Genomewide Scan for Familial Combined Hyperlipidemia Genes in Finnish Families, Suggesting Multiple Susceptibility Loci Influencing Triglyceride, Cholesterol, and Apolipoprotein B Levels

Abstract

Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol (TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed Z>2.0 in the linkage analysis: 10p11.2, Z=3.20 (theta=.00), with the TG trait; and 21q21, Z=2.24 (theta=.10), with the apoB trait. Furthermore, two more chromosomal regions produced Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced Z=2.59 with the TC trait and Z=2.29 with FCHL, and 2q31 produced Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.

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

“…Recent reports indicate that a number of predisposing FCHL genes are on their way toward being identified and confirmed, but much remains to be performed before the genetics of this disorder is fully understood, and thoughts can turn to risk prediction and specific treatment targets. A successful example is the report of linkage 10 and association of USF-1 in Finnish FCHL pedigrees, 16 with support for linkage of triglycerides to this region found in Dutch FCHL families, 18 as well as diabetes-related traits found in other independent cohorts. [27][28][29] FCHL is a genetically complex disease, and the consensus is that innovative and more in-depth trait definitions and alternative analytic strategies are required to obtain insight.…”

“…Searches for lipid disorder genes have been conducted using multiple genetic epidemiologic approaches, including full genome scans, 8 -14 extensive candidate gene analyses, 15 and analyses of the FCHL diagnosis in large pedigrees 10 and in nuclear families. 11 Recently, very promising findings were generated by analyzing the FCHL diagnosis or a related binary trait derived from increases over age/sex-specific cutoff values.…”

Common Hepatic Nuclear Factor-4α Variants Are Associated With High Serum Lipid Levels and the Metabolic Syndrome

“…A total of 99 Finnish dyslipidemic families (60 FCHL and 39 low-HDL cholesterol families) were recruited in the Helsinki and Turku University Central Hospitals (14,15,27). All study subjects gave their informed consent.…”

“…These families were recruited in the Instituto Nacional de Ciencias Mé dicas y Nutrició n Salvador Zubirá n (INCMNSZ) in Mexico City. The inclusion and exclusion criteria for the Mexican FCHL families (28) are fully comparable with the Finnish criteria for FCHL (14,27). The age/sex-specific 90th percentiles for total cholesterol and triglycerides, based on a previous survey of the Mexican population (29), were used to classify the FCHL affection status.…”

Genome-wide scans of three independent sets of 90 Irish multiplex schizophrenia families and follow-up of selected regions in all families provides evidence for multiple susceptibility genes

“…At the moment, the following ten regions are, arguably, those most deserving of higher density mapping and follow-up studies: 1q21-22, 19 67 and Xp11. 64,[68][69][70][71] The Irish Study of High Density Schizophrenia Families (ISHDSF) contains 1425 individuals with DNA available in 270 families systematically ascertained from psychiatric facilities in Ireland and Northern Ireland. In previous studies with these families we have, in conjunction with other research groups, generated support for the presence of four loci influencing the vulnerability to schizophrenia, on chromosomes 5q21-31, 29 6p24-p21, 34 8p22-21, 42 and 10p15-11.…”