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X Chromosome Locus Is Associated with Lower Atherogenic Lipids, Favorable Cardiometabolic Traits

Key findings

  • This study explored associations between whole-genome sequencing data and lipid levels in a multi-ancestry cohort (n=65,322), replicated in 456,893 European participants
  • Multiple common single-nucleotide polymorphisms on chromosome Xq23 were strongly associated with reduced total cholesterol, low-density lipoprotein cholesterol and triglycerides, with similar effects in males and females
  • Lipid-lowering variants were also associated with reduced odds of coronary heart disease (CHD) and type 2 diabetes
  • Co-localization analyses strongly implicated increased expression of the CHRDL1 gene in adipose tissues with these favorable cardiometabolic indices
  • Whether the variants influence the lipoprotein lipase pathway or represent a novel lipid-related pathway for combined CHD and diabetes, these results suggest the possibility of new approaches to therapies for cardiometabolic diseases

Lipid levels and the risk of coronary heart disease (CHD) are well known to differ by sex, but they've also been linked to X chromosome "dosage." For example, women with Turner syndrome (monosomy X) have higher total cholesterol, low-density lipoprotein (LDL) cholesterol and triglyceride concentrations, even apart from gonadal deficiency. Men with Klinefelter syndrome (additional X chromosome) have higher rates of dyslipidemia and CHD. Therefore, the team more broadly examined X chromosome genetic variation with lipids and cardiometabolic traits.

Pradeep Natarajan, MD, MMSc, director of the Cardiovascular Disease Prevention Center and investigator in the Cardiovascular Research Center at Massachusetts General Hospital, Gina M. Peloso, PhD, of the Department of Biostatistics at Boston University, and an international team of colleagues have linked this sexual dimorphism in lipid levels to X chromosome genomic variation. Their report appears in Nature Communications.

X-Chromosome Variants and Lipids

The team analyzed 65,322 individuals who had lipid levels and whole-genome sequencing data available from the National Institutes of Health Trans-Omics for Precision Medicine (TOPMed) program. The cohort was multi-ancestry: 45.2% white, 25.2% Black, 20.6% Latinx, 7.2% Asian, 1.8% Samoan and 0.1% Native American.

Sequencing identified 19,898,222 variants on the X chromosome. In a meta-analysis of the TOPMed data, the UK Biobank (n=390,606) and the Nord-Trøndelag Health (HUNT) study in Norway (n=66,287), the three lead common single-nucleotide polymorphisms on chromosome Xq23 (chrXq23) that met stringent thresholds for statistical significance:

  • rs5942634-T, downstream from RTL9, was associated with 1.95-mg/dL lower concentration of total cholesterol
  • rs5942648-A, between RTL9 and CHRDL1, was associated with 1.53-mg/dL lower concentration of LDL cholesterol
  • rs5985504-T, nearer CHRDL1, was associated with a 2% lower triglycerides concentration

The effects on lipids were similar for males and females and the effect on total cholesterol was of similar magnitude across ancestries.

Variants and Cardiometabolic Traits

  • Analysis of the UK Biobank, the HUNT study and 176,899 participants of FinnGen showed 2% lower odds of CHD for each rs5942634-T allele
  • The effect sizes of the three variants on total cholesterol correlated with their effects on coronary artery disease, type 2 diabetes and increased BMI

Gene Expression

  • rs5942634 was associated with reduced expression of CHRDL1 in skeletal muscle, subcutaneous adipose tissue, visceral adipose tissue and liver
  • rs5942634 was also associated with increased expression of RTL9 in skeletal muscle
  • Increased expression of CHRDL1 showed consistent co-localization with decreased cholesterol across tissues, pointing to CHRDL1 as the likely causal gene in the region

Implications for Therapy

ChrXq23 lipid-lowering alleles appear to have favorable cardiometabolic effects that reduce the risk of CHD and type 2 diabetes. Despite the association with increased BMI, they also seem to affect adiposity favorably, such as expanding protective fat stores.

It remains to be determined whether the variants influence the lipoprotein lipase pathway or represent a novel lipid-related pathway for combined CHD and diabetes. Whichever the case, these results suggest the possibility of new approaches to therapies for cardiometabolic diseases.

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