Neil Normand

Unique variation in genetic selection among Black North American women and its potential influence on pregnancy outcome.

We hypothesize that variations in the frequency of genetic polymorphisms, reflecting ancestral differences in living conditions and exposure to microorganisms, increase susceptibility to adverse pregnancy outcome among present day Black North American women. Striking differences were observed in the frequency of genetic variants between Black and White or Hispanic women in 5 genes (IL1RN, MBL2, PPARA, ATG16L1, CIAS1) associated with inflammation and anti-microbial immunity. The CIAS1 and IL1RN polymorphisms were associated with altered interleukin-1β serum levels; the MBL2 polymorphism resulted in a decreased serum mannose-binding lectin concentration. Gene polymorphisms associated with an alteration in innate immunity were most frequent in Black women. This may reflect an evolutionary selection in response to an ancient environment containing a high multitude of microorganisms, and may increase susceptibility of Black women to infection-associated preterm birth in the current North American environment.

Genetic polymorphism in an inflammasome component, cervical mycoplasma detection and female infertility in women undergoing in vitro fertilization

The inflammasome is an inducible cytoplasmic structure that is responsible for production and release of biologically active interleukin-1 (IL-1). A polymorphism in the inflammasome component NALP3 has been associated with decreased IL-1 levels and increased occurrence of vaginal Candida infection. We hypothesized that this polymorphism-induced variation would influence susceptibility to infertility. DNA was obtained from 243 women who were undergoing in vitro fertilization (IVF) and tested for a length polymorphism in intron 2 of the gene coding for NALP3 (gene symbol CIAS1). At the conclusion of testing the findings were analyzed in relation to clinical parameters and IVF outcome. The frequency of the 12unit repeat allele, associated with maximal inflammasome activity, was 62.3% in cases of female infertility vs. 75.6% in cases where only the male partner had a detectable fertility problem (p=0.0095). Conversely, the frequency of the 7unit repeat allele was 28.9% in those with a female fertility problem, 17.0% in women with infertile males and 18.4% in idiopathic infertility (p=0.0124). Among the women who were cervical culture-positive for mycoplasma the frequency of the 7unit repeat was 53.7% as opposed to 19.5% in those negative for this infection (p<0.0001). We conclude that the CIAS1 7unit repeat polymorphism increases the likelihood of mycoplasma infection-associated female infertility.

Fas (TNFRSF6) gene polymorphism in pregnant women with hemolysis, elevated liver enzymes, and low platelets and in their neonates

OBJECTIVE: To estimate whether an A>G polymorphism at position −670 in the gene coding for Fas (gene symbol TNFRSF6) is associated with hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome. METHODS: In a retrospective study, buccal swabs from 81 women with the complete form of HELLP syndrome and 83 normotensive control women with uncomplicated full-term pregnancy, and 110 of their neonates, were analyzed for the presence of the TNFRSF6–670 polymorphism. Investigators were blinded to clinical outcomes. RESULTS: Pregnant women heterozygous for the TNFRSF6–670 genotype were more likely than those homozygous for TNFRSF6–670*A allele to have HELLP syndrome (P = .01; odds ratio 2.7, 95% confidence interval 1.2–5.9). Moreover, patients with homozygous carriage of the TNFRSF6–670*G allele were more likely than those homozygous for the wild type of the Fas gene (TNFRSF6–670*A/A) to have HELLP syndrome (P = .006; odds ratio 4.0, 95% confidence interval 1.7–9.8). In contrast, TNFRSF6–670 genotype distribution of neonates born to mothers with HELLP syndrome was not statistically different from that found in neonates born to healthy pregnant women (P = .4). In patients with HELLP syndrome, no association between TNFRSF6 genotype distribution and severity of hemolysis, platelet counts or liver enzymes levels was noted. CONCLUSION: A single A>G nucleotide substitution at position −670 in the maternal but not neonatal TNFRSF6 gene coding for Fas is associated with a higher risk for HELLP syndrome. LEVEL OF EVIDENCE: II-2

Association of cyclooxygenase-2 and interleukin-1 receptor antagonist gene polymorphisms with the time interval between labor induction and delivery

OBJECTIVE The interval between induction and delivery may change in association with different polymorphisms in genes regulating inflammation. STUDY DESIGN Seventy participants in a trial for induction of labor at term were tested for a -765 G>C cyclooxygenase-2 and an intron 2 length interleukin-1 receptor antagonist gene polymorphism. RESULTS The interleukin-1 receptor antagonist allele 2 frequency was 33.3% in the 12 women who delivered at < or =10 hours, compared with 13.8% in those delivered >10 hours (P = .03). The interleukin-1 receptor antagonist allele 2 frequency was 25.0% in women induced because of postdates as opposed to 7.9% induced for other indications (P = .01). The cyclooxygenase-2 allele C frequency was 30.0% in 35 women delivered at < or =20 hours as opposed to 11.4% in women delivered at >20 hours (P = .01). The cyclooxygenase-2 allele C frequency was 26.9% in 26 subjects induced because of postdates as opposed to 13.6% induced for other indications (P = .07). CONCLUSION Cyclooxygenase-2 allele C and interleukin-1 receptor antagonist allele 2 are associated with a reduced time interval from labor induction to delivery.

Interferon-gamma gene polymorphism influences the frequency of a Chlamydia trachomatis cervical infection in young women.

Summary Cervicitis associated with Chlamydia trachomatis is frequent worldwide, but the factors determining susceptibility to infection remain incompletely determined. We evaluated whether a functional single nucleotide polymorphism at position +874 in the gene coding for interferon gamma (rs2430561) influenced the likelihood of having a cervical C. trachomatis infection. This was a cross-sectional study of 142 sexually-active women attending a general gynaecology service on the outskirts of the city of Fortaleza in northeastern Brazil between August 2011 and August 2012. Endocervical swabs were evaluated for C. trachomatis DNA using hybrid capture. DNA from buccal swabs was utilised for detection of the interferon gamma 874 T/A single nucleotide polymorphism by gene amplification, endonuclease digestion and gel electrophoresis. Nineteen women (13.4%) were positive for C. trachomatis in their cervix. Positivity was 21.7% in women with the A,A genotype versus 7.0% in women with one or two T alleles (p = 0.0227). The variant T allele frequency, associated with elevated interferon gamma production, was 36.2% in women who were negative for C. trachomatis as opposed to 18.4% in women who were positive for a cervical infection with this organism (p = 0.0415). Possession of the T allele at position +874 in the gene coding for interferon gamma is associated with a reduced likelihood of a C. trachomatis cervical infection.