Objective: Recently, imbalance in the vasopressin (VP) system, measured as elevated levels of copeptin in plasma, the c-terminal part of the AVP pro-hormone, was linked to development of abdominal obesity. Now we aimed (1) to investigate if genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity, (2) to identify loci associated with elevated copeptin levels using metabochip analysis and (3) to test if any copeptin-associated loci is (are?) associated with measures of obesity.Design and method: Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1994. (1) 4 tag SNPs (rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC),associated with measures of obesity and significant SNPs were replicated in another 24344 MDC individuals (MDC replication cohort). (2) Copeptin was measured in MDC-CC and the metabochip was genotyped in 2143 MDC-CC participants. Nineteen SNPs associating with copeptin level at p-value<0.00038, were selected for replication of copeptin association in the remaining of MDC-CC (n=3960). (3) Copeptin-associated SNPs were tested for association with measures of obesity. Results: In MDC-CC, after age and sex adjustment, the major allele of rs35810727 was associated with BMI (P=0.02) and waist (P=0.02). The association with BMI was replicated in the MDC replication cohort (P<0.001), whereas that with waist remained only borderline significant (P=0.06). Out of 19 copeptin associated metabochip SNPs, the major allele of rs6835657 was associated with high levels of copeptin in both the metabochip-genotyped subset of MDC-CC (p=0.0002) and in the remaining part of MDC-CC (P=0.005). Furthermore, the rs6835657 allele associated with high copeptin was associated with high waist (P=0.03) in the entire MDC-CC.Conclusions: Genetic variants of a locus associated with elevated VP (copeptin) (rs6835657), as well as genetic variance of the AVPR1B, can contribute to overweight. Our data points at a causal relationship between disturbance of the pharmacologically modifiable VP system and body weight regulation
Genetic variance in Vasopressin V1b Receptor and a locus associated with high vasopressin level in plasma are associated with body mass index and waist circumference.
FAVA, Cristiano;
2012-01-01
Abstract
Objective: Recently, imbalance in the vasopressin (VP) system, measured as elevated levels of copeptin in plasma, the c-terminal part of the AVP pro-hormone, was linked to development of abdominal obesity. Now we aimed (1) to investigate if genetic variation of the human AVP receptor 1b gene (AVPR1B) is associated with measures of obesity, (2) to identify loci associated with elevated copeptin levels using metabochip analysis and (3) to test if any copeptin-associated loci is (are?) associated with measures of obesity.Design and method: Malmö Diet and Cancer study (MDC) is a population-based prospective cohort examined 1991-1994. (1) 4 tag SNPs (rs35810727, rs28373064, rs35439639, rs35608965) of AVPR1B were genotyped in the cardiovascular cohort (n=6103) of MDC (MDC-CC),associated with measures of obesity and significant SNPs were replicated in another 24344 MDC individuals (MDC replication cohort). (2) Copeptin was measured in MDC-CC and the metabochip was genotyped in 2143 MDC-CC participants. Nineteen SNPs associating with copeptin level at p-value<0.00038, were selected for replication of copeptin association in the remaining of MDC-CC (n=3960). (3) Copeptin-associated SNPs were tested for association with measures of obesity. Results: In MDC-CC, after age and sex adjustment, the major allele of rs35810727 was associated with BMI (P=0.02) and waist (P=0.02). The association with BMI was replicated in the MDC replication cohort (P<0.001), whereas that with waist remained only borderline significant (P=0.06). Out of 19 copeptin associated metabochip SNPs, the major allele of rs6835657 was associated with high levels of copeptin in both the metabochip-genotyped subset of MDC-CC (p=0.0002) and in the remaining part of MDC-CC (P=0.005). Furthermore, the rs6835657 allele associated with high copeptin was associated with high waist (P=0.03) in the entire MDC-CC.Conclusions: Genetic variants of a locus associated with elevated VP (copeptin) (rs6835657), as well as genetic variance of the AVPR1B, can contribute to overweight. Our data points at a causal relationship between disturbance of the pharmacologically modifiable VP system and body weight regulation
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