Sequence Diversity in 36 Candidate Genes for Cardiovascular Disorders

Abstract

Two strategies involving whole-genome association studies have been proposed for the identification of genes involved in complex diseases. The first one seeks to characterize all common variants of human genes and to test their association with disease. The second one seeks to develop dense maps of single-nucleotide polymorphisms (SNPs) and to detect susceptibility genes through linkage disequilibrium. We performed a molecular screening of the coding and/or flanking regions of 36 candidate genes for cardiovascular diseases. All polymorphisms identified by this screening were further genotyped in 750 subjects of European descent. In the whole set of genes, the lengths explored spanned 53.8 kb in the 5' regions, 68.4 kb in exonic regions, and 13 kb in the 3' regions. The strength of linkage disequilibrium within candidate regions suggests that genomewide maps of SNPs might be efficient ways to identify new disease-susceptibility genes, provided that the maps are sufficiently dense. However, the relatively large number of polymorphisms within coding and regulatory regions of candidate genes raises the possibility that several of them might be functional and that the pattern of genotype-phenotype association might be more complex than initially envisaged, as actually has been observed in some well-characterized genes. These results argue in favor of both genomewide association studies and detailed studies of the overall sequence variation of candidate genes, as complementary approaches.

Polymorphisms of the Human Matrix Gla Protein ( MGP ) Gene, Vascular Calcification, and Myocardial Infarction

“…As has been reported for other genes, 24 most polymorphisms were in tight linkage disequilibrium (online Table I). Eight haplotypes accounted for most of the variability of the MGP gene, and only 3 of them, haplotypes 1, 2, and 3, accounted for 88% of In individuals with femoral atherosclerotic plaques, calcifications were more frequent in carriers of the AϪ7 allele (64.1%) than in GGϪ7 homozygotes (45.6%) (PϽ0.025).…”

Identification of genomic organisation, sequence variants and analysis of the role of the human dishevelled 1 gene in late onset Alzheimer's disease

“…We also detected one synonymous SNP per 1979 bp coding region screened, corresponding to a nucleotide diversity of = 0.000105 ± 0.000022. Although these values are lower than average nucleotide diversities previously described, [25][26][27] they are consistent with the nucleotide diversity values for some of the genes investigated in these studies. 25,27 The pathological changes seen in AD, such as JNK and GSK3␤ mediated phosphorylation of tau and the disruption of ␤-catenin turnover, which are probably very relevant to the pathogenesis of AD, are not due to Molecular Psychiatry polymorphic variation we have detected in the DVL1 gene.…”

SELPLG Gene Polymorphisms in Relation to Plasma SELPLG Levels and Coronary Artery Disease

“…The entire exonic sequence and the flanking intronic sequences, as well as 417 bp in the 5 region and 514 bp in the 3 UTR region of SELPLG, were explored. DNA sequence variations were identified by PCR/SSCP and followed by sequencing, as previously described (Cambien et al 1999).…”