Common nonsynonymous variants in PCSK1 confer risk of obesity

Benzinou, Michael; Creemers, John W.M.; Choquet, Hélène; Lobbens, Stéphane; Dina, Christian; Durand, Emmanuelle; Guérardel, Audrey; Boutin, Philippe; Jouret, Béatrice; Heude, Barbara; Balkau, Beverley; Tichet, Jean; Marre, Michel; Potoczna, Natascha; Horber, Fritz F.; Stunff, Catherine Le; Czernichow, Sébastien; Sandbæk, Annelli; Lauritzen, Torsten; Borch‐Johnsen, Knut; Andersen, Gitte; Kieß, Wieland; Körner, Antje; Kovacs, Peter; Jacobson, Peter; Carlsson, Lena; Walley, Andrew J.; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf; Meyre, David; Froguel, Philippe

doi:10.1038/ng.177

Cited by 267 publications

(269 citation statements)

References 9 publications

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“…In this study, we found that the rs6235 SNP was significantly associated with BP, hypertension and the levels of renin, ANG II and ALD. Consistent with previous studies, 11 our study also confirms the effects of rs6235 on BMI and obesity. Our results provide evidence of an association between the common variants of PCSK1 and hypertension in the Han Chinese population.…”

Section: Discussionsupporting

confidence: 93%

“…11,14,30 Consistent with this previous study, we found a significant association between the PCSK1 rs6235 SNP and BMI and obesity in our control group, which comprised 1053 normotensive and euglycemic subjects.…”

Section: Discussionsupporting

confidence: 91%

“…Most of these studies focused on the SNPs rs6232 and rs6235. [11][12][13] It was also reported that these two PCSK1 SNPs were associated with proinsulin conversion. 12 The PCSK1 SNP rs6234, which is in strong linkage disequilibrium with rs6235 and encodes the Q655E-S690T pair of residues in the C terminus of the PCSK1 protein, was also associated with body mass index (BMI) and being overweight in men in a population-based sample of Han Chinese subjects.…”

Section: Introductionmentioning

confidence: 91%

“…In humans, loss-of-function mutations in PCSK1 cause monogenic obesity, impaired glucose tolerance and other related disorders. [4][5][6] In both genome-wide linkage studies [7][8][9][10] and candidate gene strategy studies, 11 single-nucleotide polymorphisms (SNPs) in the PCSK1 gene were associated with obesity. Most of these studies focused on the SNPs rs6232 and rs6235.…”

Section: Introductionmentioning

confidence: 99%

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The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population

Ling

et al. 2012

Hypertens Res

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Proprotein convertase subtilisin/kexin-type 1 (PCSK1) is a prohormone convertase that has an important role in prohormone maturation including the process of prorenin to renin. We studied the association of the PCSK1 single-nucleotide polymorphism (SNP) rs6235 (encoding an S690T substitution) with essential hypertension (EH), obesity and related traits in the Han Chinese population. The rs6235 SNP in the PCSK1 gene was investigated using a case-control study design, with 1034 hypertension cases and 1112 normotensive controls. In this study, the rs6235 SNP was significantly associated with hypertension (OR ¼ 1.26, 95% CI (1.10-1.46), P ¼ 0.001); the odds ratios of GC vs GG and CC vs GG were 1.30 (95% CI (1.06-1.58), P ¼ 0.010) and 1.55 (95% CI (1.12-2.13), P ¼ 0.007), respectively. In the controls, the C-allele was associated with increased systolic (P ¼ 0.010) and diastolic (P ¼ 0.010) blood pressure levels. In all of the EH patients and EH patients without a history of renin-angiotensin-aldosterone (RAA) system-related antagonists, the C-allele was associated with increased plasma renin activity (P ¼ 0.00004 and 0.002, respectively) and aldosterone levels (P ¼ 0.018 and 0.005, respectively). The C-allele was also associated with increased body mass index (BMI) (P ¼ 0.010) in the normotensive controls. In conclusion, the PCSK1 SNP rs6235 was associated with EH and blood pressure in the Han Chinese population, and this association may be mediated by the SNP's effect on RAA levels. rs6235 was also associated with BMI in this population.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population

Ling

et al. 2012

Hypertens Res

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“…8 Despite the long list of positive findings, meta-analyses showed sufficient evidence for an association with BMI or obesity for five genes only (PPARY2, FTO, MC4R, TNFa, PCSK1). [12][13][14][15][16] The inconsistencies among individual studies can partly be explained by a lack of power to replicate the typically moderate-to-small effects of a single locus on polygenic obesity. 6,17 Currently, a limited number of cohort studies evaluated associations between genetic variation in candidate genes and waist.…”

Section: Introductionmentioning

confidence: 99%

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

et al. 2009

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Background: As nuclear receptors and transcription factors have an important regulatory function in adipocyte differentiation and fat storage, genetic variation in these key regulators and downstream pathways may be involved in the onset of obesity. Objective: To explore associations between single nucleotide polymorphisms (SNPs) in candidate genes from regulatory pathways that control fatty acid and glucose metabolism, and repeated measurements of body mass index (BMI) and waist circumference in a large Dutch study population. Methods: Data of 327 SNPs across 239 genes were analyzed for 3575 participants of the Doetinchem cohort, who were examined three times during 11 years, using the Illumina Golden Gate assay. Adjusted random coefficient models were used to analyze the relationship between SNPS and obesity phenotypes. False discovery rate q-values were calculated to account for multiple testing. Significance of the associations was defined as a q-value p0.20. Results: Two SNPs (in NR1H4 and SMARCA2 in women only) were significantly associated with both BMI and waist circumference. In addition, two SNPs (in SIRT1 and SCAP in women only) were associated with BMI alone. A functional SNP, in IL6, was strongly associated with waist. Conclusion: In this explorative study among participants of a large population-based cohort, five SNPs, mainly located in transcription mediator genes, were strongly associated with obesity phenotypes. The results from whole genome and candidate gene studies support the potential role of NR1H4, SIRT1, SMARCA2 and IL6 in obesity. Although replication of our findings and further research on the functionality of these SNPs and underlying mechanism is necessary, our data indirectly suggest a role of GATA transcription factors in weight control.

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Posttranslational Processing of Secretory Proteins

Seidah

Guillemot

2016

Molecular Neuroendocrinology

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Common nonsynonymous variants in PCSK1 confer risk of obesity

Cited by 267 publications

References 9 publications

The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population

The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population

Genetic variations in regulatory pathways of fatty acid and glucose metabolism are associated with obesity phenotypes: a population-based cohort study

Posttranslational Processing of Secretory Proteins

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