(JAMA: UK Biobank 基因揭密) Belly Fat, abdominal adiposity腹部肥胖/ Waist-to-Hip Ratio --糖尿病/心臟病關係

基因傾向「蘋果型」身材 易患糖尿或心臟病 2017-02-15 12:02中央社 邁阿密14日綜合外電報導研究人員今天表示，基因上有腹部容易囤積脂肪的傾向，或「蘋果型」身材的人，罹患第2型糖尿病或心臟病的風險較高。法新社報導，這項刊載在「美國醫學會期刊」（JAMA）的研究認為，人的基因組成可能與未來的健康問題有關。研究資深作者哈佛醫學院醫學副教授凱瑟瑞桑（Sekar Kathiresan）指出：「每個人儲存脂肪的地方各異，有些人在腹部，我們稱為腹部肥胖，有些人則在臀部與大腿。」「我們實驗基因傾向是否與第2型糖尿病及冠狀動脈心臟病有關，結果發現答案為肯定的『是的』。」過去觀察研究已揭露腹部脂肪與第2型糖尿病與心臟病的關連，但缺乏原因與影響的證明。為了進一步了解，研究人員仔細檢查2007到2015年針對約40萬名受測者基因組進行分析的6項研究。研究第一作者麻州綜合醫院（Massachusetts General Hospital）研究人員恩姆丁（Connor Emdin）說：「這些研究結果顯示，可以運用基因的方法，來判斷腹部肥胖等某種特徵，對心血管代謝結果的影響程度。」

Apples and Pears: Genetic Analysis Points to Causal Role for Belly Fat in Heart Disease and Diabetes One study author recommends greater use of the waist-to-hip ratio in practice to prevent disease in high-risk patients. By Yael L. Maxwell February 14, 2017 Apples and Pears: Genetic Analysis Points to Causal Role for Belly Fat in Heart Disease and Diabetes New genetic evidence is supporting the idea that people who are predisposed to carrying fat in their belly as opposed to their hips and thighs are also at greater risk for developing heart disease and type 2 diabetes. Prior observational studies have linked abdominal adiposity with cardiometabolic disease, but it has remained unclear whether it plays a causal role. For their analysis published today in JAMA, Connor Emdin, DPhil (Massachusetts General Hospital, Boston, MA), and colleagues constructed a polygenic risk score of 48 single-nucleotide polymorphisms (SNPs) for waist-to-hip ratio adjusted for body mass index (BMI). Applying this score to individual-level data from the UK Biobank, they found higher risks of type 2 diabetes (OR 1.77; 95% CI 1.57-2.00) and coronary heart disease (OR 1.46; 95% CI 1.32-1.62) associated with each standard deviation increase in waist-to-hip ratio. As for why this might be, those with higher waist-to-hip ratios seemed to have higher levels of triglycerides, 2-hour glucose, and systolic blood pressure (P < 0.001 for all). "The relationship to heart disease and diabetes did not surprise us," senior author Sekar Kathiresan, MD (Massachusetts General Hospital), told TCTMD, noting however that he and his colleagues "were a little surprised" that the level of triglycerides in the blood could explain the relationship between belly fat and disease risk. There are a number of different theories that could clarify this, he said, but "the abdominal fat cells seem to secrete a lot of bad factors that go into the blood and that actually lead to delayed clearance of the fat from the blood, which [leads] to higher levels of triglyceride-rich lipoproteins." While there is definitely "something about the visceral fat is different from the fat that is in the thighs and hips," further research is needed to clarify it, Kathiresan observed. "It's a completely fertile ground, because there's very little known about what the factors are that lead to the apple shape versus the pear shape. And it's hard to model in organisms, like mice for example, because they just have a totally different body fat distributions than humans." In his experience, physicians often focus more on overall weight or BMI in their patients, and not specifically where the fat is stored. But the waist-to-hip ratio is "an easily available marker for who is at particularly [high] risk for diabetes and heart disease," Kathiresan said, advising clinicians to pay more attention to it in practice. For the long term, understanding the genetics "that actually change the body fat distribution away from abdominal adiposity . . . may actually be as beneficial as focusing on the overall weight," potentially leading to the development of safe and effective medications for weight loss, he said.

Championing Mendelian Randomization In an accompanying editorial, George Davey Smith, MD, DSc, Lavinia Paternoster, PhD, and Caroline Relton, PhD (University of Bristol, England), suggest that the current study could serve as an example for future avenues of investigation. Mendelian randomization—the reliance on how genes are randomly assigned without bias as a basis for clinical research and what Emdin et al used in their study—"can be considered analogous to randomization in an RCT," they argue. Early studies "tended to use single genetic variants and focus on a specific risk factor-disease association within a single study population," they explain. Now, however, "large numbers of genetic variants [are] being identified for many exposures." Given the causal relationship between abdominal adiposity and heart disease/diabetes shown in this study, "such conditional measures are likely to become increasingly adopted in studies in the future, as more complex aspects of disease causation are investigated," the editorialists predict. Smith, Paternoster, and Relton point out that reducing obesity through public health efforts and interventions has proven to be difficult, so it would make sense that specifically targeting belly fat would be even more challenging. "Abdominal adiposity is shown to influence several such mediators in the report by Emdin et al, and triglyceride levels were demonstrated to be potentially important with respect to CHD risk," they write. "A formal Mendelian randomization mediation analysis could be applied that would more robustly quantify the contribution of potentially treatable intermediaries, and targeting such could have important public health benefit." Looking at recent studies, the editorialists suggest that attention to Mendelian randomization could have "prevented very expensive late-stage clinical trial failures. . . . Indeed, the adoption of Mendelian randomization to prioritize (or deprioritize) major investment in RCTs before their inception should be actively encouraged."

Sources Emdin CA, Khera AV, Natarajan P, et al. Genetic association of waist-to-hip ratio with cardiometabolic traits, type 2 diabetes, and coronary heart disease. JAMA. 2017;317:626-634. Smith GD, Paternoster L, Relton C. When will Mendelian randomization become relevant for clinical practice and public health? JAMA. 2017;317:589-591. 

Genetic Association of Waist-to-Hip Ratio With Cardiometabolic Traits, Type 2 Diabetes, and Coronary Heart Disease JAMA. 2017;317(6):626-634. doi:10.1001/jama.2016.21042 Question Is genetic evidence consistent with a causal relationship among waist-to-hip ratio adjusted for body mass index (a measure of abdominal adiposity), type 2 diabetes, and coronary heart disease? Findings In this mendelian randomization study, a polygenic risk score for increased waist-to-hip ratio adjusted for body mass index was significantly associated with adverse cardiometabolic traits and higher risks for both type 2 diabetes and coronary heart disease. Meaning These results provide evidence supportive of a causal association between abdominal adiposity and the development of type 2 diabetes and coronary heart disease.

Importance In observational studies, abdominal adiposity has been associated with type 2 diabetes and coronary heart disease (CHD). Whether these associations represent causal relationships remains uncertain.

Objective To test the association of a polygenic risk score for waist-to-hip ratio (WHR) adjusted for body mass index (BMI), a measure of abdominal adiposity, with type 2 diabetes and CHD through the potential intermediates of blood lipids, blood pressure, and glycemic phenotypes.

Design, Setting, and Participants A polygenic risk score for WHR adjusted for BMI, a measure of genetic predisposition to abdominal adiposity, was constructed with 48 single-nucleotide polymorphisms. The association of this score with cardiometabolic traits, type 2 diabetes, and CHD was tested in a mendelian randomization analysis that combined case-control and cross-sectional data sets. Estimates for cardiometabolic traits were based on a combined data set consisting of summary results from 4 genome-wide association studies conducted from 2007 to 2015, including up to 322 154 participants, as well as individual-level, cross-sectional data from the UK Biobank collected from 2007-2011, including 111 986 individuals. Estimates for type 2 diabetes and CHD were derived from summary statistics of 2 separate genome-wide association studies conducted from 2007 to 2015 and including 149 821 individuals and 184 305 individuals, respectively, combined with individual-level data from the UK Biobank.  

Results Among 111 986 individuals in the UK Biobank, the mean age was 57 (SD, 8) years, 58 845 participants (52.5%) were women, and mean WHR was 0.875. Analysis of summary-level genome-wide association study results and individual-level UK Biobank data demonstrated that a 1-SD increase in WHR adjusted for BMI mediated by the polygenic risk score was associated with 27-mg/dL higher triglyceride levels, 4.1-mg/dL higher 2-hour glucose levels, and 2.1–mm Hg higher systolic blood pressure (each P < .001). A 1-SD genetic increase in WHR adjusted for BMI was also associated with a higher risk of type 2 diabetes (odds ratio, 1.77 [95% CI, 1.57-2.00]; absolute risk increase per 1000 participant-years, 6.0 [95% CI, CI, 4.4-7.8]; number of participants with type 2 diabetes outcome, 40 530) and CHD (odds ratio, 1.46 [95% CI, 1.32-1.62]; absolute risk increase per 1000 participant-years, 1.8 [95% CI, 1.3-2.4]; number of participants with CHD outcome, 66 440).

Conclusions and Relevance A genetic predisposition to higher waist-to-hip ratio adjusted for body mass index was associated with increased risk of type 2 diabetes and coronary heart disease. These results provide evidence supportive of a causal association between abdominal adiposity and these outcomes.