Apolipoprotein A-II, genetic variation on chromosome 1q21–q24, and disease susceptibility Jesu ´s M. Martı´n-Campos a,b , Joan Carles Escola ` -Gil a , Vicent Ribas a and Francisco Blanco-Vaca a 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. Keywords HDL, familial combined hyperlipidemia, insulin resistance, type 2 diabetes mellitus, amyloidosis, reverse cholesterol transport Curr Opin Lipidol 15:247–253. # 2004 Lippincott Williams & Wilkins. a Servei de Bioquı´mica i Institut de Recerca, Hospital de la Santa Creu i Sant Pau, and b Departament de Bioquı´mica i Biologia Molecular, Universitat Auto ` noma de Barcelona, Barcelona, Spain Correspondence to Dr F. Blanco-Vaca, Hospital de la Santa Creu i Sant Pau, Servei de Bioquı´mica, C/ Antoni M. Claret 167, 08025 Barcelona, Spain Tel: +34 93 2919451; fax: +34 932919196; e-mail: fblancova@hsp.santpau.es Current Opinion in Lipidology 2004, 15:247–253 Abbreviations ABCA1 ATP-binding cassette transporter A1 apo apolipoprotein CAD coronary artery disease DM2 type 2 diabetes mellitus FCHL familial combined hyperlipidemia RXR retinoid X receptor SAMP senescence-accelerated mouse prone SAMR senescence-accelerated mouse resistant SR-BI scavenger receptor class B, type I SNP single nucleotide polymorphism # 2004 Lippincott Williams & Wilkins 0957-9672 Introduction Apolipoprotein (apo) A-II is a member of the apolipo- protein multigene superfamily, which includes genes encoding soluble apolipoproteins. The human apoA-II gene (APOA2) has been mapped to chromosome 1q21?1q24 [1,2,3 . ]. Publication of the human genome draft has given rise to a more precise location of the gene within the 1q23.3 band, approximately 158 megabases (Mb) from the p end. ApoA-II is the second major protein of HDL, accounting for approximately 20% of its protein content; however, its function is still unclear [1,2,3 . ]. ApoA-II is predominantly synthesized in the liver and its transcription is controlled by a complex array of regulatory elements in the APOA2 promoter region [1,4]. Recently, Hatzivassiliou et al. [5 . ] presented evidence that the proximal APOA2 regulatory region AIIAB contains a functional thyroid hormone response element that strongly binds retinoid X receptor (RXR) a/ T3Rb heterodimers and mediates transactivation of the apoA-II promoter in the presence of 9-cis retinoic acid or triiodothyronine. The present review summarizes recent findings on apoA-II and, especially, those associated with disease susceptibility. The APOA2 genomic region Approximately 1.7 kb from the end of the APOA2 promoter begins a gene called Q969M1, which presents 63% of sequence similarity with the central component of the preprotein translocase of the mitochondrial outer membrane (TOM40). The function of this complex is to transport proteins from cytosol to the mitochondrial intermembrane compartment. Interestingly, the TOM40 gene is located on chromosome 19q13.2, very close to the apoE/apoC-II/apoC-I/apoC-IV gene cluster, a region DOI: 10.1097/01.mol.0000130087.23887.97 247