**3. Genetics influence on infection and risk of infertility**

microorganisms contacting with sperm and eventually monitoring the health of male genito‐ urinary organs. In fact, re-evaluating sperm characteristics of patients treated would help to

Initially, in the 1980s, human immunodeficiency virus (HIV) was found in the mononuclear cell fraction of the semen of one HIV-1-seropositive man and two men developing acquired immunodeficiency syndrome. [61] In the early period of the epidemic, those individuals diagnosed as HIV positive were not estimated to live a long life. [62] Since the HIV and AIDS were identified, in the management and long-term prognosis for infected people, vital

According to the WHO, about 75 million people have been infected with the HIV and more than 30 million humans have died of it. During the past 20 years, it has been extensively researched on the field of HIV infection, which invades the human immune system. In Sub-Saharan Africa remaining severely influenced, about 1 in 20 adults is infected by HIV and the

With the appearance and especially the development of the immunodeficiency syndrome pandemic, attention of the sexual transmission of viruses in human population and its health effects has peaked accordingly. [61] HIV that causes AIDS is the most enormously studied virus among the sexually transmitted viruses. Some studies assessed the influence of HIV infection on sperm parameters in HIV-positive men. Researchers analyzed the association between markers of HIV infection and characteristics of semen. For example, a significant correlation between sperm count and CD4 cell count was demonstrated. Compared with fertile men, HIV-positive men's semen volume, sperm motility, and total sperm count were impaired. Dulioust et al. [64] investigated almost 200 HIV-infected men free from AIDS symptoms on the semen characteristics. Standardized methodology was used to analyze the semen samples collected. However, they did not observe any relation between HIV infection and semen characteristics. In the study of HIV-infected men, the semen changes may be not remarkable enough to affect fecundity greatly. The perfect study design of larger patient size is a longitu‐ dinal cohort study, which describes semen parameters during the development of an HIV

Studies showed that fertility was lower in HIV-1–infected women than the controls in Sub-Saharan Africa. It was the first time to suggest that HIV/AIDS was related to the fertility defects. [66] Recently, more studies indicate that fertility rates in HIV-infected women have decreased in the United States. [67] Among HIV-1–infected women, subfertility may be explained by biological alterations in reproductive physiology. Based on a reproductive endocrinology, HIV-infected women are more likely to have amenorrhea and protracted anovulation com‐ pared to the uninfected women. [68, 69] Many studies have linked HIV infection with prema‐ ture ovarian failure. Additionally, pregnancy-related problems will continue after conception. In several clinical studies, it is more common that HIV-infected women may have pregnancy loss. [66] The correlation between HIV infection and infertility is a significant area for further research and investigation. The observations of those studies demonstrate that access to

confirm the role of bacterial presence of the observed sperm abnormalities.

**2.9. Human immunodeficiency virus infection and infertility**

number accounts for 71% of the infected people globally. [63]

advances have been made.

242 Genital Infections and Infertility

infection. [65]

About7%ofmenfromthegeneralpopulationareinfertileand11.3%ofmarriedwomensuffering from infertility. [70, 71] Genetic inheritance could influence risk of many diseases like infertili‐ ty. Over the last two decades, the genes responsible for many rare reproductive disorders have been identified by genetic linkage mapping with multiple affected individuals. [72] In male infertility, a cause for infertility cannot be identified in almost half cases. Severe spermatogen‐ esis impairment is likely a genetic condition in many male infertility cases. [73] In female infertility, genetic factors also contribute to risk of many diseases, such as uterine fibroids, endometriosis, and tubal damage. Common genetic variants in complex diseases are simpler to detect by population studies (case–control study). Genome-wide association study (GWAS) is a developed method to study the genetic variants in population-based studies. GWAS methods could provide a powerful approach for mapping disease gene. [74] Single nucleo‐ tide polymorphisms (SNP) array and next-generation sequencing (NGS) could provide critical new date on rare variants. More than 30 million SNPs that segregate in human population have been identified. Gene discoveries from GWAS may not provide results that translated immedi‐ ately into the clinic. They are the starting point to understand disease biology and already provided novel insights into biological pathways and novel biomarkers. [74]

In previous part, we have reviewed the association of infection and infertility, since gene polymorphism could influence infertility and infection status could also been influenced by gene polymorphism; therefore, we summarize the literatures reporting genetics influence on infection and risk of infertility below, because male and female infertility have different causes and subgroups; here we discussed them in two aspects.

#### **3.1. Gene polymorphism influence infection and risk of male infertility**

Even though many articles have been reported the association of gene polymorphism with male infertility, the association between gene polymorphism influencing infection and male infertility is limited to only two reports. [75, 76] As we know, unique immune environment of the testis is very important for spermatogenesis. Cytokines play critical roles in the mainte‐ nance of immune environment of the testis. Members of the interleukin-1 (IL-1) family are pleiotropic cytokines involved in the regulation of junction dynamics during spermatogenesis and further increase on infection. Recently, the polymorphism of the human IL-1B gene (C +  3953T) has been reported to associate with male infertility in asthenozoospermic patients from an Indian population. [75] In that study, the author found that the genotype frequencies of the IL-1B Taq C/T polymorphism were significantly higher in asthenozoospermic patients (OR=10.4; CI, 2.50–43.96). Meanwhile, the author also found the association of variable number tandem repeat (VNTR) polymorphism of the interleukin (IL)-1 receptor antagonist gene (ILRN) with male infertility before. [76] The study indicated that risk of IL1RN2 polymorphism with male infertility (OR=1.43; CI, 1.1546–1.7804). In these two articles, we can find that the polymorphisms of IL-1 were both studied in these articles. One reason might be that these two studies carried by one research group and another reason might be that IL-1 plays important roles in testicular microenvironment. However, the total numbers of male subjects recruited in these two studies were limited to 452–689. So, it may lack sufficient statistical data to show the real association. Besides, the males in these studies were all Indians; therefore, further confirmation of the association in other ethnic population are needed. In addition, interactions of gene–gene and gene–environment factors were not considered. Environmental exposure of some chemicals or habits and customs of subjects such as smoking or drinking could influence the association of gene polymorphism and infertility. [77, 78] So we have reason to believe that the infection status could also impact the association of polymorphism and risk of infertility. Subjects with the same polymorphisms but different infection status may have different risk of infertility. Similarly, subjects with the same infection status but different polymorphisms may also have different risks. Thus, more complete researches are needed to determine the association of genetic polymorphism influencing infection and risk of male infertility in different subgroups and different infection status.

The associations between gene polymorphism and male infertility have been relatively widely investigated. However, the associations of gene polymorphism influencing infection and risk of male infertility were rarely confirmed. This may be the reason that researchers often focus on the polymorphism of genes playing roles in spermatogenesis. Since infection could increase the risk of infertility, more gene polymorphisms influencing infection are needed to be confirmed to be associated with male infertility in the future.

#### **3.2. Gene polymorphisms influence infection and risk of female infertility**

Tubal factor infertility (TFI) is one of the most common female infertility, and chronic inflam‐ mation induced by *C. trachomatis* can lead to TFI. The immune response is linked to cytokine secretion pattern, which is influenced by the host genetic background. So the associations between polymorphism of cytokine and TFI have caused researchers' concern. The HLA systems control immune responses by representing antigenic epitopes to immune T cells. By analyzing HLA class II alleles (DQA1 and DQB1) and CHSP60-specific lymphoproliferative responses in TFI patients and healthy controls, Kinnunen et al. [79] found that DAQ1\*0102 and DQB1\*0602 alleles together with IL-10-1082AA genotype were more significantly frequently in the TFI patients. Cohen et al. [80] also found that HLA-DR1\*1503 and DRB5\*0101 alleles were more commonly in *C. trachomatis* microimmunofluorescence seronegative women with infertility, and these alleles may lead to an immunologically mediated mechanism of protection against *C. trachomatis* infection–induced TFI. In 2015, Jansen et al. [81] analyzed the association of HLA-A rs1655900: G>A and susceptibility of *C. trachomatis* infection in a STD cohort and found that the carriage of HLA-A rs1655900 has no effect on susceptibility but might be protective to the development of late complications, especially tubal pathology could be relevant.

(OR=10.4; CI, 2.50–43.96). Meanwhile, the author also found the association of variable number tandem repeat (VNTR) polymorphism of the interleukin (IL)-1 receptor antagonist gene (ILRN) with male infertility before. [76] The study indicated that risk of IL1RN2 polymorphism with male infertility (OR=1.43; CI, 1.1546–1.7804). In these two articles, we can find that the polymorphisms of IL-1 were both studied in these articles. One reason might be that these two studies carried by one research group and another reason might be that IL-1 plays important roles in testicular microenvironment. However, the total numbers of male subjects recruited in these two studies were limited to 452–689. So, it may lack sufficient statistical data to show the real association. Besides, the males in these studies were all Indians; therefore, further confirmation of the association in other ethnic population are needed. In addition, interactions of gene–gene and gene–environment factors were not considered. Environmental exposure of some chemicals or habits and customs of subjects such as smoking or drinking could influence the association of gene polymorphism and infertility. [77, 78] So we have reason to believe that the infection status could also impact the association of polymorphism and risk of infertility. Subjects with the same polymorphisms but different infection status may have different risk of infertility. Similarly, subjects with the same infection status but different polymorphisms may also have different risks. Thus, more complete researches are needed to determine the association of genetic polymorphism influencing infection and risk of male infertility in

The associations between gene polymorphism and male infertility have been relatively widely investigated. However, the associations of gene polymorphism influencing infection and risk of male infertility were rarely confirmed. This may be the reason that researchers often focus on the polymorphism of genes playing roles in spermatogenesis. Since infection could increase the risk of infertility, more gene polymorphisms influencing infection are needed to be

Tubal factor infertility (TFI) is one of the most common female infertility, and chronic inflam‐ mation induced by *C. trachomatis* can lead to TFI. The immune response is linked to cytokine secretion pattern, which is influenced by the host genetic background. So the associations between polymorphism of cytokine and TFI have caused researchers' concern. The HLA systems control immune responses by representing antigenic epitopes to immune T cells. By analyzing HLA class II alleles (DQA1 and DQB1) and CHSP60-specific lymphoproliferative responses in TFI patients and healthy controls, Kinnunen et al. [79] found that DAQ1\*0102 and DQB1\*0602 alleles together with IL-10-1082AA genotype were more significantly frequently in the TFI patients. Cohen et al. [80] also found that HLA-DR1\*1503 and DRB5\*0101 alleles were more commonly in *C. trachomatis* microimmunofluorescence seronegative women with infertility, and these alleles may lead to an immunologically mediated mechanism of protection against *C. trachomatis* infection–induced TFI. In 2015, Jansen et al. [81] analyzed the association of HLA-A rs1655900: G>A and susceptibility of *C. trachomatis* infection in a STD cohort and found that the carriage of HLA-A rs1655900 has no effect on susceptibility but might be

different subgroups and different infection status.

244 Genital Infections and Infertility

confirmed to be associated with male infertility in the future.

**3.2. Gene polymorphisms influence infection and risk of female infertility**

As one of the most important cytokines, the associations between IL polymorphisms and *C. trachomatis*–related female infertility also have been widely studied. To investigate the genetic basis of Chlamydia-associated infertility and various manifestations of tubal damage, Ohman et al. [82] studied polymorphisms in cytokine genes, including IL-10, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta1, and IL-6, by a case–control study. The results suggested that IL-10 AA genotype and the TNF-alpha A-allele could increase the risk of severe tubal damage in women with *C. trachomatis* –related TFI. Meanwhile, in an *in vitro* study, to study the relationship between IL-10 promoter polymor‐ phism and cell-mediated immune response, the researcher analyzed lymphocyte proliferation and cytokine, including IL-10, IFN-gamma, TNF-alpha, IL-2, IL-4, and IL-5, in subjects with different IL-10 genotypes. Results indicated that impaired cell-mediated response to *C. trachomatis* is associated with IL-10 genotype in subjects with high IL-10–producing capacity. [83] Unlike mentioned in male infertility, IL-B and IL-1RN gene polymorphisms are not associated with *C. trachomatis* –related TFI. [84] A polymorphism of NALP3 (gene symbol CIAS1) has been associated with decreased IL-1 levels and increased occurrence of vaginal Candida infection. Witkin et al. [85] selected women undergoing *in vitro* fertilization and tested polymorphism in intron 2 of the gene coding for NALP3 from their DNA. Researcher con‐ cluded that the CIAS1 7 unit repeat polymorphism could increase the likelihood of mycoplas‐ ma infection–associated female infertility.

Mannose-binding lectin (MBL) could activate the complement, modifies inflammation, and is involved in apoptotic cell clearance. [86] To study the role of MBL in tubal damage and female fertility, in 2010, Laisk et al. [87] performed a case–control study and found that MBL2 lowproducing genotypes were associated with an increased incidence of pathogens associated with genital tract infections, hyper-producing MBL2 genotype HYA/HYA and low-producing MBL2 genotypes were associated with susceptibility to TFI, high-producing genotype HYA/LYA has a protective effect. In 2011, Laisk et al. [88] also compared four polymorphisms in MBL2 by a case–control study and found that the low-producing MBL2 genotypes were associated with susceptibility to TFI. Besides, the low-producing genotypes showed associa‐ tion of early pregnancy loss in IVF treatment.

Besides the most studied genetic polymorphisms, major histocompatibility complex class I chain–related A (MICA) gene is a potential host genetic candidate for *C. trachomatis* infections. To study the effect of MICA on the susceptibility to *C. trachomatis* infection and its association with tubal pathology, researcher selected 214 infertile women and found that women with tubal infertility more often had antibodies to *C. trachomatis*. Results suggested that the MICA locus might modify host susceptibility to *C. trachomatis* infection. [89]

From the literatures mentioned above, we can see that most of them are mainly in the study of TFI induced by *C. trachomatis*, the reason may be that *C. trachomatis* is the most common bacterial cause of sexually transmitted infections. [90] The numbers of subjects recruited in above studies are also limited (from 113 [79] to 811 [81]), and most of them were below 300 subjects. The mechanism of the genetic polymorphism is also limited. Besides, the interactions of these genetic polymorphisms were not carried in these studies. Thus, further study, including more detail mechanism and more subjects from different countries or race, is needed.

In conclusion, genetic inheritance influences the risk of many reproductive disorders; genetic polymorphism could also increase the risk of infertility. The studies demonstrating the polymorphisms influencing infection and infertility were relatively rare. To date, studies on reproductive and genetic inheritance have used relatively small samples. More and more cohorts have been established or in preparation, so further genetic maker studies in larger samples with detail phenotypes and clinical information should be considered into disease risk classification. Along with detail environment and gene information, gene–gene and gene– environment interactions also shall be added in further studies. Since GWAS method has been widely improved to study other diseases, we can carry out infection and infertility researches by GWAS, so more and more genetic polymorphisms influencing infection and risk of infertility can be found out in the future. The system researches can provide theoretical and experimental support for clinical diagnosis and treatment guide.
