背景:肽基甘氨酸-α-酰胺化单加氧酶(PAM)是内分泌系统中负责激活的关键酶,通过酰胺化,生物活性肽。
目的:定义与PAM酰胺化活性受损(PAM-AMA)相关的基因突变携带者的临床表型。
方法:我们使用了来自队列研究的遗传和表型数据:马尔默饮食与癌症(MDC;1991-1996;2002-2012年的重新检查),马尔默预防项目(MPP;2002-2006),和英国生物银行(UKB;2012)。
方法:使用全外显子组关联分析来鉴定与降低的PAM-AMA相关的功能丧失(LoF)变异,并随后用于与结果的关联。
方法:这项研究包括来自MDC(MDC-心血管队列)子队列的n~4500名参与者,来自MPP的n~4500,和来自UKB的n~300,000。
方法:先前文献提出的内分泌代谢特征,肌肉质量,肌肉功能,和肌少症.
结果:PAM基因中的两个LoF变体,Ser539Trp(次要等位基因频率:0.7%)和Asp563Gly(5%),独立地减少了2.33[95%置信区间(CI):2.52/2.15;P=2.5E-140]和0.98(1.04/0.92;P=1.12E-225)的PAM-AMA的SD单位,分别。LoF的累积效应与糖尿病有关,胰岛素分泌减少,以及更高水平的GH和IGF-1。此外,携带者的肌肉质量和功能降低,其次是肌肉减少症的风险较高。的确,Ser539Trp突变使肌肉减少症的风险增加了30%(比值比1.31;95%CI:1.16/1.47;P=9.8E-06),与年龄和糖尿病无关。
结论:PAM-AMA基因缺陷导致糖尿病前期的肌少症表型。PAMLoF载体的早期鉴定将允许有针对性的运动干预,并呼吁恢复酶活性的新疗法。
BACKGROUND: Peptidylglycine-α-amidating monooxygenase (PAM) is a critical enzyme in the endocrine system responsible for activation, by amidation, of bioactive peptides.
OBJECTIVE: To define the clinical phenotype of carriers of genetic mutations associated with impaired PAM-amidating activity (PAM-AMA).
METHODS: We used genetic and phenotypic data from cohort studies: the Malmö Diet and Cancer (MDC; 1991-1996; reexamination in 2002-2012), the Malmö Preventive Project (MPP; 2002-2006), and the UK Biobank (UKB; 2012).
METHODS: Exome-wide association analysis was used to identify loss-of-function (LoF) variants associated with reduced PAM-AMA and subsequently used for association with the outcomes.
METHODS: This study included n∼4500 participants from a subcohort of the MDC (MDC-Cardiovascular cohort), n∼4500 from MPP, and n∼300,000 from UKB.
METHODS: Endocrine-metabolic traits suggested by prior literature, muscle mass, muscle function, and sarcopenia.
RESULTS: Two LoF variants in the PAM gene, Ser539Trp (minor allele frequency: 0.7%) and Asp563Gly (5%), independently contributed to a decrease of 2.33 [95% confidence interval (CI): 2.52/2.15; P = 2.5E-140] and 0.98 (1.04/0.92; P = 1.12E-225) SD units of PAM-AMA, respectively. The cumulative effect of the LoF was associated with diabetes, reduced insulin secretion, and higher levels of GH and IGF-1. Moreover, carriers had reduced muscle mass and function, followed by a higher risk of sarcopenia. Indeed, the Ser539Trp mutation increased the risk of sarcopenia by 30% (odds ratio 1.31; 95% CI: 1.16/1.47; P = 9.8E-06), independently of age and diabetes.
CONCLUSIONS: PAM-AMA genetic deficiency results in a prediabetic sarcopenic phenotype. Early identification of PAM LoF carriers would allow targeted exercise interventions and calls for novel therapies that restore enzymatic activity.