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Copy-Number Level of Amylase Gene Linked to Obesity Risk

NEW YORK (GenomeWeb News) — Researchers have linked low copy-number levels of the salivary amylase gene to obesity risk, a finding they reported in Nature Genetics yesterday.

The international group of researchers led by Philippe Froguel at Imperial College London and King's College London's Timothy Spector examined gene expression and CNV patterns in nearly 150 Swedish families discordant for obesity, finding differences in signal intensity surrounding the amylase gene clusters. Salivary amylase breaks down carbohydrate bonds in the mouth, and higher copy numbers of the enzyme is thought to have evolved as humans began to consume starchier foods.

They further homed in on the salivary amylase gene AMY1, finding that increases in its copy number were associated with increased amylase expression and serum levels of the enzyme and that reduced numbers of the amylase gene were linked to increased BMI and risk of obesity.

"While studies to date have mainly found small effect genes that alter eating behavior," Spector said in a statement, "we discovered how the digestive 'tools' in your metabolism vary between people — and the genes coding for these — can have a large influence on your weight."

Drawing on DNA array signal intensity data coupled to transcriptomic data from adipose tissue derived using famCNV, the researchers examined patterns in 149 Swedish families with siblings discordant for obesity. Some 76 probes that hybridized within CNV regions appeared to have a dose-dependent effect on gene expression. Only one probe, which mapped to the amylase gene cluster, was also associated with adiposity and fat mass.

Spector and his colleagues replicated this finding in more than 970 people from the TwinsUK project using signal intensity data from DNA arrays. While this confirmed an association in the region of the amylase genes, it did not allow them to determine whether it was the salivary or pancreatic amylase gene that was behind the association.

Instead, they turned to a qPCR approach to examine the copy-number levels of the AMY1 and AMY2 genes in 481 people from the Swedish families. This approach, the researchers noted, still didn't give absolute copy-number genotypes, but provided relative estimates.

While three copy-number states, ranging between one and three copies, were found near the pancreatic amylase gene AMY2, none of them was associated with either BMI or fat mass. However, copy-number estimates near AMY1, ranging between two and 14 copies, were associated with both BMI and fat mass.

The investigators found a similar association using digital PCR on 96 samples form the French Data from the Epidemiological Study on Insulin Resistance (DESIR) syndrome project.

They also replicated their findings in 1,479 women from the TwinsUK cohort and 2,137 men and women from the DESIR cohort using qPCR. Meta-analysis on those groups also found a significant association between low AMY1 copy number and increased BMI.

To further assess how copy-number variation affects obesity risk, the researchers measured copy number using qPCR in obese and normal-weight people from the TwinsUK, DESIR, and French Adult Obesity cohorts. Between the top and bottom deciles of AMY1 copy number — more than nine copies or less than four — the researchers calculated an eight-fold difference in obesity risk.

To extend their findings beyond a European population, Spector and his colleagues turned to a Chinese Singaporean cohort case-control sample from the Singapore Prospective Study Program. From that population, they used qPCR to measure AMY1 copy number in 136 obese, 197 overweight, and 325 matched normal-weight subjects, and in those, they noted that reduced estimated copy number of AMY1 was also associated with increased obesity risk.

By examining amylase copy number, serum amylase levels, and BMI in some 468 morbidly obese French participants from the Atlas Biologique de l'Obésité Sévère, Spector and his colleagues found that salivary and pancreatic amylase levels were about the same in serum and that these levels corresponded with copy number variation of their respective genes.

"Whereas individual salivary amylase levels vary in response to environmental factors, including psychological stress, they are genetically influenced by and directly correlate with the highly variable copy number at AMY1," the researchers said.

BMI, they added, was inversely associated with serum salivary amylase levels as well as with serum pancreatic amylase levels, though to a lesser degree.

Amylase levels, they noted, could be used as a biomarker for obesity susceptibility and, perhaps, to guide treatment and diets.

"In the future, a simple blood or saliva test might be used to measure levels of key enzymes such as amylase in the body and therefore shape dietary advice for both overweight and underweight people," Spector said. "Treatments are a long way away but this is an important step in realizing that all of us digest and metabolize food differently — and we can move away from 'one-size fits all diets' to more personalized approaches."