Muhammad B. Yunus, MD

Although familial occurrence of fibromyalgia syndrome (FMS) has been commonly observed, data on genetic role in this condition are limited. A few studies have reported familial aggregation and association with HLA, and we have studied genetic linkage of FMS with HLA in multicase families.

Familial Aggregation, Pellegrino, et al (Arch Phys Med Rehabil 1989; 70: 61-63) studied 17 patients with FMS from a support group and their 50 close relatives (parents and siblings), and found that 52% of the relatives studied had fibromyalgia. Based on their analysis, they suggested an autosomal dominant inheritance. Buskila, et al (J Rheumatolo 1997; 24:941-944) randomly selected 30 patients with FMS from their rheumatology clinic and studies 91 of their first degree relatives (FDRs) (parents, siblings and children) and found that 26% of the FDRs had FMS (14% among males and 41% in the female). Since the prevalence of FMS in the community is around 2-3%, these data suggest familial aggregation. However, such aggregation may result from a common family environment and/or from genetic influence.

HLA Association, Burda, et al (Clin Exp Rheumatol 1986; 4: 355-357) HLA typed class I and II antigens among 18 patients with FMS and 23 normal controls and found a significant association with DR4. The numbers studied are obviously small. Branco, et al (J Musculoske Pain 1996; 4: 21-27) studied 52 patients with FMS and 869 normal controls with HLA typing and found a statistically significant association with HLA B58, DR8 and DR5. However, Horven, et al in an earlier report (J Rheumatol 1992; 19: 1269-1270) found no HLA association among 60 patients with FMS, as compared with 159 controls. These inconsistencies of results from different centers may reflect a weak or no true association of FMS with HLA, or perhaps the confounding effects of heterogeneity among the fibromyalgia patients.

HLA Linkage Study. While HLA association of a disease may be due to genetic factors, it may also result from several biases, including selection or referral bias. HLA linkage analysis of multicase families, on the other hand, is very helpful in determination of genetic linkage. We studied 40 multicase families with fibromyalgia where at least one FDR besides the proband also had FMS. Forty probands of 107 of there available FDRs were studied by a clinical protocol and HLA typed for class I and II antigens. Depression was assessed by Zung depression scale. FMS was diagnosed by ACR criteria. Haplotypes were determined without any knowledge of the diagnosis. For linkage analysis, we used two powerful sibship tests, ie, criterion N (which tests for significant haplotype sharing among affected sibs) and criterion T (which tests for significant non-sharing of haplotypes between affected and non-affected sibs) (Green and Shah, Ann Hum Gen 1992; 56: 331-338). The criteria and there means and variances of each sibship was added and normalized criterion, S, was compared with standard normal results. Clinical evaluation showed that 74% of the siblings, 53% of children and 42% of the parents had FMS. Linkage analysis showed an S value of 1.897 (P=0.029), without significant differences between depressed and non-depressed groups (Yunus, et al, Arthritis Rheum 1996; 39: 8275). The results thus showed a significant linkage of a disease susceptibility gene to HLA in fibromyalgia.

Conclusion. Familial aggregation in FMS has been documented, but only limited studies are available at this time on the role of genetics in FMS. Results of HLA association are currently inconclusive. Our study of 40 multicase families showed a rather weak linkage with an HLA haplotype. Independent confirmation of our finding is warranted. Further genetic studies should explore both HLA and non-HLA markers.

Presented at the National Fibromyalgia Research Association's New Dimensions in Fibromyalgia Symposium, September 14-15, 1997, in Portland, Oregon.