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Use of genotype frequencies in medicated groups to investigate prescribing practice: APOE and statins as a proof of principle

Use of genotype frequencies in medicated groups to investigate prescribing practice: APOE and statins as a proof of principle
Use of genotype frequencies in medicated groups to investigate prescribing practice: APOE and statins as a proof of principle
Background: if treatments are used to modify a trait, then patients with high-risk genotypes for the trait should be found at higher frequency in treatment groups than in the general population. The frequency ratio of high- to low-risk genotypes treated should reflect the mean threshold above which the treatment is given in the population. As an example, we hypothesized that because APOE (apolipoprotein E) alleles affect the LDL cholesterol (LDLc) concentration, APOE genotype frequencies in statin takers should act as a proxy for the prevailing treatment threshold of LDLc.

Methods: we used LDLc, statin usage, and APOE genotype data from the British Women's Heart and Health Study (n = 2289; age, 60–79 years) and calculated the genotype ratio treatment index (GRTI) by dividing the proportion of ?3/?2 or ?3/?4 participants prescribed a statin by the proportion of ?3/?3 participants prescribed a statin, both overall and according to socioeconomic class, geographic region, and coronary heart disease (CHD) status. Genotype-specific LDLc distributions were used to calculate the mean LDLc treatment threshold.

Results: for genotype ?3/?2, the GRTI was 0.52 (95% CI, 0.30–0.87) for statin takers overall, 0.22 (95% CI, 0.00–0.56) for those without CHD, and 0.69 (95% CI, 0.31–1.18) for those with CHD. The GRTIs for those without and with CHD backcalculate to LDLc thresholds of 5.65 mmol/L (95% CI, 5.50–5.82 mmol/L) and 4.39 mmol/L (95% CI, 4.21–4.59 mmol/L), respectively. Scotland and North England showed dissimilar GRTIs, which backcalculated to LDLc thresholds of 5.06 mmol/L (95% CI, 4.83–5.28 mmol/L) and 5.44 mmol/L (95% CI, 5.19–5.69 mmol/L), respectively, for all women.

Conclusions: the findings illustrate how genotype frequencies can be a proxy for treatment thresholds used in clinical practice. Genome-wide studies have identified >500 disease-relevant polymorphisms. GRTIs from cost-efficient genotyping, in combination with phenotypic data, may have wide potential in health services research
502-510
Davies, Neil M.
b15dea1b-7c11-452d-8787-bead29709b07
Windmeijer, Frank
d80de85f-f6a1-4c73-b53a-448ed9d4516c
Martin, Richard M.
ce5c4184-4432-4435-bd1e-221f665d42d8
Abdollahi, Mohammad
96ec68db-6302-4216-9aaf-9951a44be8b8
Smith, George Davey
f5bc8327-f2cb-49a0-8eae-4a6ba63207a2
Lawlor, Debbie A.
799826df-f115-4fb7-83ea-53c246c220d4
Ebrahim, Shah
0f2ade5c-4ef6-4ca7-9f9b-9b60ba192b13
Day, Ian N.M.
b749b30a-1f4c-40eb-af0e-a50427388b39
Davies, Neil M.
b15dea1b-7c11-452d-8787-bead29709b07
Windmeijer, Frank
d80de85f-f6a1-4c73-b53a-448ed9d4516c
Martin, Richard M.
ce5c4184-4432-4435-bd1e-221f665d42d8
Abdollahi, Mohammad
96ec68db-6302-4216-9aaf-9951a44be8b8
Smith, George Davey
f5bc8327-f2cb-49a0-8eae-4a6ba63207a2
Lawlor, Debbie A.
799826df-f115-4fb7-83ea-53c246c220d4
Ebrahim, Shah
0f2ade5c-4ef6-4ca7-9f9b-9b60ba192b13
Day, Ian N.M.
b749b30a-1f4c-40eb-af0e-a50427388b39

Davies, Neil M., Windmeijer, Frank, Martin, Richard M., Abdollahi, Mohammad, Smith, George Davey, Lawlor, Debbie A., Ebrahim, Shah and Day, Ian N.M. (2011) Use of genotype frequencies in medicated groups to investigate prescribing practice: APOE and statins as a proof of principle. Clinical Chemistry, 57 (3), 502-510. (doi:10.1373/clinchem.2010.156356). (PMID:21228258)

Record type: Article

Abstract

Background: if treatments are used to modify a trait, then patients with high-risk genotypes for the trait should be found at higher frequency in treatment groups than in the general population. The frequency ratio of high- to low-risk genotypes treated should reflect the mean threshold above which the treatment is given in the population. As an example, we hypothesized that because APOE (apolipoprotein E) alleles affect the LDL cholesterol (LDLc) concentration, APOE genotype frequencies in statin takers should act as a proxy for the prevailing treatment threshold of LDLc.

Methods: we used LDLc, statin usage, and APOE genotype data from the British Women's Heart and Health Study (n = 2289; age, 60–79 years) and calculated the genotype ratio treatment index (GRTI) by dividing the proportion of ?3/?2 or ?3/?4 participants prescribed a statin by the proportion of ?3/?3 participants prescribed a statin, both overall and according to socioeconomic class, geographic region, and coronary heart disease (CHD) status. Genotype-specific LDLc distributions were used to calculate the mean LDLc treatment threshold.

Results: for genotype ?3/?2, the GRTI was 0.52 (95% CI, 0.30–0.87) for statin takers overall, 0.22 (95% CI, 0.00–0.56) for those without CHD, and 0.69 (95% CI, 0.31–1.18) for those with CHD. The GRTIs for those without and with CHD backcalculate to LDLc thresholds of 5.65 mmol/L (95% CI, 5.50–5.82 mmol/L) and 4.39 mmol/L (95% CI, 4.21–4.59 mmol/L), respectively. Scotland and North England showed dissimilar GRTIs, which backcalculated to LDLc thresholds of 5.06 mmol/L (95% CI, 4.83–5.28 mmol/L) and 5.44 mmol/L (95% CI, 5.19–5.69 mmol/L), respectively, for all women.

Conclusions: the findings illustrate how genotype frequencies can be a proxy for treatment thresholds used in clinical practice. Genome-wide studies have identified >500 disease-relevant polymorphisms. GRTIs from cost-efficient genotyping, in combination with phenotypic data, may have wide potential in health services research

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e-pub ahead of print date: 12 January 2011
Published date: March 2011
Organisations: Cancer Sciences

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Local EPrints ID: 364362
URI: http://eprints.soton.ac.uk/id/eprint/364362
PURE UUID: 9f90199f-d0b6-4bea-9b1a-f62151e01fd7

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Date deposited: 25 Apr 2014 10:52
Last modified: 14 Mar 2024 16:34

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Contributors

Author: Neil M. Davies
Author: Frank Windmeijer
Author: Richard M. Martin
Author: Mohammad Abdollahi
Author: George Davey Smith
Author: Debbie A. Lawlor
Author: Shah Ebrahim
Author: Ian N.M. Day

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