Not so free associations

Abstract

According to PubMed, there have been 62 872 genetic association studies published, about 2 for every gene in the human genome. That assessment is of course incorrect. Both the notorious insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) gene and polymorphisms in the angiotensinogen gene have representative papers numbering in the thousands. However, the adrenergic receptors have not been sleeping in this regard; their polymorphism paper number currently stands at 1334 reports. In this issue of Nephrol Dial Transplant appears the next such paper. Fung et al. [1] reported that adrenergic beta1 receptor (ADB1R) genetic variation predicts the rate of estimated glomerular filtration rate (eGFR) decline in participants of the African American Study of Kidney Disease and Hypertension (AASK) study cohort. The authors obtained a similar result in a second cohort from San Diego, CA, USA, termed the ‘replication’ cohort. Do we now have the genetic basis for the decline in eGFR over time in patients with hypertension-induced kidney damage? AASK was a (US National Institutes of Health sponsored) drug study in black Americans [2]. The study was heroic in that participants underwent a renal biopsy to verify that they indeed had hypertension-associated nephrosclerosis. The study compared two levels of blood pressure reduction and three antihypertensive drug classes and tested the effect on eGFR. Briefly, AASK detected no additional benefit of slowing progression of hypertensive nephrosclerosis with the lower blood pressure goal. The authors stated that ACE inhibitors appeared to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline. However, they also admitted that none of the drug group comparisons showed consistent significant differences in the eGFR slope. Disappointing surely for the participants was the fact that in many AASK patients, eGFR declined relentlessly although they controlled their blood pressure to contemporary guideline goals. eGFR declined relentlessly even though they did everything their doctors asked. With such a result, we could conclude either that blood pressure control and drug classes are not as important as we all believe or that something else (genes for instance) is at fault. Large drug trials, irrespective of the sponsors, are favourite for polymorphism studies and most, if not all, feature one or more genetic ‘spin-off’ studies. For instance, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) featured an entire polymorphism consortium disingenuously entitled GENHAT. This group published the presence of an absence of an interaction between the ACE gene insertion–deletion polymorphism and pravastatin in cardiovascular disease in ALLHAT patients [3]. The AASK study has already been milked for polymorphisms. A paper on G-protein-coupled receptor kinase 4 polymorphisms and response to metoprolol in the AASK cohort has recently been published. Several authors on the current report also appear on that paper [4]. Why did the authors pick ADB1R? The hypothesis is not directly stated. However, the senior author is specifically interested in adrenergic mechanisms in hypertension and perhaps that is the reason. Did the authors make a good choice in selecting polymorphisms? Yes, they did. First, adrenergic tone is decidedly increased with diminished renal function. The issue has been studied with direct measurement of muscle sympathetic nerve activity. Converse et al. recorded the rate of postganglionic sympathetic-nerve discharge to the blood vessels in skeletal muscle by means of microelectrodes inserted into the peroneal nerve in 18 patients with native kidneys who were undergoing long-term treatment with haemodialysis, 5 patients receiving haemodialysis who had undergone bilateral nephrectomy and 11 normal subjects [5]. They showed unequivocally that chronic renal failure is accompanied by reversible sympathetic activation, which appears to be mediated by an afferent signal arising in the failing kidneys. The literature on the issue is extensive. A recent review outlines all the findings in detail [6]. Too bad that the sympatholytic drugs are not renoprotective. Metoprolol, a predominantly ADB1R blocker, did not seem to help the AASK participants very much. The authors got their best mileage out of the Ser49Gly polymorphism in ADB1R, with minimal decline in persons homozygous for Gly49Gly. This finding is a bit surprising, because the most highly touted polymorphism, at least for a risk of heart failure in ADB1R has been Arg389Gly [7], which was only in partial linkage disequilibrium with Ser49Gly according to the authors [1]. The authors’ polymorphism is located towards the aminoterminus of the receptor, at the other end compared to the Arg389Gly