Gender-Specific Association Between FSHR and PPARG Common Variants and Human Longevity

Rosa Maria Corbo,1,3 Alessandro Pinto,2 and Renato Scacchi3

Abstract

Men and women have different life expectancies. Not unexpectedly, several genes involved in life span deter- mination have been found to influence the probability of achieving longevity differently in men and women. This investigation examines the association between longevity and polymorphisms of follicle-stimulating hor- mone receptor (FSHR, Asn680Ser polymorphism) and peroxisome proliferator-activated receptor gamma (PPARG, Pro12Ala polymorphism), two genes that previous investigations suggested may exert a gender- specific influence on human longevity. A sample of 277 individuals (mean age, 82.9 – 5.7years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving over 90 years (long-lived) or not (controls). The frequency of the FSHR 680 Ser/Ser genotype was significantly higher in the sample of long-lived women compared to controls, indicating that the FSHR 680 Ser/ Ser genotype may favor survival to more than 90 years of age only in women (odds ratio [OR] = 4.21; 95% confidence interval [CI], 1.10–16.10, p = 0.036). In contrast, the frequency of the PPARG Pro/Ala genotype was significantly higher in the sample of male subjects who died before 90 years of age than in the long-lived, suggesting that carrying the PPARG Pro/Ala genotype may prevent the attainment of advanced age only in men (OR = 0.13; 95% CI, 0.02–0.79; p = 0.03). We then searched the literature for studies reporting a differential role for the genetic component in male and female longevity. To do this, we selected longevity genes with a gender- specific effect. A review of the studies showed that genetic factors tend to have a greater relevance in deter- mining longevity in men than in women. The possible impact of this phenomenon is discussed.

Introduction

disease.2–4 Not unexpectedly, among the various genetic factors involved in life span determination, some have been found to have a gender-specific effect, influencing the probability of achieving longevity differently between men and women.5–7

life expectancies. This widespread phenomenon can be traced back across populations at least to the 18th century.1 Epidemiological data indicate that the higher mortality of men for all leading causes of death, including accidents and such diseases as cancer or heart disease, influenza, and pneumonia, could account for this gender gap in aging.1

In the present study, we investigated the possible associ- ation between longevity and follicle-stimulating hormone receptor (FSHR) and peroxisome proliferator-activated re- ceptor gamma (PPARG), two genes that could have a gen- der-specific influence on human longevity. The FSHR gene (OMIM 136435), located on chromosome 2p21, encodes the receptor of the follicle-stimulating hormone (FSH), a go- nadotropin essential for normal reproductive function in males and females.8 It is a member of the hypothalamic– pituitary–gonadal axis that regulates the production of sex steroids, including estrogen. Its action is mediated by the FSH receptor, a member of the family of G protein–coupled receptors, located on the surface of Sertoli cells in the testis and the granulosa cells in the ovary.8

Much research has gone into attempts to clarify to what extent human aging and longevity are dependent on genetic factors. Numerous studies using animal models (Cae- norhabditis elegans, Drosophila melanogaster) have helped to identify longevity genes in the strict sense, i.e., those be- longing to pathways that delay the onset and/or reduce the rate of aging (e.g., stress resistance and oxidative damage or inflammation or DNA repair).2–4 Studies on human longev- ity have suggested that some polymorphic genes may in- fluence life span through their association with common

1Department of Biology and Biotechnology, La Sapienza University, Rome, Italy. 2Experimental Medicine Department, Food Science and Human Nutrition Research Unit, La Sapienza University, Rome, Italy. 3CNR Institute of Molecular Biology and Pathology, Rome, Italy.

had since died) and those aged 90 years or older in 2009. The control sample was made up of individuals who had died between 2000 and 2009 before reaching age 90 years.

Two FSHR non-synonymous single-nucleotide polymor- phisms (SNPs) (rs 6165 and rs 6166) are widely distributed in human populations (ALFRED, http://alfred.med.yale.edu/ alfred/index.asp/) and have usually been found in strong linkage disequilibrium.8 In a previous study investigating the possible determinants of the higher prevalence of late- onset sporadic Alzheimer disease (AD) in women, we found that a FSHR genotype was associated with a significantly lower risk of AD only in women, suggesting a gender- specific protective role of the FSHR genotype against AD susceptibility.9

The protocol for the collection of biological material for the scientific studies was approved by the institutional com- mittees (Local Health Unit, Salerno 3). The study was ap- proved by the Department Board (12/06/2009 session) of the former Department of Genetics and Molecular Biology of La Sapienza University, Rome. Written informed consent was obtained from all subjects.

Venous blood was drawn in ethylenediaminetetraacetic acid (EDTA) from all subjects. Genomic DNA was extracted from whole blood according to the procedure described by Miller et al.17 The two FSHR SNPs were genotyped accord- ing to the techniques reported by Sudo et al.18 The PPARG Pro12Ala polymorphism was investigated by PCR using the primers reported by Mori et al.19 The PCR product was di- gested overnight by HhaI, examined on an agarose gel, and detected using ethidium bromide.