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Backgrounds and aim Lipoprotein lipase (LPL) deficiency is a genetic disorder with a defective gene for lipoprotein lipase, leading to very high triglycerides. In the daily practice it is much more common to come across severely hypertriglyceridemia without homozygous or compound heterozygous LPL deficiency (SHTG). Methods We investigated on how to screen homozygous or compound heterozygous LPL deficiency using lipid parameters by meta-analyzing past 20 subjects on this genetic disease reported by Japanese investigators. As a comparison with LPL deficiency, 21 subjects with SHTG from recent two studies were included in this study. Results Serum HDL-C levels were significantly lower in LPL deficiency than in SHTG (0.38 ± 0.13 vs 0.94 ± 0.28 mmol/L (mean ± SD), p Conclusion We found for the first time that serum HDL-C is an extremely useful marker for discriminating LPL deficiency from SHTG in Japanese population.

Background We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment. Methods She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y. Results Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 → 13.58 mmol/l) and considerable increases in preheparin HL (66 → 76 ng/ml) and PHP-HL (660 → 1118 ng/ml) concentrations and PHP-HL activities (253 → 369U/l) despite almost no effect on LPL concentrations and activities. Conclusions These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency.

Background: We investigated the potential mechanism underlying body weight reduction by the sodium glucose cotransporter 2 (SGLT2) inhibitor, tofogliflozin, during treatment and after subsequent washout. Methods: Ten Japanese men with type 2 diabetes (average age: 66.3 years) were orally administered tofogliflozin (20 mg/day) for 8 weeks followed by a subsequent 8-week washout period (16 weeks). Results: Significant reductions were observed in blood glucose, hemoglobin A1c (HbA1c), uric acid, body weight and waist circumference with an increase in high-molecular weight (HMW) adiponectin at 8 weeks. We also evaluated these markers at 16 weeks and found that unlike HbA1c and uric acid, body weight and HMW adiponectin did not return to baseline levels. To clarify the potential mechanism underlying the body weight reduction during treatment with tofogliflozin (8 weeks) and after washout (at 16 weeks), we investigated the correlations between changes from baseline (0 week) in body weight and those in waist circumference (or HMW adiponectin). The changes in body weight between 0 weeks versus 8 weeks were not significantly correlated with those in waist circumference or HMW adiponectin. In contrast, changes in body weight between 0 and 16 weeks did show a significant correlation to those in waist circumference and HMW adiponectin. Conclusion: The body weight reduction caused by tofogliflozin may be due to several factors as well as fat reduction at 8 weeks, but is most likely due to fat reduction alone after a subsequent 8 weeks of washout of this agent. J Clin Med Res. 2019;11(1):35-41 doi: https://doi.org/10.14740/jocmr3650

Objective This study investigated associations between three indices of obesity-the body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR)-and the incidence of chronic kidney disease (CKD). Methods The employees of a company in Japan (1,725 men, 1,186 women; aged 35-55 years) had BMI, WC, and WHtR measured in health examinations. The incidence of CKD was determined at annual medical examinations over a six-year period. The hazard ratios for CKD were calculated using proportional hazard models, and the χ2 statistic was used to compare the strengths of the associations. Results The mean BMI (kg/m2), WC (cm), and WHtR were 23.6, 84.3, and 0.49 for men and 22.3, 79.7, and 0.50 for women, respectively. The incidence of CKD (/1,000 person-years) was 18.1 for men and 8.4 for women. In men, positive linear associations were observed between the BMI, WC, and WHtR and the risk of CKD, even after adjusting for the presence of metabolic abnormalities (p for trend

金沢大学附属病院循環器内科, Aim: The Japan Atherosclerosis Society (JAS) guidelines for the prevention of atherosclerotic diseases 2012 (JAS2012) proposed lipid management targets; however, less data is available regarding the attainment rates of each target in community-based settings. Therefore, we assessed the attainment rates of lipid management targets among subjects who underwent Japanese specific health checkups.\nMethods: A total of 85,716 subjects (male=29,282, 34.2%) aged 40–74 years who underwent specific health checkups from 2012 to 2014 in Kanazawa city, Japan, were included in this study. We evaluated the attainment rates of the lipid management targets according to the JAS2012 guideline and investigated the clinical characteristics of the subjects without achieving the targets.\nResults: The target for LDL cholesterol (LDL-C) was the least attained in all risk categories, 89, 72, 50, and 34% for category I, II, III, and secondary prevention, respectively, in 2014. In addition, these rates inversely correlated with the grade of risk categories (p-value for trends ＜0.001). Attainment rate of the LDL-C target in the suspected chronic kidney disease (CKD) group was significantly lower than in the groups with diabetes, stroke, or absolute risk in category III (49.2, 60.3, 63.5, 54.4%, respectively, p-value ＜0.001 for each). Moreover, the attainment rate of the LDL-C target was significantly lower in subjects that did not receive lipid-lowering therapy than in those who received it in the secondary prevention (27.7 and 40.6%, respectively, p-value ＜0.001).\nConclusions: Lipid management is inadequate in community-based settings, particularly, in subjects with CKD and secondary prevention., This article distributed under the terms of the latest version of CC BY-NC-SA defined by the Creative Commons Attribution License.

Background: Postprandial hyperglycemia and hyperlipidemia are highly related to the development of atherosclerosis. Sodium/glucose cotransporter-2 (SGLT2) inhibitors have attracted attention as a new class of anti-diabetic agents for the treatment of type 2 diabetes. We investigated the effect of tofogliflozin on postprandial glucose and lipid metabolism in Japanese male patients with type 2 diabetes. Methods: Ten Japanese men with type 2 diabetes (average age 66.3 years) were orally administered tofogliflozin (20 mg per day) for 8 weeks followed by a subsequent 8 weeks of washout of the agent. At 0, 8 and 16 weeks, postprandial metabolic parameters were measured at 0, 60 and 120 min after cookie ingestion. Results: There were significant reductions in body weight and body mass index at 8 weeks. There was a reduction in HbA1c at 8 weeks, which returned to pretreatment levels at 16 weeks. Serum insulin levels did not change during the entire study period under either fasting or postprandial state. The area under the curve of plasma glucagon significantly increased at 8 weeks. There were no changes in lipid and lipoprotein levels either in fasting or postprandial state except for tendency toward reduction in postprandial triglycerides at 8 weeks and increase in HDL-C at 16 weeks. Conclusions: Tofogliflozin treatment causes an improvement of postprandial glucose metabolism but not considerable postprandial lipid metabolism. J Clin Med Res. 2017;9(5):403-409 doi: https://doi.org/10.14740/jocmr2806w

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2&prime, deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD.

Aims: The present study aimed to investigate relationships among abdominal obesity, metabolic abnormalities, and the prevalence of chronic kidney disease (CKD) in relatively lean Japanese men and women. Participants and methods: The participants included 8133 men and 15 934 women between 40 and 75 years of age recruited from the government health check-up center in Kanazawa City, Japan. The prevalence of abdominal obesity, high blood pressure, dyslipidemia, and high fasting plasma glucose levels were assessed according to the Japanese criteria for metabolic syndrome. The estimated glomerular filtration rate (eGFR) was calculated using the modified Modification of Diet in Renal Disease equation for the Japanese population, and participants with an eGFR

The aims of this study were (1) to determine whether the accumulation of coronary plaque burden assessed with coronary computed tomography angiography (CCTA) can predict future events and (2) to estimate the onset and progression of coronary atherosclerosis in patients with familial hypercholesterolemia (FH). Consecutive 101 Japanese patients with heterozygous FH (men = 52, mean age 56 ± 16 years, mean low-density lipoprotein cholesterol 264 ± 58 mg/dl) who underwent 64-detector row CCTA without known coronary artery disease were retrospectively evaluated by assigning a score (0 to 5) to each of 17 coronary artery segments according to the Society of Cardiovascular Computed Tomography guidelines. Those scores were summed and subsequently natural log transformed. The periods to major adverse cardiac events (MACE) were estimated using multivariable Cox proportional hazards models. During the follow-up period (median 941 days), 21 MACE had occurred. Receiver operating characteristic curve analyses identified a plaque burden score of 3.35 (raw score 28.5) as the optimal cutoff for predicting a worse prognosis. Multivariate Cox regression analysis identified the presence of a plaque score ≥3.35 as a significant independent predictor of MACE (hazard ratio = 3.65; 95% confidence interval 1.32 to 25.84, p0.05). The regression equations were Y = 0.68X - 15.6 (r = 0.54, p0.05) in male and Y = 0.74X - 24.8 (r = 0.69, p0.05) in female patients with heterozygous FH. In conclusion, coronary plaque burden identified in a noninvasive, quantitative manner was significantly associated with future coronary events in Japanese patients with heterozygous FH and that coronary atherosclerosis may start to develop, on average, at age 23 and 34 years in male and female patients with heterozygous FH, respectively.

Background The relationship between plasma lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), glycosylphosphatidylinositol anchored HDL binding protein1 (GPIHBP1) concentration and the metabolism of remnant lipoproteins (RLP) and small dense LDL (sdLDL) in patients with coronary artery disease (CAD) is not fully elucidated. Methods One hundred patients who underwent coronary angiography were enrolled. The plasma LPL, HTGL and GPIHBP1 concentrations were determined by ELISA. The time dependent changes in those lipases, lipids and lipoproteins were studied at a time-point just before, and 15 min, 4 h and 24 h after heparin administration. Results The LPL concentration exhibited a significant positive correlation with HDL-C, and inversely correlated with TG and RLP-C. The HTGL concentration was positively correlated with RLP-C and sdLDL-C. The HTGL ratio of the pre-heparin/post-heparin plasma concentration and sdLDL-C/LDL-C ratio were significantly greater in CAD patients than in non-CAD patients. GPIHBP1 was positively correlated with LPL and inversely correlated with RLP-C and sdLDL-C. Conclusion The HTGL concentration was positively correlated with RLP-C and sdLDL-C, while LPL and GPIHBP1 were inversely correlated with RLP-C and sdLDL-C. These results suggest that elevated HTGL is associated with increased CAD risk, while elevated LPL is associated with a reduction of CAD risk.

Background Angiopoietin-like protein 8 (ANGPTL8) is considered to be metabolically multifunctional. One notable function still to be elucidated definitively is a betatrophic role in protecting and preserving pancreatic beta-cell function. There is, however, a paucity of data regarding the role of ANGPTL8 in the etiology of type 2 diabetes (T2D), but some findings of human research have suggested the potential for significant involvement. Objective To examine the frequency of T2D and impaired glucose tolerance (IGT) in Japanese subjects with the ANGPTL8 R59W variant. Methods ANGPTL8 R59W (Rs2278426, c.194C > T) was determined by polymerase chain reaction–restriction fragment length polymorphism using the restriction enzyme FokI in 797 consecutive Japanese individuals. Subjects with triglyceride levels greater than or equal to 150 mg/dL were considered to be hypertriglyceridemic. Results Genotype frequencies of ANGPTL8 R59W were as follows: wild-type RR (C/C) 53.5%, RW (C/T) 36.6%, and WW (T/T) 9.9%. T2D and IGT were significantly prevalent in WW and RW subjects relative to RR among all 797 subjects ( P = .0138) and also in hypertriglyceridemic subjects ( P = .0015). In multiple logistic regression models for the existence of T2D and IGT in hypertriglyceridemic subjects, the odds ratio for heterozygote RW and homozygote WW genotypes to wild-type RR was 2.406 ( P = .0017) after controlling the risk factors of age, gender, and body mass index as covariates. Conclusions The frequency of ANGPTL8 R59W is significantly higher in Japanese subjects than in other ethnic groups. The rates of T2D and IGT were greater in subjects with the R59W variant. These findings indicate that ANGPTL8 is a participant in diabetes and a potential therapeutic target for T2D prevention, especially in East Asians.

Introduction.The objective of this study was to clarify how pitavastatin affects glucose and lipid metabolism, renal function, and oxidative stress.Methods.Ten Japanese men (average age of 33.9 years) were orally administered 2 mg of pitavastatin for 4 weeks. Postprandial glucose, lipoprotein metabolism, and oxidative stress markers were evaluated at 0 and 4 weeks of pitavastatin treatment (2 mg once daily) with a test meal consisting of total calories: 460 kcal, carbohydrates: 56.5 g (226 kcal), protein: 18 g (72 kcal), lipids: 18 g (162 kcal), and NaCl: 1.6 g. Metabolic parameters were measured at 0, 60, and 120 minutes after test meal ingestion.Results.After administration of pitavastatin, serum total cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, arachidonic acid, insulin, and adjusted urinary excretion of uric acid decreased, whereas creatinine clearance (CCr) and uric acid clearance (CUA) increased. And postprandial versus fasting urine 8-hydroxydeoxyguanosine remained unchanged, while postprandial versus fasting isoprostane decreased after pitavastatin treatment. Next, we compared postprandial glucose and lipid metabolism after test meal ingestion before and after pitavastatin administration. Incremental areas under the curve significantly decreased for triglycerides (P<0.05) and remnant-like particle cholesterol (P<0.01), while those for apolipoprotein E (apoE), glucose, insulin, and high-sensitivity C-reactive protein remained unchanged.Conclusion.Pitavastatin improves postprandial oxidative stress along with hyperlipidemia.

The cause of obesity includes genetic and environmental factors, including cytokines derived from adipocytes (adipo-cytokines). Although drug therapy is available for obesity, it is highly risky. Our main focus in this review is on the traditional form of Japanese medicine, Kampo, in the treated of obesity. Two Kampo formulas, that is, bofutsushosan (防風通聖散) and boiogito (防己黄耆湯), are covered by the national health insurance in Japan for the treatment of obesity. Various issues related to their action mechanisms remain unsolved. Considering these, we described the results of basic experiments and presented clinical evidence and case reports on osteoarthritis as examples of clinical application of their two Kampo medicine. Traditional medicine is used not only for treatment but also for prevention. In clinical practice, it is of great importance to prove the efficacy of combinations of traditional medicine and Western medicine and the utility of traditional medicine in the attenuation of adverse effects of Western medicine.

The current standard treatment for cancer is a multidisciplinary therapy whereby various types of treatment are properly combined. Chemotherapy with multiple anticancer drugs is now common, and traditional, complementary, and alternative therapies are adopted as supportive measures. Medical care in Japan is distinguished by the ability for patients to access both Western and Kampo medical cares at the same time. There is a high degree of trust in the safety of Kampo therapies because they are practiced by medical doctors who are educated with fundamental diagnosis of Western medicine. Highly reliable clinical studies are being published, demonstrating that palliative or supportive care for cancer patients using Kampo preparations alleviates adverse effects of chemotherapy or radiotherapy. This paper reports the circumstances around cancer care in Japan where traditional therapeutic Kampo formulas are used for patients undergoing cancer treatment with cutting-edge chemotherapy, specifically to alleviate adverse effects of anticancer drugs.

Background This study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs. Methods The pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years). The patients were randomly divided into two groups based on the timing when ezetimibe was added. Results Plasma LPL mass concentration was significantly reduced by rosuvastatin at 20 mg/day (median = 87.4 [IQR: 71.4–124.7] to 67.5 [IQR: 62.1–114.3] ng/ml, P

Aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy is important for high-risk patients. However, sparse data exist on the impact of combined aggressive LDL cholesterol-lowering therapy in familial hypercholesterolemia (FH), particularly on side effects to changes in plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. We enrolled 17 Japanese patients with heterozygous FH (12 men, 63.9 ± 7.4 years old) with single LDL receptor gene mutations in a prospective open randomized study. Permitted maximum doses of rosuvastatin (20 mg/day), ezetimibe (10 mg/day), and granulated colestimide (3.62 g/day) were introduced sequentially. Serum levels of LDL cholesterol decreased significantly by -66.4% (p0.001) and 44% of participants achieved LDL cholesterol levels100 mg/dl. There were no serious side effects or abnormal laboratory data that would have required the protocol to have been terminated except for 1 patient with myalgia. Coadministration of ezetimibe and granulated colestimide further lowered serum LDL cholesterol more than rosuvastatin alone without changing plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. In conclusion, adequate introduction of this aggressive cholesterol-lowering regimen can improve the lipid profile of FH.

Both type I and type V hyperlipoproteinemia are characterized by severe hypertriglyceridemia due to an increase in chylomicrons. Type I hyperlipoproteinemia is caused by a decisive abnormality of the lipoprotein lipase (LPL)- apolipoprotein C-II system, whereas the cause of type V hyperlipoproteinemia is more complicated and more closely related to acquired environmental factors. Since the relationship of hypertriglyceridemia with atherosclerosis is not as clear as that of hypercholesterolemia, and since type I and V hyperlipoproteinemia are relatively rare, few guidelines for their diagnosis and treatment have been established; however, type I and V hyperlipoproteinemia are clinically important as underlying disorders of acute pancreatitis, and appropriate management is necessary to prevent or treat such complications. Against such a background, here we propose guidelines primarily concerning the diagnosis and management of type I and V hyperlipoproteinemia in Japanese.

Background: Autosomal recessive hypercholesterolemia (ARH) is an extremely rare inherited hypercholesterolemia, the cause of which is mutations in low-density lipoprotein (LDL) receptor adaptor protein 1 (LDLRAP1) gene. Methods: A total of 146 heterozygous familial hypercholesterolemic (FH) patients with a mutation in LDLR gene were screened for genes encoding proprotein convertase subtilisin/kexin type 9 (PCSK9) and LDLRAP1. Results: Among the 146 subjects, we identified a 79-year-old Japanese female with double mutations in LDLR gene (c.2431A > T) and LDLRAP1 gene (c.606dup). Two other relatives with double mutations in those genes in her family were also identified. Although the proband exhibited massive Achilles tendon xanthoma and coronary and aortic valvular disease, serum LDL-C level of subjects with double mutations was similar with that of subjects with single LDLR mutation (284.0 ± 43.5 versus 265.1 ± 57.4 mg/dl). Conclusion: Additional mutation in LDLRAP1 may account for severer phenotype in terms of xanthoma and atherosclerotic cardiovascular disease in FH patients. © 2011 Elsevier Ireland Ltd. All rights reserved.

Background We elucidated the difference between the effects of bezafibrate and atorvastatin in hypertriglyceridemia with apoE2/2 and 3/3. Methods An open randomized crossover study consisted of a 4-week treatment period with bezafibrate (400 mg daily) or atorvastatin (10 mg daily) and a 4-week wash-out period. Results Bezafibrate significantly decreased serum concentrations of triglyceride (apoE2/2, E3/3: −49.2%, −39.0%) and significantly increased high-density lipoprotein (HDL) cholesterol (+ 28.5%, + 26.1%) in both apoE phenotypes but did not change serum concentrations of low-density lipoprotein (LDL) cholesterol. Atorvastatin significantly decreased serum concentrations of LDL cholesterol (− 34.0%, −30.0%) and triglyceride (− 27.6%, −25.8%) in both apoE phenotypes but did not change HDL cholesterol concentrations. Changes in cholesterol in lipoprotein subfractions were not different between apoE2/2 and E3/3. Bezafibrate changed cholesterol distribution from small- to large-sized LDL and from large- to small-sized HDL. On the other hand, atorvastatin decreased cholesterol in all apoB-containing lipoprotein subfractions but did not change any of the HDL subfractions. Conclusion Bezafibrate and atorvastatin improve atherogenic dyslipidemia in considerably different ways. Extrapolating from the present data, we presume that the combination of these drugs may contribute to reduce LDL-C/HDL-C ratio effectively as well as lowering concentrations of serum triglyceride.

Objectives The LDL receptor relative with 11 ligand-binding repeats (LR11) is closely related to atherosclerotic disease or diabetes. The aim of the study was to clarify how soluble LR11 was related to Achilles' tendon thickness (ATT) and HbA1c in familial hypercholesterolemia. Design and methods The present study is a cross-sectional case-control study. We enrolled twenty-four patients with heterozygous FH (age 51.0 ± 20.0 year; male, 50%; 20 cases with LDL receptor mutation, 1 case with proprotein convertase subtilisin/kexin type 9 (PCSK9) E32K and 3 cases without confirmed mutations). Soluble LR11 (sLR11) was measured using a sandwich enzyme-linked immunosorbent assay method. Results Univariate regression analysis showed that sLR11 had positive correlations with age and HbA1c, and inverse correlations with apoA1 in FH. There were also positive correlations of sLR11 with apoE, IDL-C and average ATT. Multivariate regression analysis showed that there were positive correlations of sLR11 to IDL-C and HbA1c independent of age and BMI. In another multivariate regression analysis on the relationships of average ATT as a dependent variable with age, BMI and sLR11 (IDL-C and HbA1c) as independent variables, sLR11 had a positive correlation with average ATT, independent of age and BMI. However, this independency did not persist after adding IDL-C and HbA1c as confounding factors. Of special note is that HbA1c showed a significant correlation with average ATT, independent of other parameters including sLR11. Conclusion It is crucial to intervene in the existence of remnant lipoprotein as well as hypercholesterolemia from an early stage and conduct glycemic control to prevent the progression of atherosclerotic disease in FH.

Objective High-normal, the intermediate category between normal fasting glucose (NFG) and impaired fasting glucose (IFG), was introduced in the criteria of the disordered glucose metabolism in 2008. The aim of this study was to investigate the risk for future incidence of type 2 diabetes of the subjects with high-normal and to examine how other metabolic variables could be useful for their risk stratification. Methods A historical cohort study was conducted from 2001 to 2008, inclusive, in 4,165 non-diabetic employees at public schools (2,229 men and 1,936 women; age 45.8±5.9 years, range 25-55 years). They were classified at baseline as NFG with fasting plasma glucose (FPG)

Regional fat distribution rather than overall fat volume has been considered to be important to understanding the link between obesity and metabolic disorders. We aimed to evaluate the independent associations of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) with metabolic risk factors in apparently healthy middle-aged Japanese. Participants were 1,119 men and 854 women aged 38-60 years who were not taking medications for diabetes, hypertension, or dyslipidemia. VAT and SAT were measured by use of computed tomography (CT) scanning. VAT and SAT were significantly and positively correlated with each other in men (r = 0.531, P < 0.001) and women (r = 0.589, P < 0.001). In multiple regression analyses, either measure of abdominal adiposity (VAT or SAT) was positively associated with blood pressure, fasting plasma glucose, and log triglyceride (P < 0.001) and inversely with high-density lipoprotein (HDL)-cholesterol (P < 0.001). When VAT and SAT were simultaneously included in the model, the association of VAT with triglycerides was maintained (P < 0.001) but that of SAT was lost. The same was true for HDL-cholesterol in women. For fasting plasma glucose, the association with VAT was strong (P < 0.001) and the borderline association with SAT was maintained (P = 0.060 in men and P = 0.020 in women). Both VAT and SAT were independently associated with blood pressure (P < 0.001). Further adjustment for anthropometric indices resulted in the independent association only with VAT for all risk factors. In conclusion, impacts of VAT and SAT differed among risk factors. VAT showed dominant impacts on triglyceride concentrations in both genders and on HDL-cholesterol in women, while SAT also had an independent association with blood pressure.

Objective— Apolipoprotein AII (apoAII) is the second major apolipoprotein in high-density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. Methods and Results— We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were ≈30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins. Furthermore, postheparin lipoprotein lipase activity significantly decreased in Tg rabbits compared with non-Tg rabbits. Conclusions— These results indicate that apoAII plays an important role in both VLDL and HDL metabolism, possibly through the inhibition of lipoprotein lipase activity. ApoAII Tg rabbits may become a new model for the study of human familial combined hyperlipidemia.

Aim: Postprandial hypertriglyceridemia is recognized as an independent risk factor for cardiovascular disease. The aim of this study was to identify differences between fasting and postprandial TG levels, focusing on the influence of waist circumference. Methods: Subjects included 1,505 men and 798 women aged 3865 years who were not taking medications for diabetes or dyslipidemia. Fasting TG levels were measured after an overnight fast, and postprandial TG levels were measured 2 hours after a standardized rice-based lunch (total 740 kcal, 20 g fat, 30 g protein, and 110 g carbohydrates) in the afternoon on the same day. Results: Fasting and postprandial TG levels were highly correlated in both men (r=0.86, p, 出版者照会後に全文公開

Holoprosencephaly results from the incomplete development of midline structures within the cerebrum and encompasses a series of abnormalities of mid-facial development. Here, we report a case of male holoprosencephaly associated with false median cleft of upper lip. This patient belonged clinically to the DeMyer's group IV holoprosencephaly, semilobar type. An infant with this type of holoprosencephaly has been thought to die generally within 1 to 2 years after birth and to rarely benefit from an operation. In this case, the patient had cheiloplasty at the age of 2.5 years at the request of his parents and he lives currently, being 3 years and 2 months old.

In the new world-wide criteria for metabolic syndrome (MetS) by the International Diabetes Federation (IDF) in 2006, the Japanese is the only ethnicity in which the recommended waist circumference (WC) cutoff value is higher in women (>or=90cm) than in men (>or=85cm), and its validity appears to be controversial. We investigated the optimal cutoff points for the diagnosis of central obesity in Japanese men and women, using the receiver operating characteristic (ROC) curve analysis for both of WC and visceral fat area (VFA) in 1870 middle-aged Japanese. VFA was superior to WC and Body mass index (BMI) for discriminating the subjects with two or more nonadipose components of MetS. The optimal cutoff points of VFA and WC were 132.6cm(2) and 89.8cm for men and 91.5cm(2) and 82.3cm for women. The stratifications of MetS components more than 1.0 in average occurred more steeply by the accumulation of VFA in women than in men. In conclusion, setting the cutoff points of WC and VFA lower values in women than in men for the definition of central obesity is needed to identify the subjects with MetS in Japanese, as in other Asian populations.

The relationship between post-prandial plasma glucose (PPG) and post-challenge plasma glucose (PCG) within individuals was investigated in Japanese population. The oral glucose tolerance test (OGTT) and measurements of PPG 2h after ingestion of a standardized rice-based meal (PPG2h), were performed in 4471 middle-aged Japanese subjects (2774 men and 1697 women, 50.7+/-8.5 years). There was a loose correlation between PPG2h and PCG2h (r=0.327, p0.001). The diabetes group (n=170) showed the highest PPG2h, followed by the IGT group (n=786) and the NGT group (n=3414) (p0.05). At the cutoff point of 140 mg/dl (7.8 mmol/l) for PPG2h, specificities were 94.9% for IGT plus diabetes and 92.9% for diabetes, but sensitivities were as low as 23.2% for IGT plus diabetes and 44.7% for diabetes. The correlation of PPG2h with PCG2h was stronger in the obese group (BMIor=25 kg/m2) than in the lean group (BMI20 kg/m2). We conclude that the correlation between PPG2h and PCG2h was significant but not very tight. In evaluating PPG2h, if the cutoff point of 140 mg/dl (7.8 mmol/l) for PCG2h is extrapolated, the majority of subjects with dysglycemia could be overlooked.

金沢大学大学院医学系研究科, Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, increasing attention has been paid to the clinical significance of measuring serum LPL protein mass without heparin injection to the study subjects. In earlier studies, this marker was utilized to classify LPL deficient subjects, which is an extremely rare metabolic disorder with a frequency of one in one million. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma or serum LPL mass has significant relationships with serum lipids and lipoproteins, visceral fat area, insulin resistance, and even the development of coronary atherosclerosis in cross-sectional studies, although this might be a metabolic surrogate marker with almost no catalytic activities, which does not appear to be involved in catalyzing hydrolysis of TG in TG-rich lipoproteins. Recently, a prospective study has demonstrated that low serum LPL concentration predicts future coronary events. Taken together, we suggest that pre-heparin LPL mass in plasma or sera provide us with useful and important information on the development of metabolic disorders leading to atherosclerotic disease. © 2006 Elsevier B.V. All rights reserved.

Aim: The aim of this study was to investigate the effect of SNP45 of the adiponectin gene on body fat distribution and carotid atherosclerosis in Japanese obese subjects. Methods: A total of 64 obese subjects were investigated. Genotypes of SNP45 were assayed by polymerase chain reaction-restriction fragment length polymorphism. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. The progression of atherosclerosis was evaluated by plaque score (PS) of carotid artery using B-mode ultrasonography. Results: Men carrying the G allele of SNP45 showed higher VFA (172.8±50.8 vs. 147.1±58.7, p=0.005), lower SFA (209.9±101.8 vs. 273.4±142.2, p=0.007), higher VFA/SFA (V/S) ratio (1.00±0.46 vs. 0.60±0.26, p, 出版者照会後に全文公開

Background To clarify whether there are age and gender differences in the components contributing to the diagnosis of metabolic syndrome (MS) in the Japanese population. Methods and Results A total of 21,870 individuals (ie, 7,329 men aged 68±8.1 years, body mass index (BMI) 23.2±2.9 kg/m2 and 14,541 women aged 66±9.4 years, BMI 22.8±3.3 kg/m2) participated in the study. The subjects were obtained from the general population and examinations were conducted in hospitals located in Kanazawa city. MS was diagnosed according to the Japanese criteria. Information regarding medication is lacking in all participating subjects. Overall, the incidence of MS was 18.4% and 5.78% for men and women, respectively. When analyzed according to age group, the incidence of MS in men did not differ significantly, whereas its prevalence was higher in older women than in younger women. Among the indicators of MS, high blood pressure (BP; high systolic BP and/or high diastolic BP) was the most frequent, followed by dyslipidemia (high triglycerides and/or low high-density lipoprotein-cholesterol (HDL-C)), and high fasting plasma glucose was the least frequently occurring in both genders. In contrast to the high frequency of high BP, isolated high diastolic BP was rare across both genders regardless of age group. Similarly, isolated low HDL-C was quite rare. Conclusions Frequency of the components contributing to the diagnosis of MS differed considerably according to gender and age group in the Japanese population. (Circ J 2007; 71: 1734 - 1737)

Lipoprotein lipase has long been known to hydrolyse triglycerides from triglycerides-rich lipoproteins. More recently, it has been shown to promote the binding of lipoproteins to various lipoprotein receptors. Evidence is also presented regarding the possible atherogenic role of lipoprotein lipase. In theory, lipoprotein lipase deficiency should help to clarify this question. However, the rarity of this condition means that it has not been possible to conduct epidemiological studies. An alternative approach is to investigate the correlation of lipoprotein lipase with onset of cardiovascular disease in prospective studies in large population-based cohorts. Complementary with this approach, animal models have been used to explore the atherogenicity of lipoprotein lipase expressed by macrophages.

To investigate whetherBrucella abortus(BA) antigen injections lead to anemia, and to establish an appropriate Chronic Fatigue Syndrome (CFS) animal model by BA injections, 6 repeated injections of BA antigen were fulfilled every 2 weeks. At a high dose of1∗1010particles/mouse, anemia was induced within 2 weeks and then recovered a lot at the end of the research, while at a moderate dose of1∗108(3 injections) shifting to1∗109/mouse (3 injections) anemia was absent. In both groups running wheel activity remained very low even 6 weeks after the last injection.

Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for predicting of the prognosis and selecting appropriate therapy.Genetic analysis was performed in two patients with primary hypocholesterolemia born from consanguineous parents. The oral fat tolerance test (OFTT) was performed in one patient with FHBL (apoB-87.77) and one with ABL as well as in four normal control subjects. After overnight fasting, blood samples were drawn. Serum lipoprotein and remnant-like particle (RLP) fractions were determined by HPLC analysis.Both patients with homozygous FHBL were asymptomatic probably because of preserved levels of fat-soluble vitamins, especially vitamin E. The patients with FHBL were homozygous because of novel apoB-83.52 and apoB-87.77 mutations, and although one of them (apoB-87.77) had fatty liver disease, microscopic findings suggesting nonalcoholic steatohepatitis were absent. Fasting apoB-48 and RLP-triglyceride levels in the patient with homozygous FHBL, which were similar to those in normal control subjects, increased after OFTT both in normal control subjects and the patient with FHBL but not in the patient with ABL, suggesting that the fat load administered was absorbed only in the patient with FHBL.Although lipid levels in the patients with homozygous FHBL and ABL were comparable, fasting, postoral fat loading of apoB-48, as well as RLP-triglyceride levels, may help in the differential diagnosis of FHBL and ABL and provide a prompt diagnosis using genetic analysis in the future.

Study Objective. To assess the effects of fenofibrate therapy on concentrations of plasma ubiquinol-10 and ubiquinone-10—the reduced and oxidized forms, respectively, of coenzyme Q10. Design. Prospective, open-label, noncontrolled study. Setting. University clinic and laboratory. Patients. Eighteen patients with hyperlipidemia and type 2 diabetes mellitus. Intervention. Patients received fenofibrate 150 mg/day for 12 weeks. Measurements and Main Results. Metabolic parameters were assessed 4, 8, and 12 weeks after the start of fenofibrate treatment. Plasma ubiquinol-10 and ubiquinone-10 levels were measured by reverse-phase high-performance liquid chromatography. At 4, 8, and 12 weeks, significant reductions in fasting triglyceride levels and significant increases in high-density lipoprotein cholesterol levels were noted. Total cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and adiponectin levels, however, did not change significantly. Plasma ubiquinol-10 concentrations significantly increased after 8 and 12 weeks (p

Summary Objective The LMNA 1908C/T polymorphism has been reported to be associated with dyslipidaemia, metabolic syndrome, adipose tissue metabolism and obesity phenotypes, suggesting that this polymorphism presents an increased risk of atherosclerosis and vascular diseases. However, there have been no previous reports on the relationship between the LMNA 1908C/T polymorphism and vascular diseases. The aim of this study therefore was to investigate the association between the LMNA 1908C/T polymorphism and the prevalence of vascular disease in Japanese patients with type 2 diabetes. Design A cross-sectional, hospital-based study of diabetic complications with an LMNA gene background. Patients One hundred and sixty-six Japanese men with type 2 diabetes. Measurements LMNA 1908C/T polymorphism (by polymerase chain reaction restriction fragment length polymorphism, PCR-RFLP); diabetic retinopathy (by standard fundus photography); diabetic nephropathy (by urinary albumin excretion rate); diabetic neuropathy (by signs, symptoms and/or nerve conduction velocity); coronary heart disease (by symptoms of typical chest pain and/or history of myocardial infarction, and ischaemic electrocardiographic alteration and/or coronary artery bypass graft surgery); cerebral vascular disease (by ultrasonography, computed tomography and/or magnetic resonance imaging). Results Carriers of the LMNA 1908T allele manifested a significantly higher prevalence of diabetic nephropathy and cerebral vascular disease than carriers of the C allele. Multiple regression analysis showed that the LMNA 1908T allele tended to be associated with cerebral vascular disease, but was independent of age, hypertension, total cholesterol or triglyceride [odds ratio (OR) 7·03, P = 0·0611]. Similarly, the LMNA 1908T allele showed a significant association with diabetic nephropathy, not independent of total cholesterol or triglyceride. Conclusions The LMNA 1908C/T polymorphism plays an important role in the development of cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes.

Objective: The aim of this study was to determine how lipoprotein lipase (LPL) and hepatic triacylglycerol lipase (HTGL) activity relate to serum adiponectin levels. Research design and methods: Fifty-five hyperlipidemic Japanese men were recruited for this study. LPL and HTGL activity in post-heparin plasma (PHP) was measured using Triton X-100 emulsified-[ 1 4 C] triolein. The remaining activity in the presence of 1M NaCI was defined as HTGL activity. Serum adiponectin levels were determined by an enzyme-linked immunosorbent assay system. Result: LPL activity had a positive relationship with HDL 2 , but had no relation with HDL 3 , while HTGL had positive relationship with HDL 3 , but had no relationship with HDL 2 . LPL activity showed a positive relationship [r= 0.345, p= 0.010] to serum adiponectin levels, while and HTGL activity showed an inverse relationship [r= -0.365 p=0.006]. Multiple regression analysis with LPL and HTGL as dependent variables and age, BMI, serum adiponectin and the homeostasis model assessment of insulin resistance (HOMA-IR) as independent variables showed LPL and HTGL's association to adiponectin did not persist after adjustments for these covariants. However, the association of LPL activity to HOMA-IR was found to persist after adjustments of age, BMI, and serum adiponectin. Conclusions: There was a co-linearity between insulin sensitivity and adiponectin as well as insulin sensitivity and LPL/HTGL activity.

Hyperinsulinemia is widely believed to be an important coronary risk factor. We investigated the effect of plasma insulin levels on the development of coronary ectasia in Japanese men with heterozygous familial hypercholesterolemia (FH).A cross-sectional study was conducted in 20 FH men with the LDL receptor mutation (K790X) [age 42.3+/-2.8 years old, body mass index (BMI) 24.6+/-0.7 kg/m2, total cholesterol (TC) 8.68+/-0.36 mmol/l, triglycerides (TG) 1.76+/-0.23 mmol/l, high-density lipoprotein cholesterol (HDL-C) 0.977+/-0.065 mmol/l]. Subjects with diabetes mellitus were excluded. Plasma insulin levels, either fasting or during oral glucose tolerance test, were compared between subjects with and without coronary artery ectasia.FH subjects with coronary ectasia had significantly higher fasting plasma insulin levels than those without (12.6+/-1.4 vs. 7.7+/-0.5 mU/l; p0.05). Also, plasma insulin levels during oral glucose tolerance test tended to be higher in the former than in the latter.Plasma insulin level could be an important determinant of the development of coronary artery ectasia in Japanese heterozygous FH men.

Familial hypercholesterolemia (FH) results from low-density lipoprotein (LDL) receptor gene mutations. Heterozygotes have twice normal LDL-cholesterol concentrations in early childhood, and experience early myocardial infarction. We demonstrated bimodal cholesterol frequency distributions, independently confirming existence of an identifiable hypercholesterolemic subpopulation. We assayed blood lipids in 181 FH patients genetically diagnosed and 100 unaffected relatives. Receiver operating characteristics curves were constructed. Total cholesterol and LDL-cholesterol concentrations showed bimodality. A total cholesterol cutoff of 225 mg/dl produced results agreeing with DNA testing (specificity, 98.5%; sensitivity, 99.4%). An LDL-cholesterol cutoff of 161-163 mg/dl produced 98.5% specificity and 98.3% sensitivity. Areas under curves were 0.9826 +/- 0.0058 for total cholesterol, and 0.9852 +/- 0.0043 for LDL-cholesterol. In conclusion, we define total cholesterol and LDL-cholesterol levels of 225 and 160 mg/dl, respectively, as cutoff points of normal subjects and FH patients.

A 38-year-old Japanese woman was admitted to hospital for further examination of systemic xanthomas. She had a past history of genital bleeding during her third delivery at the age of 21 years. She was diagnosed with Sheehan's syndrome. Her serum total cholesterol and triglyceride concentrations were 500 and 898 mg/dl, respectively. She was also diagnosed as having type III hyperlipoproteinemia on the basis of the presence of a broad-β-band on agarose gel electrophoresis and extremely high concentrations of very-low-density lipoprotein cholesterol (310 mg/dl). The diagnosis was later confirmed by her apolipoprotein E isoforms (E2/E2) and genotypes (epsilon2/epsilon2). Thyroid and corticosteroid hormone replacement therapy cured the xanthomas, but also elevated her blood pressure. The serum concentration of intermediate-density lipoprotein cholesterol was consistently high, whereas that of low-density lipoprotein cholesterol was relatively low during the follow-up. Coronary atherosclerosis had already developed by the age of 38 years, and progressed significantly over the following 28 years. Severe stenotic lesions were observed in the bilateral renal arteries and carotid arteries, and in the abdominal aorta when she was 66 years old. These findings suggest that the continuous elevation of intermediate-density lipoprotein cholesterol for a long period contributed to the development of the atherosclerotic lesions. (Circ J 2005; 69: 746 - 751)

金沢大学大学院医学系研究科, Background: Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acid-sequestering resin, that is 4-fold as powerful at lowering low-density lipoprotein cholesterol (LDL-C) as the conventional resin (cholestyramine). Moreover, colestimide has excellent patient compliance because it is available in tablet form. Methods and Results: The clinical efficacy of colestimide coadministered with atorvastatin on lipid and apolipoprotein concentrations was examined in 15 patients (M/F = 10/5, mean±SE age=54±9 years) with heterozygous familial hypercholesterolemia (FH). After a period of wash-out of any lipid-lowering drugs, atorvastatin (20-40mg) was administered to patients for at least 8 weeks, and then 3 g of colestimide was administered for a further 8 weeks. Total and LDL-C significantly (

Background : To clarify a detailed profile of serum lipids, lipoproteins and apolipoproteins (apo) in type III hyperlipoproteinemia (HLP) with apolipoprotein E (apo E) phenotype 2/2. Methods : Nineteen consecutive Japanese type III HLP (9 men, 10 women) were studied. All had hypertriglyceridemia and 74% showed hypercholesterolemia. Results : The degree of hyperlipidemia [total cholesterol (TC) 8.1±3.2 mmol/l, triglycerides (TG) 5.2±2.9 mmol/l] was milder than that in type III HLP in western countries. Lipoprotein fractions analyzed by ultracentrifugation showed that very low density lipoprotein cholesterol (VLDL-C) concentrations were considerably increased and that intermediate density lipoprotein cholesterol (IDL-C) concentrations were also increased, whereas low-density lipoprotein cholesterol (LDL-C) concentrations were low. Serum apo A-I, A-II and B concentrations were not increased, while apo C-II, C-III and E concentrations were considerably increased. However, the increase of apo E concentrations in the study subjects was far more pronounced than that of apo C-III, causing the ratio of apo E/C-III to be considerably higher than hyperlipidemia with other apo E phenotypes. Conclusion : By using this index apo E/C-III, it is possible to segregate type III HLP with apo E2/2 phenotype from other types of hyperlipidemia.

Lipoprotein lipase (LPL) is a lipolytic enzyme involved in catalyzing the hydrolysis of triglycerides (TG) in chylomicrons and very low-density lipoprotein (VLDL) particles. Over the last decade, the clinical significance of measuring LPL mass without heparin injection has been increasingly studied. In earlier studies, it was shown that this marker was utilized to classify type 1 hyperlipoproteinemia, which is an extremely rare metabolic disorder. Later, researchers paid more attention to the clinical significance of measuring this parameter in more common metabolic disorders. Studies have shown that pre-heparin plasma LPL mass has significant relationships with serum lipid and lipoproteins, visceral fat area, and even a marker for acute inflammation, although this might be a metabolic surrogate marker which does not appear to be involved in catalyzing the hydrolysis of TG in TG-rich lipoproteins. We suggest that pre-heparin LPL mass in plasma or sera provides us with useful and important information on the pathophysiology of metabolic disorders or acute inflammation despite its simplicity from a practical point of view.

In the present study, we focused on the relationship of intra-abdominal visceral fat (VF) or subcutaneous fat (SF) mass to serum leptin levels, and also on the relationship of leptin to serum lipid and lipoprotein concentration. Subjects with obesity (26 men, 26 women) were recruited for this study. We obtained helical CT scans with a tube current of 150 mA, voltage of 120 kV and 2:1 pitch (table speed in relation to slice thickness), starting at the upper edge of the liver and continuing to the pelvis. The intra-abdominal visceral fat (VF) volume was measured by drawing a line within the muscle wall surrounding the abdominal cavity. The abdominal SF volume was calculated by subtracting the VF volume from the total abdominal fat volume. By comparison, the abdominal VF and SF areas were determined at the umbilical level by the established slice-by-slice CT scanning technique. We found: 1) abdominal SF mass, either as volume or area, was a more important determinant of serum leptin than was VF mass; 2) among TC, TG, HDL-C and LDL-C, only TG had a positive correlation to serum leptin levels in men, whereas in women no lipid parameters had any relationship with leptin; and 3) VF mass had a positive correlation to serum TC and TG in men, whereas SF did not. The present study provides considerable evidence on the relationship between abdominal fat mass and serum leptin, and shows that the relationships between serum leptin and serum lipids and lipoproteins are not straightforward. We also suggest that fat area measured by conventional CT is a better indicator than its corresponding volume assessed by helical CT, based on the present results showing its closer association to serum lipids. J Atheroscler Thromb, 2004; 11: 173–179.

+49 A/G polymorphism of CTLA-4 gene has been suggested to be associated with type 1 diabetes in some populations. However, a functional significance of the +49 A/G polymorphism is unknown, because it is believed the polymorphism does not affect the function of the CTLA-4 molecule. In this study, we examined the +49 A/G polymorphism of the CTLA-4 gene in 30 Japanese type 1 diabetic patients (14 type 1B and 16 type 1A) and 40 non-diabetic subjects in a case-control study, and stratified patients according to genotype of the polymorphism. The distribution of genotype frequencies differed between type 1 diabetic patients and controls (p