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Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi.

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Presentation on theme: "Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi."— Presentation transcript:

1 Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2013 年 4 月 11 日 8:30-8:55 8階 医局 Talmud PJ, Shah S, Whittall R, Futema M, Howard P, Cooper JA, Harrison SC, Li K, Drenos F, Karpe F, Neil HA, Descamps OS, Langenberg C, Lench N, Kivimaki M, Whittaker J, Hingorani AD, Kumari M, Humphries SE. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet. 2013 Feb 21. doi:pii: S0140-6736(12)62127-8. 10.1016/S0140-6736(12)62127-8 Mozaffarian D, Lemaitre RN, King IB, Song X, Huang H, Sacks FM, Rimm EB, Wang M, Siscovick DS. Plasma Phospholipid Long-Chain ω-3 Fatty Acids and Total and Cause-Specific Mortality in Older Adults: A Cohort Study. Ann Intern Med. 2013 Apr 2;158(7):515-25.

2 Centre for Cardiovascular Genetics, Institute of Cardiovascular Science, University College London, London, UK (Prof P J Talmud DSc, R Whittall MSc, M Futema BSc, P Howard BSc, J A Cooper MSc, S C Harrison MRCS, K Li MSc, F Drenos PhD, Prof S E Humphries PhD); UCL Genetics Institute, Department of Genetics, Environment and Evolution, University College London, London, UK (S Shah MSc, S E Humphries); NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK (F Karpe PhD); NIHR School of Primary Care Research, Department of Primary Care Health Sciences, University of Oxford, Oxford, UK (Prof H A W Neil DSc); Centre de Recherche Medicale de Jolimont, Haine St-Paul, Belgium (O S Descamps PhD); MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, UK (C Langenberg PhD); Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, London, UK (C Langenberg, Prof A D Hingorani PhD); North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, London, UK (N Lench PhD); Department of Epidemiology and Public Health, University College London, London, UK (Prof M Kivimaki PhD, M Kumari PhD); Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK (Prof J Whittaker PhD); and Quantitative Science, GlaxoSmithKline, Stevenage, Hertfordshire, UK (J Whittaker) Lancet. 2013 Feb 21. doi:pii: S0140-6736(12)62127-8. 10.1016/S0140-6736(12)62127-8

3 Background Familial hypercholesterolaemia is a common autosomal-dominant disorder caused by mutations in three known genes. DNA-based cascade testing is recommended by UK guidelines to identify affected relatives; however, about 60% of patients are mutation-negative. We assessed the hypothesis that familial hypercholesterolaemia can also be caused by an accumulation of common small-effect LDL-C-raising alleles.

4 Methods In November, 2011, we assembled a sample of patients with familial hypercholesterolaemia from three UK-based sources and compared them with a healthy control sample from the UK Whitehall II (WHII) study. We also studied patients from a Belgian lipid clinic (Hopital de Jolimont, Haine St-Paul, Belgium) for validation analyses. We genotyped participants for 12 common LDL-C- raising alleles identified by the Global Lipid Genetics Consortium and constructed a weighted LDL-C-raising gene score. We compared the gene score distribution among patients with familial hypercholesterolaemia with no confirmed mutation, those with an identified mutation, and controls from WHII.

5 cholesterol 9.16mM=354mg/dl 10.28mM=397mg/dl 6.4mM=247mg/dl 5.87mM=227mg/dl 7.03mM=271mg/dl 4.4mM=170mg/dl 4.22mM=163mg/dl 5.49mM=212mg/dl 4.4mM=170mg/dl 1.42mM= 55mg/dl 1.37mM= 53mg/dl 1.4mM=54mg/dl TG 1.82mM=161mg/dl 1.33mM=118mg/dl 1.40mM=124mg/dl T-chol <200mg/dl 0.0259 <5.18mmol/L HDL-C >35mg/dl 0.0259 0.91 mmol/L Triglyceride <250 mg/dl 0.0113 <2.8mmol/L

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10 DNA was available from 451 patients with familial hypercholesterolaemia without a known mutation from one lipid clinic in Belgium, and 273 patients with familial hypercholesterolaemia with a known mutation from the same clinic. All patients had a cholesterol concentration above the 95th percentile for age and sex (appendix) and a family history of early cardiovascular disease. The mean weighted score of the mutation-negative Belgian patients (0 ・ 99 [SD 0 ・ 19]) was significantly higher than the score of the WHII participants (p=5 ・ 2 × 10 −2 ⁰ ), with a smaller difference in score between the mutation-positive patients (0 ・ 92 [0 ・ 20]) and the WHII group (p=0 ・ 04; appendix). The weighted score in the mutation-negative group was also significantly higher than in the mutation-positive group (p=4 ・ 0 × 10 − ⁶ ). Overall, 73 (16%) had a LDL-C gene score that fell within decile 10 of the WHII LDL-C gene score distribution, and 211 (46%) fell within deciles 7–10.

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12 To add the complexity of SNP analysis for minor genes and eliminate cascade LDL-C and clinical testing of relatives of patients with polygenic familial hypercholesterolaemia does not seem to be warranted, and could even be diversionary. *Evan A Stein, Frederick J Raal Metabolic and Atherosclerosis Research Center, Cincinnati, OH 45227, USA (EAS); and Department of Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa (FJR) Polygenic familial hypercholesterolaemia: does it matter? February 22, 2013 http://dx.doi.org/10.1016/ S0140-6736(13)60187-7

13 Findings We recruited 321 mutation-negative UK patients (451 Belgian), 319 mutation-positive UK patients (273 Belgian), and 3020 controls from WHII. The mean weighted LDL-C gene score of the WHII participants (0 ・ 90 [SD 0 ・ 23]) was strongly associated with LDL-C concentration (p=1 ・ 4 × 10 − ⁷⁷ ; R2=0 ・ 11). Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1 ・ 0 [SD 0 ・ 21]) than did WHII controls (p=4 ・ 5 × 10 −1 ⁶ ), as did the mutation-negative Belgian patients (0 ・ 99 [0 ・ 19]; p=5 ・ 2 × 10 −2 ⁰ ). The score was also higher in UK (0 ・ 95 [0 ・ 20]; p=1 ・ 6 × 10 − ⁵ ) and Belgian (0 ・ 92 [0 ・ 20]; p=0 ・ 04) mutation-positive patients than in WHII controls. 167 (52%) of 321 mutation-negative UK patients had a score within the top three deciles of the WHII weighted LDL-C gene score distribution, and only 35 (11%) fell within the lowest three deciles.

14 Interpretation In a substantial proportion of patients with familial hypercholesterolaemia without a known mutation, their raised LDL-C concentrations might have a polygenic cause, which could compromise the efficiency of cascade testing. In patients with a detected mutation, a substantial polygenic contribution might add to the variable penetrance of the disease. Funding British Heart Foundation, Pfizer, AstraZeneca, Schering-Plough, National Institute for Health Research, Medical Research Council, Health and Safety Executive, Department of Health, National Heart Lung and Blood Institute, National Institute on Aging, Agency for Health Care Policy Research, John D and Catherine T MacArthur Foundation Research Networks on Successful Midlife Development and Socio-economic Status and Health, Unilever, and Departments of Health and Trade and Industry.

15 Message 英国で、既知の関連遺伝子変異陰性の家族 性高コレステロール血症( FH )患者 640 人 と対照者 3020 人を対象に、低比重リポた んぱくコレステロール亢進アレル( LDL- C-raising allele )の蓄積を発症原因の 1 つ とする仮説を症例対照研究で検討。 LDL-C 亢進遺伝子変異の加重平均は、対照群に比 べ患者群で有意に高かった。

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17 油脂の加工・精製でできるもの

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20 Iwasaki M et al., J Diabetes Invest 2012; 3: 464. 魚摂取量 EPA 摂取量 DHA 摂取量 1.0 0.5 0.0 -0.5 -1.5 -2.0 -2.5 r=-0.616 p < 0.01 HbA 1c ( NGSP )変化量 040801201600200400600800 r=-0.618 p < 0.01 03006009001200 r=-0.678 p < 0.01 ( g/ 日) ( mg/ 日) (%)(%) EPA ・ DHA 摂取量が多いほど DPP-4 阻害薬の効果が高い 薬物治療を行っていない 72 例の糖尿病患者を対象に、 DPP-4 阻害薬を 4 ヵ月間投与し、食事内容の違いが HbA1c の 低下効果に及ぼす影響を検討した。 1.0 0.5 0.0 -0.5 -1.5 -2.0 (%)(%) 1.0 0.5 0.0 -0.5 -1.5 -2.0 (%)(%)

21 050100150250200 HbA 1c ( NGSP )変化量 r=-0.675 p < 0.01 血中 EPA 濃度 0100200300500400 r=-0.729 p < 0.01 血中 DHA 濃度 0100300200 r=-0.323 p=0.165 血中アラキドン酸濃度 ( μg/mL ) Iwasaki M et al., J Diabetes Invest 2012; 3: 464. 1.0 0.5 0.0 -0.5 -1.5 -2.0 (%)(%) 血中 EPA ・ DHA 濃度は DPP-4 阻害薬の効果予測マーカーとなり得 る 薬物治療を行っていない 72 例の糖尿病患者を対象に、 DPP-4 阻害薬を 4 ヵ月間投与し、 HbA1c に及ぼす影響につい て 検討した。そのうち無作為に選択された患者における投与前の血中 EPA ・ DHA 濃度と DPP-4 阻害薬による血糖低 下作用との関係についても検討した。 1.0 0.5 0.0 -0.5 -1.5 -2.0 (%)(%) 1.0 0.5 0.0 -0.5 -1.5 -2.0 (%)(%)

22 平成 22 年水産白書 魚介類供給量と平均寿命の関係 0102030405060708090 84 82 80 78 76 74 72 70 ポルトガル 韓国 ノルウェー スペイン フランス フィンランド ポーランド トルコ スロバキア メキシコ チェコ 米国 英国 オランダ ギリシア デンマーク アイルランド カナダ スイス ドイツ オーストリア スウェーデン ニュージーランド 豪州 イタリア 日本 アイスランド (歳) ( kg/ 人 / 年) FAO 「 Food balance sheets 」(日本以外の国)、農林水産省「食料需給表」、 WHO 「 Statistical Information System ( WHOSIS )」に基づき水産庁で作成。

23 Adler AI, Boyko EJ, Schraer CD, Murphy NJ.: Lower prevalence of impaired glucose tolerance and diabetes associated with daily seal oil or salmon consumption among Alaska Natives. Diabetes Care. 1994 Dec;17(12):1498-501. In our study, the average daily consumption of ω-3 PUFAs(polyunsaturated fatty acid) from seal oil was ~8 g. We based this estimate on a 30% ω-3 PUFA content of seal oil. Compared with less-than-daily consumption, both daily seal oil (odds ratio [OR] 0.2, 95% confidence interval [CI] 0.1-0.8) and daily salmon consumption (OR 0.5, CI 0.2-1.1) were associated with a lower prevalence of glucose intolerance, controlling for age, ethnicity, body mass index, and sex. The effects were similar when limited to newly discovered cases: OR 0.3, CI 0.1-1.3 for seal oil and OR 0.4, CI 0.1-1.3 for salmon. Consumption of seal oil at least five times per week was required to reduce risk.

24 eicosapentaenoic acid (EPA).1800mg/day

25 Figure 2. Kaplan–Meier Curves for Primary and Secondary End Points. Kaplan–Meier curves are shown for the cumulative incidence of major cardiovascular events (the primary end point) and fatal coronary heart disease (a secondary end point) among 4837 patients who had had a myocardial infarction and were assigned to receive a study margarine containing supplemental eicosapentaenoic acid (EPA) combined with docosahexaenoic acid (DHA), a margarine containing alpha-linolenic acid (ALA), a margarine containing both EPA–DHA and ALA, or a placebo margarine. Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group.: n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med. 2010 Nov 18;363(21):2015-26. Low-dose supplementation with EPA–DHA or ALA did not significantly reduce the rate of major cardiovascular events

26 ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S.: n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med. 2012 Jul 26;367(4):309-18.

27 n−3 fatty acids (popularly referred to as ω−3 fatty acids or omega-3 fatty acids) are a family of unsaturated fatty acids that have in common a final carbon– carbon double bond in the n−3 position; that is, the third bond from the methyl end of the fatty acid. eicosapentaenoic acid (EPA). docosahexaenoic acid (DHA). all-cis-4,7,10,13,16-docosapentaenoic acid (osbond acid) all-cis-7,10,13,16,19-docosapentaenoic acid (clupanodonic acid) (DPA)

28 Ann Intern Med. 2013;158:515-525. Conception and design: D. Mozaffarian, I.B. King, D.S. Siscovick. Analysis and interpretation of the data: D. Mozaffarian, X. Song, H. Huang, F.M. Sacks, M. Wang, D.S. Siscovick. Drafting of the article: D. Mozaffarian. Critical revision of the article for important intellectual content: D. Mozaffarian, R.N. Lemaitre, H. Huang, F.M. Sacks, E.B. Rimm, D.S. Siscovick. Final approval of the article: D. Mozaffarian, R.N. Lemaitre, I.B. King, X. Song, H. Huang, F.M. Sacks, M. Wang, D.S. Siscovick. Statistical expertise: D. Mozaffarian, H. Huang, M. Wang. Obtaining of funding: D. Mozaffarian, R.N. Lemaitre, I.B. King, D.S. Siscovick. Administrative, technical, or logistic support: X. Song. Collection and assembly of data: D. Mozaffarian, X. Song, D.S. Siscovick.

29 Background: Long-chain ω-3 polyunsaturated fatty acids (ω3- PUFAs), including eicosapentaenoic acid (EPA) (20:5ω-3), docosapentaenoic acid (DPA) (22:5ω-3), and docosahexaenoic acid (DHA) (22:6ω-3), have been shown to reduce cardiovascular risk, but effects on cause-specific and total mortality and potential dose responses remain controversial. Most observational studies have assessed self-reported dietary intake and most randomized trials have tested effects of adding supplements to dietary intake and evaluated secondary prevention, thus limiting inference for dietary ω3-PUFAs or primary prevention. Objective: To investigate associations of plasma phospholipid EPA, DPA, DHA, and total ω3-PUFA levels with total and cause-specific mortality among healthy older adults not receiving supplements.

30 Design: Prospective cohort study. Setting: 4 U.S. communities. Participants: 2692 U.S. adults aged 74 years (±5 years) without prevalent coronary heart disease (CHD), stroke, or heart failure at baseline. Measurements: Phospholipid fatty acid levels and cardiovascular risk factors were measured in 1992. Relationships with total and cause-specific mortality and incident fatal or nonfatal CHD and stroke through 2008 were assessed.

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43 Figure 1. Multivariate-adjusted relationship of plasma phospholipid EPA, DPA, and DHA levels with total mortality, evaluated using restricted cubic splines.

44 Figure 2. Relationship between dietary EPA plus DHA consumption and plasma phospholipid EPA plus DHA concentrations, evaluated using restricted cubic splines and adjusted for age, sex, race, and education. Because the dietary questionnaire assessed only EPA plus DHA (and not DPA), for comparability we evaluated circulating EPA plus DHA (rather than EPA plus DPA plus DHA) level. Median circulating levels of EPA plus DHA in the highest quintile were approximately 5% of total fatty acids. The solid line and shaded area represent the central estimate and 95% CI, respectively. There was strong evidence for both an overall trend (P < 0.001) and nonlinearity of this relationship (P < 0.001). DHA = docosahexaenoic acid; DPA = docosapentaenoic acid; EPA = eicosapentaenoic acid.

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46 PUFA polyunsaturated fatty acid. * Values are the multivariate-adjusted estimated years of life gained after age 65 y in the highest quintile of total 3-PUFAs compared with the lowest quintile and are based on semiparametric survival models (see Table 3). † This result is representative of a participant entering the study at age 65 y with average (mean) values for each of the continuous covariates (body mass index [26.7 kg/m2], waist circumference [96.8 cm], and leisure-time physical activity [1070 kcal/wk]) and falling into the most representative category (mode) for each of the categorical covariates (sex [female], race [white], education [less than high school], enrollment site [Forsyth County, North Carolina], fatty acid measurement batch [2007–2010], smoking status [never], prevalent diabetes [no], prevalent atrial fibrillation [no], prevalent drug-treated hypertension [no], and alcohol use [none]). Table 4. Estimated Years of Remaining Life Gained After Age 65 y Among Representative Older Adults, by Plasma Phospholipid Total 3-PUFA Level

47 Results: During 30,829 person-years, 1625 deaths (including 570 cardiovascular deaths), 359 fatal and 371 nonfatal CHD events, and 130 fatal and 276 nonfatal strokes occurred. After adjustment, higher plasma levels of ω3-PUFA biomarkers were associated with lower total mortality, with extreme-quintile hazard ratios of 0.83 for EPA (95% CI, 0.71 to 0.98; P for trend = 0.005), 0.77 for DPA (CI, 0.66 to 0.90; P for trend = 0.008), 0.80 for DHA (CI, 0.67 to 0.94; P for trend = 0.006), and 0.73 for total ω3-PUFAs (CI, 0.61 to 0.86; P for trend < 0.001). Lower risk was largely attributable to fewer cardiovascular than non cardiovascular deaths. Individuals in the highest quintile of phospholipid ω3-PUFA level lived an average of 2.22 more years (CI, 0.75 to 3.13 years) after age 65 years than did those in the lowest quintile.

48 Conclusion: Higher circulating individual and total 3-PUFA levels are associated with lower total mortality, especially CHD death, in older adults. Primary Funding Source: National Institutes of Health. Limitation: Temporal changes in fatty acid levels and misclassification of causes of death may have resulted in underestimated associations, and unmeasured or imperfectly measured covariates may have caused residual confounding.

49 Message 健常な高齢者 2692 人を対象に、長鎖オメ ガ 3 多価不飽和脂肪酸( ω3-PUFA )と死亡 の関連をコホート研究で検証。血中 ω3- PUFA 高値が全死亡率の低下と関連し、最 低五分位群に対する最高分位群のハザード 比はエイコサペンタエン酸 0.83 、ドコサペ ンタエン酸 0.77 、ドコサヘキサエン酸 0.80 、全 ω3-PUFA0.73 だった。

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