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Co-heritability of hypertension and insulin resistance (IR) within families not only implies genetic susceptibility may be responsible for these complex traits but also suggests a rational that biological candidate genes for hypertension may serve as markers for features of the metabolic syndrome (MetS). Thus we determined whether the T323C polymorphism (rs5333) of endothelin type A (ET A ) receptor, a predominant receptor evoking potent vasoconstrictive action of endothelin-1, contributes to susceptibility to IR-associated hypertension in 1694 subjects of Chinese and Japanese origins. Blood pressures (BPs) and biochemistries were measured. Fasting insulin level, insulin-resistance homeostasis model assessment (HOMA IR ) score, and area under curve of insulin concentration (AUC INS ) were selected for assessing insulin sensitivity. Genotypes were obtained by methods of polymerase chain reaction-restriction fragment length polymorphism. Foremost findings were that minor allele frequency of the T323C polymorphism was noticeable lower in our overall Asian subjects compared to multi-national population reported in gene database; moreover both the genotypic and allelic frequencies of the polymorphism were significantly different between the two ethnic groups we studied. The genotype distributions at TT/TC/CC were 65, 31, 4% in Chinese and 51, 41, 8% in Japanese, respectively ( p  < 0.0001). Additionally, carriers of the C homozygote revealed characteristics of IR, namely significantly higher levels of fasting insulin, HOMA IR  score, and AUC INS  at 29.3, 35.3, and 39.3%, respectively, when compared to their counterparts with TT/TC genotypes in Chinese. Meanwhile, the CC genotype was associated with a higher level of high density lipoprotein cholesterol in Japanese. No association of the polymorphism with BP was observed. This study demonstrated for the first time that T323C polymorphism of ET A  receptor gene was associated with an adverse insulin response in Chinese and a favorite atherogenic index in Japanese.

Endothelin Type A Receptor Genotype is a Determinant of Quantitative Traits of Metabolic Syndrome in Asian Hypertensive Families: A SAPPHIRe Study