Alternative titles; symbolsCHDS5CORONARY ARTERY DISEASE, EARLY-ONSETCytogenetic location: 3q13 Genomic coordinates (GRCh38): 3:119,300,000-122,200,000▼ Mappi...
Alternative titles; symbols
Cytogenetic location: 3q13 Genomic coordinates (GRCh38): 3:119,300,000-122,200,000
To identify genetic factors for coronary artery disease (CAD), Hauser et al. (2004) performed a genomewide scan in 1,168 persons from 438 families, including 493 affected sib pairs with a documented onset of CAD before 51 years of age in men and before 56 years of age in women. They identified a region on chromosome 3q13 that is linked to early-onset CAD and identified an additional region of interest on 1q25 that also met the criteria for genomewide significance. Chromosome 3q13 achieved a maximum parametric lod score of 2.3 at D3S2460 and a multipoint lod score of 3.5 near D3S2460 at 140 cM. Using ordered subset analysis, Shah et al. (2006) found that the linkage evidence for this peak was significantly increased in families with high HDL (high density lipoprotein) cholesterol levels. Bowden et al. (2006) also reported linkage to D3S2460 for coronary artery disease and stroke in the Diabetes Heart Study, with a similar broad linkage region (multipoint lod = 2.5).
▼ Molecular Genetics
Associations Pending Confirmation
To evaluate association under the chromosome 3 linkage peak, Wang et al. (2007) completed an association-mapping study across the 1-lod-unit-down supporting interval. The peakwide survey found evidence of association in SNPs for multiple genes. The strongest associations were found in 3 SNPs from the KALRN gene (604605), especially in patients with early-onset CAD. Investigation of the KALRN gene found that an intronic SNP, rs9289231 (608901.0001), was associated with early-onset CAD in all white data sets examined (P less than 0.05). In the joint analysis of 332 white, early-onset CAD cases and 546 controls, this SNP was highly significant (P = 0.00008), with an odds ratio estimate of 2.1. Furthermore, the risk allele of this SNP was associated with atherosclerosis burden (P = 0.03) in 145 human aortas. The highly associated SNP resided in the first intron of an alternative transcript of the KALRN gene. KALRN is a protein with many functions, including the inhibition of inducible nitric oxide synthase (INOS; 163730) and guanine exchange factor activity. KALRN and 2 other associated genes identified in this study, CDGAP and MYLK (600922), participate in the Rho GTPase signaling pathway.