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Gastric inhibitory polypeptide receptor: association analyses for obesity of several polymorphisms in large study groups.

Vogel CI, Scherag A, Brönner G, Nguyen TT, Wang HJ, Grallert H, Bornhorst A, Rosskopf D, Völzke H, Reinehr T, Rief W, Illig T, Wichmann HE, Schäfer H, Hebebrand J, Hinney A - BMC Med. Genet. (2009)

Bottom Line: A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136).In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031).However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. carla.vogel@uni-due.de

ABSTRACT

Background: Gastric inhibitory polypeptide (GIP) is postulated to be involved in type 2 diabetes mellitus and obesity. It exerts its function through its receptor, GIPR. We genotyped three GIPR SNPs (rs8111428, rs2302382 and rs1800437) in German families with at least one obese index patient, two case-control studies and two cross-sectional population-based studies.

Methods: Genotyping was performed by MALDI-TOF, ARMS-PCR and RFLP. The family-study: 761 German families with at least one extremely obese child or adolescent (n = 1,041) and both parents (n = 1,522). Case-control study: (a) German obese children (n = 333) and (b) obese adults (n = 987) in comparison to 588 adult lean controls. The two cross-sectional population-based studies: KORA (n = 8,269) and SHIP (n = 4,310).

Results: We detected over-transmission of the A-allele of rs2302382 in the German families (pTDT-Test = 0.0089). In the combined case-control sample, we estimated an odd ratio of 1.54 (95%CI 1.09;2.19, pCA-Test = 0.014) for homozygotes of the rs2302382 A-allele compared to individuals with no A-allele. A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136). In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031).

Conclusion: Our data suggest a potential relevance of GIPR variants for obesity. However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies.

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LD structure of GIPR. LD structure of GIPR region using data from HapMap analysed by Haploview using the Spine LD algorithm. Only SNP rs1800437 is informative as LD in HapMap (ellipse). The physical localization for the other two SNPs (rs8111428 and rs2302382) was represented manually with arrows. The pairwise r2 values are represented in the diamonds.
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Figure 1: LD structure of GIPR. LD structure of GIPR region using data from HapMap analysed by Haploview using the Spine LD algorithm. Only SNP rs1800437 is informative as LD in HapMap (ellipse). The physical localization for the other two SNPs (rs8111428 and rs2302382) was represented manually with arrows. The pairwise r2 values are represented in the diamonds.

Mentions: We performed family-based association analyses in up to 2,563 German Caucasian individuals from 761 families. The analyses indicated some evidence for transmission disequilibrium for the investigated markers in particular for the G-allele of rs8111428 (p-value = 0.0016) and the A-allele of rs2302382 (p-value = 0.0089), both minor alleles (Table 2). In addition, for the non-synonymous SNP rs1800437, we observed a trend for the G-allele (major allele) to be more frequently transmitted to the obese offspring (p = 0.076; Table 2). To explore if a single SNP or a haplotype was involved in obesity we further analysed haplotype structure in the gene region using the CEU population data from the International HapMap Project [34] captured by Haploview software [35] (solid spine algorithm). There are two regions of increased between-marker LD (Figure 1). The first covers 24 kb and the second 5 kb. For the two markers showing the strongest signals in our study, rs8111428 and rs2302382, there are no direct HapMap data available. However, their physical positions indicate that they could be part of the first haplotype block, as confirmed when using our family data in Haploview (data not shown). For the SNP, rs1800437, LD HapMap data was available indicating that this SNP belongs to the second region which was supported by our family data (data not shown). The pairwise r2 values between the SNPs (using our family data) are shown in Table 3. Subsequently, we performed analyses of the transmitted haplotypes (Table 4). One haplotype (estimated frequency = 21%) that included the minor alleles of rs8111428 (G-allele) and rs2302382 (A-allele), was more frequently transmitted in the families (p = 0.003). Testing all haplotype combinations this haplotype had the smallest adjusted p-value of 0.0055 which is corrected for multiple testing. As the haplotype analysis revealed that no haplotype by itself leads to a stronger association signal, we decided to validate the best initial SNPs results.


Gastric inhibitory polypeptide receptor: association analyses for obesity of several polymorphisms in large study groups.

Vogel CI, Scherag A, Brönner G, Nguyen TT, Wang HJ, Grallert H, Bornhorst A, Rosskopf D, Völzke H, Reinehr T, Rief W, Illig T, Wichmann HE, Schäfer H, Hebebrand J, Hinney A - BMC Med. Genet. (2009)

LD structure of GIPR. LD structure of GIPR region using data from HapMap analysed by Haploview using the Spine LD algorithm. Only SNP rs1800437 is informative as LD in HapMap (ellipse). The physical localization for the other two SNPs (rs8111428 and rs2302382) was represented manually with arrows. The pairwise r2 values are represented in the diamonds.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2654891&req=5

Figure 1: LD structure of GIPR. LD structure of GIPR region using data from HapMap analysed by Haploview using the Spine LD algorithm. Only SNP rs1800437 is informative as LD in HapMap (ellipse). The physical localization for the other two SNPs (rs8111428 and rs2302382) was represented manually with arrows. The pairwise r2 values are represented in the diamonds.
Mentions: We performed family-based association analyses in up to 2,563 German Caucasian individuals from 761 families. The analyses indicated some evidence for transmission disequilibrium for the investigated markers in particular for the G-allele of rs8111428 (p-value = 0.0016) and the A-allele of rs2302382 (p-value = 0.0089), both minor alleles (Table 2). In addition, for the non-synonymous SNP rs1800437, we observed a trend for the G-allele (major allele) to be more frequently transmitted to the obese offspring (p = 0.076; Table 2). To explore if a single SNP or a haplotype was involved in obesity we further analysed haplotype structure in the gene region using the CEU population data from the International HapMap Project [34] captured by Haploview software [35] (solid spine algorithm). There are two regions of increased between-marker LD (Figure 1). The first covers 24 kb and the second 5 kb. For the two markers showing the strongest signals in our study, rs8111428 and rs2302382, there are no direct HapMap data available. However, their physical positions indicate that they could be part of the first haplotype block, as confirmed when using our family data in Haploview (data not shown). For the SNP, rs1800437, LD HapMap data was available indicating that this SNP belongs to the second region which was supported by our family data (data not shown). The pairwise r2 values between the SNPs (using our family data) are shown in Table 3. Subsequently, we performed analyses of the transmitted haplotypes (Table 4). One haplotype (estimated frequency = 21%) that included the minor alleles of rs8111428 (G-allele) and rs2302382 (A-allele), was more frequently transmitted in the families (p = 0.003). Testing all haplotype combinations this haplotype had the smallest adjusted p-value of 0.0055 which is corrected for multiple testing. As the haplotype analysis revealed that no haplotype by itself leads to a stronger association signal, we decided to validate the best initial SNPs results.

Bottom Line: A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136).In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031).However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany. carla.vogel@uni-due.de

ABSTRACT

Background: Gastric inhibitory polypeptide (GIP) is postulated to be involved in type 2 diabetes mellitus and obesity. It exerts its function through its receptor, GIPR. We genotyped three GIPR SNPs (rs8111428, rs2302382 and rs1800437) in German families with at least one obese index patient, two case-control studies and two cross-sectional population-based studies.

Methods: Genotyping was performed by MALDI-TOF, ARMS-PCR and RFLP. The family-study: 761 German families with at least one extremely obese child or adolescent (n = 1,041) and both parents (n = 1,522). Case-control study: (a) German obese children (n = 333) and (b) obese adults (n = 987) in comparison to 588 adult lean controls. The two cross-sectional population-based studies: KORA (n = 8,269) and SHIP (n = 4,310).

Results: We detected over-transmission of the A-allele of rs2302382 in the German families (pTDT-Test = 0.0089). In the combined case-control sample, we estimated an odd ratio of 1.54 (95%CI 1.09;2.19, pCA-Test = 0.014) for homozygotes of the rs2302382 A-allele compared to individuals with no A-allele. A similar trend was found in KORA where the rs2302382 A-allele led to an increase of 0.12 BMI units (p = 0.136). In SHIP, however, the A-allele of rs2302382 was estimated to contribute an average decrease of 0.27 BMI units (p-value = 0.031).

Conclusion: Our data suggest a potential relevance of GIPR variants for obesity. However, additional studies are warranted in light of the conflicting results obtained in one of the two population-based studies.

Show MeSH
Related in: MedlinePlus