title: Sex-specific effects of NLRP6/AVR and ADM loci on susceptibility to essential hypertension in a Sardinian population.
abstract: Coronary artery disease, heart failure, fatal arrhythmias, stroke, and renal disease are the most common causes of mortality for humans, and essential hypertension remains a major risk factor. Elucidation of susceptibility loci for essential hypertension has been difficult because of its complex, multifactorial nature involving genetic, environmental, and sex- and age-dependent nature. We investigated whether the 11p15.5 region syntenic to rat chromosome 1 region containing multiple blood pressure quantitative trait loci (QTL) detected in Dahl rat intercrosses harbors polymorphisms that contribute to susceptibility/resistance to essential hypertension in a Sardinian population. Initial testing performed using microsatellite markers spanning 18 Mb of 11p15.5 detected a strong association between D11S1318 (at 2.1 Mb, P = 0.004) and D11S1346 (at 10.6 Mb, P = 0.00000004), suggesting that loci in close proximity to these markers may contribute to susceptibility in our Sardinian cohort. NLR family, pyrin domain containing 6/angiotensin-vasopressin receptor (NLRP6/AVR), and adrenomedullin (ADM) are in close proximity to D11S1318 and D11S1346, respectively; thus we tested single nucleotide polymorphisms (SNPs) within NLRP6/AVR and ADM for their association with hypertension in our Sardinian cohort. Upon sex stratification, we detected one NLRP6/AVR SNP associated with decreased susceptibility to hypertension in males (rs7948797G, P = 0.029; OR = 0.73 [0.57-0.94]). For ADM, sex-specific analysis showed a significant association between rs4444073C, with increased susceptibility to essential hypertension only in the male population (P = 0.006; OR = 1.44 [1.13-1.84]). Our results revealed an association between NLRP6/AVR and ADM loci with male essential hypertension, suggesting the existence of sex-specific NLRP6/AVR and ADM variants affecting male susceptibility to essential hypertension.
authors.affiliation: Hypertension and Related Diseases Center, AUO-Universita' di Sassari, Sassari, Sardinia, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Glorioso
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Herrera
authors.forename: Tamara
authors.initials: T
authors.lastname: Didishvili
authors.forename: Maria F
authors.initials: MF
authors.lastname: Ortu
authors.forename: Roberta
authors.initials: R
authors.lastname: Zaninello
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fresu
authors.forename: Guiseppe
authors.initials: G
authors.lastname: Argiolas
authors.forename: Chiara
authors.initials: C
authors.lastname: Troffa
authors.forename: Nelson
authors.initials: N
authors.lastname: Ruiz-Opazo
mesh_terms: D053607:Adrenomedullin / Q000235:genetics*; D000328:Adult; D000368:Aged; D000483:Alleles; D002880:Chromosomes, Human, Pair 11; D004198:Disease Susceptibility; D000075222:Essential Hypertension; D005260:Female; D023061:Gene Order; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007558:Italy; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012737:Sex Factors; D044465:White People / Q000235:genetics*
chemical_list: C507862:ADM protein, human; D047908:Intracellular Signaling Peptides and Proteins; C468563:NLRP6 protein, human; D053607:Adrenomedullin