In a small part of a large collaborative study involving the 20 institutions of the Family Blood Pressure Program, a team of researchers has tracked high blood pressure risk to two regions on chromosomes 6 and 21 through admixture mapping.
Once the work “gets out,” said Dabeeru Rao of Washington University in St. Louis, who is one of the project’s 20 principal investigators, other hypertension researchers will compete to produce variants and pharmacogenomic applications to find which genotypes respond best to certain drugs.
The hypertension study was led by Neil Risch at Stanford University and Xiaofeng Zhu at Loyola University, and will publish its data in the February issue of Nature Genetics.
The group does not believe that the higher incidence of hypertension among African-Americans is an artifact of environment or other factors, because “the pattern of intermixture is associated with the pattern of hypertension,” said Rao. But “the ultimate proof of the pudding comes from when you find the genetic variant that explains what we found. This is not proof,” he added.
Similarly, how much of the “hypertension burden” in African-Americans is explained by genes in these two regions cannot be answered “until we have those variants,” Rao said. Limited to only ancestral data, “when you don’t know exactly what is happening, reliance on one method is not the best thing,” said Rao. Being a polygenetic disease, hypertension is “very hard to get at,” he said.
“Admixture mapping has been talked about for quite a while,” said Rao. “It has a methodology, and it has even been applied to different kinds of smaller datasets, but [it] has never been used to map real genes for real human-killing diseases,” he said.
With data collected from African-American, Mexican-American, Asian, and Caucasian hypertension patients recruited for various studies by several institutions in the FBPP and the International Collaborative Study on Hypertension in Blacks, the researchers performed a genome-wide scan of the participants, comparing genetic variation in each of the sample groups using statistical techniques that take advantage of the relatively large linkage disequilibrium blocks resulting from the recent admixture of populations.
The method relies on the identification of an “excess of ancestry” — the greater frequency of particular genomic regions found in particular ethnic groups. “The thing is, African-Americans are an admixed population, and the intermixure is relatively recent,” said Rao. The relative prevalence of markers in the two regions on chromosomes 6 and 21 in the African-American population, compared to the European-American population, was found to be “more prevalent in the founding, ancestral African population, and less prevalent in the founding European population,” he said.
“Likewise hypertension is more prevalent in Africans than in Europeans, and intermixture of those two in African-Americans has led us to look for the higher incidence of hypertension in African-Americans that goes with those regions,” Rao said.
The genome-wide scan utilized 269 genetic markers in each of the sample populations.
From this point, “the FBPP or other investigators can now zero in and do positional cloning and look for [markers] in those regions, and find actual variants,” said Rao. The FBPP is planning to undertake a genome-wide SNP scan of the human genome in the near future, he said.
The FBPP is “one of the largest multi-institutional studies … there is no larger study you can think of involving four major ethnic groups,” said Rao. The group plans to launch several ancillary studies based on its work, and to make public all of the FBPP’s resources on the group’s website this Fall, said Rao.
Rao served on the board of directors of DNAPrint, but no longer holds that position.