Cardiovascular burden of TTR gene variant among Black carriers across mid to late-life

By Dr. Priyom Bose, Ph.D.Reviewed by Danielle Ellis, B.Sc.May 15 2024

A recent JAMA Network study explored the cardiovascular burden and natural history of the V142I variant of the transthyretin (TTR) gene. This study was conducted among US Black carriers in mid- to late life.

Background 

Transthyretin cardiac amyloidosis (ATTR-CA) stems from the extracellular cardiac deposition of the misfolded transthyretin protein and is an increasingly recognized cardiomyopathy. The absence of a genetic variant (ATTRwt-CA, wild-type related) or its presence (ATTRv-CA, variant related) can lead to ATTR-CA. The amyloidogenic V142I variant of the TTR gene is a common cause of ATTRv-CA in the United States and is present in 3-4% of the US Black population.

Research has shown that carriers of this gene are at a higher risk of heart failure (HF) and all-cause mortality. More data on the V142I variant is needed concerning modifiers of risk and long-term issues in unselected carriers. Estimating the population burden of disease and accurately defining carrier risk is essential, given the emerging and established targeted treatments.

About the study

Data on Black participants from four large US-based observational studies were combined to understand the natural history of disease in V142I carriers. The geographically diverse cohorts led to more generalizable and accurate risk estimation, years of life lost among V142I carriers, analysis of effect modifiers, and the ability to assess less frequent outcomes.

The sample comprised 23,338 self-reported Black participants who were initially free from HF. The data were analyzed between May 2023 and February 2024. 3.2% of the sample, or 754 individuals, were V142I carriers, and this was the exposure measure.

Hospitalizations for HF and all-cause mortality were the main outcome. The former included subtypes of preserved and reduced ejection fraction. 10-year hazard ratios were generated to analyze outcomes. These were estimated for each age in the range of 50 to 90 years. The mean survival by carrier status was estimated using actuarial methods, and subsequently, using the census data, it was applied to the 2022 US population.

Study findings

The key contribution of this study was to provide more accurate estimates of cardiovascular risk across mid to late life, compared to previously existing analyses. A strong dependence on age was noted, but the risk was not affected by sex. This was indicative of the underdiagnosis of ATTRv-CA in women, given that some studies have documented phenotypic penetration being predominant in males.

Women with ATTRv-CA show thinner left ventricular walls than men. Underdiagnosis can also be caused by not considering body size. Based on the findings documented here, age is the most bankable clinical marker to identify the risk of progressive disease.

The earliest increase in 10-year risk, which was also statistically significant, was identified at the age of 63 for HF hospitalization and 72 for mortality. These ages were earlier compared to previous estimates. The risk for HF hospitalization stemmed from the HFrEF and not HFpEF association. 

It is important to note that ATTRv-CA is not noted in all carriers with HFrEF. This is because other causes of cardiomyopathy could also put carriers at risk. A second important reason for detecting ATTR-CA in the HFrEF population is the likelihood that some guideline-directed medical therapies will not be taken seamlessly in ATTR-CA. 

A modest relationship was noted with a higher chance of HFpEF hospitalization in late life. This could represent a survivor bias in which a more benign form of the disease is seen in patients who survive to late life.

Compared to non-carriers, carriers died 2 to 2.5 years earlier at each age across mid- to late life. This difference began to wane at the age of 85. Overall, Black carriers were projected to live approximately 1 million fewer years relative to non-carriers. 

Early detection and management of V142I carriers with ATTRv-CA could have material benefits with respect to increasing longevity among the Black population, given that treatment strategies are more effective earlier in the disease course. Greater access to genetic testing through biobanks or broad population assessments should facilitate early identification. The results documented here also advocate including this variant as a clinically actionable secondary finding. 

Conclusion

In sum, a significant and similar risk of hospitalization for HF was noted among males and females. The risks were also similar concerning all-cause mortality and showed a steep age-dependent penetrance.

A key limitation of the study was the unavailability of specific diagnoses or phenotypic markers of cardiac amyloidosis. The detection of modifiers of variant risk may be underpowered in such interaction analyses. Despite some geographical heterogeneity, the results may not be generalizable to populations outside the US, where variant prevalence rates may be high. Future research should explore the complex interplay between the V142I variant and other factors, such as biological or social determinants of health, race as a social construct, and race.