دانلود مقاله ارتباط ویتامین D با بیماری کرونری قلبی، سکته مغزی و تمام عوامل مرگ و میر

خلاصه
معرفی
مواد و روش ها
نتایج
بحث
مشارکت کنندگان
اعلام منافع
قدردانی ها
منابع

Summary
Introduction
Methods
Results
Discussion
Contributors
Declaration of interests
Acknowledgments
References

چکیده
پیشینه کارآزمایی‌های تصادفی‌سازی شده مکمل‌های ویتامین D برای بیماری‌های قلبی عروقی و مرگ و میر ناشی از همه علل عموماً یافته‌های بی‌ثمری را گزارش کرده‌اند. با این حال، تعمیم نتایج به افراد با وضعیت ویتامین D پایین نامشخص است. هدف ما مشخص کردن روابط دوز-پاسخ بین غلظت 25 هیدروکسی ویتامین D (25[OH]D) و خطر بیماری عروق کرونر قلب، سکته مغزی و مرگ و میر ناشی از همه علل در چارچوب‌های تصادفی‌سازی مندل و مشاهده بود.
روش‌ها تجزیه و تحلیل‌های مشاهده‌ای با استفاده از داده‌های 33 مطالعه آینده‌نگر شامل 500962 فرد بدون سابقه بیماری عروق کرونر قلب یا سکته مغزی در ابتدا انجام شد. تجزیه و تحلیل تصادفی سازی مندلی در چهار مطالعه کوهورت مبتنی بر جمعیت (UK Biobank، EPIC-CVD، و دو مطالعه مبتنی بر جمعیت کپنهاگ) شامل 386406 فرد میانسال از اجداد اروپایی، از جمله 33546 نفر که به بیماری عروق کرونر قلب مبتلا شده بودند، انجام شد، 18166 افرادی که سکته کرده بودند و 27885 نفر فوت کردند. پیامدهای اولیه بیماری عروق کرونر قلب بود که به عنوان بیماری ایسکمیک قلبی کشنده (طبقه بندی بین المللی بیماری ها کد بازبینی دهم I20-I25) یا انفارکتوس میوکارد غیر کشنده (I21-I23) تعریف شد. سکته مغزی، به عنوان هر بیماری عروق مغزی و مرگ و میر همه علل تعریف می شود (I60-I69).
یافته‌ها تحلیل‌های مشاهده‌ای ارتباط معکوس بین بیماری عروق کرونر قلب، سکته مغزی و پیامدهای مرگ و میر ناشی از همه علل را با غلظت 25(OH)D در غلظت‌های پایین 25(OH)D پیشنهاد کردند. در آنالیزهای ژنتیکی در سطح جمعیت، هیچ ارتباطی بین 25(OH)D پیش بینی شده ژنتیکی با بیماری عروق کرونر قلب وجود نداشت (نسبت شانس [OR] در هر 10 نانومول در لیتر غلظت 25(OH)D پیش بینی شده ژنتیکی بالاتر 0.98، 95٪ CI 0·95-1·01)، سکته مغزی (1·01، [0·97-1·05])، یا مرگ و میر همه علل (0·99، 0·95-1·02). یافته‌های پوچ نیز در آنالیزهای ژنتیکی برای پیامدهای مرگ‌ومیر خاص، و در تحلیل‌های ژنتیکی طبقه‌بندی‌شده برای همه پیامدها در تمام سطوح مشاهده‌شده غلظت‌های 25(OH)D مشاهده شد.
تفسیر، تحلیل‌های تصادفی‌سازی مندلی طبقه‌بندی‌شده، فقدان رابطه علی برای غلظت‌های 25(OH)D با پیامدهای قلبی عروقی و مرگ‌ومیر را برای افراد در تمام سطوح 25(OH)D نشان می‌دهد. یافته‌های ما نشان می‌دهد که کاهش قابل‌توجهی در مرگ و میر و عوارض قلبی عروقی به دلیل مصرف طولانی‌مدت مکمل ویتامین D با دوز پایین، بعید است، حتی اگر برای افراد با وضعیت ویتامین D پایین هدف قرار گیرد.

Summary

Background
Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.

Methods
Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.

Findings
Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0·98, 95% CI 0·95–1·01), stroke (1·01, [0·97–1·05]), or all-cause mortality (0·99, 0·95–1·02). Null findings were also observed in genetic analyses for cause-specific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.

Interpretation
Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D. Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.

Funding
British Heart Foundation, Medical Research Council, National Institute for Health Research, Health Data Research UK, Cancer Research UK, and International Agency for Research on Cancer.

Introduction

Vitamin D is an essential nutrient obtained from sunlight, dietary intake, and supplementation.1 Observational epidemiological studies have consistently found that low concentrations of circulating 25-hydroxyvitamin D (25[OH]D), a metabolite used as a clinical indicator of vitamin D status, are associated with an increased risk of cardiovascular disease and all-cause mortality, as well as other chronic diseases.2,  3 However, several large randomised trials of vitamin D supplementation have reported null results,4,  5,  6 casting doubt on the observational evidence. However, as trials have typically recruited participants irrespective of baseline 25(OH)D concentration, they have had limited power to test supplementation effects in subgroups with low 25(OH)D concentrations.7

An efficient approach for assessing the potential causal effect of vitamin D supplementation is Mendelian randomisation. Mendelian randomisation uses genetic variants specifically related to a particular exposure to compare genetically defined population subgroups with different average levels of the exposure. The independent segregation of alleles at conception means that these genetically defined subgroups should not differ systematically with respect to confounding variables, creating a natural experiment analogous to a randomised trial.8 Therefore, Mendelian randomisation analyses can provide more reliable insights into causal relationships between risk factors and disease outcomes than conventional observational analyses. Previous Mendelian randomisation analyses have reported null associations of genetically predicted 25(OH)D concentrations with coronary heart disease9,  10 and ischaemic stroke.11,  12 An inverse association has been observed between genetically predicted 25(OH)D and all-cause mortality.13 Null findings have been observed for several further outcomes, including other cardiovascular diseases and cancers.14

Results

386 406 participants from the four studies were included in genetic analyses (table 1), including 33 546 people who had coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died, and 500 962 participants were included in observational analyses (appendix 3 pp 11–13). Mean age of participants included in the genetic analysis ranged from 54·8 years (SD 9·4) to 57·5 years (12·9), with similar numbers of men and women in each study, and the mean season-shifted 25(OH)D concentrations (corresponding to an autumn measurement) were 54·5 nmol/L (SD 19·6) in UK Biobank, 46·9 nmol/L (16·4) in EPIC-CVD, and 53·8 nmol/L (25·9) in the Copenhagen studies. Mean 25(OH)D estimates did not notably differ by assay type (appendix 3 p 21). The focused genetic risk score explained 4·7% of the variance in 25(OH)D concentrations in UK Biobank study, 5·8% in EPIC-CVD, and 1·8% in the Copenhagen studies. This genetic risk score was not associated with a range of cardiovascular risk factors in UK Biobank, except for BMI and HDL cholesterol, although these associations were small (appendix 3 p 22). The genome-wide score was strongly associated with LDL cholesterol and triglycerides (appendix 3 p 23), and so Mendelian randomisation estimates using this score are unreliable.