Effect of body mass index-z score on adverse levels of cardiovascular disease risk factors.

BACKGROUND: Cardiovascular disease (CVD) risk factors are associated with body mass index z-score (BMISD) and/or insulin resistance (IR). However, the correlation between adverse levels of these risk factors and BMISD, and the effect of IR on these associations are not fully understood in children. The aim of this study was to evaluate the association between adverse levels of CVD risk factors and BMISD, and the effect of IR on these associations in schoolchildren. METHODS: Conventional CVD risk factors, C-reactive protein (CRP), uric acid (UA) and adiponectin were determined in 757 boys and 494 girls aged between 7 and 12 years. IR was assessed by the homeostasis model approximation index. RESULTS: BMISD were linearly associated with relative risks having adverse levels of all factors, except for glucose and low-density lipoprotein cholesterol (LDL-C) in boys, and except for glucose, LDL-C and adiponectin in girls (P < 0.01-0.001). These associations were weakened after adjustment for IR, but still significant in cases of UA and CRP in boys and UA, high-density lipoprotein cholesterol and CRP in girls (P < 0.01-0.001). CONCLUSION: The relative risk of having adverse levels of most CVD risk factors in school children increased across the entire range of BMISD. IR contributed to most of these relative risks, but BMISD itself also contributed to these relative risks. To prevent future development of CVD, it might be important for schoolchildren to maintain BMISD within normal range. However, in cases of hyper LDL-cholesterolemia, we should consider causes other than BMISD.

Relationship between lipid abnormalities and insulin resistance in Japanese school children.

OBJECTIVE: Dyslipidemia and insulin resistance (IR) are risk factors for coronary heart disease (CHD) in adults. To help prevent the development of CHD, it may be useful to understand the relationship between lipid abnormalities and IR during childhood. METHODS AND RESULTS: IR was assessed by the homeostasis model approximation index. We studied 1175 Japanese school children (642 boys and 533 girls), aged between 7 and 12 years. Obesity was defined by the body mass index standard deviation score (BMISD) (obese: BMISD > or = 2.0). BMISD was most significantly associated with IR in nonobese children (P=0.000). Associations of IR with lipid-related parameters were affected by BMISD. After being corrected by BMISD, in nonobese children, log triglycerides (TG), apoB and low-density lipoprotein (LDL) size in boys and log TG, LDL size, and high-density lipoprotein (HDL) cholesterol in girls were still significantly associated with IR (P=0.000 to 0.017). In obese children, all parameters except for LDL cholesterol in boys and LDL size in girls were significantly associated with IR (P=0.000 to 0.030). Multiple regression analysis showed that log TG and LDL size in nonobese children, log TG in obese boys and LDL size in obese girls were independently associated with IR. Children with IIb and IV hyperlipidemia had significantly higher IR than those with normolipidemia and IIa, even after correcting for BMISD and age. CONCLUSIONS: Our results suggest that in addition to controlling body weight, it may be important for school children to characterize lipid phenotypes to prevent progression to CHD and/or type 2 diabetes and to identify subjects who are at high risk for these disorders.

The influence of the acyl-CoA:cholesterol acyltransferase-1 gene (-77G-->A) polymorphisms on plasma lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects.

BACKGROUND: Acyl-CoA:cholesterol acyltransferase (ACAT) plays important roles in cellular cholesterol homeostasis. Two isoforms of ACAT have been reported (ACAT-1 and ACAT-2). ACAT inhibitors cannot only prevent atherosclerosis formation, but may also induce its regression in animals. In humans, an ACAT inhibitor was shown to have a lipid-lowering effect. The present study was carried out to clarify the relationship between ACAT-1 gene variants and hyperlipidemia. METHODS AND RESULTS: To identify genetic variants, we screened 30 subjects with hyperlipidemia by direct sequencing. As a result, a missense variant (R526G) and a variant in the 5' untranslated region (-77G-->A) were identified. The genotype frequencies of each variant were determined in 178 unrelated normolipidemic and 441 unrelated hyperlipidemic subjects. The alleles frequencies of the R526G variant in normolipidemic and hyperlipidemic subjects were 0.676 and 0.633, respectively. The alleles frequencies of the -77G-->A variant in normolipidemic and hyperlipidemic subjects were 0.503 and 0.515, respectively. Differences in allele frequencies between normolipidemic and hyperlipidemic subjects were not significant in both variants. R526G variant did not affect plasma concentrations of lipids or apolipoproteins in subjects studied. However, among hyperlipidemic subjects, plasma concentrations of HDL-C and apoA-I in subjects with -77G-->A variant were significantly higher than those in subjects without variant. CONCLUSION: Two variants in ACAT-1 gene were identified in subjects with hyperlipidemia. -77G-->A variant affects plasma HDL concentrations only in hyperlipidemic subjects. These data suggest that the intracellular FC concentration might modulate plasma HDL concentrations.

Effect of Trp64Arg mutation of the beta3-adrenergic receptor gene and C161T substitution of the peroxisome proliferator activated receptor gamma gene on obesity in Japanese children.

OBJECTIVE: Obesity is a multifactorial syndrome influenced by both genetic and behavioral factors. Trp64Arg mutation of the beta3-adrenergic receptor (AR) gene and C161T substitution of the peroxisome proliferator-activated receptor (PPAR) gamma gene have been reported to be associated with obesity or lipid metabolism in adults. However, the effects of these mutations on children have not yet been clarified. For this reason, we studied the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in Japanese children. SUBJECTS AND METHODS: In order to determine the effects of Trp64Arg mutation of the beta3-AR gene and C161T substitution of the PPARgamma gene on obesity in children, 105 obese Japanese children were screened by the polymerase chain reaction and restriction fragment-length polymorphism analysis. Plasma lipid, apolipo-protein (apo), glucose, insulin and leptin levels were also determined. RESULTS: Obese boys with Trp64Arg showed a higher obesity index and lower plasma levels of high-density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II than those of them without the mutation. Obese boys with both mutations showed a higher plasma leptin level than those with only the beta3-AR gene mutation or PPARgamma gene mutation. No significant effect of these mutations was found in obese girls. CONCLUSION: All of these data suggest that Trp64Arg mutation of the beta3-AR gene might affect obesity and HDL metabolism in obese boys. In contrast, C161T mutation of the PPARgamma gene, by itself, is unlikely to influence obesity, lipid metabolism or plasma leptin levels.

Effects of a new single-nucleotide polymorphism in the Acyl-CoA:cholesterol acyltransferase-2 gene on plasma lipids and apolipoproteins in patients with hyperlipidemia.

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes cholesterol esterification in mammalian cells. Two isoforms of ACAT have been reported to date (ACAT-1 and ACAT-2). ACAT-1 protein is ubiquitously expressed in tissues, including macrophages, hepatocytes, adrenal glands, and intestines. In contrast, ACAT-2 is expressed mainly in the intestine in humans. However, the roles of ACAT-1 and ACAT-2 in lipoprotein metabolism in humans have not yet been reported. This study was carried out to clarify the relationship between ACAT-2 gene mutations and hyperlipidemia in humans. To identify gene mutations, we screened 30 subjects with hyperlipidemia (TC > 220 mg/dl or TG >150 mg/dl) by direct sequencing. As a result, we found a new single-nucleotide polymorphism (SNP; a point mutation in intron 1, IVS1 -8 G-->C) in the ACAT-2 gene. To investigate the relationship between this SNP and both plasma lipids and apolipoproteins, 91 unrelated hyperlipidemic subjects (40 males and 51 females), and 92 unrelated normolipidemic subjects (46 males and 46 females) were screened by direct sequencing. The frequencies of the IVS1 - 8G-->C allele in normolipidemic and hyperlipidemic subjects were 0.131 and 0.125, respectively. IVS1 -8 G-->C did not affect plasma concentrations of lipids or apolipoproteins in either normolipidemic or hyperlipidemic subjects. Although further studies are needed, our data suggest that the ACAT-2 gene may not affect lipid levels in humans.

Two newly identified genomic mutations in a Japanese female patient with fructose-1,6-bisphosphatase (FBPase) deficiency.

Fructose-1,6-bisphosphatase (FBPase) (EC 3.1.3.11) catalyzes the splitting of fructose-1,6-bisphosphate into fructose 6-phosphate and inorganic phosphate. FBPase deficiency is an autosomal recessive inherited disorder caused by distraction of the fructose-1,6-bisphosphatase 1 gene (FBP1) and features severely impaired gluconeogenesis. We studied a female patient with typical FBPase deficiency symptoms. The FBPase activity of her peripheral white blood cells was undetectable. Genetic analyses of FBP1 revealed her to be a compound-heterozygote of two new mutations F194S and P284R. Gene tracking in the family revealed the mother to be a heterozygote of F194S, and the father and a sister to be heterozygotes of P284R. As both Phe194 and Pro284 of FBPase are highly conserved in many species and close to crucial amino acid residues to FBPase functions, these mutations could be responsible for the loss of FBPase activities.