Professor Brian Tomlinson of the Faculty of Medicine of Macau University of Science and Technology is an author on a paper recently published in the journal Nature with the title “Identification of type 2 diabetes loci in 433,540 East Asian individuals”.

This study is thought to be the largest meta-analyses of genome-wide association studies (GWAS) in East Asians performed to identify the genetic loci associated with type 2 diabetes (T2D) and it provides the most comprehensive and precise catalogue of East Asian T2D genetic association effects available so far. It involves nearly half a million people with T2D or healthy control individuals from 23 East Asian studies and is similar in size to the largest studies performed in people of European populations. The main analysis identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index (BMI) and sex, 61 loci were identified that are newly implicated in predisposition to T2D.

Previous meta-analyses of GWAS of individuals with European ancestry have identified more than 240 loci associated with T2D. The common variants that have been associated with T2D in European populations showed strongly correlated effect sizes in the East Asian populations in this new study.

The newly identified associations include signals in or near the GDAP1, PTF1A, SIX3, and ALDH2 genes, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping signals for T2D affect the two genes, NKX6-3 and ANK1, in different tissues.

In the sex-stratified analyses, six novel sex-specific loci were identified: three male-specific loci near FOXK1, PDE3A, and IFT81 and one female-specific locus near LMTK2 in models without adjustment for BMI, and one male-specific locus near LINC00851 and one female-specific locus near CPS1 in models with adjustment for BMI. The strongest difference between sexes was seen at a region near ALDH2 which showed strong association in males but no association in females. ALDH2 encodes aldehyde dehydrogenase, a key enzyme in alcohol metabolism that converts acetaldehyde into acetic acid. Variants at this locus leading to reduced ALDH2 enzyme activity and reduced alcohol metabolism are associated with flushing, nausea, and headache following alcohol consumption in East Asians. The T2D risk allele near ALDH2 is associated with better tolerance for alcohol, increased BMI, blood pressure and high-density lipoprotein cholesterol, but decreased low-density lipoprotein cholesterol and lower cardiovascular risk.

This study emphasizes substantial shared genetic susceptibility to T2D of populations with East Asian ancestry and with European individuals, as shown by the strong correlation of effect sizes among T2D-associated genetic variants with common allele frequencies. However, compared to a recent study of T2D-associated genetic variants in individuals of European ancestry, there was less attenuation of effects on T2D in analyses adjusted for BMI in the East Asian subjects. In East Asian populations, T2D typically occurs at lower BMI or waist circumference levels than in European populations. The loci which had a greater effect on T2D after adjusting for BMI include loci with lipodystrophy-like traits that have been identified only in East Asian individuals.

This adds support to the observation that factors beyond overall BMI, such as visceral adiposity or lipodystrophy, may contribute more to T2D in East Asian individuals. Novel associations in East Asian individuals were identified because they have higher allele frequencies in East Asian populations, exhibit larger effect sizes, and/or are influenced by other environmental or behavioural factors such as alcohol consumption and the ALDH2 locus. Some of the novel variants identified had a relatively low minor allele frequency such as variants near GDAP1, which encodes ganglioside-induced differentiation-associated protein 1, a protein that regulates mitochondrial proteins and metabolic flux in skeletal muscle, and PTF1A, which encodes pancreas transcription factor 1 subunit alpha, a transcription factor that is required for pancreatic acinar cell development.

The loci which have been identified point to multiple plausible molecular mechanisms and many new candidate genes that link the susceptibility to T2D to diverse biological processes. The annotation of loci identified in this East Asian meta-analysis supports a substantial role for insulin resistance in the pathogenesis of T2D among East Asian individuals, through skeletal muscle, adipose tissue and liver development and function. Furthermore, multiple distinct association signals in the same region do not necessarily act through the same gene. Conditionally distinct association signals which are in close proximity can affect different genes that may act in different tissues by different mechanisms, emphasizing the value of identifying functional variants that enable variant-to-gene links to be examined directly.

These results provide a foundation for future biological research into the pathogenesis of T2D and offer potential targets for interventions designed to modify disease risk. Association studies in diverse populations like this are important to identify additional loci and elucidate disease-associated genes, biology, and pathways.

Reference: https://www.nature.com/articles/s41586-020-2263-3