Genetic Variant Linked with Kidney Failure in Women with Type 1 Diabetes But Not Men

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Within the nondiabetic population, women are relatively protected from kidney failure until menopause, but this protection is reduced in diabetic women. A new study published in the Journal of the American Society of Nephrology now helps explain gender-specific differences in kidney failure, as well as why some diabetic women are prone to develop it.

“More than 371 million people have diabetes worldwide, and diabetes is the leading cause of end stage renal disease that requires dialysis or kidney transplant for patient survival,” said first author Niina Sandholm, MSc, of Helsinki University Central Hospital and Folkhälsan Research Center, in Finland. “As gender differences exist in the development of kidney disease, our aim was to detect genetic variants that predispose diabetic patients to end stage renal disease in a gender-specific manner,” she explained.

Genetic clues revealed

Despite evidence that sex influences the risk of kidney failure in patients with type 1 diabetes, no large-scale sex-specific genetic studies had been reported until now. Sandholm, along with senior author Per-Henrik Groop, MD, DMSc, and their colleagues, conducted a genome-wide association study in a cohort of 3652 patients with type 1 diabetes who participated in the Finnish Diabetic Nephropathy (FinnDiane) Study.

The FinnDiane discovery cohort included 258 women and 387 men with kidney failure. These patients were compared with those without signs of diabetic nephropathy despite having a long duration of diabetes. To ensure that any genetic association with kidney failure was due to diabetes, the investigators excluded all patients with diabetes known to have end stage renal diseaes due to any nondiabetic cause.

The researchers identified a genetic variant, called rs4972593, on chromosome 2 that was linked with kidney failure in the women in the study. Additional analyses revealed that it was also linked with kidney failure in diabetic women in the United Kingdom, the United States, and Italy.

“The women with the risk variant had a nearly twofold risk of developing end stage renal disease, compared with the non-carriers,” Sandholm said. “We did not find any association with end stage renal disease in any of the studied groups of men.”

The genetic variant is located close to a gene—called SP3—that codes for a transcription factor that interacts with the estrogen receptor and also helps regulate kidney function. It will be interesting to see if this factor plays a role in the gender-specific protection against kidney failure seen in this study, researchers said.

Additional experiments revealed potential transcription factor–binding sites within rs4972593 and predicted eight estrogen-responsive elements within 5 kb of this locus, but the investigators stressed that a causal link cannot be made until more studies are performed.

“The identified risk variant is located between the SP3 and CDCA7 genes, and whereas the SP3 gene seems the most plausible causal gene of the region, we do not have any mechanistic information about how this variant predisposes diabetic women to end stage renal disease,” said Sandholm. The CDCA7 gene encodes a transcription factor that regulates cell proliferation and is frequently overexpressed in human cancers.

Additional studies needed

In an accompanying editorial, Marcus Pezzolesi, PhD, and Andrzej Krolewski, MD, PhD, both of the Joslin Diabetes Center in Boston, commented: “In identifying evidence of an association with end stage renal disease exclusively in women, this study offers the strongest evidence to date of a sex-specific genetic factor for diabetic nephropathy.” They added, however, that the findings need to be verified by additional studies.

They also stressed that a number of unanswered questions remain. For example, they asked, “Could the variant identified by Sandholm et al. purely be associated with increased survival among women with end stage renal disease rather than risk of end stage renal disease?”

“Although not addressed in this study, it remains possible that sex-specific competing risks could allow more women to survive end stage renal disease than men, Pezzolesi and Krolewski said. If true, the variant may be a consequence of its association with sex-specific survival of kidney failure rather than sex-specific risk for it, they explained.

The experts also stated that the study reflects an emerging shift in the strategy that investigators are using to search for diabetic kidney disease susceptibility genes. They believe that the genetic etiology underlying the risk of diabetic nephropathy and the factors that contribute to its development will eventually be discovered, the researchers said.

Notes

[1] Study co-authors include Amy Jayne McKnight, PhD, Rany M. Salem, PhD, Eoin P. Brennan, PhD, Carol Forsblom, DMSc, Valma Harjutsalo, PhD, Ville-Petteri Mäkinen, DSc(Tech), Gareth J. McKay, PhD, Denise M. Sadlier, MD, Winfred W. Williams, MD, Finian Martin, Prof BSc PhD, Nicolae Mircea Panduru, MD, MSc, PhD , Lise Tarnow, MD DMSc , Jaakko Tuomilehto, Prof. MD PhD, Karl Tryggvason, MD, PhD, Gianpaolo Zerbini, MD, Mary E. Comeau, BS, Carl D. Langefeld, PhD, Catherine Godson, BSc, PhD, Joel N. Hirschhorn, MD, PhD, Alexander P. Maxwell, MD, PhD, and Jose C. Florez, MD, PhD.

[2] Disclosures: Jose C. Florez has received consulting honoraria from Novartis, Lilly and Pfizer. Per-Henrik Groop has received lecture honorariums from Abbot, Boehringer Ingelheim, Cebix, Eli Lilly, Genzyme, Novartis, Novo Nordisk, MSD, and research grants from Eli Lilly, Roche. Per-Henrik Groop is also an advisory board member of Boehringer Ingelheim and Novartis.

[3] The article, entitled “Chromosome 2q31.1 Associates with ESRD in Women with Type 1 Diabetes,” is available online at http://jasn.asnjournals.org/, doi: 10.1681/ASN.2012111122.


January 2014 (Vol. 6, Number 1)