GENE-ENVIRONMENT (G×E) INTERACTIONS IN HEALTH AND DISEASE
G×E interactions describe external exposures that modify the relation between a genetic variant(s) and a trait of interest. The demonstration of how sugar-sweetened beverage consumption modifies the association between a 32-gene variant panel for body mass index (BMI) and obesity (BMI≥30 kg/m2) represents an example of a G×E interaction.1 Collectively, the association between the 32-gene variant panel and obesity was stronger for people consuming more sugar-sweetened beverages than for people consuming lower quantities of these beverages. The public health message is that although sugar-sweetened beverages contribute to the obesity epidemic, there are people who are particularly vulnerable to become obese because of their genetic predisposition to higher BMI. Certainly, patients armed with the knowledge that they harbor many BMI-increasing variants might be particularly motivated to change their dietary behavior.
Herein, we will propose candidate G×E interaction terms that might contribute to the development of exfoliation syndrome (XFS). Currently there is only 1 set of gene variants in the lysyl oxidase-like 1 gene (LOXL1) that is associated with increased risk of XFS, and environmental risk factors for this condition are just emerging. The LOXL1 variants that contribute to XFS are common and the discovery of whether they interact with environmental factors could lead to genotype-specific primary prevention measures for XFS.
WHY MIGHT G×E INTERACTIONS EXIST IN XFS?
XFS prevalence varies considerably around the world. For example, the prevalence among people residing in Australia and Sweden is ∼1%2 and >20%,3 respectively. Yet the percent of cases and controls with the top disease-associated LOXL1 variant is similar in both locales (95% of cases and 84% of controls in Australia,4 and 99% of cases and 88% of controls in Sweden5). Clearly the fraction of subjects with disease-associated variants does not account for the difference in prevalence in both locations and perhaps some environmental factor(s) that interact with disease-associated LOXL1 variants accounts for the different disease burdens in these locations. It is interesting to note that the proportion of cases and controls with LOXL1 variants is fairly constant at ∼95% and 80%, respectively, throughout the world.
Although variants in LOXL1 become the obvious gene for candidate G×E interaction terms in XFS, the question remains as to whether environmental risk factors exist for this disease. First, it is important to address the perception that XFS is entirely a genetic disease because the burden is so high in Scandinavian countries. A study of incident XFS cases located throughout the United States demonstrated that self-reported Scandinavian heritage was not associated with XFS.6 In contrast, people of African, Asian, and Hispanic heritage are not necessarily protected from this condition. Although the prevalence of XFS among Asians in China is considered to be only 0.4%,7 the condition is more common in Japan (3.4%)8 and India (6.0%).9 Furthermore, although XFS is considered infrequent among African Americans,10 it is quite common among Africans in South Africa (7%).11 As the best evidence suggests that the frequency of disease-associated alleles does not vary in these populations (although genotyping at all these locations is incomplete), it seems likely other factors are responsible for disease manifestation in different places. One genetic study actually noted a high concordance among married couples, suggesting shared environment is important in this disorder.12
ENVIRONMENTAL RISK FACTORS FOR XFS
Crude point prevalence studies of XFS performed in Europe and Asia from 2006, suggest that the burden of disease increases as a function of latitude; specifically, there is a trend toward increasing disease prevalence as one moves away from the equator. To further test whether disease burden increased as function of latitude, Stein et al13 used a relational health care database with representation of covered lives located throughout the continental US where there is a 15-degree span of latitude. Using XFS and exfoliation glaucoma (XFG) as determined by ICD-9 codes as the outcome and after controlling for multiple covariates, most recent residence in the northern US tier was associated with increased risk of XFS/XFG compared with living in the middle US tier. Living in the southern tier was associated with a reduced risk of XFS/XFG compared with living in the middle tier. As the database was deidentified, the relation between lifetime residence and XFS/XFG could not be assessed. However, using data from 2 population-based cohorts also located throughout the continental US where more detailed residential history was available, the relation between latitude and XFS disease burden was retested.6 Using incident XFG suspects and XFG cases identified prospectively from self-reports and confirmed by chart review or by eye care provider questionnaires, the latitude effect was confirmed. Participants with lifetime residence in the middle US tier and participants with lifetime residence in the southern US tier had 47% and 75% reduced risk of XFG, respectively, relative to lifetime residence in the northern US tier (Fig. 1). Notably, in models assessing the independent relations between residence during different life phases (birth, age 15, age 25, and current residence) and XFG/XFG suspect status, living in the middle or southern tier at age 15 was most strongly inversely associated with XFG risk, followed by current residence. This suggests that environmental factors that drive the latitude effect are operative in the teenage years, even though the disease does not manifest itself until the sixth or seventh decade of life.
We reasoned that environmental factors contributed to the latitude effect and explored whether climatic factors played a role in XFS. Using the health care relational database mentioned above and inputting state-wide climatic data, Stein et al13 found that colder ambient temperature and increased solar exposure were associated with increased risk of XFS/XFG. The role solar exposure may play in XFS is consistent with the association between climatic keratopathy and XFS previously reported.14 The role lower ambient temperature may play in XFS is consistent with the fact that the prevalence of XFS among whites residing in Finland (22.4%)15 is approximately double the prevalence of XFS in whites residing in Greece (11.9%).16
People in Norway, Sweden, and Demark are the largest consumers of coffee in the world.17 In the Nurses’ Health Study and Health Professional Follow-up Study, coffee consumption patterns were documented every 2 years before a self-report of any glaucoma.18 In that study, compared with participants who did not drink coffee, those who drank ≥3 cups every day had a 66% increased risk of XFG. The risk was particularly strong among people with a positive family history of glaucoma. Interestingly, randomized clinical trial data indicate that immediately after coffee consumption, serum homocysteine levels increase.19,20 Homocysteine is a biomarker that is robustly associated with XFS.21 In mice, homocysteine infusion causes upregulation of matrix metalloproteinases and cerebrovascular leakage. Perhaps, chronic coffee consumption contributes to dysregulated extracellular matrix metabolism that ultimately triggers the formation of exfoliation material.
CANDIDATE G×E INTERACTIONS IN XFS
To prove that the relation between LOXL1 variants and XFS is modified by solar exposure, coffee consumption, or other factors, one needs to perform a case-control study to assess these exposures in people who have LOXL1 genotypes. The sample size needed to prove LOXL1 variant-environment interactions in XFS can be rather large if one takes an agnostic approach to discovering them; however, for candidate interactions such as solar exposure-LOXL1 variant interactions, sample sizes needed are attainable because there is good biological rationale to think such an interaction exists, the effect sizes for the gene and environment terms are large, and the multiple comparison problem is minimized. The anterior uveal tract, namely the iris, is a critical target in XFS and chronic UV exposure could exacerbate impaired elastogenesis in iris radial vessels induced by LOXL1 variants. Similarly, coffee consumption raises homocysteine levels, which in turn may enhance matrix mellatoproteinase activity. Interestingly, homocysteine enhances neurovascular leakage through matrix mellatoproteinase-9 activation in a murine model.22 Coffee consumption could raise homocysteine levels and exacerbate preexisting vascular leakage in the blood-aqueous barrier23 due to impaired elastogenesis induced by the LOXL1 gene in XFS. Even if genetic factors act independent of environmental factors, a pathogenetic view of XFS with an early and prolonged preclinical phase emerges (Fig. 2); for example, single-nucleotide polymorphisms inherited from birth along with UV and ambient temperature exposure patterns during the teenage years (as well as other factors) conspire to work over decades before disease becomes clinically manifest. An understanding of how factors work during the preclinical phase will lead to primary prevention measures for XFS.
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