Researchers expand understanding of hernia genetics

Kaiser Permanente analysis finds several novel genome locations associated with a frequently diagnosed lower abdominal condition

By Jan Greene

A Kaiser Permanente genetic analysis found 41 new locations on the human genome related to risk of hernia in the lower abdomen, known as inguinal hernia. The study, published in Human Molecular Genetics, also identified for the first time 2 locations associated with inguinal hernia risk in people with African ancestry and another 8 that show sex-specific effects.

Helene Choquet, PhD, research scientist, Division of Research.

Doctors have long known that inguinal hernias – a weakening in the abdominal wall in the groin – are more likely to develop in patients with a known family history of this condition. “Learning the specific genetic information related to causes of the disorder could lead to prevention and new treatments,” said lead author Hélène Choquet, PhD, a research scientist with the Kaiser Permanente Division of Research.

Inguinal hernias are among the most commonly diagnosed conditions, with a lifetime prevalence of 20% to 27% in men and 3% to 6% in women. Men are much more likely than women to have an inguinal hernia, while African American men have a lower incidence compared with non-Hispanic white men. Also, there is a higher risk among people with a family history of inguinal hernia, particularly for women.

“This is the first large, multiethnic genome-wide association meta-analysis of inguinal hernia risk,” Choquet said. “Our findings echo what clinicians see among patients – that there are differences in risk between men and women and by ethnic background. We found that risk is likely due to genetic effects. This is further evidence of the great value in large-scale genomic studies in ancestrally diverse populations to better understand disease.”

The databases used include people of more varied ethnicity than those used in previous research on this topic. The data came from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, a group of more than 100,000 Kaiser Permanente Northern California members who volunteered their genetic and medical information for research. GERA is part of the Kaiser Permanente Research Program on Genes, Environment and Health, which is associated with the Kaiser Permanente Research Bank. The researchers also used data from the UK Biobank, which contains genetic and health information from about a half million residents of the United Kingdom. They confirmed their findings using data from genetics firm 23andMe.

The analysis involved a total of 513,120 adults, including 35,774 with an inguinal hernia and 477,346 people who had not had an inguinal hernia from the GERA and UK Biobank databases. The findings were validated using the 23andMe research cohort, which included 33,491 people who had been diagnosed with an inguinal hernia and 694,927 who had not.

Functional analysis

To explore the roles of the identified genes in tissues relevant to hernia, the authors collaborated with Nadav Ahituv, PhD, a professor in the Department of Bioengineering and Therapeutic Sciences and the Institute for Human Genetics at the University of California, San Francisco. Ahituv and his team conducted functional characterization analyses using mouse connective tissue to identify regulatory elements in the specific hernia risk genetic locations.

“Understanding which regulatory elements that affect hernia risk and how alterations in these elements influence hernia development can provide crucial insights for hernia prevention and development of non-surgical treatments,” Choquet said.

Co-author Rouzbeh Mostaedi, MD, a general surgeon and hernia specialist with The Permanente Medical Group.

“It was exciting to participate in research that has provided us with new biological insights into this common condition,” said co-author Rouzbeh Mostaedi, MD, a general surgeon with The Permanente Medical Group and an expert in the treatment of hernias. “Inguinal hernias are common and can display with a wide range of symptoms, including severe pain or intestinal obstruction, that are a real burden for patients.”

The study follows on work by co-author Eric Jorgenson, PhD, a former Division of Research investigator now with Regeneron, who identified 4 new genetic loci associated with inguinal hernia risk in individuals of European ancestry using the GERA cohort. That study was published in Nature Communications in 2015.

The new study expands on this previous work by including more participants from diverse ancestry populations. It found 41 new genome locations associated with inguinal hernia risk. Interestingly, it also found 8 locations specific to sex, offering clues on how the genome contributes to differing hernia risk between men and women. The researchers also identified for the first time 2 locations associated with inguinal hernia risk in people with African ancestry.

Choquet said future research is planned to look at genetic associations with other types of hernias, and at the genetics of individuals who have recurrent hernias.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.

Co-authors also included Jie Yin, MS, of the Kaiser Permanente Division of Research; Weiyu Li, PhD, Rachel Bradley, MS, and Thomas J. Hoffman, PhD, of University of California, San Francisco; and Priyanka Nandakumar, PhD, and Chao Tian, PhD, from the 23andMe Research Team.

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About the Kaiser Permanente Division of Research

The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and society at large. It seeks to understand the determinants of illness and well-being, and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 600-plus staff is working on more than 450 epidemiological and health services research projects. For more information, visit divisionofresearch.kaiserpermanente.org or follow us @KPDOR.

 

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