Family Matters: Parental History Predicts MI Over Genes and INTERHEART Risk Factors

Shelley Wood

January 25, 2011

January 25, 2011 (New York, New York) — A new analysis of more than 12 000 subjects participating in the global INTERHEART study shows that having one or both parents who have had an MI is a strong predictor of future MI in their offspring, independent of behavioral, biological, psychosocial, and genetic factors [1]. Moreover, the strength of the association with parental history persists across world regions, as well as across socioeconomic, age, and gender groups.

"Having one parent with a history of MI nearly doubles your risk of future MI even after accounting for a list of other established risk factors and some genetic risk factors," lead author on the study, Dr Clara Chow (George Institute for Global Health, Sydney, Australia),told heartwire in an email. "Risk more than doubles if two parents are affected or the history of MI is premature."

Chow et al's study is published online January 24, 2011 in the Journal of the American College of Cardiology.

As previously reported by heartwire , the multinational INTERHEART study first grabbed headlines when investigators for the study reported that 90% of the global risk for acute MI could be predicted by the presence of nine traditional and modifiable risk factors.

In this latest research, however, not only was parental history of MI higher among INTERHEART participants who went on to have an MI than among control participants, it was only modestly attenuated, if at all, when behavioral, biological, and psychosocial factors identified in the original INTERHEART study were taken into account.

The association with parental MI persisted after further adjustment for sex, age, and region, regardless of whether it was the mother or father who had had the MI and regardless of socioeconomic factors, such as household income.

"A number of researchers have raised questions regarding the validity of self-reported health history and a concern that in certain population groups--perhaps those with less knowledge or access to healthcare or those less connected with their families--self-reported health history is less reliable," Chow commented. This study "puts to rest to these concerns that it may be less valid or less important in certain populations."

Odds Ratio for MI, According to Parental History of MI

Groups and adjustments

Mother or father odds ratio

Mother and father odds ratio

Unadjusted

1.62 (1.51–1.73)

2.43 (1.96–3.01)

Adjusted for age, sex, and region

1.81 (1.69–1.94)

2.65 (2.14–3.29)

Adjusted for age, sex, and region plus INTERHEART risk factors

1.74 (1.58–1.92)

2.26 (1.68–3.06)

Adjusted for age, sex, and region plus INTERHEART risk factors and genotype score

1.50 (1.32–1.70)

2.28 (1.64–3.17)

Parental History Trumps Genes in Subset Analysis

In a subset of INTERHEART subjects, investigators analyzed MI risk according to genetic data. Here again, the odds ratio associated with a parental history of MI remained after adjustment for genotype score. While genotype score was higher among the MI subjects than it was among those who did not have MIs, it was not any higher in those who had a parental history of MI than it was in those who didn't--something researchers say has been seen in other studies.

"This indicates to me that measurement of current genetic variants does not add much above clinical risk factors to patient assessment at this stage," Chow commented. "This also indicates to me that we don’t really know what family history is a marker of. It probably is a marker of multiple exposures that include but are not limited to genetics that cluster in families--eg, common early life exposures or environmental factors."

Asked to comment on the study, Dr Rongling Li (National Human Genome Research Institute, Bethesda, MD) observed that Chow et al genotyped 1536 single nucleotide polymorphisms (SNPs) from 103 genes that have been linked to MI in previous studies, then selected the top 20 most significant SNPs from univariable analyses, finally selecting the nine SNPs that remained significant in logistic regression models.

"Definitely, there are other genetic variants--SNPs, copy number variations, or other known and unknown forms of genetic markers--that may account for the genetic risk of disease, but they may not [do so] above and beyond parental history because genes are inherited from parents," Li said. "Gene mutations may occur in offspring, but based on our current knowledge, genetic mutation associated with complex diseases are not common. In addition, there are always environmental factors behind genetic mutations."

Moreover, Li added, echoing a point also raised by Dr Themistocles L Assimes (Stanford University, CA) in an editorial accompanying the INTERHEART paper [2], the relatively small sample size of this genetic subanalysis may have precluded the discovery of already-genotyped SNPs that may have a weak association with MI or of relevant gene-gene and gene-environment interactions.

Paying More Attention to Parental History

But importantly, says Li, "This study further confirms that parental history of MI accounts for a significant portion of disease risk that is due to family aggregation of unknown genetic, cultural, and environmental factors. Thus, it is important to include parental history of MI in clinical practice guidelines and clinical decision-support systems to help clinicians to identify high-risk patients for early diagnosis and treatment."

Indeed, Chow believes all individuals with a family history should have a CV risk assessment.

"This doesn’t happen now," she pointed out to heartwire . "A number of studies have shown that these individuals do not have their risk assessed. I think for clinicians who see these individuals, the presence of a family history should trigger them to think about other tests for these individuals--for example, a CT calcium score--as traditional risk calculators underestimate the risk in this group. In low-income countries, family history is a very simple-to-measure risk factor and should be considered for inclusion in 'low-information' tools advocated by the WHO and other groups for risk assessment in these regions. While you may not be able to change your family history, certainly there are a lot of other things that you can modify to lower your risk." 

Chow, Li, and Assimes disclosed having no financial conflicts of interest. A range of pharmaceutical companies helped fund the INTERHEART study through unrestricted grants.

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