The investigators' objectives are to examine the longitudinal association of obesity and obesity-related factors and risk of incident herpes zoster (HZ), also known as shingles, and the longitudinal association of obesity and obesity-related factors and risk of developing post-herpetic neuralgia (PHN) among those with HZ. The investigators propose to examine more refined assessments of adiposity, leveraging the resources of several large-scale ongoing cohort studies of women and men with decades of follow-up and rich health-related data, including multiple validated anthropomorphic measures, medical history, dietary intake, and lifestyle factors. The investigators will also examine existing data on plasma adipokines, cytokines, and plasma metabolomics. The investigators will use the Nurses' Health Study (NHS I), Nurses' Health Study II (NHS II), and the Health Professionals Follow-up Study (HPFS) (total N>200,000) to prospectively investigate whether obesity and obesity-related factors influence the risk of developing HZ. The investigators have already identified >30,000 cases of incident HZ among the 3 cohorts (reported with high validity) and information on HZ continues to be collected. In addition, the investigators obtained detailed information on HZ course, complications (including PHN), treatment and other related factors on a Zoster Supplemental Questionnaire (ZSQ) administered to those participants in the NHS I and II who reported "shingles" on the main questionnaires (n=10,123 to date). The investigators will also administer the ZSQ to newly identified HZ cases identified on the 2023 NHS I and NHS II biennial questionnaires. No previous study has investigated the longitudinal relation between adiposity and risk of post-herpetic neuralgia (PHN). This study could provide important new insight into how obesity and obesity-related factors influence the risk of HZ, and the risk of developing PHN among individuals with HZ, and how alterations in circulating metabolites and metabolic pathways, including those that are obesity-related, are associated with risk of developing HZ and PHN.

Research Questions: Hypotheses

1. The investigators hypothesize that greater body adiposity is associated with increased risk of developing herpes zoster (HZ). Specifically, the investigators hypothesize that higher body mass index (BMI), larger waist circumference, and higher waist to hip ratio, waist to height ratio, predicted fat mass, predicted percent fat and ABSI are associated with increased risk of developing HZ. The investigators will also examine whether these associations differ by age, sex and other factors.
2. The investigators hypothesize that plasma biomarkers of obesity and of inflammation are independently and longitudinally associated with risk of HZ. Specifically, The investigators hypothesize that lower plasma total and high-molecular-weight (HMW) adiponectin, and higher plasma leptin, IL-6 and CRP are independently associated with higher risk of HZ.
3. The investigators hypothesize that greater body adiposity is associated with increased risk of developing postherpetic neuralgia (PHN). Specifically, The investigators hypothesize that higher body mass index, larger waist circumference, and higher waist to hip ratio, waist to height ratio, predicted fat mass, predicted percent fat and ABSI are associated with increased risk of developing post-herpetic neuralgia (PHN) among those who develop HZ.
4. The investigators hypothesize that obesity-related metabolic dysregulation contributes to HZ risk. Specifically, The investigators hypothesize that circulating levels of metabolites and metabolic pathways that are altered by adiposity and may influence cell-mediated immune function, such as glutamine, arginine, the branched chain amino acids isoleucine, leucine and valine, the tryptophan metabolite kynurenine, and certain fatty acids, such as lysophosphatidylcholines, are associated with risk of developing HZ.
5. The investigators hypothesize that obesity-related metabolic dysregulation contributes to risk of developing PHN among women with HZ. Specifically, the investigators hypothesize that alterations of plasma levels of certain metabolites and metabolic pathways previously implicated in chronic neuroimmune inflammation and increased neurosensitivity, including abnormal fatty acid and amino acid metabolism (e.g. arachidonic acid derived eicosanoids, glutamate-aspartate, tryptophan-kynurenine, and arginine-ornithine metabolic pathways), are associated with the development of PHN among women with HZ.

III. Objectives

A. Objective 1a: To examine whether anthropomorphic measures of obesity from early through middle and later adult life are independently and longitudinally associated with risk of HZ. The investigators will use information on BMI, waist circumference, hip circumference, predicted fat mass and percent fat, ABSI and HZ that has been longitudinally collected across the lifespan among >200,000 women and men. WThe investigators e hypothesize that higher body mass index (BMI), larger waist circumference, higher waist to hip ratio, higher waist to height ratio, higher predicted fat mass, predicted percent fat and ABSI are associated with increased risk of developing HZ. The investigators will also examine whether these associations differ by age, sex and other factors.

B. Objective 1b: To examine whether plasma biomarkers of obesity, the immunomodulatory adipokines leptin and adiponectin, and markers of inflammation, interleukin-6 (IL-6) and C-reactive protein (CRP), are independently and longitudinally associated with risk of HZ. Using existing plasma biomarker information from >19,000 participants, including over 2,500 that developed HZ after the time of the blood collection (incident HZ), the investigators will examine associations of these plasma biomarkers and risk of developing HZ, and examine whether the proposed association between obesity and HZ risk is mediated through immunomodulatory adipokines or inflammation. The investigators hypothesize that lower total and high-molecular-weight (HMW) adiponectin, and higher plasma leptin, IL-6 and CRP are independently associated with higher risk of HZ.

C. Objective 1c: To investigate whether anthropomorphic measures of obesity are associated with higher risk of developing postherpetic neuralgia (PHN) among women with HZ. In a substudy of over 10,000 NHS I and NHS II participants who reported a history of "shingles," the investigators collected detailed information on HZ course, treatment and related complications on a Zoster Supplemental Questionnaire (ZSQ). Information on PHN was validated by medical record review. The investigators hypothesize that higher body mass index, larger waist circumference, and higher waist to hip ratio, waist to height ratio, predicted fat mass, predicted percent fat and ABSI are associated with increased risk of developing PHN.

D. Objective 2a: To assess how obesity-related metabolic dysregulation contributes to HZ risk.

The investigators will conduct an agnostic analysis to identify individual metabolites and metabolic pathways associated with obesity among >13,000 women and men for whom the investigators have comprehensive information on plasma metabolomics profiles. The investigators hypothesize that circulating levels of metabolites and metabolic pathways that are altered by body adiposity and may influence cell-mediated immune function, such as glutamine, arginine, the branched chain amino acids isoleucine, leucine and valine, the tryptophan metabolite kynurenine, and certain fatty acids, such as lysophosphatidylcholines, are associated with risk of developing HZ. The investigators will create a metabolite-based obesity score and assess the degree to which the association between obesity and HZ risk is mediated by the metabolite-based obesity score. Secondarily, the investigators will conduct an agnostic investigation to identify individual metabolites and metabolic pathways associated with risk of developing HZ.

E. Objective 2b: To assess how obesity-related metabolic dysregulation contributes to risk of developing postherpetic neuralgia (PHN) among women with HZ. Among participants who had HZ and completed the Zoster Supplementary Questionnaire (ZSQ) that collected additional details about HZ course, complications and treatment, and for whom information on metabolomics information is available (n=1,005 to date), the investigators will assess the degree to which the potential association between obesity and PHN risk is mediated by the metabolite-based obesity score (developed in Aim 2a above). Secondarily, the investigators will conduct an agnostic investigation to identify individual metabolites and metabolic pathways associated with risk of developing PHN. The investigators hypothesize that alterations of plasma levels of certain metabolites and metabolic pathways previously implicated in chronic neuroimmune inflammation and increased neurosensitivity, including abnormal fatty acid and amino acid metabolism (e.g. arachidonic acid derived eicosanoids, glutamate-aspartate, tryptophan-kynurenine, and arginine-ornithine metabolic pathways), are involved in the development of PHN among women with HZ.

Inclusion Criteria:

• Participant in the NHS I, NHS II or HPFS cohort studies (n ~290,000)
• Provided information on weight and height at least one time
• Responded to at least one biennial questionnaire that included questions about HZ
• For the analyses examining obesity and risk of PHN, only participants in NHS I and NHS II who completed the ZSQ will be included

Exclusion Criteria:

• Reported date of HZ occurred before the study baseline
• Date of HZ cannot be determined
• Exposure information not available for the specific analysis

Objective 1a: All participants from the NHS I, NHS II and HPFS (n ~209,000) who were enrolled at baseline and responded to a questionnaire that asked about HZ will be considered for inclusion.

Objective 1b: All participants from the NHS I, NHS II and HPFS for whom plasma biomarker information is available will be considered for inclusion (n > 19,000).

Objective 1c: All NHS I and NHS II participants who completed the Zoster Supplemental Questionnaire (ZSQ) and for whom information on metabolomics information is available will be considered for inclusion (n=1,005 to date).

Objective 2a: All participants from the NHS I, NHS II and HPFS for whom we have comprehensive information on plasma metabolomics profiles (n >13,000) will be considered for inclusion.

Objective 2b: All NHS I and NHS II participants who completed the ZSQ and for whom information on metabolomics information is available will be considered for inclusion (n=1,005 to date).

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