Development of a multi-gene risk score to determine individual cut-off limits for safe drinking habits


Project Number
N09 08-225 2015

Project title
Development of a multi-gene risk score to determine individual cut-off limits for safe drinking habits

Project leader
Van Velden, D P

Institution
University of Stellenbosch. Faculty of Health Sciences. Department of Pathology

Team members
Van Velden, D P
Kotze, M J
Luckoff, H K
Van der Merwe, N
Kidd, M
Nutt, L
Cronge, J

Objectives & Rationale
The objective of this study was to identify genetic risk factors implicated in impaired cellular
detoxification and a decreased antioxidant defence capacity that may be influenced by alcohol
consumption, with the aim to integrate the research findings into an existing pathology supported
genetic testing platform for clinical application. Several studies have shown that
moderate consumption of antioxidant-rich alcoholic beverages such as red wine has a
favourable effect on cardiovascular disease (CVD) risk factors. However, excess alcohol intake
is associated with an increased risk of various types of cancer.

Methods
The main study population included 37 healthy individuals (19 males, 18 females; aged 26-71)
participating in an intervention study of moderate alcohol intake. After a two-week washout
period, 50% of the participants consumed 250/175 ml red wine per day for 28 days,
(corresponding to 33.75 g and 23.63 g alcohol per day) and 50% consumed 50/40 ml brandy
per day for 28 days (21.5 g and 17.2 g alcohol per day), respectively for men and women. This
intervention was followed immediately by a cross-over period of wine or brandy consumption for
28 days. The reduced to oxidized glutathione ratio (GSH:GSSG) was measured according to
standard laboratory protocols. All study participants were genotyped for the GSTT1 and GSTM1
deletion polymorphisms, as well as the low-penetrance HFE C282Y (rs1800562 G>A) and
H63D (rs1799945 C>G) mutations forming part of a previously-described multi-gene CVD
assay including 10 functional polymorphisms. Genotyping was performed using real-time
polymerase chain reaction (PCR) methodology. The results were incorporated into a pre-screen
algorithm for whole exome sequencing (WES), which was applied in an extended sample based
on specific eligibility criteria.

Key Results
Wine consumption (p=0.019) was associated with a lesser increase in GSSG from baseline
compared to brandy (p=0.004). A significant decrease in GSH from baseline was however only
demonstrated for the brandy (p<0.001) and not wine intervention group (p=0.510). In addition, a
significant interaction between HFE genotype and alcohol consumption on the GSH:GSSG ratio
was found for both intervention groups, with a significant reduction in the ratio found to be
restricted to HFE C282Y and/or H63D mutation carriers (p=0.034). Since no interaction was
detected between GSTT1/GSTM1 and alcohol consumption, the deletion variants were not
included in the WES pre-screen algorithm.

Conclusion/Discussion
The opposing effects of alcohol on CVD and cancer risk present a clinical dilemma that may
partly be addressed by genetic testing to identify high-risk individuals who should preferably
abstain from alcohol consumption. Calculation of a multigene risk score by counting the number
of alleles found to interact with alcohol intake may therefore increase awareness about
individual cut-off limits for safe drinking habits previously defined for males and females.
Analytical validation of the multi-gene CVD assay used to screen for actionable variants known
to interact with alcohol, facilitated the development of a screening algorithm for selection of
individuals eligible for WES. Our findings may contribute to the development of healthcare
policies aimed at promoting safer drinking habits at an individual level.

Popular articles
Lückhoff, H K, van Rensburg, S J, Kotze, MJ, van Velden, D P. 2016. Genetiese toets evalueer die effek van cholesterol en alkohol-inname, Wineland, Mnth July (p. 61-62)
Article.pdf

Van Velden DP. Die Pasiënt as Vennoot. ISBN 978-1-4853-0698-6 Protea Boekhuis Pretoria, 2018. www.proteaboekhuis.com

Scientific articles

Van der Merwe, N, Peeters, A V, Pienaar, F M, Bezuidenhout, J, van Rensburg, S J. 2017. Exome sequencing in a family with luminal-type breast cancer underpinned by variation in the methylation pathway, International Journal of Molecular Science, Mnth February v. 18 (2) (p. 476)
https://dx.doi.org/10.3390%2Fijms18020467

Luckhoff HK, Kidd M, van Rensburg SJ, van Velden DP, Kotze MJ. Apolipoprotein E genotyping and questionnaire-based assessment of lifestyle risk factors in dyslipidaemic patients with a family history of Alzheimer’s disease: test development for clinical application. Metab Brain Dis 2016; 31(1): 213-224.

Van der Merwe N, Kotze MJ. Implementation of a pathology-supported genetic testing strategy to detect common risk factors shared between breast carcinoma and associated comorbidities. Proceedings of the Women in Science Without Borders Conference, March 2018, pp 75-76.

Herbert E, Engel-Hills P, Hattingh C, Fouche JP, Kidd M, Lochner C, Kotze MJ, van Rensburg SJ. Fractional anisotropy of white matter, disability and blood iron parameters in multiple sclerosis. Metab Brain Dis 2018, 33: 545-557.

 

 

  – Record end –

Generic selectors
Exact matches only
Search in title
Search in content