysis. Setting Copenhagen City Heart Study, Copenhagen General Population Study, and Copenhagen Ischemic Heart Disease Study. Participants 95 766 white participants of Danish descent from three cohorts, with median follow-up times of 19.1, 5.8, and 7.9 years, genotyped for genetic variants in DHCR7 and CYP2R1 affecting plasma 25-hydroxyvitamin D concentrations; 35 334 also had plasma 25-hydroxyvitamin D measurements. Participants were followed from study entry through 2013, during which time 10 349 died. Main outcome measures All cause mortality and cause specific mortality, adjusted for common risk factors for all cause mortality based on the World Health Organization’s global health status. Results The multivariable adjusted hazard ratios for a 20 nmol/L lower plasma 25-hydroxyvitamin D concentration were 1.19 (95% confidence interval 1.14 to 1.25) for all cause mortality, 1.18 (1.09 to 1.28) for cardiovascular mortality, 1.12 (1.03 to 1.22) for cancer mortality, and 1.27 (1.15 to 1.40) for other mortality. Each increase in DHCR7/CYP2R1 allele score was associated with a 1.9 nmol/L lower plasma 25-hydroxyvitamin D concentration and with increased all cause, cancer, and other mortality but not with cardiovascular mortality. The odds ratio for a genetically determined 20 nmol/L lower plasma 25-hydroxyvitamin D concentration was 1.30 (1.05 to 1.61) for all cause mortality, with a corresponding observational multivariable adjusted odds ratio of 1.21 (1.11 to 1.31). Corresponding genetic and observational odds ratios were 0.77 (0.55 to 1.08) and 1.13 (1.03 to 1.24) for cardiovascular mortality, 1.43 (1.02 to 1.99) and 1.10 (1.02 to 1.19) for cancer mortality, and 1.44 (1.01 to 2.04) and 1.17 (1.06 to 1.29) for other mortality. The results were robust in sensitivity analyses. Conclusions Genetically low 25-hydroxyvitamin D concentrations were associated with increased all cause mortality, cancer mortality, and other mortality but not with increased cardiovascular mortality. These findings are compatible with the notion that genetically low 25-hydroxyvitamin D concentrations may be causally associated with cancer and other mortality but also suggest that the observational association with cardiovascular mortality could be the result of confounding.

Exposure to selective serotonin reuptake inhibitors and the risk of congenital malformations: a nationwide cohort study

Objectives To analyse the relation between selective serotonin reuptake inhibitor (SSRI) use and major congenital malformations, with focus on malformations of the heart. Design Register-based retrospective nationwide cohort study, using the Danish Medical Birth Registry. Setting Denmark. Participants Pregnant women in Denmark between 1997 and 2009 and their offspring. Primary outcome measures For each SSRI, ORs for major congenital malformations were estimated using multivariable logistic regression models for women exposed to an SSRI during the first trimester and for women with paused exposure during pregnancy. Results The authors identified 848 786 pregnancies; 4183 were exposed to an SSRI throughout the first trimester and 806 pregnancies paused exposure during pregnancy. Risks of congenital malformations of the heart were similar for pregnancies exposed to an SSRI throughout the first trimester, adjusted OR 2.01 (95% CI 1.60 to 2.53), and for pregnancies with paused SSRI treatment during pregnancy, adjusted OR 1.85 (95% CI 1.07 to 3.20), p value for difference: 0.94. The authors found similar increased risks of specific congenital malformations of the heart for the individual SSRIs. Furthermore, the authors found no association with dosage. Conclusions The apparent association between SSRI use and congenital malformations of the heart may be confounded by indications. The moderate absolute risk increase combined with uncertainty for causality still requires the risk versus benefit to be evaluated in each individual case.

Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study

BACKGROUND Low plasma 25-hydroxyvitamin D (25[OH]D) concentration and high BMI have been associated with increased risk of diabetes. We tested the hypotheses that genetic variants associated with low concentrations of 25(OH)D are associated with diabetes, and that the effect on diabetes of genetic variants associated with high BMI is partly mediated through reduced plasma 25(OH)D concentration. METHODS In this mendelian randomisation study, we genotyped 96 423 white Danes aged 20-100 years from three studies. 5037 of these participants had type 2 diabetes. All individuals were surveyed for diabetes from 1977 to 2011. 31 040 participants had their plasma 25(OH)D concentration measured and 90 169 had their BMI measured. We assessed the effects of genetic variation in DHCR7 (related to endogenous production) and CYP2R1 (related to liver conversion) on plasma 25(OH)D concentration, and the effects of variation in FTO, MCR4, and TMEM18 on BMI. We then assessed the effect of genetic variation in these genes on risk of type 2 diabetes, and the association of measured plasma 25(OH)D concentration and BMI with risk of type 2 diabetes. We did a mediation analysis to assess how much of the effect of BMI genotype on risk of diabetes was mediated through plasma 25(OH)D concentration. FINDINGS The odds ratios for type 2 diabetes for participants who had a 20 nmol/L reduction in plasma 25(OH)D concentration as determined by genetics were 1·51 (95% CI 0·98-2·33) for DHCR7 and 1·02 (0·75-1·37) for CYP2R1. The DHCR7 allele score was significantly associated with increased risk of type 2 diabetes (p for trend=0·04), whereas the allele score for CYP2R1 was not. For participants who had a measured 20 nmol/L reduction in plasma 25(OH)D concentration, the adjusted odds ratio for type 2 diabetes was 1·16 (1·08-1·25). For participants who had a 10 kg/m(2) increase in BMI as determined by genetics, the odds ratio for type 2 diabetes was 19·4 (6·4-59·1); this was associated with an 11·1 nmol/L (2·6-19·6) lower plasma 25(OH)D concentration. For a 10 kg/m(2) increase in measured BMI, the adjusted odds ratio for type 2 diabetes was 4·33 (3·70-5·07); this was associated with a 9·1 nmol/L (8·4-9·7) lower plasma 25(OH)D concentration. Mediation analysis showed that 3% (1-5) of the effect of BMI on risk of type 2 diabetes was mediated through lowered plasma 25(OH)D concentrations. INTERPRETATION Genetic variants associated with low plasma 25(OH)D concentrations are associated with type 2 diabetes and low plasma 25(OH)D concentrations might be a modest mediator between obesity and increased risk of diabetes. Genetic variants associated with endogenous production of 25(OH)D might partially explain this increased risk; however, as findings for DHCR7 were not statistically significant, our results require independent confirmation. FUNDING Danish Heart Foundation, Copenhagen University Hospital.

Reduced 25-hydroxyvitamin D and risk of Alzheimer's disease and vascular dementia.

Vitamin D deficiency has been implicated as a risk factor for dementia in several cross‐sectional studies. We tested the hypothesis that reduced plasma 25‐hydroxyvitamin D (25[OH]D) is associated with increased risk of Alzheimers disease (AD) and vascular dementia in the general population.

Low Plasma 25-Hydroxyvitamin D and Risk of Tobacco-Related Cancer

BACKGROUND Tobacco smoke chemicals may influence vitamin D metabolism and function, and conversely vitamin D may modify the carcinogenicity of tobacco smoke chemicals. We tested the hypothesis that lower plasma 25-hydroxyvitamin D [25(OH)D] is associated with a higher risk of tobacco-related cancer in the general population. METHODS A prospective population-based cohort of 9791 individuals from the Copenhagen City Heart Study who were free of cancer at baseline was followed from 1981-1983 until December 2008 with 100% complete follow-up. RESULTS During up to 28 years of follow-up, 1081 participants developed a tobacco-related cancer and 1506 developed other cancers. Decreasing 25(OH)D concentrations, subdivided by clinical categories or by seasonally adjusted percentile categories, were associated with increasing cumulative incidence of tobacco-related cancer (log-rank trend P = 2 × 10(-6) and P = 5 × 10(-9)). Multivariable adjusted hazard ratios of tobacco-related cancer were 1.75 (95% CI, 1.33-2.30) for 25(OH)D <5 vs ≥20 ng/mL, and 2.07 (1.63-2.62) for ≤5th vs >66th percentile. Also, multivariable adjusted hazard ratios for a 50% reduction in 25(OH)D were 1.20 (1.13-1.28) for any tobacco-related cancer, 1.19 (95% CI, 1.09-1.31) for lung cancer, 1.44 (1.19-1.73) for head and neck cancer, 1.28 (1.06-1.54) for bladder cancer, 1.34 (1.04-1.73) for kidney cancer, and 0.95 (0.89-1.01) for other cancers. CONCLUSIONS Lower plasma 25(OH)D was associated with higher risk of tobacco-related cancers, but not with risk of other cancers.

Risk of cancer among HIV-infected individuals compared to the background population: impact of smoking and HIV.

Background:The relative impact of immune deficiency and lifestyle-related factors on risk of cancer in the HIV-infected population is controversial. We aimed to estimate the population-attributable fractions (PAFs) associated with smoking, being HIV-infected and with immune deficiency. Methods:In a Danish, nationwide, population-based cohort study (1995–2011), incidences of cancer were compared between an HIV-infected cohort and a population-based matched cohort in analyses stratified on cancer category, smoking status and for HIV patients: low CD4+ cell count. Results:We included 3503 HIV patients [baseline CD4+ 450 cells/&mgr;l (inter-quartile range 310–630)] and 12 979 population controls. Smoking-related and virological cancers accounted for 23 and 43% of cancers in the HIV-infected population. The risk of these cancers were higher among HIV patients compared to controls [incidence rate ratio (IRR) 2.8, 95% confidence interval (CI) 1.6–4.9; and IRR 11.5, 95% CI 6.5–20.5], whereas the risk of other cancers did not differ (IRR 1.0, 95% CI 0.7–1.3). Non-smoking HIV patients did not have increased risk of non-virological cancers compared to non-smoking controls (IRR 1.2, 95% CI 0.7–2.1). The PAFs of cancer associated with smoking and with being HIV-infected were 27 and 49%, respectively. For cancers not strongly related to smoking or viral infections, the PAFs associated with being HIV-infected and with immune deficiency were 0%. Conclusion:The risk of cancer is increased in HIV patients compared to the background population. In absence of smoking, the increase in risk is confined to cancers related to viral infections, whereas the risk of other cancers is not elevated and does not seem to be associated with immune deficiency.

Myocardial Infarction Among Danish HIV-Infected Individuals: Population-Attributable Fractions Associated With Smoking

BACKGROUND Human immunodeficiency virus-infected individuals have increased risk of myocardial infarction (MI); however, the contribution from smoking and potentiating effects of HIV are controversial. METHODS From the Danish HIV Cohort Study and the Copenhagen General Population Study, we identified 3251 HIV-infected individuals and 13 004 population controls matched on age and gender. Data on MI were obtained from the National Hospital Registry and the National Registry of Causes of Death. We calculated adjusted incidence rate ratios (aIRR) for risk of MI and population-attributable fractions (PAF) of MI associated with smoking. RESULTS In never smokers, HIV was not associated with an increased risk of MI (aIRR, 1.01; 95% confidence interval [CI], .41-2.54). In previous and current smokers, HIV was associated with a substantially increased risk of MI (aIRR, 1.78; 95% CI, .75-4.24 and aIRR, 2.83; 95% CI, 1.71-4.70). The PAF associated with ever smoking (previous or current) was 72% (95% CI, 55%-82%) for HIV-infected individuals and 24% (95% CI, 3%-40%) for population controls. If all current smokers stopped smoking, 42% (95% CI, 21%-57%) and 21% (95% CI, 12%-28%) of all MIs could potentially be avoided in these 2 populations. CONCLUSIONS Smoking is associated with a higher risk of MI in the HIV-infected population than in the general population. Approximately 3 of 4 MIs among HIV-infected individuals are associated with ever smoking compared with only 1 of 4 MIs among population controls. Smoking cessation could potentially prevent more than 40% of MIs among HIV-infected individuals, and smoking cessation should be a primary focus in modern HIV care.

Change in Body Mass Index Associated With Lowest Mortality in Denmark, 1976-2013

IMPORTANCE Research has shown a U-shaped pattern in the association of body mass index (BMI) with mortality. Although average BMI has increased over time in most countries, the prevalence of cardiovascular risk factors may also be decreasing among obese individuals over time. Thus, the BMI associated with lowest all-cause mortality may have changed. OBJECTIVE To determine whether the BMI value that is associated with the lowest all-cause mortality has increased in the general population over a period of 3 decades. DESIGN, SETTING, AND PARTICIPANTS Three cohorts from the same general population enrolled at different times: the Copenhagen City Heart Study in 1976-1978 (n = 13,704) and 1991-1994 (n = 9482) and the Copenhagen General Population Study in 2003-2013 (n = 97,362). All participants were followed up from inclusion in the studies to November 2014, emigration, or death, whichever came first. EXPOSURES For observational studies, BMI was modeled using splines and in categories defined by the World Health Organization. Body mass index was calculated as weight in kilograms divided by height in meters squared. MAIN OUTCOMES AND MEASURES Main outcome was all-cause mortality and secondary outcomes were cause-specific mortality. RESULTS The number of deaths during follow-up was 10,624 in the 1976-1978 cohort (78% cumulative mortality; mortality rate [MR], 30/1000 person-years [95%CI, 20-46]), 5025 in the 1991-1994 cohort (53%; MR, 16/1000 person-years [95%CI, 9-30]), and 5580 in the 2003-2013 cohort (6%;MR, 4/1000 person-years [95%CI, 1-10]). Except for cancer mortality, the association of BMI with all-cause, cardiovascular, and other mortality was curvilinear (U-shaped). The BMI associated with the lowest all-cause mortality increased by 3.3 from the 1976-1978 cohort compared with the 2003-2013 cohort. [table: see text] The multivariable-adjusted hazard ratios for all-cause mortality for BMI of 30 or more vs BMI of 18.5 to 24.9 were 1.31 (95%CI, 1.23-1.39;MR, 46/1000 person-years [95%CI, 32-66] vs 28/1000 person-years [95%CI, 18-45]) in the 1976-1978 cohort, 1.13 (95%CI, 1.04-1.22; MR, 28/1000 person-years [95%CI, 17-47] vs 15/1000 person-years [95%CI, 7-31]) in the 1991-1994 cohort, and 0.99 (95%CI, 0.92-1.07;MR, 5/1000 person-years [95%CI, 2-12] vs 4/1000 person-years [95%CI, 1-11]) in the 2003-2013 cohort. CONCLUSIONS AND RELEVANCE Among 3 Danish cohorts, the BMI associated with the lowest all-cause mortality increased by 3.3 from cohorts enrolled from 1976-1978 through 2003-2013. Further investigation is needed to understand the reason for this change and its implications.