A coding polymorphism in the 12-lipoxygenase gene is associated to essential hypertension and urinary 12(S)-HETE

Abstract

The arachidonic acid-derived metabolite 12-(S)hydroxyeicosatetraenoic acid (12(S)-HETE), catalyzed by 12-lipoxygenase (12-LOX, ALOX12), exhibits a variety of biological activities with implications in cardiovascular disease. Previous studies have shown higher urinary excretion of this metabolite in essential hypertension. The aim of this study was to analyze the association of polymorphisms in ALOX12 with hypertension and urinary levels of 12(S)-HETE. We studied 200 patients with essential hypertension (aged 56+/-1 years, mean+/-s.e.m., 97 males) and 166 matched controls (aged 54+/-1 years, 91 males). Out of six polymorphisms in the coding region of ALOX12, only R261Q determined a nonconservative amino-acid change and was evaluated by polymerase chain reaction and restriction digestion. Urinary 12(S)-HETE was measured in Sep-Pack-extracted samples using specific enzyme-linked immunosorbent assay. The distribution of genotypes of the R261Q polymorphism was significantly different between patients and controls: patients 92 (0.46) GG, 84 (0.42) GA, 24 (0.12) AA vs controls 56 (0.34) GG, 78 (0.47) GA, 32 (0.19) AA (P=0.030). On the contrary, no association was observed for two intronic polymorphisms. The urinary excretion of 12(S)-HETE (ng/mg creatinine) was significantly higher in GG homozygous patients (13.0+/-1.5) than in GA (8.2+/-1.8) or in AA (8+/-1.5) patients (P=0.018). These results indicate that a nonsynonymous polymorphism in ALOX12 is associated to essential hypertension and to urinary levels of 12(S)-HETE, thus suggesting a role for this gene in this disease.

Association of a functional polymorphism (Gln261Arg) in 12-lipoxygenase with breast cancer

“…as shown in table ii, the frequencies of the variants identified in the Indian population (present study) were compared to the frequencies reported in caucasians (42,43), Blacks (42), chinese (40), Koreans (44), Brazilians (45) and Spanish (27). the frequencies appeared to vary in the various populations.…”

“…One recent publication also reported the association of alOx12 with the onset of natural menopause in caucasian females (54), indicating a role for alOx12 in hormone-related events in females. the alOx12 polymorphism has been shown to be associated with diseases, including hypertension, diabetic nephropathy and colorectal cancer (27). however, little information exists on the association of the alOx12 polymorphism with other types of cancers.…”

“…as the polymorphism alters the amino acid from glutamine to arginine, it is likely to alter the enzyme kinetics which may affect the levels of the alOx12 metabolites (40,56,57). hypertensive patients with GG homozygous variants were found to have higher amounts of urinary 12-hEtE when compared to patients with either the aa or aG variant (27). as 12-hEtE and other metabolites are implicated in various processes, including cell proliferation, adhesion and invasiveness of cancer cells (1,58-62), anomalies in the generation of these metabolites are likely to play a role in the development of cancer, its growth and metastasis.…”

“…hence, any imbalance in eicosanoids may lead to abnormal generation of ROS, inflammation and the development of cancer (19)(20)(21)(22). Several lines of evidence have implicated alOxs and their products in various pathologies linked with inflammation, including Alzheimer's disease (23,24), atherosclerosis (25,26), hypertension (27), stroke (27)(28)(29) and cancer (7). Evidence links up-regulated alOx12 expression to the development of cancer, sustenance, growth and metastasis (11,(30)(31)(32)(33)(34).…”

Analysis of candidate genes of QTL and chromosomal regions for essential hypertension in the rat model

“…In a study of 200 patients with essential hypertension (aged 56  1 years, mean  s.e.m., including 97 males) and 166 matched controls (aged 54  1 years, 91 males), Quintana et al, [42] found that a non-synonymous polymorphism in ALOX12 is associated with both essential hypertension and urinary levels of 12(S)-HETE.…”