Our study reports on the association between the TCF7L2 rs7903146 polymorphism and retinal microvascular lesions and retinal vascular caliber in a middle-aged African-American and Caucasian population. No associations were noted except for focal arteriolar narrowing in Caucasians. The TCF7L2 rs7903146 was significantly associated with a greater frequency of focal arteriolar narrowing among Caucasians with hypertension or without diabetes, but not among those without hypertension or with diabetes, suggesting an interaction between TCF7L2 variants and hypertension and diabetes status in Caucasians.
To our knowledge, there are few studies for direct comparison. An earlier case-control study in a French population reported the lack of an association with severe retinopathy (effect estimates not reported) [10
], which is consistent with our findings on retinopathy in Caucasians. The InCHIANTI study of elderly Europeans reported an association with diabetic retinopathy in 127 persons with diabetes. However the number of participants with diabetic retinopathy was very small (n
= 12) and results were not statistically significant [11
]. Notably, these two studies did not report the definition for retinopathy used, which may differ from ours.
We observed an association between TCF7L2
rs7903146 and focal arteriolar narrowing in Caucasians, but not in African Americans. The lack of association in the African American examinees could reflect confounding by unmeasured covariates that are differentially distributed in African American and Caucasian participants, which warrants further investigation. More likely however, the limited power to detect such a modest effect in the African American sample (calculated as 26% for a relative risk of 1.15) may explain our findings (Additional file 1
, Figure S1
). The latter is supported by the observation of very similar effect size estimates between African American and Caucasian participants, and therefore warrants further study in additional African American populations.
It is not known why TCF7L2
rs7903146 was associated with retinal focal arteriolar narrowing. To determine whether the effect of TCF7L2
rs7903146 on focal arteriolar narrowing was due to hyperglycemia, we further adjusted for fasting glucose values in the models, but no attenuation of genetic effects were noted. It is possible that the TCF7L2
rs7903146 variant may be related to focal arteriolar narrowing not through its effect on diabetes but through other, retinal-specific mechanisms (i.e. pleiotropic effects). The Wnt/β-catenin/T-cell factor (TCF) (canonical) signaling pathway may inhibit the adipogenic differentiation of pericytes (a contractile cell in small retinal arterioles), which may have a later effect in regulating retinal microvascular function. This pathway also regulates vascular smooth muscle cell proliferation, suggesting that it may be involved in intimal thickening [23
]. Prolonged exposure to elevated blood pressure may lead to retinal vessel vasospasm, intimal thickening, medial hyperplasia and arteriosclerosis manifesting as either generalized or focal arteriolar narrowing [24
]. However, we found only a relation with focal and not generalized arteriolar narrowing as measured by CRAE and biological mechanisms remain speculative.
An alternate explanation of our positive findings could be chance considering the large number of comparisons made in assessing association in the context of possible effect modification. To minimize the impact of the multiple tests we could apply a crude Bonferroni correction (five phenotypes in the context of multiple strata defined by diabetes, hypertension, combined diabetes and hypertension grouping, and the full sample N = 30), noting that such an approach is an over-correction because many of the analytic runs assessed the same dependent variable. If such a correction were applied, most of the results reported in this paper would not be statistically significant except in the subgroup with hypertension AND without diabetes.
Our study has notable strengths, including a large, population-based cohort, standardized assessment of retinal photographs, and detailed information on a variety of risk factors. To our knowledge, this is the first population-based study that systematically examines the association between TCF7L2 rs7903146 and retinal microvascular lesions and caliber in middle-aged African Americans and Caucasians.
Several important limitations also deserve mention. First, grading was performed from a single 45° fundus photograph that was taken through a nonpharmacologically dilated pupil. This can underestimate the prevalence of retinal microvascular lesions, which could have biased the results toward the null. Second, we found that the TCF7L2
rs7903146 is related to higher risk of retinal AV nicking only in Caucasians who had hypertension (P
= 0.03). This association could have arisen by chance; the pathophysiology underlying any relationship between AV nicking and rs7903146 has not been established. Third, as diabetes and fasting glucose values are plausibly intermediate variables between TCF7L2
and retinal phenotypes, our analyses conditional on diabetes/fasting glucose values need to be interpreted with caution as this method may introduce confounding [25
]. Fourth, as polymorphisms within TCF7L2
possibly impair the glucagon like peptide-1 induced insulin secretion [9
], which in turn could lead to a lower postprandial insulin secretion, we might expect to see a stronger effect among patients with impaired glucose tolerance. However, the oral glucose tolerance test was not performed at visit 3 when the fundus photographs were taken. Finally, our samples of African American and diabetic Caucasians are limited to 2,199 and 1,206 examinees, respectively, thus true associations between retinal lesions and the TCF7L2
variant could have been missed in these subpopulations. Replication of our findings in other large, population-based studies could help better elucidate these relationships.