Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: Analysis of a large pedigree from the Bogalusa heart study

Heiba, Ibrahim M.; DeMeester, Cynthia A.; Xia, Yu‐Rong; Diep, Anh; George, Varghese; Amos, Christopher I.; Srinivasan, Sathanur R.; Berenson, Gerald S.; Elston, Robert C.; Lusis, Aldons J.

doi:10.1002/ajmg.1320470615

Cited by 24 publications

(13 citation statements)

References 58 publications

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“…A linkage study of data from the Framingham Study families 39 reported nominal evidence for QTLs, influencing log TG levels (LODϭ1.5) and log TG/ HDL (LODϭ1.1) within 10 cM of the markers nearest the multipoint peak in our analyses. Penetrance-model-based linkage analyses of data from the Bogalusa Heart Study 22 and a study by Heiba et al 40 yielded nominal evidence for linkage (LODϭ1.7 and PϽ0.05, respectively) between a QTL for HDL-C levels and a haptoglobin locus marker situated within 5 cM of the marker loci nearest our multipoint peak. In contrast, MacPherson et al 41 found no evidence for a QTL for plasma HDL-C levels linked to the CETP locus in their study of data from 104 nuclear families.…”

Section: Discussionmentioning

confidence: 59%

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Mahaney

Almasy

Rainwater

et al. 2003

ATVB

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Objective-We conducted a whole-genome, multipoint linkage screen to localize a previously reported major locus accounting for 56% to 67% of the additive genetic effects on covariate-adjusted plasma HDL cholesterol (HDL-C) levels in Mexican Americans from the San Antonio Family Heart Study (SAFHS). Methods and Results-After using complex segregation analysis to recover the major locus in 472 SAFHS participants from 10 genotyped families, we incorporated covariates required to detect that major locus, including plasma levels of triglycerides and apolipoprotein A-I, in a maximum-likelihood-based variance-components linkage screen. Only chromosome 16 exhibited convincing evidence for a quantitative trait locus (QTL), with a peak multipoint log of the odds (LOD)ϭ3.73 (Pϭ0.000034). Subsequent penetrance model-based linkage analysis, incorporating genotypes at the marker locus nearest the multipoint peak (D16S518) into the segregation model, detected linkage with the previously detected major locus (LODϭ2.73, Pϭ0.000642). Initial estimates place this QTL within a 15-cM region of chromosome 16q near the structural loci for lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). Key Words: HDL Ⅲ genome screen Ⅲ linkage Ⅲ heritability Ⅲ Mexican Americans W e previously reported a major locus influencing quantitative variation in plasma HDL cholesterol (HDL-C) levels in Mexican-American families from the San Antonio Family Heart Study (SAFHS). 1 This major-locus effect, accounting for 56% to 67% of the additive genetic variance in HDL-C in those families, was detected only when the effects of age and sex terms plus plasma levels of apolipoprotein A-I (apo A-I) and triglycerides (TG), exogenous sex hormone use, and menopause status were included in the complex segregation analysis model for the trait. In males and females, respectively, the major locus accounted for 11% and 4% of the total phenotypic variance in plasma total HDL-C levels and for 55% and 21% of the residual phenotypic variance, ie, the proportion of the phenotypic variance not attributable to the effects of covariates. Because genotype data were not available for a whole-genome linkage screen when this major locus first was detected, we attempted to identify a locus responsible for this effect by means of combined segregation and linkage analysis with genotype data for likely candidate loci. Results of these analyses 1 were both definitive and negative, excluding linkage between the major locus for residual HDL-C and structural loci for several proteins of lipoprotein metabolism, namely, APOA-I, APOB, LDLR, LIPC, and LPL, on chromosomes 11q, 2p, 19p, 15q, and 8p, respectively. Conclusions-A QTL influencing plasma levels of HDL-C inAlthough subsequent analyses of data from the SAFHS and other studies have mapped quantitative trait loci (QTLs) for HDL-C-related measures to chromosome 1q 2 , chromosome 13q, 3,4 and chromosome 9p 5 , other reports localize HDL-Crelated QTLs to some chromosomal regions containing candidate loci ...

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Section: Discussionmentioning

confidence: 59%

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Mahaney

Almasy

Rainwater

et al. 2003

ATVB

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“…As with I405V, the Taq1B studies were subjected to a formal meta-analysis as described above. Data were excluded if they reported data on subjects specifically selected by abnormal lipid criteria (68,69,77,83,88,107), on alcoholics (75), on related individuals (91), and specifically on patients with non-CAD related disease (76,78). Duplicate publications and publications with patient overlap were excluded.…”

Section: Wild-type Proteinmentioning

confidence: 99%

Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease

Boekholdt

Thompson

2003

Journal of Lipid Research

153

117

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Since the identification of cholesteryl ester transfer protein (CETP), its role in the modulation of HDL levels and cardiovascular disease has been debated. With the early detection of genetic variants followed by the finding of families deficient in CETP, genetic studies have played a large role in the attempts to understand the association of CETP with lipids and disease; however, results of these studies have often led to disparate conclusions. With the availability of a greater variety of genetic polymorphisms and larger studies in which disease has been examined, it is now possible to compare the breadth of CETP genetic studies and draw better conclusions. The most broadly studied polymorphism is TaqIB for which over 10,000 individuals have been genotyped and had HDL levels determined. When these studies are subjected to a meta-analysis, the B2B2 homozygotes are found to have higher HDL levels than B1B1 homozygotes (0.12 mmol/l, 95% CI ‫؍‬ 0.11-0.13, P Ͻ 0.0001). A similar analysis of the I405V polymorphism yields 0.05 mmol/l higher HDL levels in 405VV homozygotes than in 405II homozygotes (95% CI ‫؍‬ 0.03-0.07, P Ͻ 0.0001). The implications of these studies for cardiovascular disease will be addressed. -Boekholdt, S. M., and J. F. Thompson. Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease. J. Lipid Res. 2003. 44: 1080-1093.

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“…The Bogalusa heart studies [30][31][32][33] have presented a considerable body of evidence on the genetic and epidemiological dynamics of lipids and apolipoprotein concentrations as they relate to the risk of CHD across races and genders, but have no endpoint data as yet. The few studies that have examined the association of hyperlipidaemia with CHD in minorities have shown that total cholesterol was a predictor of CHD risk.…”

Section: Agt235 Polymorphism and Cad Riskmentioning

confidence: 99%

AGT and RH blood group polymorphisms affect blood pressure and lipids in Afro-Caribbeans

Robinson

Wilson²,

Nicholson

et al. 2004

J Hum Hypertens

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Population blood pressure variation is most likely due to multiple genes. This is likely the reason why monogenic testing with the angiotensinogen (AGT) gene polymorphisms on chromosome 1 (1q42-43), especially M235T, has met with negative results, especially in those of African descent. The RH blood group system, also on chromosome 1 (1 p36.2-34), has likewise been associated with blood pressure variation in AfricanAmericans and with the rise in blood pressure with age in whites. Using a random sample of the population, we investigated the combined effects of single and combined variation of the AGTN M235T and RH genotypes on blood pressure, lipids, and lipoprotein concentrations in Afro-Caribbeans aged 18-60 years from the island nation of Dominica. In monogenic analysis, AGT M235T was not associated with blood pressure. However, it was associated with HDL (MM 42723, MT 44712, TT 52714 (P ¼ 0.002)). RH genotype was significantly associated with systolic blood pressure (P ¼ 0.006) and Apo-A (P ¼ 0.003). These effects remained after adjustment for age, gender, weight, and BMI. In the polygenetic analysis, AGT M235T and RH were significantly associated with systolic blood pressure (P ¼ 0.037; interaction effects, P ¼ 0.068). The association of the AGT M235T with blood pressure across RH blood group haplotypes was then tested. Of the five RH haplotypes available for analysis, the AGT M235T was significantly associated with blood pressure within the ''D'' haplotype (P ¼ 0.01). The RH blood group and gender were significantly associated with systolic blood pressure and Apo-A levels (P ¼ 0.005 and 0.012, respectively). All interactions were independent of age and weight. In conclusion, we demonstrate a significant association of AGT M235T with blood pressure and cholesterol metabolism in an Afro-Caribbean population in the ''genetic context'' of the RH blood group system. Further investigation of these interactions may help understand the effects of genetic factors on cardiovascular risk in African-derived and other populations.

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Genetic contributions to quantitative lipoprotein traits associated with coronary artery disease: Analysis of a large pedigree from the Bogalusa heart study

Cited by 24 publications

References 58 publications

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

A Quantitative Trait Locus on Chromosome 16q Influences Variation in Plasma HDL-C Levels in Mexican Americans

Natural genetic variation as a tool in understanding the role of CETP in lipid levels and disease

AGT and RH blood group polymorphisms affect blood pressure and lipids in Afro-Caribbeans

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