A deep dive into lipid genetics reveals how ancestry-specific molecular pathways could be driving higher diabetes and heart disease risk, bringing researchers closer to more precise, population-tailored treatments.
Study: Identification of lipid quantitative trait loci linked with cardiometabolic disease in Asian Indians and Europeans: A genome-wide association study and mendelian randomization. Image credit: New Africa/Shutterstock.com
A new study conducted in Asian Indian populations identifies lipid-linked genetic pathways that predispose people to cardiometabolic diseases, including cardiovascular disease and type 2 diabetes. The study is published in PLOS Medicine.
South Asians face a disproportionate diabetes and heart disease burden
The increasing prevalence of cardiometabolic diseases, including cardiovascular disease, type 2 diabetes, and obesity, has become a leading public health crisis in recent times. The prevalence of diabetes is expected to increase from 463 million in 2019 to 700 million by 2045. Among various races and ethnicities, South Asians have a higher incidence of diabetes and are significantly more likely to develop cardiovascular disease.
A unique body composition characterized by low muscle mass and high abdominal fat has predisposed South Asians to increased chronic low-grade inflammation and insulin resistance, which are major hallmarks of cardiometabolic diseases. However, exact mechanisms linking Asian Indian populations to increased disease risk remain largely unknown.
Several genome-wide association studies (GWAS) of blood lipids have shown that various lipid subclasses are differentially associated with cardiometabolic and neurodegenerative diseases and cancers. However, the majority of these studies have been conducted in European populations, restricting the evaluation of molecular pathways of disease development among diverse ethnic groups.
The current study, led by researchers from the University of Oklahoma, was designed to evaluate the genetic connection between blood lipid metabolites (small molecules produced during lipid metabolism) and cardiometabolic diseases in a Punjabi population from India.
The research team, led by Dharambir Sanghera of the University of Oklahoma, performed metabolite GWAS using 516 lipid metabolites in the blood of 3,000 Punjabi Sikh individuals, and validated the findings in more than 1 million Europeans and 15,000 individuals with South Asian ancestry.
Large-scale lipid GWAS uncovers novel variant–metabolite associations
The GWAS of 516 lipid metabolites identified 236 genetic variant-metabolite pairs that showed significant associations with cardiovascular disease and type 2 diabetes. Following multiple testing correction, 36 associations remained significant, 33 of which were reported for the first time, showing significant associations with cardiovascular disease and type 2 diabetes. Three of these associations were found to be specific to the Asian Indian population.
These genetic variant-metabolite associations were further analyzed using colocalization analysis, polygenic risk scores, and mendelian randomization approaches, which led to the identification of two variants that linked specific lipid metabolites to these diseases.
One metabolite was LPC O-16:0, a lysophosphatidylcholine, which showed a significant positive association with type 2 diabetes. This metabolite was represented by a lead variant in CD45, which is a key regulator of T- and B-cell antigen receptor signaling and inflammation. An elevated blood level of this metabolite was found to significantly increase the risk of type 2 diabetes based on genetic evidence, potentially through inflammatory and metabolic pathways such as insulin resistance.
Another metabolite was PC 38:4, a glycerophospholipid, which showed a significant negative association with cardiovascular disease. This metabolite was represented by a variant in the untranslated region in the FADS1/2 genes, which may be specific to the Indian population and could not be confirmed in Europeans because of extensive pleiotropy (a genetic condition where a single gene influences multiple unrelated phenotypic traits) in this region. This genetic variant was found to potentially protect against cardiovascular disease in Asian Indians by altering the blood levels of PC 38:4.
Lipid genetics reveals immune and metabolic disease connections
The study identifies new lipid-linked genetic signals and pathways in Asian Indians that contribute to type 2 diabetes and cardiovascular disease. The findings highlight the influence of immune system signaling on human metabolic health.
The researchers strongly believe that these findings would help understand the disease better and provide a basis for developing ancestry-specific medical interventions to address these highly prevalent cardiometabolic diseases, particularly in higher-risk populations like Asian Indians. They encourage more studies among people with differing genetics, lifestyles, and cultures to understand the different subtypes of diseases, different ancestries, and design personalized therapeutics.
They highlight one major limitation of the study: the absence of an independent validation cohort of Asian Indians from India. Dietary patterns can alter blood lipid levels, which can subsequently influence the ethnic differences and disrupt genetic associations through gene-diet or gene-environment interactions.
They also mention that this study reports only genetic association for structurally characterized (annotated) lipid metabolite peaks. Further studies characterizing genetic signals in unannotated peak regions are required to identify additional disease pathways.
Given the significant clinical implications of the study findings, they highlight the need for more studies on human lipidomics to identify downstream effects of the genome and the impacts on human cardiometabolic health.
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