87 research outputs found
A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes
No full textAbstract Background Left ventricular mass (LVM) is an important risk factor for cardiovascular disease. Previously we found evidence for linkage to chromosome 12p11 in Dominican families, with a significant increase in a subset of families with high average waist circumference (WC). In the present study, we use association analysis to further study the genetic effect on LVM. Methods Association analysis with LVM was done in the one LOD critical region of the linkage peak in an independent sample of 897 Caribbean Hispanics. Genotype data were available on 7085 SNPs from 23 to 53 MB on chromosome 12p11. Adjustment was made for vascular risk factors and population substructure using an additive genetic model. Subset analysis by WC was performed to test for a difference in genetic effects between the high and low WC subsets. Results In the overall analysis, the most significant association was found to rs10743465, downstream of the SOX5 gene (p = 1.27E-05). Also, 19 additional SNPs had nominal p TMTC1. Twelve additional SNPs in or near 6 genes had p Conclusions The current study supports previously identified evidence by linkage for a genetic effect on LVM on chromosome 12p11 using association analysis in population-based Caribbean Hispanic cohort. SOX5 may play an important role in the regulation of LVM. An interaction of TMTC1 with abdominal obesity may contribute to phenotypic variation of LVM.</p
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Genetic linkage of serum homocysteine in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis
No full textBackground and Purpose-Homocysteine levels are determined by genetic and environmental factors. Several studies have linked high plasma levels of total homocysteine to the increased risk of cardiovascular disease, stroke, and many other conditions. However, the exact mechanism of documented and novel total homocysteine quantitative trait loci to that risk is unknown.Methods-We have performed linkage analysis in 100 high-risk Dominican families with 1362 members. Probands were selected from the population-based Northern Manhattan Study. A set of 405 microsatellite markers was used to screen the whole genome. Variance components analysis was used to detect evidence for linkage after adjusting for stroke risk factors. Ordered-subset analysis based on Dominican Republic enrollment was conducted.Results-Total homocysteine levels had a heritability of 0.44 (P<0.0001). The most significant evidence for linkage was found at chromosome 17q24 (maximum logarithm of odds [MLOD]=2.66, P=0.0005) with a peak at D17S2193 and was significantly increased in a subset of families with a high proportion of Dominican Republic enrollment (MLOD=3.92, P=0.0022). Additionally, modest evidence for linkage was found at chromosome 2p21 (MLOD=1.77, P=0.0033) with a peak at D2S1356 and was significantly increased in a subset of families with a low proportion of Dominican Republic enrollment (MLOD=2.82, P=0.0097).Conclusions-We found a strong evidence for novel quantitative trait loci on chromosomes 2 and 17 for total homocysteine plasma levels in Dominican families. Our family study provides essential data for a better understanding of the genetic mechanisms associated with elevated total homocysteine levels leading to cardiovascular disease after accounting for environmental risk factors. (Stroke. 2010;41:1356-1362.
Genomewide Linkage and Peakwide Association Analyses of Carotid Plaque in Caribbean Hispanics
No full text
Background and Purpose—
Atherosclerosis is a complex subclinical cardiovascular disorder with a substantial genetic component. This study sought to identify genetic loci influencing carotid plaque in 2 independent samples.
Methods—
B-mode ultrasound was performed to determine the presence and area of carotid plaque. Variance components analysis was used to test for linkage using 383 autosomal microsatellite markers in 1308 subjects from 100 Dominican families. Multiple linear and logistic regression models were used to investigate the association between plaque traits and 18 904 single nucleotide polymorphisms under the 1-logarithm of odds unit down regions of linkage peaks in an independent community-based data set (N=941, 41% Dominicans) from the Northern Manhattan Study.
Results—
After adjustment for age, hypertension, diabetes mellitus, cigarette pack-years, body mass index, and waist-to-hip ratio, significant heritability was detected for plaque presence (h
2
=0.50±0.14,
P
<0.0001) and plaque area (h
2
=0.17±0.04,
P
<0.0001). Quantitative and dichotomous trait linkage analyses obtained similar results and identified 4 regions with multipoint logarithm of odds scores ≥2.00 on 7q36, 11p15, 14q32, and 15q23. In the association analysis of the 4 linkage peaks, several single nucleotide polymorphisms in or near
SOX6, FSD2, AP3S2, EFTUD1
, and
MYOD1
were associated with carotid plaque traits with a nominal
P
≤0.0005 in the Northern Manhattan Study data set and with a
P
≤0.01 in Northern Manhattan Study Dominican subset.
Conclusions—
Carotid plaque has considerable heritability and may be influenced by loci on chromosomes 11p15, 14q32, and 15q23. The
SOX6
gene within the bone morphogenic protein pathway could be a candidate for carotid plaque. Larger independent studies are needed to validate these findings.
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A Comprehensive Genetic Study on Left Atrium Size in Caribbean Hispanics Identifies Potential Candidate Genes in 17p10
No full text
Background—
Left atrial (LA) enlargement is associated with cardiovascular disease and stroke. Genetic factors contributing to the LA dimension are poorly understood. We sought to map susceptibility genes for LA size in a large Dominican family data set and an independent population-based sample from the Northern Manhattan Study.
Methods and Results—
One hundred Dominican families comprising 1350 individuals were studied to estimate heritability and map quantitative trait loci for LA size using variance components analysis. LA dimension was measured by transthoracic echocardiography. A polygenic covariate screening was used to identify significant covariates. LA size had a moderate estimate of heritability (h
2
=0.42) after adjusting for significant covariates. Linkage analysis revealed suggestive evidence on chromosome 10p19 (D10S1423, MLOD=2.00) and 17p10 (D17S974, MLOD=2.05). Ordered subset analysis found significantly enhanced (
P
<0.05 for increase of LOD score) evidence for linkage at 17p10 (MLOD=2.9) in families with lower LDL level. Single nucleotide polymophisms (n=2233)were used to perform a peak-wide association mapping across 17p10 in 825 NOMAS individuals. Evidence for association were found in
NTN1
,
MYH10
,
COX10
, and
MYOCD
genes (
P
=0.00005 to 0.005).
Conclusions—
Using nonbiased genome-wide linkage followed by peak-wide association analysis, we identified several possible susceptibility genes affecting LA size. Among them, MYOCD has been shown to serve as a key transducer of hypertrophic signals in cardiomyocytes. Our data support that polymorphisms in
MYOCD
modify LA size.
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DNA Methylation Variation Is Identified in Monozygotic Twins Discordant for Non-syndromic Cleft Lip and Palate
No full textNon-syndromic cleft lip with or without cleft palate (NSCLP) is the most common craniofacial birth defect. The etiology of NSCLP is complex with multiple genes and environmental factors playing causal roles. Although studies have identified numerous genetic markers associated with NSCLP, the role of epigenetic variation remains relatively unexplored. Because of their identical DNA sequences, monozygotic (MZ) twins discordant for NSCLP are an ideal model for examining the potential contribution of DNA methylation to non-syndromic orofacial clefting. In this study, we compared the patterns of whole genome DNA methylation in six MZ twin pairs discordant for NSCLP. Differentially methylated positions (DMPs) and regions (DMRs) were identified in NSCLP candidate genes, including differential methylation in
MAFB
and
ZEB2
in two independent MZ twin pairs. In addition to DNA methylation differences in NSCLP candidate genes, we found common differential methylation in genes belonging to the Hippo signaling pathway, implicating this mechanosensory pathway in the etiology of NSCLP. The results of this novel approach using MZ twins discordant for NSCLP suggests that differential methylation is one mechanism contributing to NSCLP, meriting future studies on the role of DNA methylation in familial and sporadic NSCLP
Novel quantitative trait locus is mapped to chromosome 12p11 for left ventricular mass in Dominican families: the Family Study of Stroke Risk and Carotid Atherosclerosis
No full textAbstract Background Left ventricular mass (LVM) is an important risk factor for stroke and vascular disease. The genetic basis of LVM is unclear although a high heritability has been suggested. We sought to map quantitative trait loci (QTL) for LVM using large Dominican families. Methods Probands were selected from Dominican subjects of the population-based Northern Manhattan Study (NOMAS). LVM was measured by transthoracic echocardiography. A set of 405 microsatellite markers was used to screen the whole genome among 1360 subjects from 100 Dominican families who had complete phenotype data and DNA available. A polygenic covariate screening was run to identify the significant covariates. Variance components analysis was used to estimate heritability and to detect evidence for linkage, after adjusting for significant risk factors. Ordered-subset Analysis (OSA) was conducted to identify a more homogeneous subset for stratification analysis. Results LVM had a heritability of 0.58 in the studied population (p Conclusion We mapped a novel QTL near D12S1042 for LVM in Dominicans. Enhanced linkage evidence in families with larger waist circumference suggests that gene(s) residing within the QTL interact(s) with abdominal obesity to contribute to phenotypic variation of LVM. Suggestive evidence for linkage (LOD = 1.99) has been reported at the same peak marker for left ventricular geometry in a White population from the HyperGEN study, underscoring the importance of this QTL for left ventricular phenotype. Further fine mapping and validation studies are warranted to identify the underpinning genes.</p
Genome-wide linkage and peak-wide association study of obesity-related quantitative traits in Caribbean Hispanics
No full textAlthough obesity is more prevalent in Hispanics than non-Hispanic whites in the United States, little is known about the genetic etiology of the related traits in this population. To identify genetic loci influencing obesity in non-Mexican Hispanics, we performed a genome-wide linkage scan in 1,390 subjects from 100 Caribbean Hispanic families on six obesity-related quantitative traits: body mass index (BMI), body weight, waist circumference, waist-to-hip ratio, abdominal and average triceps skinfold thickness after adjusting for significant demographic and lifestyle factors. We then carried out an association analysis of the linkage peaks and the
FTO
gene in an independent community-based Hispanic subcohort (
N
= 652, 64% Caribbean Hispanics) from the Northern Manhattan Study. Evidence of linkage was strongest on 1q43 with multipoint LOD score of 2.45 (
p
= 0.0004) for body weight. Suggestive linkage evidence of LOD > 2.0 was also identified on 1q43 for BMI (LOD = 2.03), 14q32 for abdominal skinfold thickness (LOD = 2.17), 16p12 for BMI (LOD = 2.27) and weight (LOD = 2.26), and 16q23–24 for average triceps skinfold thickness (LOD = 2.32). In the association analysis of 6,440 single nucleotide polymorphisms (SNPs) under 1-LOD unit down regions of our linkage peaks on chromosome 1q43 and 16p12 as well as in the
FTO
gene, we found that two SNPs (rs6665519 and rs669231) on 1q43 and one
FTO
SNP (rs12447427) were significantly associated with BMI or body weight after adjustment for multiple testing. Our results suggest that in addition to
FTO
, multiple genetic loci, particularly those on 1q43 region, may contribute to the variations in obesity-related quantitative traits in Caribbean Hispanics
Genetic loci for blood lipid levels identified by linkage and association analyses in Caribbean Hispanics
No full textTo identify genetic loci influencing blood lipid levels in Caribbean Hispanics, we first conducted a genome-wide linkage scan in 1,211 subjects from 100 Dominican families on five lipid quantitative traits: total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), and LDL-C/HDL-C ratio. We then investigated the association between blood lipid levels and 21,361 single nucleotide polymorphisms (SNP) under the 1-logarithm of odds (LOD) unit down regions of linkage peaks in an independent community-based subcohort (N = 814, 42% Dominican) from the Northern Manhattan Study (NOMAS). We found significant linkage evidence for LDL-C/HDL-C on 7p12 (multipoint LOD = 3.91) and for TC on 16q23 (LOD = 3.35). In addition, we identified suggestive linkage evidence of LOD > 2.0 on 15q23 for TG, 16q23 for LDL-C, 19q12 for TC and LDL-C, and 20p12 for LDL-C. In the association analysis of the linkage peaks, we found that seven SNPs near
FLJ45974
were associated with LDL-C/HDL-C with a nominal
P
< 3.5 × 10
−5
, in addition to associations (
P
< 0.0001) for other lipid traits with SNPs in or near
CDH13
,
SUMF2
,
TLE3
,
FAH
,
ARNT2
,
TSHZ3
,
ZNF343
,
RPL7AL2
, and
TMC3
. Further studies are warranted to perform in-depth investigations of functional genetic variants in these regions
A Candidate Gene Study Revealed Sex-Specific Association Between the <i>OLR1</i> Gene and Carotid Plaque
No full text
Background and Purpose—
Sex differences have been recognized in stroke risk; however, the sex-dependent genetic contribution to stroke is unclear. We sought to examine the sex-dependent associations between genes involved in lipid metabolism and carotid atherosclerotic plaque, a subclinical precursor of stroke.
Methods—
For the Genetic Determinant of Subclinical Carotid Disease study, 287 Dominicans ascertained through the Northern Manhattan Study were examined for carotid plaque using high-resolution ultrasound. Sixty-four single nucleotide polymorphisms (SNPs) in 11 lipid-related genes were genotyped. Plaque presence and plaque subphenotypes, including multiple, thick, irregular, and calcified plaque, were analyzed. First, the interaction between each SNP and sex was evaluated for association with each plaque phenotype using multiple logistic regression and controlling for age, smoking, and the main effects of sex and SNP. For SNPs with suggestive evidence for interaction with sex (
P
<0.1 for the interaction term), stratification analysis by sex was performed to evaluate the sex-specific association between the SNP and plaque phenotypes.
Results—
The most compelling finding is with the missense SNP rs11053646 (K167N) in the
OLR1
gene, which encodes lectin-like oxidized low-density lipoprotein receptor. Stratification analysis revealed a strong association between rs11053646 and all plaque phenotypes in women (OR, 2.44 to 5.86;
P
=0.0003 to 0.0081) but not in men (OR, 0.85 to 1.22;
P
=0.77 to 0.92).
Conclusions—
Genetic variation in genes involved in lipid metabolism may have sex-dependent effects on carotid plaque burden. Our findings provide a plausible biological basis underlying the sex difference in cardiovascular risk.
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