It is a long-standing belief that health, attractiveness, and longevity are all a matter of what genes we inherit. Scientists are exploring how a family’s genetic mutations may now provide insight into treatment strategies to help fight the future battle against diabetes and other metabolic diseases.

On July 22, 2022, researchers from the University of Utah (U of U) College of Health in Salt Lake City published their study in npj Genomic Medicine.

Marcus Pezzolesi, PhD, MPH, corresponding author of this new study and associate professor of internal medicine in the Division of Nephrology at the U of U College of Health, and colleagues set out to build upon previous studies identifying genetic mutations that resulted in the manifestation of type 2 diabetes, obesity, and other metabolic physical health complications. Earlier research identified these variants, observed either in or near the gene (ADIPOQ) that encodes adiponectin, and their association with the consequences of divergent levels of adiponectin in the body.

In their current work, which builds upon these previous findings, the authors described a family’s generational mutations in ADIPOQ with diabetes and end stage renal disease (ESRD). These are rare mutations resulting in significantly diminished circulating adiponectin, which the authors suggested is a protective substance negating the harm caused by ceramide accumulation, resulting in an increased risk of diabetes and renal disease.

With the goal of identifying a potential genetic link to the cause of diabetes and significant ESRD, the research team included three siblings, two parent-offspring pairs, two affected first-cousin pairs, and two pairs of affected first cousins once removed.

Using unified linkage analysis and rare variant association testing, where the enrichment of rare variants among these cases was compared with 524 ethnically matched background controls, the team identified a heterozygous 10-nucleotide deletion in exon 3 ADIPOQ (chromosome 3: 186,572,030; CCCGAGGCTTT-->C) shared by all six affected family members.

“In the past, we’ve seen sporadic cases here and there, but this is the first family to demonstrate that this mutation can be inherited,” stated Dr. Pezzolesi, who elaborated further, saying, “What’s exciting is that there are therapies being developed that could improve this condition not just within this family but more broadly among a vast spectrum of patients with diabetes who are at risk of kidney disease.”

According to corresponding author of the study, William Holland, PhD, associate professor of nutrition and integrative physiology at U of U College of Health, “What’s most exciting for me is that this finding allows us to confirm decades of research in animals.” Dr. Holland added, “The biological effects of adiponectin in regulating insulin sensitivity, glucose tolerance, and ceramide levels is well established in mice, and the current study shows that a loss of adiponectin impairs metabolic health in humans.”

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