Kathiresan, S., Melander, O., Guiducci, C., Surti, A., Burtt, N. P. et al. Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nat. Genet. 40, 189-197

Cardiology Division, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Nature Genetics (Impact Factor: 29.35). 02/2008; 40(2):189-97. DOI: 10.1038/ng.75
Source: PubMed


Blood concentrations of lipoproteins and lipids are heritable risk factors for cardiovascular disease. Using genome-wide association data from three studies (n = 8,816 that included 2,758 individuals from the Diabetes Genetics Initiative specific to the current paper as well as 1,874 individuals from the FUSION study of type 2 diabetes and 4,184 individuals from the SardiNIA study of aging-associated variables reported in a companion paper in this issue) and targeted replication association analyses in up to 18,554 independent participants, we show that common SNPs at 18 loci are reproducibly associated with concentrations of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and/or triglycerides. Six of these loci are new (P < 5 x 10(-8) for each new locus). Of the six newly identified chromosomal regions, two were associated with LDL cholesterol (1p13 near CELSR2, PSRC1 and SORT1 and 19p13 near CILP2 and PBX4), one with HDL cholesterol (1q42 in GALNT2) and five with triglycerides (7q11 near TBL2 and MLXIPL, 8q24 near TRIB1, 1q42 in GALNT2, 19p13 near CILP2 and PBX4 and 1p31 near ANGPTL3). At 1p13, the LDL-associated SNP was also strongly correlated with CELSR2, PSRC1, and SORT1 transcript levels in human liver, and a proxy for this SNP was recently shown to affect risk for coronary artery disease. Understanding the molecular, cellular and clinical consequences of the newly identified loci may inform therapy and clinical care.

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    • "The variant rs599839 located in the 3-untranslated region of the PSRC1 gene shows strong linkage disequilibrium with other SNPs in this LD block [12]. In particular, rs599839 is the SNP that has the highest correlation with CAD and LDL-C in most studies [14] [15] [19] [20]. The minor allele in European populations (G, MAF0.33 in HapMap CEU; was found to be associated with a lower risk of CAD and lower levels of LDL-C. "
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    ABSTRACT: Background: Several polymorphisms of a locus on chromosome 1p13.3 have a significant effect on low-density lipoprotein cholesterol (LDL-C), atherosclerosis, and acute coronary syndrome (ACS). Methods: We aimed to investigate the association between rs599839, rs646776, and rs4970834 of locus 1p13.3 and serum LDL-C and severity of coronary artery stenosis in ACS patients. Genotyping of the rs599839, rs646776, and rs4970834 polymorphisms was performed on Arab patients undergoing coronary angiography for ACS. Patients were divided into group A (ACS with insignificant stenosis (<50%)) and group B (with significant stenosis (≥ 50%)). Results: Patients carrying the minor G allele in rs599839 had significantly lower mean of LDL-C (2.58 versus 3.44 mM, P = 0.026) than homozygous A allele carriers (GG versus AA). Carriers of minor C allele in rs64776 had significantly higher mean of HDL-C (2.16 versus 1.36 mM, P = 0.004) than carriers of the T alleles (AA versus GG). The odd ratio and 95% confidence interval for dominant model for G allele carriers of rs599839 were 0.51 (0.30-0.92), P = 0.038, among patients with significant stenosis. Conclusions: Polymorphisms rs646776 and rs599839 of locus 1p13.3 were significantly associated with LDL-C and other lipid parameters. In addition, the G-allele carriers of variant rs599839 had a significant protective effect against the atherosclerosis.
    BioMed Research International 03/2015; 2015. DOI:10.1155/2015/678924 · 2.71 Impact Factor
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    • "(LPL), rs12740374 (CELSR2) and rs7412 (APOE); have been reported to be associated with some lipid metabolism disturbances (hypertriglyceridemia, hypercholesterolemia, high low density lipoprotein - LDL-levels or low high density lipoprotein -HDL-levels) by GWAS (Willer et al. 2008; Kathiresan et al. 2008; Sandhu et al. 2008; Kettunen et al. 2012). The SNP rs429358 (APOE) has been associated with some lipid metabolism disorders by a meta-analysis of association studies (Bennet et al. 2007); and three SNPs, rs1799983 (NOS3) rs1800777 (CETP) and rs1800206 (PPARA), by association studies (Ferguson et al. 2010; Chrysohoou et al. 2004; Lu et al. 2008; Tai et al. 2002). "
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    ABSTRACT: There is little evidence about genetic risk score (GRS)-diet interactions in order to provide personalized nutrition based on the genotype. The aim of the study was to assess the value of a GRS on obesity prediction and to further evaluate the interactions between the GRS and dietary intake on obesity. A total of 711 seekers of a Nutrigenetic Service were examined for anthropometric and body composition measurements and also for dietary habits and physical activity. Oral epithelial cells were collected for the identification of 16 SNPs (related with obesity or lipid metabolism) using DNA zip-coded beads. Genotypes were coded as 0, 1 or 2 according to the number of risk alleles, and the GRS was calculated by adding risk alleles with such a criterion. After being adjusted for gender, age, physical activity and energy intake, the GRS demonstrated that individuals carrying >7 risk alleles had in average 0.93 kg/m(2) of BMI, 1.69 % of body fat mass, 1.94 cm of waist circumference and 0.01 waist-to-height ratio more than the individuals with ≤7 risk alleles. Significant interactions for GRS and the consumption of energy, total protein, animal protein, vegetable protein, total fat, saturated fatty acids, polyunsaturated fatty acids, total carbohydrates, complex carbohydrates and fiber intake on adiposity traits were found after adjusted for confounders variables. The GRS confirmed that the high genetic risk group showed greater values of adiposity than the low risk group and demonstrated that macronutrient intake modifies the GRS association with adiposity traits.
    Genes & Nutrition 01/2015; 10(1):445. DOI:10.1007/s12263-014-0445-z · 2.79 Impact Factor
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    • "Rather than conservatively correcting for multiple testing, validation through re-testing in an independent population is preferable. Such validation is a standard requirement in both candidate gene-based Bottcher et al. (2009); Traurig et al. 2009) and genomewide association mapping studies in humans (Jallow et al. 2009; Kathiresan et al. 2008) and permits discrimination of real and false positives without inflating the false negative rate. While preferred, independent replication for validation is often difficult to achieve in practice. "
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    ABSTRACT: The moderate to high levels of nucleotide diversity and low linkage disequilibrium found in many forest tree species make them ideal candidates for association mapping. Here, we report candidate gene-based association mapping results for complex wood quality and growth traits in Eucalyptus globulus Labill. ssp. globulus, the most widely grown eucalypt in temperate regions of the world. Ninety-eight single nucleotide polymorphisms (SNPs) from 20 wood quality candidate genes were assayed in a discovery population consisting of 385 trees sourced from a provenance-progeny trial. Twenty-five selected SNPs with significant associations (P .
    Tree Genetics & Genomes 12/2014; 10(6):1-18. DOI:10.1007/s11295-014-0787-0 · 2.45 Impact Factor
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