Genetics of hypertension

An important paper describing genetic factors involved in blood pressure and heart disease was published this week. 29 loci were identified - 16 of these novel. This is impressive, but not so surprising as both diastolic and systolic blood pressure are complex, heritable traits. Many, many factors are at play here. In fact, the authors describe a risk score based on genotypes at 29 genome-wide significant variants, which was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function.

Some time ago, I wrote about the genome of the SHR (spontaneous hypertensive rat). This rat and the FHH strain are models for hypertension. The genome of the SHR strain showed that 788 genes contained variants with respect to the reference rat genome. Whether any or all of those variants function in producing the hypertension phenotype is not clear, but reasoning went that these variants would be a logical place from which to build list of candidate genes.

Well, I thought it would be a fun and quick exercise to see how many of these 29 loci detected by genome-wide associations in nearly 70,000 individuals of European ancestry (with validation of top signals in up to 133,000 additional individuals of European descent) compare to those genes that possess genetic variants in either the FHH or SHR rat strains. This may give insight into the applicability of sequencing the genomes of specific model organism strains and into how many or how often genes are identified by both GWAS and whole-genome sequencing. To do this, I used the Rat Genome Browser hosted by the Medical College of Wisconsin.

Of the 29 human loci, 23 map in the rat genome within a QTL for blood pressure. This looks good, but consider that there are numerous blood pressure (BP) QTL mapped throughout the rat genome. In fact, the rat Adm gene maps within 27 different BP QTL and three other gene regions, Furin - Fes, Plekha7 and Mov10, map within more than 20 different BP QTL. Some of these QTL are large, spanning many genes, which means that fine-mapping is needed - such as a GWAS - to identify more precisely candidate loci.

Only 18 of the human BP genes identified in the paper contain SNPs in either the FHH or SHR strains. Often, the variants are shared in both strains. Both synonymous and nonsynonymous SNPs were noted, but synonymous far outnumbered those variants that altered the underlying amino acid sequence. No SNPs in gene control regions were noted, which may indeed be the case or a limitation of the data sources used here.

The human genes whose rat versions contain SNPs in the hypertensive-susceptible strains are:

SLC39A8
ATP2B1
GNAS - EDN3
MTHFR - NPPB
FGF5
CYP1A1 - ULK3
FURIN - FES
FLJ32810 - TMEM133
NPR3 - C5orf23
EBF1
PLCE1
BAT2-BAT5
ZNF652
TBX5 - TBX3
JAG1
GUCY1A3 - GUCY1B3
MECOM
ULK4

SNPs altering gene expression still need to be added to this analysis. Nonetheless, the numbers and types of genes that share genetic variation in hypertensive mammals (human, rat) is revealing. It is likely that the 788 identified genes with variation in the SHR rat are not all important for hypertension, but that strain does carry variants in 17 of these new BP genes. Or is that just 17?

The Complexity of a Complex Disorder

A group of researchers led by Timothy Aitman of the MRC Clinical Sciences Centre and Imperial College London used the SHR (spontaneously hypertensive rat) to identify the few genes they thought predisposed this strain to hypertension (several genes had already been identified but the group knew or felt a few others remained to be discovered). Sequencing this SHR rat with the NextGen approach and comparing those data to the rat reference genome, led to quite a surprise. 788 genes are mutated in SHR compared to the reference genome, including 60 that are deleted altogether.

My take on this is many genes are likely involved in a complex disorder and many genes - with specific variants - may work in concert to produce the disease phenotype – either via gene-gene interactions or affecting interconnecting pathways.

This type of result is very likely to be repeated with other metabolically sensitive disorders and afflictions such as dyslipidemia, obesity and type 2 diabetes. A series of variations in genes combined with deviations from a standard environment - both in terms of diet and microbiome - are likely to combine to tip the balance and enhance onset and/or progression of said affliction.

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Reference

EurekAlert: Hypertensive rat genome sequence expected to uncover genetic basis of human hypertension

Atanur SS, Birol I, Guryev V, Hirst M, Hummel O, Morrissey C, Behmoaras J, Fernandez-Suarez XM, Johnson MD, McLaren WM, Patone G, Petretto E, Plessy C, Rockland KS, Rockland C, Saar K, Zhao Y, Carninci P, Flicek P, Kurtz T, Cuppen E, Pravenec M, Hubner N, Jones SJM, Birney E, Timothy J. Aitman TJ. (2010) The genome sequence of the spontaneously hypertensive rat: Analysis and functional significance. Genome Res. (in press).