Burden of Common Complex Disease Variants in the Exomes of Two Healthy Centenarian Brothers.

Background: It is not understood whether long-term good health is promoted by the absence of disease risk variants, the presence of protective variants, or both. We characterized the exomes of two exceptionally healthy centenarian brothers aged 106 and 109 years who had never been diagnosed with cancer, cardiovascular disease, diabetes, Alzheimer's disease, or major pulmonary disease.

Objective: The aim of this study was to gain insight into whether exceptional health and longevity are a result of carrying fewer disease-associated variants than typical individuals.

Functional characterization of genetic polymorphisms in the H2AFX distal promoter.

Due to the critical role of the H2AX histone variant in double-strand break repair, genetic variants in the H2AX gene, H2AFX, may influence cancer susceptibility. Genetic association studies have correlated H2AFX upstream variants with cancer risk; however it is unclear if any are causal. H2AFX has at least two alternate transcripts that encode the same reading frame; a short 0.

Sex- and subtype-specific analysis of H2AFX polymorphisms in non-Hodgkin lymphoma.

H2AFX encodes a histone variant involved in signaling sites of DNA damage and recruiting repair factors. Genetic variants in H2AFX may influence risk of non-Hodgkin lymphoma (NHL), a heterogeneous group of lymphoid tumors that are characterized by chromosomal translocations. We previously reported that rs2509049, a common variant in the promoter of H2AFX, was associated with risk for NHL in the British Columbia population.

Genetic polymorphisms at TIMP3 are associated with survival of adenocarcinoma of the gastroesophageal junction.

The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma.

Genetic variation within the hypothalamus-pituitary-ovarian axis in women with recurrent miscarriage.

Background: Recurrent miscarriage affects 1-2% of couples trying to conceive, and is idiopathic in nearly half. Female fertility is controlled by the hypothalamus-pituitary-ovarian (HPO) axis and we hypothesize that genetic polymorphisms affecting the function of genes involved in regulating the HPO axis will be associated with recurrent miscarriage.

Methods: Whole peripheral blood DNA from 227 women with recurrent miscarriage and 130 control women was obtained for this study.

Fertility and aging: do reproductive-aged Canadian women know what they need to know?

Objective: Female fertility declines with age; however, women are increasingly delaying childbearing until later in their reproductive years. One of the factors that may contribute to this trend is a general lack of knowledge about the decline in fertility with age.

Design: Self-report survey.

Telomere length and reproductive aging.

Background: Rate of reproductive aging may be related to rate of biological aging. Thus, indicators of aging, such as short telomere length, may be more frequent in women with a history suggestive of premature reproductive senescence.

Methods: Telomere-specific quantitative PCR was used to assess telomere length in two groups of women with evidence of reproductive aging: (i) patients with idiopathic premature ovarian failure (POF, N = 34) and (ii) women with a history of recurrent miscarriage (RM, N = 95); and two control groups: (1) women from the general population (C1, N = 108) and (2) women who had a healthy pregnancy after 37 years of age (C2, N = 46).

Estrogen receptor alpha gene polymorphisms are associated with idiopathic premature ovarian failure.

Objective: To assess the role of hormone receptor/binding protein variants in genetic predisposition to premature ovarian failure (POF).

Design: Case-control study.

Setting: Academic.

Skewed X-chromosome inactivation is associated with primary but not secondary ovarian failure.

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40, and may present with either primary or secondary amenorrhea. Numerous cases of POF in women with X-chromosome deletions or translocations have been reported; thus, it is possible that smaller rearrangements undetectable by conventional cytogenetics may contribute to POF in some patients. In females with an abnormal X chromosome, cells with inactivation of the normal X may be selected against, causing skewed X-chromosome inactivation (XCI).

The association of skewed X chromosome inactivation with aneuploidy in humans.

Recently, we reported that skewed X chromosome inactivation (XCI) was more common in women who had experienced a trisomic pregnancy as compared to control women. Rather than an overall shift in the distribution of skewing there appears to only be an excess of extreme (= 95%) skewing. Further analysis of our data reveals that the increase in skewed XCI is dependent on which chromosome is involved in the trisomy and how many trisomies the woman has experienced, although sample sizes in each group are small.

FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure.

Premature ovarian failure (POF) is the occurrence of menopause before the age of 40 and affects 1% of the female population. Whereas the etiology of POF is largely unexplained, FMR1 premutation carriers are known to be at increased risk of POF compared with the general population. The FMR1 premutation alleles have 55-200 copies of a CGG repeat in the 5' untranslated region of the FMR1 gene.