Association of ALOX12 gene polymorphism with all-cause and cardiovascular mortality in diabetic nephropathy

Cardiovascular (CV) events are the first cause of death in patients with chronic renal disease (CKD) and in patients with type 2 diabetes mellitus (DM2). The combination of CKD and DM2 elevates the risk of both cardiovascular disease (CVD) and death in this high-risk population. Besides traditional risk factors, such as dyslipidemia, smoking, obesity, and carotid atherosclerosis, novel factors are under investigation such as genetic polymorphisms. Lipoxygenases (LOXs) and their genes are of critical importance in oxidative stress, inflammation, and atherosclerosis. The aim of the study is to clarify a potential ALOX12 role in CVD presence and progress of diabetic patients in different stages of nephropathy.

We studied 145 patients with a documented history of DM2 for at least 10 years and diabetic nephropathy (DN), mean age 68 ± 9 years, body mass index 31 ± 5 kg/m², and different stages of renal disease, depending on glomerular filtration rate. The sample population consisted of two groups: 108 DM2 patients with DN in all five stages of CKD and 37 DM2 patients as controls. Anthropometric and clinical characteristics, interview for history of previous CV event, and assessment of carotid intima-media thickness (cIMT) were recorded at baseline. All patients were genotyped for ALOX12 polymorphisms with focus on rs14309. Genotypes (AA, AG, and GG) were evaluated for any possible role in CVD, and grouping was performed on A genotype, which is the dominant model. All participants were followed over a period of 7 years, and the end points studied were all-cause mortality, CV mortality, and CV events. CV events were defined as myocardial infarction (MI), stroke, or peripheral artery disease.

The GG genotype has been significantly associated with cIMT levels above 0.86 mm and with history of MI. Regarding the presence of an atherosclerotic plaque in either carotid artery, no significant association was found when the genotypes were assessed on their own. After grouping, though, GG genotype revealed a significant association between carotid plaque formation and atheromatosis. Kaplan-Meier analysis revealed that ALOX12 gene GG genotype predicted all-cause mortality, CV mortality, and CV events. Similarly, when AA and AG genotypes were grouped, Kaplan-Meier analysis showed that patients with GG genotype presented an even more significant higher all-cause mortality, CV mortality, and CV events compared with AA and AG genotypes combined. After adjustment for several traditional risk factors, multivariate Cox proportional hazard analysis showed that patients with the GG genotype had a significant higher risk of all-cause mortality, a threefold increase in CV mortality, and a twofold increased risk for CV events compared to patients with the AA or the AG genotype.

ALOX12 rs14309 GG genotype expression was found to be significantly associated with MI, higher cIMT, increased CV events, CV, and overall mortality. This phenomenon could be partially explained by the increased platelet proaggregatory activity of AA products and the control they exert in thrombotic occurrence and plaque formation.