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Study Identifies Genetic Susceptibility for Hernia

In the first large-scale genetic study of hernia risk in adults, researchers at University of California, San Francisco (UCSF) and Kaiser Permanente have identified variations at four locations in the genome that underlie the risk of inguinal hernia, the most common type of hernia. The study was published today in Nature Communications.

“Surgical repair of inguinal hernias is one of the most commonly performed operations in the world, yet little is known about the genetic mechanisms that predispose individuals to develop them,” said lead author Eric Jorgenson, PhD, research scientist at the Kaiser Permanente Division of Research. “These findings provide insight into the origins of hernia development and highlight genetic pathways for studies of its treatment.”

Abdominal hernias are one of the most frequently diagnosed conditions in clinical practice, and inguinal hernias are the most prevalent. Men have a 27 percent lifetime risk of developing an inguinal hernia, while women have six percent lifetime risk. Risk increases with age, and more than 750,000 surgeries are conducted in the U.S. annually to treat the condition.

A hernia is usually a sac formed by the lining of the abdominal cavity. The sac comes through a hole or weak area in the fascia, the strong layer of the abdominal wall that surrounds the muscle. Depending on their severity, hernias can strangulate blood vessels or a section of the bowel — cutting off blood flow, and posing a risk of obstruction. Emergency hernia surgery to treat these conditions is associated with a substantial risk of death. A subset of patients experience hernia recurrence and chronic pain after surgery.

Researchers conducted a genome-wide association study (GWAS) among participants in Kaiser Permanente’s Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort who had surgically-confirmed inguinal hernias. The GERA cohort is one of the nation’s largest and most diverse genomics projects, linking genetic data to electronic medical records for more than 110,000 members who have voluntarily participated, enabling investigations into many diseases and conditions. The cohort is a collaboration of UCSF and Kaiser Permanente Northern California.

The top associations in the four regions were replicated in a large independent sample of research participants with self-reported hernia repair surgery from 23andMe, a personal genomics and biotechnology company based in Mountain View, California. The 23andMe cohort provided informed consent under an approved protocol.

Researchers at UCSF then analyzed the expression of genes in these regions in mice. “We observed expression of four genes in these regions in mouse connective tissue, which suggests they could have a role in hernia development,” explained Nadav Ahituv, PhD, associate professor in the Department of Bioengineering and Therapeutic Sciences. “We also found through network analyses that at least two of these genes operate in the same biological pathway, pointing to new areas of investigation.”

“Taken together, our findings suggest that these four new regions affect the development of inguinal hernias through the regulation of both collagen and elastin maintenance,” added co-lead author Nadja Makki, PhD, a member of the UCSF research team in the UCSF schools of Pharmacy and Engineering.

“Further research into the precise mechanisms through which these regions act may improve our understanding of hernia formation and point the way to more effective preventative, operative and non-surgical treatments of this common disorder,” Jorgenson concluded.

Other authors of the study include Ling Shen and Andrew Avins, MD, MPH, Kaiser Permanente Division of Research; Walter L. Eckalbar, PhD, Department of Bioengineering and Therapeutic Sciences, UCSF; David C. Chen, MD, David Geffen School of Medicine at UCSF; and David Hinds, 23andMe Inc.

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