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Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Pharmacology.
Gothenburg Univ, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden.
Sahlgrens Univ Hosp, Dept Gastroenterol & Hepatol, Gothenburg, Sweden.
Gothenburg Univ, Sahlgrenska Acad, Dept Mol & Clin Med, Gothenburg, Sweden.
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2018 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0194668Article in journal (Refereed) Published
Abstract [en]

Multiple genetic studies have linked copy number variation (CNV) in different genes to body mass index (BMI) and obesity. A CNV on chromosome 10q11.22 has been associated with body weight. This CNV region spans NPY4R, the gene encoding the pancreatic polypeptide receptor Y4, which has been described as a satiety-stimulating receptor. We have investigated CNV of the NPY4R gene and analysed its relationship to BMI, waist circumference and self-reported dietary intake from 558 individuals (216 men and 342 women) representing a wide BMI range. The copy number for NPY4R ranged from 2 to 8 copies (average 4.6 +/- 0.8). Rather than the expected negative correlation, we observed a positive correlation between NPY4R copy number and BMI as well as waist circumference (r = 0.267, p = 2.65x 10(-7) and r = 0.256, p = 8x10(-7), respectively). Each additional copy of NPY4R correlated with 2.6 kg/m(2) increase in BMI and 5.67 cm increase in waist circumference (p = 3.3x10(-7) and p = 1x10(-6), respectively) for women. For men, there was no statistically significant correlation between CNV and BMI. Our results suggest that NPY4R genetic variation influences body weight in women, but the exact role of this receptor appears to be more complex than previously proposed.

Place, publisher, year, edition, pages
PUBLIC LIBRARY SCIENCE , 2018. Vol. 13, no 4, article id e0194668
National Category
Genetics
Identifiers
URN: urn:nbn:se:uu:diva-352692DOI: 10.1371/journal.pone.0194668ISI: 000429206800023PubMedID: 29621259OAI: oai:DiVA.org:uu-352692DiVA, id: diva2:1215638
Funder
Swedish Research Council, K2013-54X-11285-19Swedish Research Council, K2013-55X-22189-01-2The Swedish Brain Foundation, F02016-0217Available from: 2018-06-08 Created: 2018-06-08 Last updated: 2019-01-03Bibliographically approved
In thesis
1. The human pancreatic polypeptide receptor Y4: Genetic and functional variation
Open this publication in new window or tab >>The human pancreatic polypeptide receptor Y4: Genetic and functional variation
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Humans are evolutionarily adapted to an environment where food is scarce, but today many live in a world of food abundance. Paired with low physical activity, this may lead to weight gain and obesity. Efficient anti-obesity treatments require understanding of the mechanisms that control hunger, satiety, energy metabolism and body weight. This thesis investigates possible genetic and physiological mechanisms behind these processes.

Genetic correlation between body-mass index (BMI) and a highly polymorphic region on chromosome 10 was analysed with regard to single nucleotide polymorphisms (SNPs) and gene copy number variation (CNV). This region contains the gene NPY4R encoding the pancreatic polypeptide (PP) receptor Y4, which has been reported to reduce appetite.

The results show that the NPY4R gene was duplicated before the divergence of modern humans from the Neanderthals and the Denisovans (approximately to 400,000–800,000 years ago). The CNV of the NPY4R gene region was investigated by read depth analysis based on genome sequences and droplet digital PCR (ddPCR). The read depth results revealed a CNV range of 3-7 copies per genome, while the ddPCR results demonstrated a range of 2–11. Most humans have a total of 4–5 copies, in contrast to the two copies presumed by previous studies.

Investigation of an association between the NPY4R CNV and body mass index (BMI) led to interesting and ambiguous results. A study of 558 Swedish individuals with a wide range of BMI suggested, surprisingly, a positive correlation between NPY4R copy number and BMI for women. On the other hand, a study of 1009 individuals from Northern Sweden found no correlation between BMI and NPY4R copy number. These diverging findings may be due to geographical variation or lack of power in one of these studies.

Twelve naturally-occurring amino acid variants of the Y4 receptor were investigated pharmacologically in cell culture. Three of these showed no functional response, which may be explained by altered conformation of the receptors. For two receptor variants PP had a significantly decreased potency. A 3D model of the Y4 receptor was generated based on the crystal structure of the human Y1 receptor. The functional responses of the Y4 variants agree well with the 3D model and with the degree of evolutionary conservation of the positions.

In conclusion, these studies reveal unexpectedly large CNV as well as extensive SNP for the NPY4R gene and a possible correlation with BMI that may be due to the differing responses of the naturally occurring receptor variants.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 53
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1479
Keywords
NPY4R, Y4, obesity, CNV
National Category
Biochemistry and Molecular Biology Genetics
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-356573 (URN)978-91-513-0389-5 (ISBN)
Public defence
2018-09-18, C2:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
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Supervisors
Available from: 2018-08-24 Created: 2018-08-01 Last updated: 2018-09-07

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Shebanits, KaterynaFeuk, LarsLarhammar, Dan

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