Quantitative Trait Loci for Apolipoprotein B, Cholesterol, and Triglycerides in Familial Combined Hyperlipidemia Pedigrees

Abstract

Objective-Familial combined hyperlipidemia (FCHL) is a genetically complex lipid disorder that is diagnosed in families by combinations of increased cholesterol, triglycerides, and/or apolipoprotein B (apoB) levels in patients and their first-degree relatives. Identifying the predisposing genes promises to reveal the primary risk factors and susceptibility pathways and suggest methods of prevention and treatment. As with most genetically complex disorders, a clinical definition of disease may not be the most useful phenotype for finding the complement of predisposing genes, and the quantitative traits used to define the disorder can provide important information. This is a report of a quantitative trait loci (QTL) analysis of FCHL. Methods and Results-A full genome scan of 377 multi-allelic markers genotyped at Ϸ10 centimorgan (cM) intervals was conducted in 150 sibling pairs from 22 nuclear families in FCHL pedigrees. These data were analyzed by 2 multipoint QTL linkage methods using the nonparametric and Haseman-Elston procedures of the Genehunter software. Using a criterion of PϽ0.001 by the nonparametric analysis, we found evidence of 2 apoB QTL at 1p21-31 (PϽ0.000009) and 17p11-q21 (PϽ0.000009), a total serum cholesterol QTL at 12p13 (PϽ0.0001), and a serum triglycerides QTL at 4p15-16 (PϽ0.0002). Using the criterion of PϽ0.03 for at least 2 traits at the same locus, additional evidence for cholesterol (PϽ0.01) and a triglycerides PϽ0.02) was observed at 17p11-21, as well as suggestive evidence for apoB (PϽ0.02) and triglycerides (PϽ0.01) at 4q34-35, and cholesterol (PϽ0.01) and triglycerides (PϽ0.02) and a binary FCHL trait (lodϭ1.5) at 16p12-13. Conclusions-QTL analyses of the traits that define FCHL are effective for localizing disease-predisposing genes.

Studies of the association of the GNB3 825C>T polymorphism with components of the metabolic syndrome in white Danes

“…Human GNB3 is located in a gene-rich cluster on chromosome 12p13 [37,38]-a locus that has shown linkage with an autosomal-dominant form of hypertension [39] and with BMI [40] and fasting serum total cholesterol levels [41]. Initially, the 825T allele was found to be associated with an increased risk of hypertension in a sample of approximately 850 subjects [1], and this observation was confirmed in independent studies of various sample sizes [5,17].…”

Triglycerides and Cardiovascular Disease

“…87,88 It is observed in affected relatives in successive generations, and the diagnosis is made when in the face of increased levels of cholesterol, triglyceride, or apo B, at least 2 of the lipid abnormalities identified in the patient also segregate among the patient's first-degree relatives. 137 The variable clinical Obesity as indicated by increased waist-to-hip ratio can greatly increase apo B production in these patients; usually onset is in adulthood, but pediatric obesity may allow for earlier diagnosis Dysbetalipoproteinemia (also known as familial type III) Autosomal recessive; rare; requires an acquired second "hit" for clinical expression…”

Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

“…marshfieldclinic.org/research/genetics/), as described previously (7). Markers of Marshfield panel 10 were used with an average intermarker distance of 9.4 centimorgan (cM).…”