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Serum D and C-reactive protein (CRP)

Posted on: February 1, 2012   by  JA Larson


Drs Amer and Qayyam recently published a study in the American Journal of Cardiology that pulled data on serum D and CRP from the Center for Disease Control (CDC) historical national survey. Their findings have raised the question in several large media outlets, does increased D increase cardiovascular disease risk?

Amer M, Qayyum R. Relation Between Serum 25-Hydroxyvitamin D and C-Reactive Protein in Asymptomatic Adults (From the Continuous National Health and Nutrition Examination Survey 2001 to 2006). Am J Cardiol. 2011 Oct 12.

The short answer is no. You can’t draw any conclusions about CVD risk because this was a correlation of two serum levels between two unmatched groups. It was not an intervention study, and it did not measure CVD. More details? Read on:

They divided their data into two groups at the median D level of 21 ng/ml:

  • “Low D” (<21 ng/ml)(<52.5 nmol/L)
  • “High D” (≥21 ng/ml)( ≥52.5 nmol/L)

They stated that in the single variable linear correlation (using a log of the CRP):

  • The Low D group CRP decreased as D increased. The CRP level decreased 0.285 mg/dl for each 10 ng/ml D change.
  • The High D group CRP change decreased less, almost leveling off, but still decreased a little. The CRP decreased 0.05 mg/dl for each 10 ng/ml change in D.

The authors found that vitamin D has a bigger effect in D deficient folks compared with those who had sufficient D levels.

However, when they ran the data as a multiple variable regression (and adjusted for demographic variables, obesity, hypertension, serum glucose, cholesterol, smoking, white blood cell count, and renal function), they concluded:

  • The Low D group CRP decreased 0.105 mg/dl for each 10-ng/ml D increase
  • The High D group CRP increased 0.06 mg/dl for each 10-ng/ml D increase

Remember, the big chunks in looking at a study are population, interventions (if applicable) and findings.

Since this was a retrospective study on serum D and CRP from historical files, there was no intervention, no subject randomization, and no objective health outcome (these were healthy adults and they did not look at actual CVD disease or death rates).

The Low D and High D groups were different by race, hypertension, gender, obesity, CRP, serum glucose, kidney function, and smoking (note: most of these affect CRP levels).

It should be no surprise to VDC readers that the overall D levels were very low, basically deficient and inadequate. Black, obese, and smoker D levels were worse than average. What this means is that the study didn’t have enough higher D scores to do a complete analysis (an inadequate ceiling). Hmm, what happens above 50 ng/ml (125 nmol/L)?

The American Heart Association’s (AHA) CRP average risk range is 1.0 to 3.0 mg/L. The Low D group’s mean CRP was 2.2 mg/L. The High D group’s mean CRP was 1.7 mg/L. So, both groups were in the middle of the average risk range.

It’s important to understand what CRP is.  CRP is a liver protein that indicates general inflammation with a wide range of causes. Kruas et al found that,

“Serum hsCRP for predicting risk of CVD is confounded by obesity, ethnicity, gender and comorbidities.”

Kraus VB, Stabler TV, Luta G, Renner JB, Dragomir AD, Jordan JM. Interpretation of serum C-reactive protein (CRP) levels for cardiovascular disease risk is complicated by race, pulmonary disease, body mass index, gender, and osteoarthritis. Osteoarthritis Cartilage. 2007 Aug;15(8):966-71. Epub 2007 Mar 28. PubMed PMID: 17395501; PubMed Central PMCID: PMC2682321.

A CRP over 3 mg/L has been postulated as a CVD risk marker (it is associated with CVD), but it is not a risk factor (it does not cause CVD). This is the big distinction. The CDC and American Heart Association (AHA) Working Group states:

“hs-CRP for high- or low-risk adults… are not recommended (Class III). The lack of support for these tests may change as more evidence is acquired.”


What does all this mean to us? Is the sky falling? Is anyone who ventures into the sun doomed? Should we stop all vacations to Florida and Hawaii and deem them dangerous to our health?

No. This is at best a number drill. It is not an intervention study with controls. There is a difference between statistical significance and clinical utility. The multivariable High D group CRP mean change goes up by 0.06 mg/dL every 10 ng/ml increase in D (given 2 unmatched groups with an inadequate D range), but the single variable analysis shows CRP decreasing.

We don’t know why the adjusted multiple variable CRP went up because they did not control for population variables, other nutrients, or diseases. In theory, increased D might decrease magnesium levels that would increase the CRP. Or Rheumatoid Arthritis, etc…

The authors were correctly conservative in their conclusion:

“It is possible that the role of vitamin D supplementation to reduce inflammation is beneficial only among those with a lower serum 25(OH)D.”

In my opinion, they should have been more conservative in terms of their study’s limitations and the limits of CRP scores. I’d like to have seen the actual data plot.

But the press headlines were not that conservative:

“Risks: When Too Much Vitamin D Is Too Much. Too much vitamin D may be just as bad as too little, a recent study suggests.”

“Vitamin D: Too Much May Erase Heart Benefit.”

I can’t say it often enough: correlation is not causation. I went to Hawaii a few years ago. My D went up, my CRP went up, my sleep hours went down, my carbohydrate consumption increased, and my blood alcohol levels went up. Did D cause my CRP to rise?

8 Responses to Serum D and C-reactive protein (CRP)

  1. James Larsen

    You’ll note the High D group’s median CRP was LOWER than the Low D Group. Hmmm. 🙂

  2. James Larsen
  3. [email protected]

    I wonder if there are “just a few” participants in the study with higher vitamin D levels AND higher CRP? In Marfan Syndrome (1 in about 5000 or 10000 people) people quite often have a blocked vitamin D receptor AND high CRP. Maybe the high CRP is based on the body’s inability to use the vitamin D – and if the body can’t use the D, wouldn’t your D level go up? Remember previous vitamin D studies leading to false conclusions based on a couple kids with Williams syndrome in the study? (just thinking out loud – would like to know what Dr. Cannell thinks)

  4. Nandyal

    thanks, this was helpful to put at least a small wet blanket on the detractors of higher range D levels. please keep more of it’s kind coming…..

  5. Brant Cebulla

    Also note in a study that looked at vitamin D and strokes, once again raw data shows that the higher your vitamin D, the lower your CRP: http://vitd-dev.minervation.net/2012/02/03/new-study-suggests-vitamin-d-deficiency-linked-to-increased-stroke-risk/


    I find it really strange that Drs. Amer and Qayyum really let the media make more of their study than they ought have. I have seen a couple of other studies as well that show in raw data, no increase in CRP the higher your vitamin D level.


    I know it wasn’t the authors’ intentions, but it almost seems like they went fishing for a v-shaped curve and started adjusting for variables until they got one. I’m wondering if you took a look at all the studies that measure vitamin D and CRP, would the literature support a headline that states “Vitamin D: Too Much May Erase Heart Benefit”? Or even “Vitamin D: Too Much Increases CRP”?

    I think the answer is no.

  6. Jim Larsen


    Observational studies are inexpensive to conduct and are only capable of suggesting areas for further research.

    However, folks and the media often jump to conclusions. “Health” is correlated to “education,” so some folks jump to the idea that more education will make us healthier. “Height” is correlated to “job success” so if we issue heel lifts more folks will be successful? It’s basically silly.

    I agree that looking across studies is useful. The serious folks want to look at high quality studies and the overall body of work. That takes a lot of time.

  7. PeterVermont

    The multivariate analysis adjusts for additional factors. If the factors you adjust for, such as hypertension and obesity are causally related to vitamin D, then it is quite possible to over-adjust and I suspect that is what happened here.

  8. Jim Larsen
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