Five variants of a lipid transporter gene associated with an increased risk of developing type 2 diabetes among Mexicans and other Latin Americans are also seen in a Neanderthal genome sequence, according to a study from the Slim Initiative in Genomic Medicine for the Americas (SIGMA) Type 2 Diabetes Consortium, published online December 25 in Nature.
The same disease may derive predominantly from different gene variants in different populations. The goal of SIGMA is to discover the genomic underpinnings of the doubled prevalence of type 2 diabetes in Mexican and other Latin American populations compared with the US non-Hispanic white population.
The SIGMA researchers, who are from the United States and Mexico, evaluated 9.2 million single nucleotide polymorphisms (SNPs) in the genomes of 3848 Mexicans and other Latin Americans who have type 2 diabetes and 4366 individuals from the same populations who do not.
The genome-wide association study confirmed earlier findings of 2 risk loci (TCF7L2 and KCNQ1) and identified a new risk locus in a region of 2 solute carrier genes, SLC16A11 andSLC16A13 (P = 3.9 × 10−13; odds ratio, 1.29). The association was stronger in younger, leaner people with diabetes and was replicated in independent samples (P = 1.1 × 10−4; odds ratio, 1.20).
The genome region that influences diabetes risk has 4 amino acid substitutions and 1 silent mutation, all in SLC16A11. The researchers call the 5 linked gene variants the " '5 SNP' haplotype." Each copy elevates risk by about 20%, so a homozygote would have a 40% elevation in risk. The haplotype "would be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations," the researchers write.
The 5 SNP haplotype is common among people with recent Native American ancestry (50% frequency), but less so in East Asians (~10%) and rare in modern European and most African genomes. However, when the degree to which the haplotype differs from wild-type suggested an ancient origin, the researchers analyzed a Neanderthal genome and found the same 5 SNP haplotype. Most modern human populations have 1% to 4% of DNA from Neanderthals; sub-Saharan Africans have none.
To analyze the protein's normal function, the researchers expressed the gene in HeLa cells and observed an altered lipid metabolism: increases in levels of triacylglycerol and diacylglycerols and decreases in cholesterol ester, lysophosphatidylcholine, and sphingomyelin. The gene is normally expressed in liver cells.
Previous studies have associated accumulation of intracellular lipids and serum increases in triacylglycerol with increased risk for future insulin resistance and development of type 2 diabetes.
In addition to contributing to understanding the etiology of diabetes in Mexican and other Latin American populations, the identification of the 5 SNP haplotype may improve risk assessment and provide new drug targets. The study underscores the importance of identifying risk genes in understudied populations to expand knowledge of the pathophysiology of a disease.
The same disease may derive predominantly from different gene variants in different populations. The goal of SIGMA is to discover the genomic underpinnings of the doubled prevalence of type 2 diabetes in Mexican and other Latin American populations compared with the US non-Hispanic white population.
The SIGMA researchers, who are from the United States and Mexico, evaluated 9.2 million single nucleotide polymorphisms (SNPs) in the genomes of 3848 Mexicans and other Latin Americans who have type 2 diabetes and 4366 individuals from the same populations who do not.
The genome-wide association study confirmed earlier findings of 2 risk loci (TCF7L2 and KCNQ1) and identified a new risk locus in a region of 2 solute carrier genes, SLC16A11 andSLC16A13 (P = 3.9 × 10−13; odds ratio, 1.29). The association was stronger in younger, leaner people with diabetes and was replicated in independent samples (P = 1.1 × 10−4; odds ratio, 1.20).
The genome region that influences diabetes risk has 4 amino acid substitutions and 1 silent mutation, all in SLC16A11. The researchers call the 5 linked gene variants the " '5 SNP' haplotype." Each copy elevates risk by about 20%, so a homozygote would have a 40% elevation in risk. The haplotype "would be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations," the researchers write.
The 5 SNP haplotype is common among people with recent Native American ancestry (50% frequency), but less so in East Asians (~10%) and rare in modern European and most African genomes. However, when the degree to which the haplotype differs from wild-type suggested an ancient origin, the researchers analyzed a Neanderthal genome and found the same 5 SNP haplotype. Most modern human populations have 1% to 4% of DNA from Neanderthals; sub-Saharan Africans have none.
To analyze the protein's normal function, the researchers expressed the gene in HeLa cells and observed an altered lipid metabolism: increases in levels of triacylglycerol and diacylglycerols and decreases in cholesterol ester, lysophosphatidylcholine, and sphingomyelin. The gene is normally expressed in liver cells.
Previous studies have associated accumulation of intracellular lipids and serum increases in triacylglycerol with increased risk for future insulin resistance and development of type 2 diabetes.
In addition to contributing to understanding the etiology of diabetes in Mexican and other Latin American populations, the identification of the 5 SNP haplotype may improve risk assessment and provide new drug targets. The study underscores the importance of identifying risk genes in understudied populations to expand knowledge of the pathophysiology of a disease.
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