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JM Peacock1,
DK Arnett1, LD Atwood2, RH Myers2, H Coon3, SS Rich4, MA Province5,
G Heiss6 on behalf of the Investigators of the NHLBI Family Heart
Study
1 University of Minnesota, 2 Boston University School
of Medicine, 3 University of Utah,4 Wake Forest University School
of Medicine, 5 Washington University Medical School, 6 University
of North Carolina, Chapel Hill
We conducted
a genome-wide linkage scan for quantitative trait loci (QTLs) influencing
total HDL-c concentration in the NHLBI Family Heart Study (FHS).
To maximize the relative contribution of genetic components of variance
to the total variance of HDL-c, the HDL-c phenotype was adjusted
for age, age2, body mass index, and field center, and standardized
HDL-c residuals were created separately for men and women. All analyses
were completed using the variance components method, as implemented
in version 2.1 of the program GENEHUNTER using 383 anonymous markers
typed at the NHLBI Mammalian Genotyping Service (MGS) in Marshfield,
WI. We previously reported evidence for linkage of residual HDL-c
near marker D5S1470 at location 39.9 centiMorgans (cM) from the
p-terminal of chromosome 5 (LOD =3.64, 2 df, p=.0002) in a sample
of 1,027 Whites from 101 families. Suggestive linkage was detected
near marker D13S1493 at location 27.5 cM on chromosome 13 (LOD =
2.36, p=.004). We also found nominally-significant linkage (2 df
LOD=1.30, p=.05) to locations on Chromosomes 1, 3, 7, 11, and 19,
some of which have been previously identified in other study populations.
To confirm these possible QTLs, an additional 1,986 Whites from
300 families participating in FHS were also genotyped by MGS as
a replication sample. In this separate genome-wide scan the highest
LOD on chromosome 5 shifted 30 cM toward the centromere (LOD = 1.31,
p=.05). We also found evidence for linkage to locations 47 cM on
chromosome 15 (LOD = 2.95, p=.001) and 109 cM on chromosome 12 (LOD
= 1.38, p=.04), both within 15 cM of previously-reported QTLs influencing
HDL2a in Mexican-American families. The location on chromosome 13
was not confirmed. We conclude that inter-individual variation in
HDL-c is likely influenced by several genes with small, but significant
influences on the trait.
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