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Less Painful Childbirth Associated With Rare Variant in Ion Channel Gene

NEW YORK – Researchers have uncovered a rare gene variant that may make giving birth less painful for some women.

While childbirth is commonly a painful experience, the level of pain women encounter during labor varies. For their study, a group led by researchers at the University of Cambridge identified about 1,000 women in the UK who did not request pain relief during the full-term, vaginal birth of their first child. 

After finding that this group of women had slightly higher pain thresholds than women who sought pain relief, the researchers identified a rare variant in the KCNG4 gene, which encodes an ion channel, that was more common among the women who did not need pain relief. They further found through mouse studies that this variant affects neuron excitability, as they reported in Cell Reports on Tuesday.

"It is unusual for women to not request gas and air or epidural for pain relief during labor, particularly when delivering for the first time," first author Michael Lee, an anesthesiologist at Cambridge, said in a statement. "When we tested these women, it was clear their pain threshold was generally much higher than it was for other women."

After further screening the women,189 who met the inclusion criteria provided consent and DNA samples for analysis. Of those, 39 women further consented to psychometric and sensory testing. 

Compared to a cohort of 33 control women who sought pain relief during labor, the test group exhibited a higher pain threshold for heat, cold, and mechanical pressure, but no difference in emotional or cognitive abilities that would affect pain perception.

The researchers split their cohort of 158 women who did not need pain relief and provided enough DNA for molecular analysis into a discovery cohort of 100 women and a replication cohort of 58 women. After sequencing the exomes of the discovery cohort, the researchers noticed a rare allele affecting KCNG4 that was overrepresented among the women, appearing three times instead of the expected 0.7 times. These three individuals were heterozygous for the allele, which the researchers confirmed through Sanger sequencing. One additional woman in the replication cohort was also heterozygous for the allele.

KCNG4 encodes a voltage-gated potassium channel and the rare allele causes a missense change. Three of the women with this allele underwent pain threshold tests and had an increased cuff-pressure pain threshold as compared to controls, suggesting the rare allele can influence labor pain.

In a series of mouse studies, the researchers found that the KCNG4 variant affects the function of the Kv6.4 subunit. Typically, this subunit trafficks to the plasma membrane with Kv2.1, but those affected by the rare variant do not form heterotetramers with Kv2.1 and do not traffic to the plasma membrane. Additionally, mouse uterine neurons that overexpress the altered subunit have a higher-than-usual action potential threshold, which could account for why women with this variant experience less pain.

"The genetic variant that we found in women who feel less pain during childbirth leads to a 'defect' in the formation of the switch on the nerve cells. In fact, this defect acts like a natural epidural," senior co-author Ewan St. John Smith said in a statement. "It means it takes a much greater signal — in other words, stronger contractions during labor — to switch it on. This makes it less likely that pain signals can reach the brain." 

 The researchers added that Kv6.4 could represent a possible druggable target to mitigate labor pain.