TY - JOUR
T1 - LIPC variants in the promoter and intron 1 modify HDL-C levels in a sex-specific fashion
AU - Feitosa, Mary F.
AU - Myers, Richard H.
AU - Pankow, James S.
AU - Province, Michael A.
AU - Borecki, Ingrid B.
N1 - Funding Information:
This work was supported by the NHLBI grant 5R01HL06889106.
PY - 2009/5
Y1 - 2009/5
N2 - We previously reported linkage for plasma levels of high-density lipoprotein cholesterol (HDL-C) on 15q21 in Caucasian families from the National Heart, Lung, and Blood Institute Family Heart Study (NHLBI FHS). Hepatic lipase gene (LIPC), which has a major role in lipoprotein metabolism, resides within the linkage region and constitutes an obvious candidate gene. While hepatic lipase is a known player in HDL metabolism, the relationship between common LIPC variants and HDL-C levels remains unclear. In the current study, we employed population-based and family-based tests of association with both quantitative HDL-C levels and a dichotomous dyslipidemia trait (affected men: HDL < 40 mg/dL and women: HDL < 50 mg/dL, denoted as low HDL). We genotyped 19 tag-SNPs spanning 139.9 kb around the LIPC in the 591 families (2238 subjects). Strong association in a proxy-promoter 5′ SNP (rs261342) and HDL-C levels was detected in women, but not in men. The less common allele was associated with an increase of ∼14% in HDL-C levels, and a decrease of ∼30% in risk of low HDL. In addition, strong association in women of an intron 1 SNP (rs12593008) and low HDL and moderate association in men (rs8028759) with both HDL-C levels and low HDL phenotype were found and may represent either functional single nucleotide polymorphisms (SNPs), or more likely, SNPs in linkage disequilibrium with functional variants. Because of the association of lipid abnormalities with diabetes, and other lifestyle parameters, we also performed association analyses using different covariate adjustments as well as strategically selected sub-samples. The sex-specific association of rs261342, rs12593008 or rs8028759 remained substantially the same through these analyses. Finally, we found that a common haplotype was overtransmitted to offspring with low HDL-C. The sex-specific associations found in our study could be due to the interactions with the endogenous hormonal environment, lifestyle and/or genetic factors, although the underlying physiologic mechanisms are not understood.
AB - We previously reported linkage for plasma levels of high-density lipoprotein cholesterol (HDL-C) on 15q21 in Caucasian families from the National Heart, Lung, and Blood Institute Family Heart Study (NHLBI FHS). Hepatic lipase gene (LIPC), which has a major role in lipoprotein metabolism, resides within the linkage region and constitutes an obvious candidate gene. While hepatic lipase is a known player in HDL metabolism, the relationship between common LIPC variants and HDL-C levels remains unclear. In the current study, we employed population-based and family-based tests of association with both quantitative HDL-C levels and a dichotomous dyslipidemia trait (affected men: HDL < 40 mg/dL and women: HDL < 50 mg/dL, denoted as low HDL). We genotyped 19 tag-SNPs spanning 139.9 kb around the LIPC in the 591 families (2238 subjects). Strong association in a proxy-promoter 5′ SNP (rs261342) and HDL-C levels was detected in women, but not in men. The less common allele was associated with an increase of ∼14% in HDL-C levels, and a decrease of ∼30% in risk of low HDL. In addition, strong association in women of an intron 1 SNP (rs12593008) and low HDL and moderate association in men (rs8028759) with both HDL-C levels and low HDL phenotype were found and may represent either functional single nucleotide polymorphisms (SNPs), or more likely, SNPs in linkage disequilibrium with functional variants. Because of the association of lipid abnormalities with diabetes, and other lifestyle parameters, we also performed association analyses using different covariate adjustments as well as strategically selected sub-samples. The sex-specific association of rs261342, rs12593008 or rs8028759 remained substantially the same through these analyses. Finally, we found that a common haplotype was overtransmitted to offspring with low HDL-C. The sex-specific associations found in our study could be due to the interactions with the endogenous hormonal environment, lifestyle and/or genetic factors, although the underlying physiologic mechanisms are not understood.
KW - BMI
KW - Cardiovascular disease
KW - Diabetes
KW - Hepatic lipase
KW - Lipids
KW - Polymorphism
UR - http://www.scopus.com/inward/record.url?scp=67349208491&partnerID=8YFLogxK
U2 - 10.1016/j.atherosclerosis.2008.09.007
DO - 10.1016/j.atherosclerosis.2008.09.007
M3 - Article
C2 - 19101670
AN - SCOPUS:67349208491
SN - 0021-9150
VL - 204
SP - 171
EP - 177
JO - Atherosclerosis
JF - Atherosclerosis
IS - 1
ER -