Tissue-specific genomics uncovers coregulators in telomere biology that affect risk of ischemic heart disease

Tissue-specific genomics uncovers coregulators in telomere biology that affect risk of ischemic heart disease. Download PDF Abstract Leukocyte telomere length (TL) attrition, a hallmark of cardiovascular aging, is a known risk factor for ischemic heart disease (IHD). The tissue-specific genetic dysregulation that affects telomere homeostasis and the mechanisms underlying their effects on IHD remain unclear.

We performed a transcriptome-wide association study (TWAS) using gene expression data from eight different tissue types known to play a role in IHD, including arteries, adipose tissues, liver, and others. This was combined with genome-wide association study data associated with TL, collected from 23,622 participants in the Singapore Chinese Health Study. Our analysis identified 51 significant TWAS associations ( P < 2.74 ×10 -6).

Multiple complementary statistical approaches such as colocalization, conditional and fine-mapping analyses refined these to three candidate genes supported by convergent statistical evidence: NKX2-3 in visceral adipose, MPHOSPH6 in arteries, adipose and liver, and RTEL1 mainly in arterial tissues. Genetic variants that regulated these genes affected TL in respective tissues and were also associated with mortality from IHD ( P values ranging from 6.35 ×10 -3 to 0.037). Our findings nominate NKX2-3, RTEL1, and MPHOSPH6 as candidate genes within tissue-specific pathways that may potentially contribute to telomere biology and cardiovascular aging, and warrant prioritization for future functional validation studies.

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