The UCLA research, published in Genome Biology, found certain genes were more active in people who reported feelings of social isolation.
Many of the genes identified have links to the immune system and tissue inflammation - which may be damaging.Other studies have shown clear links between lack of social support and illnesses such as heart disease.
The researchers said that quality, not quantity, of friendships, appeared to be important.
The link between genes and loneliness has been explored before - a recent Dutch study of 8,000 twins also pointed to the connection.
The UCLA research looked in more detail at which genes might be involved.
They took 14 volunteers and assessed their level of social interaction using a scoring system.
They then looked at genetic activity in their white blood cells and tried to compare the results.
In their "lonely" volunteers, various genes tended to be "over expressed" compared with those at the opposite end of the scoring scale.
These often had known links to the body's mechanisms for fighting off disease, such producing inflammation. Too much inflammation can damage tissues and cause disease.
Other genes, including those thought to be important in fighting viruses and producing immune antibodies, were less active compared with the non-lonely volunteers.
Dr Steven Cole, who led the study, said: "What this shows us is the biological impact of social isolation reaches down into some of our most important basic internal processes - the activity of our genes.
"These findings provide molecular targets for our efforts to block the adverse health effects of social isolation." Source: http://news.bbc.co.uk