Apolipoprotein A-II, genetic variation on chromosome 1q21-q24, and disease susceptibility

PURPOSE OF REVIEW: Apolipoprotein (apo) A-II is the second most abundant HDL apolipoprotein; however its function remains largely unknown. Owing to the lack of consequences of apoA-II deficiency in humans, it has long been considered an apolipoprotein of minor importance. Overexpression of apoA-II in transgenic mice, however, causes combined hyperlipidemia and, in some cases, insulin resistance. This, and the location of the apoA-II gene in chromosome 1q23, a hot region in the search for genes associated with familial combined hyperlipidemia, insulin resistance and type 2 diabetes mellitus, has greatly increased interest in this protein. RECENT FINDINGS: ApoA-II is biochemically and genetically linked to familial combined hyperlipidemia. Given that the chromosome 1q21-q24 region is associated with insulin resistance or type 2 diabetes, this region is a now a focus of interest in the study of these complex, often overlapping diseases. However, no polymorphisms that increase apoA-II levels have been identified to date in humans. Other nonstructural loci may regulate apoA-II plasma concentration. Further, plasma apoA-II concentration is increased by saturated fat intake. Several reports have added to our understanding of the relationship between apoA-II mutations and amyloidosis both in humans and mice. SUMMARY: An increased plasma concentration of apoA-II might contribute to familial combined hyperlipidemia or type 2 diabetes mellitus expression, which emphasizes the need to understand its function and metabolism. Genetic studies in well characterized patients and genomic and proteomic approaches in cell and mouse models may help to achieve this understanding.     

Gene polymorphisms in patients with type 2 diabetes and diabetic nephropathy

A considerable variability in the incidence and prevalence of diabetic nephropathy (DN) coheres with an important contribution of multigenetic predisposition in the development of DN. Some genes, which probably participate in the pathogenesis of diabetic nephropathy, also play a role in the regulation of blood pressure, familial hyperlipidemia, familial hypertension and other diseases of the cardiovascular system. We have examined the association of diabetic nephropathy, nephropathy of non-diabetic origin, hypertension and of type 2 diabetes itself with several genetic polymorphisms (the insertion/deletion polymorphism in the gene for angiotensin-converting enzyme, the G/T polymorphism in the glucose transporter 1 gene, the G/T (894) polymorphism and the T/C (−786) polymorphism in the eNOS gene in three groups of patients with diabetes mellitus: 1) patients without diabetic nephropathy (DM); 2) patients with DN; 3) patients with nephropathy of non-diabetic origin (NDRD). Angiotensin-converting enzyme is an important factor in a development of arterial hypertension, but in our groups of Central European diabetic patients the I/D polymorphism was not associated with diabetic nephropathy. Furthermore, we have confirmed that the T/C (T786C) polymorphism in the eNOS gene is associated with metabolic syndrome including type 2 diabetes.     

Lipodystrophy of the extremities. A dominantly inherited syndrome associated with lipatrophic diabetes.

A female patient with the following symptoms has been observed: complete absence of subcutaneous fat on the arms and legs, well developed adipose tissue on the trunk and face, severe hyperlipidemia, eruptive xanthomas, insulin resistant diabetes mellitus with lack of ketoacidosis, hepatomegaly and elevated basal metabolic rate. The patient thus exhibited all characteristics of lipatrophic diabetes (Lawrence type of diabetes). The mother and a sister of the patient were found to have the same peculiar appearance and a slight hyperlipidemia but no diabetes mellitus. The combination of this type of partial lipodystrophy with severe hyperlipidemia, insulin resistant diabetes mellitus without ketoacidosis and elevated basal metabolic rate was further observed in 2 unrelated patients without known familial occurrence. Thus partial lipodystrophy of the extremities is another, previously undescribed, syndrome associated with the Lawrence type of diabetes mellitus. In the 1 family the syndrome of lipodystrophy and hyperlipidemia is dominantly inherited. Besides the autosomal recessively inherited syndrome of congenital generalized lipodystrophy there is a heterogenous group of dominantly inherited syndromes with various types of lipodystrophy.     

Identification of differentially expressed genes in subcutaneous adipose tissue from subjects with familial combined hyperlipidemia

Subjects with familial combined hyperlipidemia (FCHL) are characterized by a complex metabolic phenotype with hyperlipidemia, insulin resistance, and central obesity. FCHL is due to impaired adipose tissue function superimposed on hepatic overproduction of lipoproteins. We investigated adipose tissue as an interesting target tissue for differential gene expression in FCHL. Human cDNA expression array analyses, in which adipose tissue from five FCHL patients was compared with that from four age, gender, and BMI matched controls, resulted in the identification of 22 up-regulated and three down-regulated genes. The genes differentially expressed imply activation of the adipocyte cell cycle genes. Furthermore, the differential expression of the genes coding for tumor necrosis factor alpha, interleukin 6, and intracellular adhesion molecule 1 support a role for adipose tissue in insulin resistance in FCHL subjects. The observed changes represent a primary genetic defect, an adaptive response, or a contribution of both.     

S323I polymorphism of the C5L2 gene was not identified in a Chinese population with familial combined hyperlipidemia or with type 2 diabetes

C5L2, a G protein-coupled receptor, is known to be a functional receptor of acylation-stimulating protein, which is a stimulator of triglyceride synthesis and glucose transport. A novel C5L2 variant (S323I) was identified and its association with familial combined hyperlipidemia (FCH) was recently reported. We looked for this SNP in three Chinese ethnic groups, including Han, Uygur, and Kazakh controls and patients with FCH and type 2 diabetes. One hundred and eighty-two unrelated subjects (77 of Han, 57 of Uygur, and 48 of Kazakh) with FCH were genotyped by direct sequencing, and 852 subjects (342 of Han, 338 of Uygur, 172 of Kazakh) with type 2 diabetes and 200 healthy controls (67 of Han, 72 of Uygur, and 61 of Kazakh) chosen from a cardiovascular risk survey study were genotyped with PCR-RFLP analysis. All 182 subjects with FCH, 99.5% of the type 2 diabetes patients and 100% of the healthy controls were successfully genotyped. Neither the FCH subjects nor the type 2 diabetes patients were found to have the S323I variant. This variant was also not identified in the healthy controls. We found no evidence to demonstrate that the S323I polymorphism contributes to familial combined hyperlipidemia or type 2 diabetes in the Chinese population.     

Adenoviral insulin gene therapy prolongs survival of IDDM model BB rats by improving hyperlipidemia.

Diabetes is frequently associated with hyperlipidemia, which results in atherogenic complications. Insulin-dependent diabetes mellitus (IDDM) model BB/Wor//Tky (BB) rats exhibit both hyperglycemia and hyperlipidemia and die within 3 weeks after the onset of diabetes unless insulin therapy is given. We performed insulin gene therapy in BB rats with adenovirus vectors through the tail vein. After infusion, plasma triglyceride levels dropped quickly and maintained low levels for 1 week, whereas blood glucose levels showed a slight decrease. The survival period of diabetic BB rats was prolonged to up to 75 days by infusing insulin gene-expressing adenoviral vectors. We suggest that the control of hyperlipidemia can be a life-saving measure when combined with hyperglycemia control in the treatment of diabetes.     

Novel genes for familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is a complex genetic disorder of unknown etiology. Recently, 'modifier' genes of the FCHL phenotype, such as the apolipoprotein AI-CIII-AIV gene cluster and LPL, have been identified in several populations. A 'major' gene for FCHL has been identified in a Finnish isolate which maps to a region syntenic to murine chromosome 3 where a locus for combined hyperlipidemia has been identified. We review these and other recent studies which indicate that FCHL is genetically heterogeneous.