Nucleotide diversity and haplotype structure of the human angiotensinogen gene in two populations.
Variation in the angiotensinogen gene, AGT, has been associated with variation in plasma angiotensinogen levels. In addition, the T235M polymorphism in the AGT product is associated with an increased risk of essential hypertension in multiple populations, making AGT a good example of a quantitative-trait locus underlying susceptibility to a common disease. To better understand genetic variation in AGT, we sequenced a 14.4-kb genomic region spanning the entire AGT and identified 44 single-nucleotide polymorphisms (SNPs). Forty-two SNPs were observed both in 88 white and in 77 Japanese unselected subjects. Six major haplotypes accounted for most of the variation in this region, indicating less allelic complexity than in many other genomic regions. Although the two populations were found to share all of the major AGT haplotypes, there were substantial differences in haplotype frequencies. Pairwise linkage disequilibrium (LD), measured by the D', r(2), and d(2) statistics, demonstrated a general pattern of decline with increasing distance, but, as expected in a small genomic region, individual LD values were highly variable. LD between T235M and each of the other 39 SNPs was assessed in order to model the usefulness of LD to detect a disease-associated mutation. Among the Japanese subjects, 13 (33%) of the SNPs had r(2) values >0.1, whereas this statistic was substantially higher for the white subjects (occurring in 35/39 [90%]). LD between a hypertension-associated promoter mutation, A-6G, and 39 SNPs was also measured. Similar results were obtained, with 33% of the SNPs showing r(2)>0.1 in the Japanese subjects and 92% of the SNPs showing r(2)>0.1 in the white subjects. This difference, which occurs despite an overall similarity in LD patterns in the two populations, reflects a much higher frequency of the M235-associated haplotype in the white sample. These results have important implications for the usefulness of LD approaches in the mapping of genes underlying susceptibility to complex diseases.
Nakajima
Toshiaki
T
Division of Genetic Diagnosis, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Jorde
Lynn B
LB
Ishigami
Tomoaki
T
Umemura
Satoshi
S
Emi
Mitsuru
M
Lalouel
Jean-Marc
JM
Inoue
Ituro
I
D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D044466:Asian People / Q000235:genetics*; D019143:Evolution, Molecular; D005091:Exons / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D014644:Genetic Variation / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D007564:Japan; D015810:Linkage Disequilibrium / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D002679:Pan troglodytes / Q000235:genetics; D010802:Phylogeny; D017354:Point Mutation / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D044465:White People / Q000235:genetics*
D000808:Angiotensinogen