Unusual genetic variants associated with hypercholesterolemia in Argentina.

BACKGROUND AND AIMS: Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levels ≥ 190 mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. METHODS: In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300 mg/dL and/or LDL-C≥190 mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. RESULTS: In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (n = 20, 2 novel), ABCG5/8 (n = 7, 2 novel), APOB (n = 3, 1 novel), CYP27A1 (n = 3, 1 novel), LIPA (n = 2, 1 novel), APOE (n = 2), LIPC (n = 1, novel), LIPG (n = 1, novel), and SCARB1 (n = 1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. CONCLUSIONS: Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy.

Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency.

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.

Clinical presentation, laboratory values, and coronary heart disease risk in marked high-density lipoprotein-deficiency states.

Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.

Common mitochondrial DNA deletion associated with sudden natural death in adults.

One of the most frequent causes of death in developed countries is sudden natural death (SND), which is the most common indication for medico-legal autopsies. Cardiac diseases are frequently detected among SND. Mitochondrial DNA (mtDNA) is easily damaged by reactive oxygen species, and it may cause dysfunction in tissues, leading to early events in cardiovascular disease. A specific mtDNA deletion of 4977 bp is associated to aging, myocardial dysfunction, and bioenergetic deficit. The potential link between mtDNA damage and SND has not been investigated before. Our aim was to evaluate the accumulation of the common mtDNA4977-deletion in cardiac muscle samples from autopsies of SND in adults (n = 14) in comparison to control samples from unnatural deaths (n = 12). Serial dilution-polymerase chain reaction method was performed to estimate the proportion of the total mtDNA harboring the mtDNA4977-deletion. Coefficient variation intra-assay was 8%, and inter-assay was 12%. MtDNA4977-deletion percentage was higher in samples obtained from victims of SND than in those from subjects who died of unnatural causes (p < 0.05). No differences in mtDNA4977-deletion were found between SND victims 39-51 years old, and no correlation was found between these samples and age, r = 0.30, p = 0.29 while it was significant among control samples, r = 0.68, p < 0.05. The association between mtDNA4977 deletion with SND victims might offer a tool to provide additional information to clarify complex SND investigations.

Analisis genetico poblacional de 9 Y-SRs en grupo etnico de Bolivia / Population genetic Analisys of 9 Y-TRs in etnico group of Bolivia

En Bolivia la población ameriñdia de la Amazonia, contiene cierto número de pequeños grupos humanos, que mantienen poco o ningún contacto con otros pueblos indígenas o con grupos humanos civilizados. Los estudios de la variabilidad del cromosoma Y, en poblaciones amerindias nativas han sido provechosos para comprender algunos aspectos de la historia genética. Con el objeto de investigar las posibles relaciones entre las distintas etnias que habitan Bolivia, se analizaron 9 marcadores microsatélites del cromosoma Y, (DYS393, DYS39O, DYS394, DYS392, DYS391, DYS385 1-II, DYS389 1-II). De esta manera se obtuvo 23 haplotipos diferentes y una alta frecuencia de algunos alelos, como el 13 para el locus DYS393 y DYS394. Estos resultados posiblemente se deban al componente amerindio, como lo indican otros estudios similares en este mismo tipo de poblaciones del continente americano