113There are few data on genetic variants associated with RH. One study aimed to
identify SNPs associated with RH in hypertensive participants with coronary artery
disease (CAD) from INVEST-GENES (the International VErapamil-SR Trandolapril
STudy-GENEtic Substudy). They concluded that ATP2B1 rs12817819 A allele is
associated with increased risk for RH in hypertensive participants with documented
CAD or suspected ischemic heart disease [ 190 ].
A recent analysis from the Genetics of Hypertension Associated Treatment Study
assessed the association of 78 candidate gene polymorphisms with RH and con-
cluded that The Met allele of rs699 and the G allele of rs5051 were positively asso-
ciated with RH [ 191 ]. Recent GWA studies have revealed that the ATP2B1 gene is
associated with HT not only in people of European origin but also in Japanese,
Chinese, and Koreans, while recently investigations have suggested that the ATP2B1
gene may be involved in mechanisms responsible for calcium homeostasis [ 192 ].
Ethnic Differences in Genetic Predisposition to Hypertension
Transethnic meta-analyses of GWA studies have identified eight blood pressure-
associated loci which seem to be shared by three ethnic groups – Europeans and
East and South Asians. The possible sources of heterogeneity have been outlined by
four genetic mechanisms, from incidence of allelic heterogeneity to variations in
linkage disequilibrium structure, to gene-gene and gene-environment interactions,
and, finally, to deficiencies of target variants in other ethnic groups. These mecha-
nisms appear to be the foundation for the considerable ethnic differences reported
in clinical presentation of HT, response to treatment, salt sensitivity, and impact of
obesity. It is currently believed that the transethnic meta-analyses are the most use-
ful investigation approach which could prove of use in identifying new susceptibil-
ity loci and pathophysiological pathways and in enabling fine mapping of common
variants [ 193 ].
One GWA study reported results of the Korean Association REsource (KARE,
8842 subjects) and recorded ten SNPs that showed significant association with
hypertension. Of these ten SNPs, three were replicated in the Health2 project (7861
subjects) with the aim to identify an association with systolic or diastolic blood
pressure. The three significant SNPs were located on four distinct genes: the previ-
ously reported ATP2B1 (rs17249754), the c-src tyrosine kinase gene (rs1378942),
and the arylsulfatase G gene (rs12945290). Another SNP was associated with the
increased risk of hypertension, namely, rs995322, located in the CUB and Sushi
multiple domains 1 (CSMD1) [ 194 ].
Future research in this area will be facilitated by enhancing collaboration between
research groups through consortia such as the International Consortium for
Antihypertensive Pharmacogenomics Studies, with the goal of translating repli-
cated findings into clinical implementation [ 195 ] and into the design and implemen-
tation of the concept of genetic risk score.
7 Pathophysiological Insights in Resistant Hypertension