Genome Scans Provide Evidence for Low-HDL-C Loci on Chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish Families

Soro, Aino; Pajukanta, Päivi; Lilja, Heidi E.; Ylitalo, Kati; Hiekkalinna, Tero; Perola, Markus; Cantor, Rita M.; Viikari, Jorma; Taskinen, Marja‐Riitta; Peltonen, Leena

doi:10.1086/339988

Cited by 86 publications

(99 citation statements)

References 26 publications

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“…Previous reports of linkage on chromosome 6 (7) are ?17 Mb upstream from our signal. The chromosome 13q13.2 (32.9 Mb) peak for apoB is in the same region as two previous linkage findings for low levels of serum HDL cholesterol (29,30), and our peak on chromosome 6 is ,20 cM downstream from a previously reported HDL 3 linkage region (31).…”

Section: Discussionsupporting

confidence: 88%

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

Sherva

Yue

Schonfeld

et al. 2007

Journal of Lipid Research

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High plasma apolipoprotein B (apoB) and LDL cholesterol levels increase cardiovascular disease risk. These highly correlated measures may be partially controlled by common genetic polymorphisms. To identify chromosomal regions that contain genes causing low plasma levels of one or both parameters in Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL), we conducted a wholegenome scan using 443 microsatellite markers typed in nine multigenerational families with at least two members with FHBL. Both variance components and regression-based linkage methods were used to identify regions of interest. Common linkage regions were identified for both measures on chromosomes 10q25.1-10q26.11 [maximum log of the odds (LOD) 5 4.2 for LDL and 3.5 for apoB] and 6q24.3 (maximum LOD 5 1.46 for LDL and 1.84 for apoB). There was also evidence for linkage to apoB on chromosome 13q13.2 (LOD 5 1.97) and to LDL on chromosome 3p14.1 at 94 centimorgan (LOD 5 1.52). Bivariate linkage analysis provided further evidence for loci contributing to both traits (6q24.3, LOD 5 1.43; 10q25.1, LOD 5 1.74). We evaluated single nucleotide polymorphisms (SNPs) in genes within our linkage regions to identify variants associated with apoB or LDL levels. The most significant finding was for rs2277205 in the 5 ¶ untranslated region of acyl-coenzyme A dehydrogenase short/branched chain and LDL (P 5 10 27 ). Three additional SNPs were associated with apoB and/or LDL (P , 0.01). Although only the linkage signal on chromosome 10 reached genome-wide statistical significance, there are likely multiple chromosomal regions with variants that contribute to low levels of apoB and LDL and that may protect against coronary heart disease.-Sherva, R., P. Yue, G. Schonfeld, and R. J. Neuman. High plasma apolipoprotein B (apoB) and LDL cholesterol concentrations are equally and independently associated with an increased long-term relative risk of coronary heart disease (1, 2). Patients in the highest tertile of apoB and LDL have an ?2-fold increase in coronary heart disease risk over those in the lower tertiles after multivariate adjustment. Other studies suggest that increased apoB levels may be associated with an even greater risk of coronary heart disease than high LDL cholesterol concentrations (3, 4).Data from twin studies show that there is a strong heritability for apoB and LDL levels (5, 6), and numerous genome scans have attempted to identify loci linked to lipid levels. A recent summary of the results from various lipid genome scans lists significant or suggestive evidence for linkage on chromosomes 1, 2, 3, 6, and 11 for apoB and on chromosomes 1,3,4,5,6,10,11,13,15,17,19, and X for LDL (7). In addition, linkage scans for loci influencing both traits have identified regions on chromosomes 2, 11, and 18 (7).In this study, we performed genome-wide linkage analysis in a cohort of Caucasian families ascertained for familial hypobetalipoproteinemia (FHBL). FHBL is a disorder in which subjects have extremely low levels of apoB and L...

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Section: Discussionsupporting

confidence: 88%

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

Sherva

Yue

Schonfeld

et al. 2007

Journal of Lipid Research

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“…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.…”

Section: Methodsmentioning

confidence: 99%

“…The study design was approved by the ethics committees of the participating centers. The inclusion criteria for FCHL and low-HDL cholesterol families were premature CHD and abnormal lipid profile with total cholesterol and/or triglyceride levels greater than or equal to the age/sex-specific 90th Finnish population percentile for FCHL probands and HDL cholesterol levels less than or equal to the age/sex-specific 10th percentile for HDL cholesterol probands (14,15). Additional lipid criteria for the low-HDL cholesterol probands were total cholesterol Յ6.3 mmol/l in men and Յ6.0 mmol/l in women and triglycerides Յ2.3 mmol/l in both sexes.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2006

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Hepatic nuclear factor-4␣ (HNF-4␣), a transcription factor involved in the regulation of serum lipid and glucose levels, has recently been associated with type 2 diabetes. The HNF-4␣ gene (HNF4A) resides on chromosome 20q12-q13.1, which, in addition to type 2 diabetes, has also previously been linked to high triglycerides in Finnish familial combined hyperlipidemia (FCHL) families. FCHL, characterized by elevated levels of serum total cholesterol, triglycerides, or both, is a common dyslipidemia observed in up to 20% of patients with premature coronary heart disease. Considering the clear phenotypic overlap between type 2 diabetes and FCHL, both predisposing to high serum triglycerides and glucose intolerance, we tested this gene for association in dyslipidemic families originating from two distinct populations, Finnish and Mexican, and comprising 1,447 subjects. Our data show that common HNF4A variants and haplotypes are associated with elevated serum lipid levels and the metabolic syndrome (P ‫؍‬ 0.008 -0.04), as well as with elevated glucose parameters (P ‫؍‬ 0.008 -0.03), using family-based association analysis. Importantly, both Finnish and Mexican families shared two common lipid-associated HNF4A haplotypes (P ‫؍‬ 0.005 for total cholesterol and 0.006 for triglycerides). In conclusion, we show for the first time that common HNF4A variants are associated with high serum lipid levels and the metabolic syndrome.

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“…Both are typical complex disorders, influenced by several environmental and genetic factors. FCHL is characterized by increased levels of serum total cholesterol (TC) and triglycerides (TGs), or both, and also expresses low HDL-C as a component trait (2)(3)(4). It has been estimated that the genetic component accounts at least 50% of the variation in HDL-C levels (5).…”

Section: Supplementary Abstractmentioning

confidence: 99%

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia

Lilja

Suviolahti

Soro‐Paavonen

et al. 2004

Journal of Lipid Research

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Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs ( P ϭ 0.0006) and for a combined trait of HDL-C and TGs ( P ϭ 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and

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Genome Scans Provide Evidence for Low-HDL-C Loci on Chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish Families

Cited by 86 publications

References 26 publications

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

Evidence for a quantitative trait locus affecting low levels of apolipoprotein B and low density lipoprotein on chromosome 10 in Caucasian families

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

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia

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