The Association of Common Genetic Variants in the APOA5, LPL and GCK Genes with Longitudinal Changes in Metabolic and Cardiovascular Traits

Overview

Journal Diabetologia

Specialty Endocrinology

Date 2008 Nov 20

PMID 19018513

Citations 17

Authors

R J Webster

N M Warrington

M N Weedon

A T Hattersley

P A McCaskie

J P Beilby

L J Palmer

T M Frayling

Affiliations

Soon will be listed here.

Abstract

Aims/hypothesis: Common genetic variants influence plasma triacylglycerol, HDL-cholesterol (HDL-C) and glucose levels in cross-sectional studies. However, the longitudinal effects of these established variants have not been studied. Our aim was to examine the longitudinal associations of four such variants in the apolipoprotein A-V (APOA5), lipoprotein lipase (LPL), and glucokinase (GCK) genes with fasting glucose or lipid levels.

Methods: The individuals analysed were participants in the Busselton Health Survey (n = 4,554). Cross-sectional analyses of family data used the total association test. Longitudinal association analyses of unrelated participant data (n = 2,864) used linear mixed-effects models.

Results: The findings of cross-sectional association analyses replicated those of previous studies. We observed associations of the G and C alleles at the APOA5 single nucleotide polymorphisms (SNPs) rs662799 and rs3135506 with raised triacylglycerol levels (p = 0.0003 and p < 0.0001, respectively), the 447X allele at the LPL SNP rs328 with reduced triacylglycerol levels (p = 0.0004) and raised HDL-C levels (p = 0.0004), and the A allele of the GCK SNP rs1799884 with raised fasting glucose level (p = 0.015). Longitudinal association analyses showed that most of these associations did not change in the same individuals over an average follow-up time of 17.4 years, though there was some evidence that the association of the 447X allele of rs328 with raised HDL-C level significantly increased with age (p = 0.01), and that the association of the C allele of rs3135506 with raised triacylglycerol level significantly increased over time (p = 0.0007).

Conclusions/interpretation: The current study suggests that the effects of established gene variants on lipid and glucose traits do not tend to alter with age during adulthood or over time.

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References

Knuiman M, Cullen K, Bulsara M, Welborn T, Hobbs M . Mortality trends, 1965 to 1989, in Busselton, the site of repeated health surveys and interventions. Aust J Public Health. 1994; 18(2):129-35. DOI: 10.1111/j.1753-6405.1994.tb00213.x. View

Wilsgaard T, Arnesen E . Change in serum lipids and body mass index by age, sex, and smoking status: the Tromsø study 1986-1995. Ann Epidemiol. 2004; 14(4):265-73. DOI: 10.1016/j.annepidem.2003.08.004. View

Frayling T, Timpson N, Weedon M, Zeggini E, Freathy R, Lindgren C . A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science. 2007; 316(5826):889-94. PMC: 2646098. DOI: 10.1126/science.1141634. View

Weedon M, Lettre G, Freathy R, Lindgren C, Voight B, Perry J . A common variant of HMGA2 is associated with adult and childhood height in the general population. Nat Genet. 2007; 39(10):1245-50. PMC: 3086278. DOI: 10.1038/ng2121. View

Pennacchio L, Olivier M, Hubacek J, Cohen J, Cox D, Fruchart J . An apolipoprotein influencing triglycerides in humans and mice revealed by comparative sequencing. Science. 2001; 294(5540):169-73. DOI: 10.1126/science.1064852. View

Laird N, Ware J . Random-effects models for longitudinal data. Biometrics. 1982; 38(4):963-74. View

James A, Palmer L, Kicic E, Maxwell P, Lagan S, Ryan G . Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking. Am J Respir Crit Care Med. 2004; 171(2):109-14. DOI: 10.1164/rccm.200402-230OC. View

Derby C, Feldman H, Bausserman L, Parker D, Gans K, Carleton R . HDL cholesterol: trends in two southeastern New England communities, 1981-1993. Ann Epidemiol. 1998; 8(2):84-91. DOI: 10.1016/s1047-2797(97)00130-0. View

. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447(7145):661-78. PMC: 2719288. DOI: 10.1038/nature05911. View

10.

Wung S, Kulkarni M, Pullinger C, Malloy M, Kane J, Aouizerat B . The lipoprotein lipase gene in combined hyperlipidemia: evidence of a protective allele depletion. Lipids Health Dis. 2006; 5:19. PMC: 1538992. DOI: 10.1186/1476-511X-5-19. View

11.

Abecasis G, Cardon L, Cookson W . A general test of association for quantitative traits in nuclear families. Am J Hum Genet. 2000; 66(1):279-92. PMC: 1288332. DOI: 10.1086/302698. View

12.

Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R . Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985; 28(7):412-9. DOI: 10.1007/BF00280883. View

13.

Gauderman W . Sample size requirements for association studies of gene-gene interaction. Am J Epidemiol. 2002; 155(5):478-84. DOI: 10.1093/aje/155.5.478. View

14.

Endo K, Yanagi H, Araki J, Hirano C, Yamakawa-Kobayashi K, Tomura S . Association found between the promoter region polymorphism in the apolipoprotein A-V gene and the serum triglyceride level in Japanese schoolchildren. Hum Genet. 2002; 111(6):570-2. DOI: 10.1007/s00439-002-0825-0. View

15.

Auro K, Kristiansson K, Zethelius B, Berne C, Lannfelt L, Taskinen M . USF1 gene variants contribute to metabolic traits in men in a longitudinal 32-year follow-up study. Diabetologia. 2007; 51(3):464-72. DOI: 10.1007/s00125-007-0892-9. View

16.

Chapman C, Palmer L, McQuillan B, Hung J, Burley J, Hunt C . Polymorphisms in the angiotensinogen gene are associated with carotid intimal-medial thickening in females from a community-based population. Atherosclerosis. 2001; 159(1):209-17. DOI: 10.1016/s0021-9150(01)00499-3. View

17.

Martin S, Nicaud V, Humphries S, Talmud P . Contribution of APOA5 gene variants to plasma triglyceride determination and to the response to both fat and glucose tolerance challenges. Biochim Biophys Acta. 2003; 1637(3):217-25. DOI: 10.1016/s0925-4439(03)00033-4. View

18.

Dongxia L, Qi H, Lisong L, Jincheng G . Association of peroxisome proliferator-activated receptorgamma gene Pro12Ala and C161T polymorphisms with metabolic syndrome. Circ J. 2008; 72(4):551-7. DOI: 10.1253/circj.72.551. View

19.

Talmud P, Hawe E, Martin S, Olivier M, Miller G, Rubin E . Relative contribution of variation within the APOC3/A4/A5 gene cluster in determining plasma triglycerides. Hum Mol Genet. 2002; 11(24):3039-46. DOI: 10.1093/hmg/11.24.3039. View

20.

Weedon M, Frayling T, Shields B, Knight B, Turner T, Metcalf B . Genetic regulation of birth weight and fasting glucose by a common polymorphism in the islet cell promoter of the glucokinase gene. Diabetes. 2005; 54(2):576-81. DOI: 10.2337/diabetes.54.2.576. View