Background: As the prevalence of obesity has steadily increased, it has rapidly emerged as a major public health concern due to a high risk of morbidity and mortality. Rare missense and nonsense mutations in the melanocortin-4 receptor (MC4R) gene are a cause of genetic forms of severe obesity, and targeted disruption of the mouse MC4R leads to obesity. The role of variation at the MC4R locus in influencing interindividual variation in body size and composition in the general population is controversial.
Objective: To test the hypothesis that polymorphic variation at the MC4R locus is significantly associated with measures of adiposity in the general population.
Methods: Two single nucleotide polymorphisms, -4599 T>G and -4850 T>C, in the 5¡¯-flanking region of MC4R were verified by resequencing in 16 individuals and genotyped in the larger sample by fluorescence polarization. 1,099 healthy, non-Hispanic white volunteers, age 30-54 years, were recruited from the Pittsburgh community. A medical and demographic history was collected and anthropomorphic measures were determined. ANOVA was used to assess the relationship between genotype and metabolic parameters.
Results: BMI was greater in participants having a -4599 G allele (GG + TG genotypes) than among TT homozygotes (p < 0.03), and this association was of similar magnitude in both men (BMI 28.2 vs. 27.4) and women (BMI 26.5 vs. 25.9). Nominally defined overweight (BMI ¡Ý 27) also varied significantly (Chi-square = 6.874, p < 0.04) across -4599 genotypes (GG: 52.4%; TG: 46.8%, TT: 40.6%). A similar relationship was seen for the -4850 T>C SNP (CC: 53.2%; TC: 48.0%; TT: 41.4%; Chi-square = 6.256, p < 0.05). Finally, subjects with any -4599 G allele had significantly higher weight (177.0 vs. 172.8; p < 0.05) and percent of body fat (29.8% vs. 28.8%; p < 0.04). Greater waist circumference was also significantly associated with both the -4599 G allele (36.3 vs. 35.6; p < 0.04) and the -4850 C allele (36.4 vs. 35.6; p < 0.05).
Conclusion: Common variation in the 5¡¯-flanking region of the MC4R gene is significantly associated with measures of adiposity in men and women in the general population.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-02272006-135055 |
| Date | 02 June 2006 |
| Creators | Lee, Mechele R. |
| Contributors | Stephen B. Manuck, PhD, M. Michael Barmada, PhD, Robert E. Ferrell, PhD |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-02272006-135055/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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