Higher CRP, Lower Schizophrenia Risk?

Pauline Anderson

November 09, 2017

Increased levels of circulating C-reactive protein (CRP), an inflammatory biomarker, were associated with a reduced risk for schizophrenia in new findings that run contrary to previous observational data.

"Our findings indicate that it's unlikely that higher CRP levels increase the risk of developing schizophrenia," Fernando Pires Hartwig, PhD, Postgraduate Program in Epidemiology, Federal University of Pelotas, Rio Grande do Sul, Brazil, and research associate, University of Bristol, United Kingdom, told Medscape Medical News.

The study was published online November 1 in JAMA Psychiatry.

Alternative to RCTs?

Researchers believe that activation of the immune system is central to the etiology of schizophrenia.

The study used a mendelian randomization (MR) design to investigate the effect of inflammatory markers on the risk for schizophrenia.

In MR, researchers evaluate the relationship between an exposure and an outcome using genotypes that are associated with the exposure as a proxy for the exposure trait.

In this study, instead of investigating the association between schizophrenia risk and measured levels of inflammatory markers, the investigators used genetic variants that are associated with levels of these markers.

In general, MR is a more robust method for causal inference than conventional observational studies, which may be prone to bias, such as reverse causation, said Dr Hartwig.

It may also offer an alterative to randomized controlled trials (RCTs), which can be expensive, time consuming, and, under certain circumstances, unethical or not feasible, he added.

Unlike an RCT in which participants are randomly assigned to either the exposed or the unexposed group, with MR, every individual is "randomly assigned" alleles at conception.

MR uses the natural allocation of higher- or lower-than-average dose of the exposure to individuals because of the alleles they have inherited.

For this new analysis, the researchers obtained summary association results for four sets of genetic instruments: liberal CRP, conservative CRP, interleukin-1 receptor agonist (IL-1Ra), and soluble interleukin-6 receptor (sIL-6R).

The summary associations between each instrument and schizophrenia risk were derived from large consortia of candidate gene or genome-wide association studies, including several epidemiologic studies with different designs.

All studies were conducted in adults of mostly European ancestry. Participants were aged 18 to 80 years or older, and the number of male participants was approximately equal to the number of female participants.

Higher CRP, Lower Risk

The researchers estimated gene-inflammatory biomarker associations in pooled samples ranging from 1645 to more than 80,000 individuals. They estimated gene-schizophrenia associations in more than 30,000 case patients and more than 45,000 ancestry-matched control persons.

The researchers used single-nucleotide polymorphisms (SNPs), which are the most common type of genetic variants, said Dr Hartwig.

There is evidence that the SNP alleles are associated with variation in the levels of inflammatory biomarkers in healthy people.

For the CRP analysis, the researchers used the 18 genome-wide significant SNPs that have been identified to test for putative causality.

The investigators used multiple methods to minimize bias due to pleiotropy, the production by a single gene of two or more apparently unrelated effects.

The analysis showed that twofold increments in circulating levels of CRP are associated with a 10% reduction in the lifetime odds of developing schizophrenia.

The odds ratio (OR) estimate used 18 CRP genetic instruments, 0.90 (random effects 95% confidence interval [CI], 0.84 - 0.97; P = .005] per twofold increment, with liberal CRP variants using the inverse variance weighting MR approach.

The results were consistent when two other MR approaches were used ― weighted median and MR Egger regression.

Results obtained using another set of four CRP-associated genetic variants were similar.

According to Dr Hartwig, this analysis was more stringent than the analysis using the wider set because all genetic variants were located in the CRP gene region, although it may hve had less statistical power to detect an association.

Consistent Results

"The fact that we observed consistent results across MR methods and sets of SNPs was reassuring," he said.

What is important, he added, is that all the results were contrary to what the conventional observational data had suggested.

These observational studies had reported higher levels of CRP in people with schizophrenia compared to control persons.

There is a myriad of possible explanations for this, said Dr Hartwig.

"Most observational studies that have addressed this research question were cross-sectional in nature, so I suspect that they were prone to reverse causation."

Assuming that this was the case, these observations represent a consequence, not cause, of disease.

A possible hypothesis is that people whose genetic makeup makes them less able to trigger an inflammatory response to an infection early in life may be more prone to develop schizophrenia later.

"If you have a genetic profile that makes you less able to produce CRP when you need it, then you are more prone to have infections, and having more infections early in life may increase your predisposition to developing schizophrenia in future," said Dr Hartwig.

The analysis also showed that the blockade of IL-6 increases schizophrenia risk by about 6%. The OR for sIL-6R was 1.06 (95% CI, 1.01 - 1.12; P = .02) per twofold increment. (sIL-6R levels were used as a proxy for inhibition of IL-6 classic signaling.)

Part of the association between IL-6 blockade and schizophrenia might be mediated by CRP levels, say the authors. They note that lower CRP levels are a downstream effect of inhibiting IL-6 classic signaling.

The estimates for IL-1Ra were inconsistent among instruments. Pooled estimates were imprecise and centered on the null, the authors note.

The study findings are limited by possible confounders, such as effects of intrauterine exposure or maternal behavior being influenced by the mother's genetic background, say the authors.

Counterintuitive Findings

Commenting on the study for Medscape Medical News, Dilip V. Jeste, MD, Distinguished Professor of Psychiatry and Neurosciences, University of California, San Diego, said the findings "seem counterintuitive."

But he pointed out that schizophrenia is a "highly heterogeneous disease," and very few biological characteristics are seen in all, or even most, patients.

"Some people even think about a group of schizophrenias rather than a single disease."

Dr Jeste stressed that researchers, including his own group, have found higher levels of inflammatory biomarkers in schizophrenia patients than in control persons; the cause-and-effect relationship between the two is unclear.

"It's likely that factors such as smoking, substance use, sedentary lifestyle, lack of exercise, obesogenic diet, and antipsychotics contribute to the biomarker profile in the illness."

In an accompanying editorial, Enda M. Byrne, PhD, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia, and colleagues note that the study highlights the value of MR in psychiatry "in identifying putative causal relationships" that may aid in prevention or treatment.

Advances to the MR method that have made it possible measure genetic effects on exposure and outcomes in independent samples have had "a transformative effect on the field of epidemiology," they write.

Although MR will not answer all questions of causality in psychiatry, it could be a "powerful tool" to guide further research into possible causal risk factors.

"At the very least, it may help to reduce wasted research spending on RCTs that are unlikely to succeed."

The editorialists advocate that MR analyses be restricted to those in which SNP-exposure associations are significant genome-wide.

The genetic variants studied and their potential influences on outcomes should not be associated with any confounders through pleiotropy, they note.

"We believe that the community and patients will be better served if we impose this stringent quality control to avoid inconclusive results that are associated with weak instruments," they write.

The study was funded by grants from the UK Medical Research Council and the University of Bristol. The authors and editorialists have disclosed no relevant financial relationships.

JAMA Psychiatry. Published online November 1, 2017. Full text, Editorial

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