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A tagging SNP in INSIG2 is associated with obesity-related phenotypes among Samoans
© Deka et al; licensee BioMed Central Ltd. 2009
Received: 17 March 2009
Accepted: 22 December 2009
Published: 22 December 2009
A genome wide association study found significant association of a sequence variant, rs7566605, in the insulin-induced gene 2 (INSIG2) with obesity. However, the association remained inconclusive in follow-up studies. We tested for association of four tagging SNPs (tagSNPs) including this variant with body mass index (BMI) and abdominal circumference (ABDCIR) in the Samoans of the Western Pacific, a population with high levels of obesity.
We studied 907 adult Samoan participants from a longitudinal study of adiposity and cardiovascular disease risk in two polities, American Samoa and Samoa. Four tagSNPs were identified from the Chinese HapMap database based on pairwise r 2 of ≥0.8 and minor allele frequency of ≥0.05. Genotyping was performed using the TaqMan assay. Tests of association with BMI and ABDCIR were performed under the additive model.
We did not find association of rs7566605 with either BMI or ABDCIR in any group of the Samoans. However, the most distally located tagSNPs in Intron 3 of the gene, rs9308762, showed significant association with both BMI (p-value 0.024) and ABDCIR (p-value 0.009) in the combined sample and with BMI (p-value 0.038) in the sample from Samoa.
Although rs7566605 was not significantly associated with obesity in our study population, we can not rule out the involvement of INSIG2 in obesity related traits as we found significant association of another tagSNP in INSIG2 with both BMI and ABDCIR. This study suggests the importance of comprehensive assessment of sequence variants within a gene in association studies.
Using genome-wide association analysis, Herbert et al.  reported a common variant, rs7566605, in the 5' region of the INSIG2 gene associated with obesity in the Framingham Heart Study population samples and also replicated this finding in four independent cohorts of European and African American ancestries. However, the association of this variant remains inconclusive with confirmation or lack thereof in several follow-up studies conducted in populations of diverse ethnicities [2–12]. Analysis of a single variant could be perceived as a limitation in assessing genetic association of a putative locus. To guard against this potential limitation we conducted a comprehensive association analysis of common tagging SNPs in the INSIG2 gene among adult Samoans, Polynesians of the Western Pacific, residing in Samoa and American Samoa.
Summary of participants, age and basic statistics (Mean ± SD) of the two phenotypes
BMI (kg/height in m2)
Range: 17.9 - 62.3
Range: 65.6 - 164.1
Combined sample (N = 907)
38.5 ± 9.3
32.0 ± 6.1
100.4 ± 15.1
Male (N = 404)
38.7 ± 9.3
30.9 ± 5.8
98.0 ± 14.8
Female (N = 503)
38.3 ± 9.3
32.9 ± 6.2
102.4 ± 15.1
Samoa (N = 502)
38.1 ± 8.7
30.0 ± 5.0
95.3 ± 13.1
Male (N = 235)
38.2 ± 8.7
29.1 ± 4.8
92.8 ± 12.5
Female (N = 267)
38.0 ± 8.7
30.9 ± 5.1
97.4 ± 13.3
American Samoa (N = 405)
39.0 ± 10.0
34.4 ± 6.3
106.7 ± 15.0
Male (N = 169)
39.5 ± 10.0
33.3 ± 6.0
105.1 ± 14.9
Female (N = 236)
38.7 ± 9.9
35.2 ± 6.5
107.9 ± 15.0
We used the GenABEL package  in R to test for association of the SNPs under the additive model. Empirical p-values maximized over the four SNPs were computed using the emp.qtscore function with 10,000 replicates. Since these empirical p-values adjust for the four SNPs, for each trait, we have carried out 5 tests on various subdivisions of the data. A stringent multiple testing correction for this would be to use the Bonferroni correction, which would require testing at the 0.05/5 = 0.01 level. We adjusted for age in all samples, for location (Samoa and American Samoa) in the combined samples and for sex in the Samoa and American Samoa samples. Of the two obesity measurements, BMI was not normally distributed; therefore, we performed logarithmic transformation of BMI to obtain normality.
Results and Discussion
Association (empirical p-values) of INSIG2 tagSNPs with BMI and ABDCIR based on additive model (adjusted for age in all samples, for location in the combined samples and for sex in the Samoa and American Samoa samples).
Although we did not find association of rs7566605 with either BMI or ABDCIR, the INSIG2 gene itself is of considerable interest for obesity-related quantitative traits as it is implicated in lipid regulation and synthesis [24, 25]. It should be noted that rs7566605 is located 10 kb upstream of INSIG2 and its functional relevance is not yet known. The putative association of rs7566605 could have resulted from linkage disequilibrium (LD) with a functional variant in INSIG2 in the study populations, in which the association was detected. The follow-up replication studies considered only this polymorphism with inconsistent results in populations irrespective of their ethnic affiliations [2–12, 26]. Among the Asian populations with whom the Samoans share a more recent ancestry, the association of rs7566605 with obesity has been largely negative [27–30], although one study found significant association with BMI in a population from Uyghur . On account of genetic diversity across populations, the extent of LD among the genetic variants is likely to vary, and this could be one of the reasons for the inconsistent findings. To guard against this potential limitation, we conducted an association analysis of common tagging SNPs in INSIG2 with two obesity-related phenotypes. It should be noted that using both genome-wide microsatellite markers at a spacing of 10 cM and over 7,000 SNPs distributed on chromosome 21, we observed a significantly higher level of LD in the Samoans compared to the European populations [18, 22] favoring the identification of a surrogate marker further away from the true variant in the relatively isolated Samoan population. We observed significant association of the most distal SNP rs9308762 with both BMI and ABDCIR in the combined Samoan sample. Although this observation is not in complete agreement with the previous report in which the most significant association was found with rs7566605 , our results do not necessarily indicate the existence of different functional variants. A possible explanation is that there is a single functional variant, which is in LD with both rs7566605 and rs9308762. Note that these two SNPs are in elevated LD in the Samoan as well as in the HapMap Chinese population, r2 = 0.37 and 0.45, respectively. It is plausible that the putative causal variant is more strongly associated in Europeans with rs7566605, while in Samoans the stronger association is with rs9308762. Although the observations are somewhat preliminary, these results reaffirm the involvement of INSIG2 in regulation of body weight or pathophysiology of obesity related phenotypes.
Although rs7566605 was not significantly associated with obesity in the Samoan population, this study suggests that sequence variants in INSIG2 likely influence the risk for obesity related traits. Our study reiterates the importance of comprehensive assessment of genetic variants within a gene in association studies.
This study was supported by NIH grants AG09375, HL52611, DK55406, and DK59642 and from the Dean's fund of the University of Cincinnati College of Medicine. This study was designed and jointly directed by Drs. McGarvey, Weeks and Deka.
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