6 research outputs found
Replication of TCF4 through Association and Linkage Studies in Late-Onset Fuchs Endothelial Corneal Dystrophy
Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of
the corneal endothelium. Although progress has been made in understanding the
genetic basis of FECD by studying large families in which the phenotype is
transmitted in an autosomal dominant fashion, a recently reported genome-wide
association study identified common alleles at a locus on chromosome 18 near
TCF4 which confer susceptibility to FECD. Here, we report
the findings of our independent validation study for TCF4 using
the largest FECD dataset to date (450 FECD cases and 340 normal controls).
Logistic regression with sex as a covariate was performed for three genetic
models: dominant (DOM), additive (ADD), and recessive (REC). We found
significant association with rs613872, the target marker reported by Baratz
et al.(2010), for all three genetic models (DOM:
P = 9.33×10−35;
ADD:
P = 7.48×10−30;
REC:
P = 5.27×10−6).
To strengthen the association study, we also conducted a genome-wide linkage
scan on 64 multiplex families, composed primarily of affected sibling pairs
(ASPs), using both parametric and non-parametric two-point and multipoint
analyses. The most significant linkage region localizes to chromosome 18 from
69.94cM to 85.29cM, with a peak multipoint
HLOD = 2.5 at rs1145315 (75.58cM) under the DOM
model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents
evidence to support the role of the intronic TCF4 single
nucleotide polymorphism rs613872 in late-onset FECD through both association and
linkage studies
Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease
Tenascin-C (
TNC
) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of
TNC
in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within
TNC
is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (
n
= 205) and the CATHGEN cardiovascular study (
n
= 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (
n
= 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with athero sclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons,
p
= 2 × 10
−6
and 5 × 10
−6
, respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in
TNC
and atherosclerosis or CAD
Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease
Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices
Abstract
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P = 8.5 × 10−72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P = 1.7 × 10−4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P = 1.4 × 10−5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids