Genome-wide association study identifies variants in casein kinase II (CSNK2A2) to be associated with leukocyte telomere length in a Punjabi Sikh diabetic cohort

Abstract

Background: Telomere length is a heritable trait, and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length with cardiometabolic risk and performed the first genome-wide association study and meta-analysis to identify variants influencing relative telomere length in a population of Sikhs from South Asia.

Methods and results: Our results revealed a significant independent association of shorter relative telomere length with type 2 diabetes mellitus and heart disease. Our discovery genome-wide association study (n=1616) was followed by stage 1 replication of 25 top signals (P<10(-6)) in an additional Sikhs (n=2397). On combined discovery and stage 1 meta-analysis (n= 4013), we identified a novel relative telomere length locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β=-0.38; P=4.5×10(-8)). We further tested 3 top variants by genotyping in UK cardiovascular disease (UKCVD) (whites n=2952) for stage 2. Next, we performed in silico replication of 139 top signals (P<10(-5)) in UK Twin, Nurses Heart Study, Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and MD Anderson Cancer Controls (n=10 033) and joint meta-analysis (n=16 998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in whites because of significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates telomeric repeat binding factor 1 and plays an important role for regulation of telomere length homoeostasis.

Conclusions: By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.

Keywords: cardiovascular diseases; diabetes mellitus, type 2; genome-wide association study; telomere length.

Figure 1

Summary of study design and key outcomes

Figure 2

(A) QQ plot of RTL GWAS of the Sikh discovery cohort after quality control of directly genotyped (474,231), and (B) imputed variants 5,904,251 (MAF≥5%) from the 1kG reference panel of 1092 world-wide subjects

Figure 3

Manhattan plot of primary RTL GWAS analysis of the Sikh discovery cohort using directly genotyped and imputed SNPs on X axis and −log10 p-value on Y axis.

Figure 4

Regional association plot for a novel GWAS locus associated with RTL represented by rs74019828 in the CSNK2A2 gene in discovery GWAS and in combined analysis of GWAS and replication studies (meta-analysis result shown as purple diamond).

Figure 5

Distribution of relative telomere length (RTL) in healthy controls, patients with coronary heart disease (CHD) and type 2 diabetes (T2D).

Figure 6

Forest plot showing the association of lead SNP in the CSNK2A2 (rs74019828) gene with RTL. The meta-analysis of Sikhs, Europeans and Multiethnic studies are shown. Meta-analysis in Sikhs shows a significant association of rs74019828 with RTL (β 0.38±0.06, P= 4.52 × 10⁻⁰⁸).

Figure 7

Overview of the telomere assembly showing binding of CSNK2A2 with Telomere Repeat Binding Factor 1 (TERF1) as substrate.