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Journal of Lipid Research
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Reference:
Yi Yu, Diego F. Wyszynski, Dawn M. Waterworth, Steven D. Wilton, Philip J. Barter,
Y. Antero Kesäniemi, Robert W. Mahley, Ruth McPherson, Gérard Waeber, Thomas P. Bersot,
Qianli Ma*, Sanjay S. Sharma, Douglas S. Montgomery, Lefkos T. Middleton, Scott S.
Sundseth, Vincent Mooser, Scott M. Grundy and Lindsay A. Farrer, J Lipid Res. 2005
Oct;46(10):2202-13. Epub 2005 Aug 1.
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Abstract:
We conducted a genome-wide scan using variance components linkage analysis to
localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high
density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol,
and total cholesterol (TC) levels in 3,071 subjects from 459 families with
atherogenic dyslipidemia. The most significant evidence for linkage to TG
levels was found in a subset of Turkish families at 11q22 [logarithm of the
odds ratio (LOD) = 3.34] and at 17q12 (LOD = 3.44). We performed sequential
oligogenic linkage analysis to examine whether multiple QTLs jointly influence
TG levels in the Turkish families. These analyses revealed loci at 20q13 that
showed strong epistatic effects with 11q22 (conditional LOD = 3.15) and at 7q36
that showed strong epistatic effects with 17q12 (conditional LOD = 3.21). We
also found linkage on the 8p21 region for TG in the entire group of families
(LOD = 3.08). For HDL-C levels, evidence of linkage was identified on chromosome
15 in the Turkish families (LOD = 3.05) and on chromosome 5 in the entire group
of families (LOD = 2.83). Linkage to QTLs for TC was found at 8p23 in the entire
group of families (LOD = 4.05) and at 5q13 in a subset of Turkish and
Mediterranean families (LOD = 3.72).
These QTLs provide important clues for the further investigation of genes
responsible for these complex lipid phenotypes. These data also indicate that a
large proportion of the variance of TG levels in the Turkish population is
explained by the interaction of multiple genetic loci.
Abbreviations:
cM, centimorgan; CVD, cardiovascular disease; FCHL, familial combined
hyperlipidemia; GEMS, Genetic Epidemiology of Metabolic Syndrome; HDL-C,
high density lipoprotein-cholesterol; LDL-C, low density lipoprotein-cholesterol;
LOD, logarithm of the odds ratio; QTL, quantitative trait locus; TC, total
cholesterol; TG, triglyceride.
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The American Journal of Cardiology
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Reference:
Wyszynski DF, Waterworth DM, Barter PJ, Cohen J, Kesaniemi YA, Mahley RW, McPherson
R, Waeber G, Bersot TP, Sharma SS, Nolan V, Middleton LT, Sundseth SS, Farrer LA,
Mooser V, Grundy SM. Relation between atherogenic dyslipidemia and the Adult
Treatment Program-III definition of metabolic syndrome (Genetic Epidemiology of
Metabolic Syndrome Project). Am J Cardiol. 2005 Jan 15; 95(2):194-8.
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Abstract:
Genetic Epidemiology of Metabolic Syndrome is a multinational, family-based
study to explore the genetic basis of the metabolic syndrome. Atherogenic
dyslipidemia (defined as low plasma high-density lipoprotein cholesterol with
elevated triglycerides (<25th and >75th percentile for age, gender, and country,
respectively) identified affected subjects for the metabolic syndrome. This
report examines the frequency at which atherogenic dyslipidemia predicts the
metabolic syndrome of the National Cholesterol Education Program Adult Treatment
Panel III (ATP-III). One thousand four hundred thirty-six (854 men/582 women)
affected patients by our criteria were compared with 1,672 (737 men/935 women)
unaffected persons. Affected patients had more hypertension, obesity, and
hyperglycemia, and they met a higher number of ATP-III criteria (3.2 ± 1.1 SD
vs 1.3 ± 1.1 SD, p <0.001). Overall, 76% of affected persons also qualified for
the ATP-III definition (Cohen's k 0.61, 95% confidence interval 0.59 to 0.64),
similar to a separate group of 464 sporadic, unrelated cases (75%). Concordance
increased from 41% to 82% and 88% for ages =35, 36 to 55, and =55 years,
respectively. Affected status was also independently associated with waist
circumference (p <0.001) and fasting glucose (p <0.001) but not systolic blood
pressure (p = 0.43). Thus, the lipid-based criteria used to define affection
status in this study substantially parallels the ATP-III definition of metabolic
syndrome in subjects aged >35 years. In subjects aged <35 years, atherogenic
dyslipidemia frequently occurs in the absence of other metabolic syndrome risk
factors.
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