Association of the protein tyrosine phosphatase nonreceptor 22 haplotypes with autoimmune thyroid disease in the Japanese population.

BACKGROUND: A missence single-nucleotide polymorphism (SNP) in the protein tyrosine phosphatase nonreceptor 22 (PTPN22) gene known as R620W (rs2476601) was recently reported to be associated with several autoimmune diseases including Graves' disease (GD). The association was repeatedly confirmed in the populations of North European ancestry. However, this amino acid was reported to be nonpolymorphic in the Asian populations. Since the gene confers an impact on autoimmune diseases, we attempt to explore an association between the PTPN22 gene and autoimmune thyroid disease (AITD) in a Japanese population without restricting to rs2476601. Previous investigations have also demonstrated that two intronic SNPs (rs706778 and rs3118470) in the interleukin-2 receptor-alpha (IL2RA) gene were associated with type 1 diabetes in the Japanese population. PATIENTS AND METHODS: We genotyped the five SNPs (rs12760457, rs2797415, rs1310182, rs2476599, and rs3789604) of the PTPN22 and the two SNPs (rs706778 and rs3118470 in the IL2RA gene) in 456 Japanese patients with AITD (286 with GD, 170 with Hashimoto's thyroiditis) and 221 matched Japanese control subjects. Seven SNPs were analyzed by either the SNAPshot method or the high-resolution melting and unlabeled probe methods. Case-control association studies were performed using the chi(2) and Fisher's exact tests with Yates correction. Haplotype was conducted using the expectation-maximization algorithm. RESULTS: No association was found between any of the individual SNPs of the PTPN22 gene and AITD. Permutation analysis revealed that the distribution of one haplotype is significantly different between patients with AITD and controls (p = 0.0036). A novel protective effect of a haplotype containing five SNPs was observed (p < 0.0001 for AITD, p < 0.0001 for GD, and p < 0.0001 for Hashimoto's thyroiditis, respectively). The GG allele of rs3118470 in the IL2RA gene was significantly associated with GD (p = 0.03), although the association was weak. CONCLUSIONS: Significant difference in the distribution of the haplotype suggests that the PTPN22 gene rather than rs2476601 is involved in the development of AITD in the Japanese population.

Small LDL-cholesterol is superior to LDL-cholesterol for determining severe coronary atherosclerosis.

AIM: Recent evidence suggests that small dense low-density lipoprotein (sd-LDL) particles are more atherogenic than large-LDL in spite of their lower cholesterol content. This study aimed to determine whether sd-LDL-cholesterol (sd-LDL-C) is superior to LDL-C as a biomarker of coronary heart disease (CHD). METHODS: LDL particle size determined by gradient gel electrophoresis and sd-LDL-C concentrations quantified by heparin-magnesium precipitation were compared between 482 stable CHD patients and 389 non-diabetic subjects without CHD who were not receiving any lipid-lowering drugs. RESULTS: Both male and female CHD patients had significantly smaller LDL particles and lower large-LDL-C concentrations (estimated by subtracting the sd-LDL-C concentration from the LDL-C concentration), and significantly higher sd-LDL-C concentrations than the control subjects. LDL-C concentrations were modestly higher and sd-LDL-C concentrations were significantly higher in 258 patients with angiographically documented severe CHD than in the patients with mild CHD irrespective of treatment by LDL-lowering drugs and history of myocardial infarction and/or coronary revascularization. Large-LDL-C concentrations, in contrast, were similar between the two groups. Multivariate logistic regression analysis revealed that sd-LDL-C levels were significantly associated with severe CHD independently of LDL-C. CONCLUSION: sd-LDL-C levels are more powerful than LDL-C levels for the determination of severe stable CHD.

Predominance of small dense low-density lipoproteins and abnormal glucose regulation in patients with acute coronary syndrome.

BACKGROUND: Although small dense low-density lipoprotein (sd-LDL) has an established association with diabetic dyslipidemia, previous studies have failed to show an association between sd-LDL and diabetes among coronary heart disease patients. This study investigated the prevalence of sd-LDL and abnormal glucose regulation in acute coronary syndrome (ACS). METHODS AND RESULTS: LDL size at the onset of ACS was measured by nondenatured gradient gel electrophoresis in 314 of 429 consecutive patients. Sd-LDL was prevalent in 54% of the patients, irrespective of the presence of previously known diabetes (50% vs 60% in nondiabetes and diabetes, respectively). Diabetes was present in 122 (28%) of the patients, and 110 patients without diabetes underwent an oral glucose tolerance test. Impaired glucose tolerance (IGT) and newly detected diabetes were found in as many as 44% and 22% of the patients tested, even though their hemoglobinA1c levels were in the normal range (5.3+/-0.5%). The prevalence of sd-LDL was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance (61% vs 42%). CONCLUSION: IGT and diabetes were far more common than normal glucose regulation in ACS patients, and the abnormal glycometabolism was closely associated with highly atherogenic sd-LDL.

Significance of small dense low-density lipoprotein-cholesterol concentrations in relation to the severity of coronary heart diseases.

We have investigated the clinical significance of small dense low-density lipoprotein-cholesterol (sd-LDL-C) concentrations in coronary heart disease (CHD). We measured the LDL size by gradient gel electrophoresis and quantified sd-LDL-C concentrations by a newly developed rapid assay using heparin-magnesium precipitation in 225 consecutive CHD patients without any lipid-lowering medication and 142 healthy middle-aged subjects as controls. The LDL size was markedly smaller and sd-LDL-C levels were significantly higher in CHD patients than in controls of both sexes, whereas LDL-C levels were comparable between CHD and controls. The LDL-C levels were significantly higher in a subpopulation of 84 patients with acute coronary syndrome than in other patients groups, while LDL size and high-density lipoprotein-cholesterol (HDL-C) were not found to vary among the patients. The sd-LDL-C increased as the number of diseased vessels or Gensini atherosclerosis score increased. Among the 123 stable CHD patients, multiple logistic regression analysis revealed that sd-LDL-C levels were significantly associated with the clinically severe cases requiring coronary revascularization independently of LDL-C, HDL-C and apolipoprotein B. The sd-LDL mass plays a more important role in the progression of CHD than the LDL size, and the sd-LDL-C concentration serves as a powerful surrogate marker for the prevention of CHD.

Association between small dense low-density lipoprotein and postprandial accumulation of triglyceride-rich remnant-like particles in normotriglyceridemic patients with myocardial infarction.

BACKGROUND: Although the small dense low-density lipoprotein (sd-LDL) is associated with hypertriglyceridemia, more than 60% of myocardial infarction (MI) patients are normotriglyceridemic in the fasting state. This study was aimed to investigate the relationship between the low-density lipoprotein (LDL) phenotype and postprandial hyperlipemia (PPL) in MI patients. METHODS AND RESULTS: Oral fat tolerance tests were performed in 71 patients with acute MI and fasting triglyceride concentrations below 200 mg/dl. Postprandial changes in the LDL particle diameter (LDL-PD) and lipids over a 6-h period after a meal were compared among 4 groups of patients classified according to fasting triglyceride levels (A, B as <150, and C, D as > or =150) and postprandial triglyceride levels (A, C as <230 and B, D as > or =230). Although fasting concentrations of triglyceride and remnant-like particle (RLP)-triglyceride were significantly higher in group C than in group B, the areas under the curves of the RLPs were significantly higher in group B. The triglyceride-to-cholesterol ratio in the RLPs was significantly higher in the PPL group than in the nonPPL group postprandially. The prevalence of sd-LDL (LDL-PD < or =25.5 nm) was significantly higher in group D but similar between groups B and C (23%, 42%, 50% and 83% in groups A, B, C and D, respectively). CONCLUSION: These results suggest that postprandial accumulation of triglyceride-rich lipoproteins is strongly associated with sd-LDL in MI patients without hypertriglyceridemia.

Small dense LDL phenotype is associated with postprandial increases of large VLDL and remnant-like particles in patients with acute myocardial infarction.

BACKGROUND: The small dense low-density lipoprotein (LDL) phenotype (pattern B), high concentrations of remnant-like particles (RLPs), and postprandial lipemia are newly recognized risk factors for coronary heart disease (CHD). However, the associations of these lipoprotein abnormalities remain unclear. The aim of this study was to investigate the relationships among LDL phenotype, very-low-density lipoprotein (VLDL) subclasses, and postprandial lipoprotein metabolism in CHD patients. METHOD: We performed an oral fat tolerance test in 32 patients with acute myocardial infarction and compared the following parameters between patients characterized by either large buoyant LDL (pattern A) versus pattern B: lipids and apolipoproteins (apo) in the plasma and Svedberg flotation rates (Sf) >400 (chylomicron), Sf 60-400 (large VLDL), and Sf 20-60 (small VLDL) fractions. RESULT: Fasting levels of triglyceride, RLP-cholesterol and RLP-triglyceride were slightly higher in the pattern B patients. Postprandial increases of RLP-cholesterol and the cholesterol and triglyceride of large VLDL fractions were significantly greater in the pattern B patients. The areas under the curves of cholesterol, triglyceride, and apo-B in large VLDL fractions were significantly higher in pattern B, while those in small VLDL were not. RLP-cholesterol and RLP-triglyceride in fasting and fed states correlated very highly with the corresponding cholesterol and triglyceride concentrations in large VLDL fractions. CONCLUSION: These results suggest that postprandial increase of large VLDL fractions and RLPs contribute to the formation of small dense LDL in CHD patients.